Patent Application
20240115591
The invention provides a method for treating biliary tract cancer in a patient in need thereof, comprising the step of intravenously administering to the patient a therapeutically effective amount of (i) devimistat, (ii) gemcitabine, and (iii) cisplatin, in order to treat the biliary tract cancer.
Biliary tract cancer (BTC) develops as a result of malignant transformation of the biliary tract mucosa and is anatomically classified as intra-hepatic, extra-hepatic (hilar and distal) and gall bladder adenocarcinoma. BTC accounts for 10-15% of all primary liver cancer cases worldwide, and its incidence is rising (Shaib, Y. and H. B. El-Serag, “The epidemiology of cholangiocarcinoma,” Semin Liver Dis, 2004, 24(2), 115-125). Advanced BTCs are aggressive tumors with median survival time from diagnosis of less than 12 months (Valle, J., H. Wasan, D. H. Palmer, D. Cunningham, A. Anthoney, A. Maraveyas, S. Madhusudan, T. Iveson, S. Hughes, S. P. Pereira, M. Roughton, J. Bridgewater and A. B. C. T. Investigators, “Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer,” N Engl J Med, 2010, 362(14), 1273-1281), and five-year overall survival (OS) of ˜5% despite therapy (Nathan, H., T. M. Pawlik, C. L. Wolfgang, M. A. Choti, J. L. Cameron and R. D. Schulick, “Trends in survival after surgery for cholangiocarcinoma: A 30-year population-based SEER database analysis,” Journal of Gastrointestinal Surgery, 2007, 11, 1488-1497). The options for systemic chemotherapy for patients with advanced BTC remains limited with only a few meaningful improvements made over the past few decades. Valle et al randomly assigned 410 patients with locally advanced or metastatic BTC to receive gemcitabine with or without cisplatin in the phase III ABC-02 trial (Valle, Wasan et al. 2010). Patients on the gemcitabine cisplatin arm demonstrated an improvement in OS (11.7 versus 8.1 months; hazard ratio (HR), 0.64; 95% CI, 0.52 to 0.80; p<0.001) as compared to the gemcitabine alone arm. The objective response rate was 26.1% in the cisplatin and gemcitabine combination arm. The following clinically relevant grade 3 and 4 adverse events were noted in the gemcitabine-cisplatin arm: neutropenia (25.3%), anemia (7.6%), thrombocytopenia (15.7%), abnormal liver function (16.7%), fatigue (18.7%), nausea (4%), vomiting (5.1%), impaired renal function (1.5%), infection (18.2%), deep vein thrombosis (2%), and thromboembolic event (3.5%). This result established the gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 combination as a standard first line regimen for patients with advanced BTC.
Patients with advanced, unresectable or metastatic BTC have a poor prognosis despite systemic chemotherapy with gemcitabine and cisplatin. There is a great medical need for better therapies that not only have less toxicity but also the potential for greater efficacy. The present invention addresses this need and provides other related advantages.
The invention provides a method for treating biliary tract cancer in a patient in need thereof, comprising the step of intravenously administering to the patient a therapeutically effective amount of (i) devimistat, (ii) gemcitabine, and (iii) cisplatin, in order to treat the biliary tract cancer
The foregoing aspects of the invention are described in more detail, along with additional embodiments, in the detailed description below.
The term “devimistat” refers to 6,8-bis(benzylsulfanyl)octanoic acid (CPI-613), having the chemical structure
As used herein, administering devimistat to a patient includes administering a pharmaceutically acceptable salt form of devimistat to the patient.
Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
As used herein, the term “overall response rate” or “ORR” refers to the sum of the complete response (CR) rate plus the partial response (PR) rate per RECIST version 1.1 criteria.
As used herein, the term “patient” refers to a human being in need of treatment for biliary tract cancer.
As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement, stabilization, or slowing progression of a condition, disease, disorder, or the like, or a symptom thereof. For example, treatment can include diminishment of a symptom of a disorder or complete eradication of a disorder. As another example, treatment can include slowing the progression of a disease, or preventing or delaying its recurrence, such as maintenance treatment to prevent or delay relapse.
“Therapeutically effective amount” refers to an amount of a compound sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a particular patient or patient population. For example, a therapeutically effective amount can be an amount of drug sufficient to slow the progression of a disease, or to prevent or delay its recurrence, such as maintenance treatment to prevent or delay relapse. A therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and patient being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
As used herein, the term “pharmaceutical composition” refers to the combination of an active agent (e.g., devimistat) with a pharmaceutically acceptable excipient, suitable for administration to a human being.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound judgment, suitable for use in contact with the tissues of human beings with acceptable toxicity, irritation, allergic response, and other problems or complications commensurate with a reasonable benefit/risk ratio.
As used herein, the term “pharmaceutically acceptable excipient” refers to any pharmaceutical excipient suitable for use in humans. For examples of such excipients, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA.
As used herein, the term “pharmaceutically acceptable salt” refers to any salt (e.g., acid or base) of a compound of the present invention which is suitable for administration to a human being. “Salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NR 3, wherein R is C1-4 alkyl, and the like.
Further examples of salts include salts made using the ion pairing agents described in U.S. Pat. No. 8,263,653, the entire disclosure of which is incorporated by reference herein. Still further ion pairing agents can be selected with guidance from Handbook of Pharmaceutical Salts Properties, Selection and Use, IUPAC, Wiley-VCH, P. H. Stahl, ed., the entire disclosure of which is incorporated by reference herein.
For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited steps.
As a general matter, compositions specifying a percentage are by weight unless otherwise specified.
The invention provides a method for treating biliary tract cancer in a patient in need thereof, comprising the step of intravenously administering to the patient a therapeutically effective amount of (i) devimistat, (ii) gemcitabine, and (iii) cisplatin, in order to treat the biliary tract cancer. The devimistat, gemcitabine, and cisplatin may be administered on the same or different days pursuant to any suitable cycle. Appropriate doses and cycles may be adapted from past experience with each agent in other cancer indications. For the convenience of the patient, it is preferred that the devimistat, gemcitabine, and cisplatin be administered on the fewest days of each cycle as possible, and for that reason it is preferred that the agents be administered on the same days of each cycle. In certain embodiments, the devimistat, gemcitabine, and cisplatin are all administered on the same days of each cycle. Any suitable cycle may be used. In certain embodiments, the cycle is 21 days. In certain embodiments, the devimistat, gemcitabine, and cisplatin are administered on days 1 and 8 of a 21 day cycle. In certain embodiments, the cycle is repeated at least once. In certain embodiments, the cycle is repeated at least five times. In certain embodiments, the cycle is repeated and treatment continues for at least one year. In certain embodiments, the cycle is repeated and treatment continues until the patient experiences disease progression, inter-current illness that prevents further treatment, or an unacceptable adverse event. In certain embodiments, the cycle is repeated and treatment continues until the patient experiences disease progression or an unacceptable adverse event.
The method may be further characterized according to the type of biliary tract cancer treated. In certain embodiments, the biliary tract cancer is metastatic biliary tract cancer. In certain embodiments, the biliary tract cancer is locally advanced. In certain embodiments, the biliary tract cancer is an intrahepatic bile duct cancer or an extrahepatic bile duct cancer. In certain embodiments, the biliary tract cancer is an intrahepatic bile duct cancer. In certain embodiments, the biliary tract cancer is an extrahepatic bile duct cancer. In certain embodiments, the biliary tract cancer is a perihilar (a.k.a. hilar) bile duct cancer. In certain embodiments, the biliary tract cancer is a distal bile duct cancer. In certain embodiments, the biliary tract cancer is a cancer of the gallbladder. In certain embodiments, the biliary tract cancer is an adenocarcinoma. In certain embodiments, the biliary tract cancer is advanced and unresectable. In certain embodiments, the biliary tract cancer is pathologically or cytologically confirmed carcinoma of the biliary tract that is not eligible for curative resection, transplantation, or ablative therapies. In certain embodiments, the biliary tract cancer is previously untreated with systemic treatments (chemotherapy or targeted therapy) for advanced biliary tract cancer.
In the method of the present invention, the devimistat is intravenously administered to the patient as a pharmaceutical composition comprising devimistat and a pharmaceutically acceptable excipient. Any suitable pharmaceutical composition may be used. The devimistat may be formulated using the free acid or a salt thereof.
In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of devimistat and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises devimistat and a pharmaceutically acceptable excipient capable of forming an ion pair with devimistat. In certain embodiments, the pharmaceutical composition comprises devimistat and a pharmaceutically acceptable excipient capable of forming an ion pair with devimistat, wherein the pharmaceutically acceptable excipient comprises an aqueous solution of an ion pairing agent. Exemplary ion pairing agents include, for example, tertiary amines (such as triethanolamine), other amines such as diethanolamine, monoethanolamine, mefenamic acid and tromethamine, and combinations thereof. Other suitable ion pairing agents include organic Bronsted bases, alkali metal hydroxides, and alkaline earth metal hydroxides, such as, for example, cesium hydroxide. Additional exemplary ion pairing agents that may be used to prepare salts of devimistat include, for example, monoalkylamines, dialkylamines, trialkylamines, amino-substituted aliphatic alcohols, hydroxymonoalkylamines, hydroxydialkylamines, hydroxytrialkylamines, amino-substituted heteroaliphatic alcohols, alkyldiamines, substituted alkyldiamines, optionally substituted heteroaryl group containing at least one ring nitrogen atom, polyethyleneimine, polyglutamic acid, ammonia, L-arginine, benethamine benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2′,2″-nitrilotris(ethanol)), tromethamine, and zinc hydroxide. Additional ion pairing agents that may be used to prepare salts of devimistat include diisopropanolamine, 3-amino-1-propanol, meglumine, morpholine, pyridine, niacinamide, tris(hydroxymethyl)aminomethane, 2-((2-dimethylamino)ethoxy)ethanol, 2-(dimethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, and ammonium hydroxide.
In certain embodiments, the pharmaceutical composition comprises devimistat and triethanolamine. In certain embodiments, the pharmaceutical composition comprises devimistat and an aqueous solution of triethanolamine. In certain embodiments, the pharmaceutical composition of devimistat comprises a 50 mg/mL solution of devimistat in 1M aqueous triethanolamine.
In certain embodiments, the pharmaceutical composition is diluted with dextrose and water prior to intravenous administration. In certain embodiments, the pharmaceutical composition of devimistat comprises a 50 mg/mL solution of devimistat in 1M aqueous triethanolamine, which is diluted from 50 mg/mL to about 12.5 mg/mL with sterile aqueous 5% dextrose for injection (D5W) prior to administration to the patient. In certain embodiments, the pharmaceutical composition of devimistat comprises a 50 mg/mL solution of devimistat in 1M triethanolamine, and each 1 mL thereof is diluted with about 3 mL D5W prior to administration to a patient. In certain embodiments, the D5W-diluted solution of devimistat has a pH of about 8.4 to about 8.8. Preferably, the D5W-diluted solution of devimistat is stable for at least 24 hours. In certain embodiments, the D5W-diluted devimistat is administered by IV infusion at the rate of about 4 mL/min on day 1 and day 8 of each 21-day cycle. In certain embodiments, the D5W-diluted devimistat is administered by an IV infusion lasting about two hours on each of days 1 and 8 of a 21-day cycle. In certain embodiments, the devimistat infusion is administered concurrently with D5W. Preferably, the diluted devimistat pharmaceutical composition is administered concurrently with D5W, wherein the concurrent D5W is administered at the rate of about 125 mL/hour.
Preferably, the pharmaceutical composition of devimistat is administered via a central venous catheter. Preferably, the pharmaceutical composition of devimistat is administered via an infusion pump.
In certain embodiments, the devimistat used to prepare the pharmaceutical composition has a purity of at least about 90% (w/w). In certain embodiments, the devimistat used to prepare the pharmaceutical composition has a purity of at least about 95% (w/w). In certain embodiments, the devimistat used to prepare the pharmaceutical composition has a purity of at least about 98% (w/w). In certain embodiments, the devimistat used to prepare the pharmaceutical composition has a purity of at least about 99% (w/w). In certain embodiments, the devimistat used to prepare the pharmaceutical composition has a purity of at least about 99.3% (w/w). In certain embodiments, the devimistat used to prepare the pharmaceutical composition has a purity of at least about 99.5% (w/w).
The therapeutic method may be further characterized according to the dose of devimistat administered to the patient. The amount of devimistat to be administered is based on the body surface area (BSA) of the patient in square meters (m 2). In certain embodiments, the devimistat is administered at a dose that is at or near its maximum tolerated dose (MTD) when administered in combination with therapeutically effective amounts of gemcitabine and cisplatin. A suitable clinical trial for determining the MTD of devimistat is described in Example 1, below. In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 500 mg/m2 to about 3000 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 500 mg/m2 to about 2000 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 500 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 1000 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 1500 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 2000 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 2500 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the devimistat is intravenously administered to the patient at a dose of about 3000 mg/m2 on each day the devimistat is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In the 21-day cycle, devimistat is preferably administered on days 1 and 8 prior to administration of gemcitabine and cisplatin. The administered dose of devimistat may be adjusted during treatment. For example, the administered dose of devimistat may be reduced if the patient experiences an adverse event. Dose adjustments suitable for use in the method of the present invention are described in Example 1, below.
In certain embodiments, the devimistat is administered intravenously to the patient in the form of a pharmaceutical composition comprising devimistat, water, and triethanolamine. In certain embodiments, the pharmaceutical composition comprises devimistat at a concentration of 50 mg/mL and triethanolamine at a concentration of 1M. In certain embodiments, the pharmaceutical composition further comprises dextrose.
In the method of the present invention the gemcitabine (chemical name 2′-deoxy-2′,2′-difluorocytidine (β-isomer)) is intravenously administered to the patient as a pharmaceutical composition comprising gemcitabine and a pharmaceutically acceptable excipient. The gemcitabine may be formulated using the free base or a salt thereof. Preferably, the gemcitabine is intravenously administered as the HCl salt. Any suitable pharmaceutical composition may be used. Preferably, a commercially available pharmaceutical composition of gemcitabine is used. Gemcitabine is commercially available as a lyophilized powder in 200 mg and 1 g single-dose vials containing 200 mg gemcitabine (equivalent to 227.7 mg gemcitabine hydrochloride) and 1 g gemcitabine (equivalent to 1.139 g gemcitabine hydrochloride), respectively. The powder may be reconstituted with 5 mL (200 mg vial) or 25 mL (1 g vial) of 0.9% sodium chloride injection, USP to yield a solution. Prior to intravenous administration, the appropriate dose of gemcitabine is preferably withdrawn from the vial and then diluted with additional 0.9% sodium chloride injection, USP to a final concentration of at least 0.1 mg/mL.
The amount of gemcitabine to be administered is based on the body surface area (BSA) of the patient in square meters (m 2). A suitable gemcitabine dose may be determined with reference to the FDA-approved prescribing information for gemcitabine, and to prior experience with gemcitabine, including experience treating the same and similar indications. In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 500 mg/m2 to about 1500 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 500 mg/m2 to about 1250 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 640 mg/m2 to about 1000 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 800 mg/m2 to about 1000 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 500 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 640 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 800 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 1000 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the gemcitabine is intravenously administered to the patient at a dose of about 1250 mg/m2 on each day the gemcitabine is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). Preferably, the gemcitabine is intravenously administered to the patient at a dose of about 1000 mg/m2 on days 1 and 8 of a 21 day cycle as an infusion of about 25-35 minutes. Preferably, the gemcitabine is intravenously administered immediately after administration of the devimistat. The administered dose of gemcitabine may be adjusted during treatment. For example, the administered dose of gemcitabine may be reduced if the patient experiences an adverse event. Dose adjustments suitable for use in the method of the present invention are described in Example 1, below, and also in the FDA-approved prescribing information for gemcitabine.
In certain embodiments, the gemcitabine is administered intravenously to the patient in the form of a pharmaceutical composition comprising gemcitabine hydrochloride and water.
In certain embodiments, the gemcitabine is administered intravenously to the patient after devimistat has been administered intravenously to the patient.
In the method of the present invention the cisplatin (chemical name cis-diaminedichloroplatinum) is intravenously administered to the patient as a pharmaceutical composition comprising cisplatin and a pharmaceutically acceptable excipient. Any suitable pharmaceutical composition may be used. Preferably, a commercially available pharmaceutical composition of cisplatin is used. Cisplatin is commercially available as a lyophilized powder in 50 mg single-dose vials. The lyophilized powder may be reconstituted with 50 mL of sterile water for injection to yield a solution containing 1 mg/mL cisplatin. Prior to intravenous administration, the appropriate dose of cisplatin is preferably withdrawn from the vial and then diluted with about 1-2 L of a compatible infusion solution.
The amount of cisplatin to be administered is based on the body surface area (BSA) of the patient in square meters (m 2). A suitable cisplatin dose may be determined with reference to the FDA-approved prescribing information for cisplatin, and to prior experience with cisplatin in the same and similar indications. In certain embodiments, the cisplatin is intravenously administered to the patient at a dose of about 25 mg/m2 on each day the cisplatin is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the cisplatin is intravenously administered to the patient at a dose of about 20 mg/m2 on each day the cisplatin is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). In certain embodiments, the cisplatin is intravenously administered to the patient at a dose of about 16 mg/m2 on each day the cisplatin is administered to the patient (e.g., on each of days 1 and 8 of a 21 day cycle). Preferably, the cisplatin is intravenously administered to the patient at a dose of about 25 mg/m2 on days 1 and 8 of a 21 day cycle as an infusion of about 25-65 minutes. Preferably, the cisplatin is intravenously administered immediately after administration of the gemcitabine. The administered dose of cisplatin may be adjusted during treatment. For example, the administered dose of cisplatin may be reduced if the patient experiences an adverse event. Dose adjustments suitable for use in the method of the present invention are described in Example 1, below, and also in the FDA-approved prescribing information for cisplatin.
In certain embodiments, the cisplatin is administered intravenously to the patient after gemcitabine has been administered intravenously to the patient.
Patients treated pursuant to the method of the present invention preferably meet at least one of the following eligibility criteria: a) pathologically or cytologically confirmed carcinoma of the biliary tract that is not eligible for curative resection, transplantation, or ablative therapies; b) ≥18 years of age; c) Eastern Cooperative Oncology Group (ECOG) Performance status of 0-1; d) adequate organ function within 2 weeks prior to treatment. In certain embodiments, patients treated pursuant to the method of the present invention meet at least a) and b) of the above eligibility criteria. In certain embodiments, patients treated pursuant to the method of the present invention meet all of the above eligibility criteria. With respect to eligibility criterion d), adequate organ function may be evidenced by: i) absolute neutrophil count [ANC]≥1500/mm3; ii) hemoglobin ≥9 g/dL; iii) platelets ≥100,000/mm3; iv) serum creatinine ≤1.5×ULN; v) creatinine clearance ≥50 mL/min; vi) albumin ≥3.0 g/dL; vii) AST/ALT≤3.0×UNL (≤5×UNL if liver metastasis); viii) total bilirubin ≤1.5×UNL; and ix) INR≤1.5×UNL.
The therapeutic method of the present invention may be further characterized by the efficacy and safety of the treatment. Preferably, the method provides an acceptable safety profile, with the benefit of treatment outweighing the risk. When tested in a phase II or phase III clinical trial in which the method of the present invention is tested in one arm and standard therapy with gemcitabine and cisplatin is tested in a second arm, the method of the present invention preferably provides a median overall survival (OS) of at least three months. In certain embodiments, the phase II or phase III trial is conducted as described in Example 1. Preferably, the phase II or phase III clinical trial comprises at least 30 patients. More preferably, the phase II or phase III clinical trial comprises at least 40 patients. More preferably, the phase II or phase III clinical trial comprises at least 50 patients. More preferably, the phase II or phase III clinical trial comprises at least 75 patients. More preferably, the phase II or phase III clinical trial comprises at least 100 patients. More preferably, the phase II or phase III clinical trial comprises at least 200 patients. More preferably, the phase II or phase III clinical trial comprises at least 300 patients. More preferably, the phase II or phase III clinical trial comprises at least 400 patients. More preferably, the phase II or phase III clinical trial comprises at least 500 patients. Preferably, when tested in such a phase II or phase III clinical trial the method of the present invention provides an OS of at least 4 months. More preferably, the OS is at least 5 months. More preferably, the OS is at least 6 months. More preferably, the OS is at least 7 months. More preferably, the OS is at least 8 months. More preferably, the OS is at least 9 months. More preferably, the OS is at least 10 months. More preferably, the OS is at least 11 months. More preferably, the OS is at least 12 months. More preferably, the OS is at least 13 months. More preferably, the OS is at least 14 months. More preferably, the OS is at least 15 months. More preferably, the OS is at least 16 months. More preferably, the OS is at least 17 months. More preferably, the OS is at least 18 months. More preferably, the OS is at least 19 months. More preferably, the OS is at least 20 months. More preferably, the OS is at least 21 months. More preferably, the OS is at least 22 months. More preferably, the OS is at least 23 months. More preferably, the OS is at least 24 months. Preferably, when tested in such a phase II or phase III clinical trial the method of the present invention provides an OS higher than the control (standard gemcitabine-cisplatin) arm. Preferably, the OS is at least 1 month longer than the control arm (e.g., if the OS of the patients in the control arm of the clinical trial is 4 months, 7 months, or 11 months, then the OS of the patients in the clinical trial treated according to the method of the present invention is ≥5 months, ≥8 months, or ≥12 months, respectively). More preferably, the OS is at least 2 months longer than the control arm. More preferably, the OS is at least 3 months longer than the control arm. More preferably, the OS is at least 4 months longer than the control arm. More preferably, the OS is at least 5 months longer than the control arm. More preferably, the OS is at least 6 months longer than the control arm. More preferably, the OS is at least 7 months longer than the control arm. More preferably, the OS is at least 8 months longer than the control arm. More preferably, the OS is at least 9 months longer than the control arm. More preferably, the OS is at least 10 months longer than the control arm. More preferably, the OS is at least 11 months longer than the control arm. More preferably, the OS is at least 12 months longer than the control arm. More preferably, the OS is at least 13 months longer than the control arm. More preferably, the OS is at least 14 months longer than the control arm. More preferably, the OS is at least 15 months longer than the control arm. More preferably, the OS is at least 16 months longer than the control arm. More preferably, the OS is at least 17 months longer than the control arm. More preferably, the OS is at least 18 months longer than the control arm. Preferably, when tested in such a phase II or phase III clinical trial, the method of the present invention provides an OS longer than the historical OS level, i.e., the OS observed in previous clinical trials testing treatment of similar patients with a similar regimen of gemcitabine-cisplatin alone. Preferably, the OS is at least 2 months longer than the historical OS level (e.g., if the historical OS level is 5 months, then the OS of the patients in the clinical trial treated according to the method of the present invention is at least 7 months). More preferably, the OS is at least 3 months longer than the historical OS level. More preferably, the OS is at least 4 months longer than the historical OS level. More preferably, the OS is at least 5 months longer than the historical OS level. More preferably, the OS is at least 6 months longer than the historical OS level. More preferably, the OS is at least 7 months longer than the historical OS level. More preferably, the OS is at least 8 months longer than the historical OS level. More preferably, the OS is at least 9 months longer than the historical OS level. More preferably, the OS is at least 10 months longer than the historical OS level. More preferably, the OS is at least 11 months longer than the historical OS level. More preferably, the OS is at least 12 months longer than the historical OS level. More preferably, the OS is at least 13 months longer than the historical OS level. More preferably, the OS is at least 14 months longer than the historical OS level. More preferably, the OS is at least 15 months longer than the historical OS level. More preferably, the OS is at least 16 months longer than the historical OS level. More preferably, the OS is at least 17 months longer than the historical OS level. More preferably, the OS is at least 18 months longer than the historical OS level.
Preferably, when tested in a phase II or phase III clinical trial as described herein, the method of the present invention provides a median progression free survival (PFS) of at least three months. More preferably, the method of the present invention provides PFS of at least 4 months. More preferably, the PFS is at least 5 months. More preferably, the PFS is at least 6 months. More preferably, the PFS is at least 7 months. More preferably, the PFS is at least 8 months. More preferably, the PFS is at least 9 months. More preferably, the PFS is at least 10 months. More preferably, the PFS is at least 11 months. More preferably, the PFS is at least 12 months. More preferably, the PFS is at least 13 months. More preferably, the PFS is at least 14 months. More preferably, the PFS is at least 15 months. More preferably, the PFS is at least 16 months. More preferably, the PFS is at least 17 months. More preferably, the PFS is at least 18 months. More preferably, the PFS is at least 19 months. More preferably, the PFS is at least 20 months. More preferably, the PFS is at least 21 months. More preferably, the PFS is at least 22 months. More preferably, the PFS is at least 23 months. More preferably, the PFS is at least 24 months. Preferably, the PFS is longer than the control (standard gemcitabine-cisplatin) arm, i.e., the PFS of the patients in the clinical trial treated according to the method of the present invention is longer than the PFS of the patients in the control (standard gemcitabine-cisplatin) arm of the clinical trial. Preferably, the PFS is at least 1 month longer than the control arm (e.g., if the PFS of the patients in the control arm of the clinical trial is 4 months, 7 months, or 11 months, then the PFS of the patients in the clinical trial treated according to the method of the present invention is ≥5 months, ≥8 months, or ≥12 months, respectively). More preferably, the PFS is at least 2 months longer than the control arm. More preferably, the PFS is at least 3 months longer than the control arm. More preferably, the PFS is at least 4 months longer than the control arm. More preferably, the PFS is at least 5 months longer than the control arm. More preferably, the PFS is at least 6 months longer than the control arm. More preferably, the PFS is at least 7 months longer than the control arm. More preferably, the PFS is at least 8 months longer than the control arm. More preferably, the PFS is at least 9 months longer than the control arm. More preferably, the PFS is at least 10 months longer than the control arm. More preferably, the PFS is at least 11 months longer than the control arm. More preferably, the PFS is at least 12 months longer than the control arm. More preferably, the PFS is at least 13 months longer than the control arm. More preferably, the PFS is at least 14 months longer than the control arm. More preferably, the PFS is at least 15 months longer than the control arm. More preferably, the PFS is at least 16 months longer than the control arm. More preferably, the PFS is at least 17 months longer than the control arm. More preferably, the PFS is at least 18 months longer than the control arm. Preferably, when tested in a phase II or phase III clinical trial as described herein, the method of the present invention provides a PFS longer than the historical PFS level, i.e., the PFS observed in previous clinical trials testing treatment of similar patients with a similar regimen of gemcitabine-cisplatin alone. Preferably, the PFS is at least 1 month longer than the historical PFS level (e.g., if the historical PFS level is 5 months, then the PFS of the patients in the clinical trial treated according to the method of the present invention is at least 6 months). More preferably, the PFS is at least 2 months longer than the historical PFS level. More preferably, the PFS is at least 3 months longer than the historical PFS level. More preferably, the PFS is at least 4 months longer than the historical PFS level. More preferably, the PFS is at least 5 months longer than the historical PFS level. More preferably, the PFS is at least 6 months longer than the historical PFS level. More preferably, the PFS is at least 7 months longer than the historical PFS level. More preferably, the PFS is at least 8 months longer than the historical PFS level. More preferably, the PFS is at least 9 months longer than the historical PFS level. More preferably, the PFS is at least 10 months longer than the historical PFS level. More preferably, the PFS is at least 11 months longer than the historical PFS level. More preferably, the PFS is at least 12 months longer than the historical PFS level. More preferably, the PFS is at least 13 months longer than the historical PFS level. More preferably, the PFS is at least 14 months longer than the historical PFS level. More preferably, the PFS is at least 15 months longer than the historical PFS level. More preferably, the PFS is at least 16 months longer than the historical PFS level. More preferably, the PFS is at least 17 months longer than the historical PFS level. More preferably, the PFS is at least 18 months longer than the historical PFS level.
Preferably, when tested in a phase II or phase III clinical trial as described herein, the method of the present invention provides an overall response rate (ORR) of at least 10%. More preferably, the ORR is at least 20%. More preferably, the ORR is at least 25%. More preferably, the ORR is at least 30%. More preferably, the ORR is at least 35%. More preferably, the ORR is at least 40%. More preferably, the ORR is at least 45%. More preferably, the ORR is at least 50%. More preferably, the ORR is at least 55%. More preferably, the ORR is at least 60%. More preferably, the ORR is at least 65%. More preferably, the ORR is at least 70%. More preferably, the ORR is at least 75%. More preferably, the ORR is at least 80%. More preferably, the ORR is at least 85%. More preferably, the ORR is at least 90%. More preferably, the ORR is at least 95%. Preferably, when tested in a phase II or phase III clinical trial as described herein, the method of the present invention provides an ORR higher than the historical ORR level, i.e., the ORR observed in previous clinical trials testing treatment of similar patients with a similar regimen of gemcitabine-cisplatin alone. Preferably, the ORR is at least 5% higher than the historical ORR level (e.g., if the historical ORR level is 25%, then the ORR of the patients in the clinical trial treated according to the method of the present invention is at least 30%). More preferably, the ORR is at least 10% higher than the historical ORR level. More preferably, the ORR is at least 15% higher than the historical ORR level. More preferably, the ORR is at least 20% higher than the historical ORR level. More preferably, the ORR is at least 25% higher than the historical ORR level. More preferably, the ORR is at least 30% higher than the historical ORR level. More preferably, the ORR is at least 35% higher than the historical ORR level. More preferably, the ORR is at least 40% higher than the historical ORR level. More preferably, the ORR is at least 45% higher than the historical ORR level. More preferably, the ORR is at least 50% higher than the historical ORR level. More preferably, the ORR is at least 55% higher than the historical ORR level. More preferably, the ORR is at least 60% higher than the historical ORR level. More preferably, the ORR is at least 65% higher than the historical ORR level. More preferably, the ORR is at least 70% higher than the historical ORR level. More preferably, the ORR is at least 75% higher than the historical ORR level. More preferably, the ORR is at least 80% higher than the historical ORR level. Preferably, the ORR is higher than the control (standard gemcitabine-cisplatin) arm, i.e., the ORR of the patients in the clinical trial treated according to the method of the present invention is higher than the ORR of the patients in the control (standard gemcitabine-cisplatin) arm of the clinical trial. Preferably, the ORR is at least 5% higher than the control arm (e.g., if the ORR of the control arm patients is 45%, 55%, or 70%, then the ORR of the patients in the clinical trial treated according to the method of the present invention is ≥50%, ≥60%, or ≥75%, respectively). More preferably, the ORR is at least 10% higher than the control arm. More preferably, the ORR is at least 15% higher than the control arm. More preferably, the ORR is at least 20% higher than the control arm. More preferably, the ORR is at least 25% higher than the control arm. More preferably, the ORR is at least 30% higher than the control arm. More preferably, the ORR is at least 35% higher than the control arm. More preferably, the ORR is at least 40% higher than the control arm. More preferably, the ORR is at least 45% higher than the control arm. More preferably, the ORR is at least 50% higher than the control arm. More preferably, the ORR is at least 55% higher than the control arm. More preferably, the ORR is at least 60% higher than the control arm. More preferably, the ORR is at least 65% higher than the control arm. More preferably, the ORR is at least 70% higher than the control arm. More preferably, the ORR is at least 75% higher than the control arm. More preferably, the ORR is at least 80% higher than the control arm.
Another aspect of the invention provides a medical kit containing a therapeutic agent and/or pharmaceutical composition described herein, along with instructions for using the kit to treat biliary tract cancer according the methods described herein. In certain embodiments, the medical kit comprises (i) devimistat, and (ii) instructions for treating biliary tract cancer in a patient with devimistat, gemcitabine, and cisplatin as described herein.
The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
This is a multi-center randomized phase IB/II study of gemcitabine and cisplatin with or without devimistat as first line therapy for patient with advanced unresectable biliary tract cancer.
Primary Objectives:
Secondary Objectives:
Exploratory Objectives:
Endpoints Assessment:
68-78 subjects.
Phase IB and Phase II Arm A (days 1, 8 Q21 days): Gemcitabine 1000 mg/m2 IV (obtained via reconstitution and dilution of gemcitabine hydrochloride lyophilized powder per commercial package insert); Cisplatin 25 mg/m2 IV; CPI-613 at dose level or RP2D IV.
Phase II Arm B (days 1, 8 Q21 days): Gemcitabine 1000 mg/m2 IV (obtained via reconstitution and dilution of gemcitabine hydrochloride lyophilized powder per commercial package insert); Cisplatin 25 mg/m2 IV.
Protocol treatment must start within 14 calendar days of enrollment otherwise the patient will be taken off study. Re-screening is allowed.
Phase IB Dose Levels, Regimen, and Dose Limiting Toxicities (DLTs)
aInfusion times may be extended as needed for safety (e.g. infusion reaction occurs). These instances should be documented in the patient medical records.
bPatients may not be treated on study for longer than 2 years
A DLT will be any of the following occurring during the first 3 weeks of therapy, including cycle 2 day 1, attributed (possibly, probably, or definitely) to the drug combination following day 1 treatment and occurring in the 22-day interval as assessed using the NCI CTCAE v5.0.
Phase II Arm A Regimen
aInfusion times may be extended as needed for safety (e.g. infusion reaction occurs). These instances should be documented in the patient medical records.
bPatients may not be treated on study for longer than 2 years
cper commercial package insert
Phase II Arm B Regimen
aInfusion times may be extended as needed for safety (e.g. infusion reaction occurs). These instances should be documented in the patient medical records.
bPatients may not be treated on study for longer than 2 years
cper commercial package insert
Toxicities and Dosing Delays/Dose Modifications
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient will be assessed for the development of toxicity according to the Time and Events Table (below). Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made according to the system showing the greatest degree of toxicity.
All dose reductions will be permanent unless otherwise noted. If more than one toxicity occurs requiring dose reduction, the dose administered should be based on the most severe toxicity. Treatment delay of more than 28 days from last intended therapy will result in treatment discontinuation. If one of the drugs is discontinued due to toxicity attributed to that agent, the patient will be allowed to continue a modified regimen with the remaining study arm agent/s. However, monotherapy with cisplatin is not permitted, though monotherapy with gemcitabine is allowed. Additionally, if both gemcitabine and cisplatin are held on day 1, then also hold devimistat. If both gemcitabine and cisplatin are discontinued, then devimistat should also be discontinued. Investigators should consider dose re-calculation of gemcitabine and/or cisplatin with change in BSA as per standard of care/institutional guidelines. However, a change in BSA by 10% or more requires a dose re-calculation. If a patient experiences neutropenic fever at any point in the treatment cycle, chemotherapy will be delayed until ANC>1,000 and antibiotic treatment of the event is completed. When treatment resumes, proceed with one dose level reduction for one or more agents. Doses will not be modified for cholangitis attributable to biliary obstruction/stent occlusion unless this occurs in the setting of >grade 3 neutropenia. Laboratory abnormalities that are not clinically relevant (i.e., lymphopenia) do not require modification of dosing. Missed Dose: If the regimen held or missed was to be given on Day 1 then that next cycle will not be considered to start until the day the first dose is actually administered. Held doses of either or all drugs on Day 8 will be considered omitted.
aNote:
aNote:
Concomitant Medications/Treatments. The following concomitant medications or treatments are not permitted while the patient is currently receiving therapy on the protocol:
The following concomitant medications may require additional monitoring during cisplatin therapy:
Duration of Therapy. Treatment may continue for a total of 2 years or until one of the following criteria apply:
Off Treatment Criteria. Patients will be removed from protocol therapy when any of the criteria listed above under Duration of Therapy apply. Document in the source the reason for ending protocol therapy and the date the patient was removed from treatment. All patients who discontinue treatment should comply with protocol specific follow-up procedures as outlined below under Off Study Criteria. The only exception to this requirement is when a subject withdraws consent for all study procedures or loses the ability to consent freely.
Duration of Follow-Up. After treatment discontinuation, follow-up for survival and initiation of any other anti-cancer therapies will be documented every 3 months via telephone or office visit documentation for up to 2 years from treatment discontinuation or until death, whichever comes first, or 3 years after first date of treatment initiation for those that remain on treatment. Patients removed from treatment for unacceptable adverse events will also be followed more closely until resolution or stabilization of the adverse event.
Off Study Criteria. Patients can be taken off study at any time at their own request, or they may be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) for discontinuation from study will be documented and may include:
Patient Replacement. All patients who receive at least one dose of study therapy will be considered evaluable. Patients enrolled in the study will be considered non-evaluable under the following case scenarios and replaced by additional patients:
Antitumor Effect-Solid Tumors. Objective response assessment will be determined by review of CT or MR scans of the chest, abdomen and pelvis using RECIST v1.1 every 8 weeks+/−1 week while patients are on treatment (Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe and J. Verweij, “New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1),” Eur J Cancer, 2009, 45(2): 228-247).
Disease Parameters
Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
Note: Tumor lesions that are situated in a previously irradiated area will only be considered measurable, if they have had subsequent progression by at least 5 mm.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm using CT scan), are considered non-measurable disease. Bone lesions without measurable soft tissue component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (non-nodal lesions with the longest diameter), be representative of all involved organ(s), but in addition should be those that lend themselves to reproducible repeated measurements.
Lymph nodes merit special mention since they are normal anatomical structures that may be visible by imaging even if not involved by tumor. Pathological nodes that are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of >15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For example, an abdominal node which is reported as being 20 mm×30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the nodal measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and should not be recorded or followed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum of diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.
Non-target lesions. All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required, and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression.’ In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
Guidelines for Evaluation of Measurable Disease
Response Criteria
Evaluation of Target Lesions
Evaluation of Non-Target Lesions
Evaluation of the Best Overall Response. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Note: If subjects respond to treatment and are able to have their disease resected, the patient's response will be assessed prior to the surgery.
Duration of Response
Safety/Tolerability. Analyses will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE version 5.0 for reporting of adverse events (http://ctep.cancer.govireporting/ctc.html).
Adverse Event Reporting Requirements.
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies using similar agents. Data on adverse events will be collected from the time of the initial study treatment administration through 100 days after the last dose of study treatment. Any serious adverse event that occurs more than 100 days after the last study treatment and is considered related to the study treatment or intervention must also be reported. Serious Adverse Events (SAEs) will continue to be followed until:
The investigator is responsible for the detection, documentation, grading and assignment of attribution of events meeting the criteria and definition of an AE or SAE. The definitions of AEs and SAEs are given below. It is the responsibility of the principal investigator to ensure that all staff involved in the trial is familiar with the content of this section.
Any medical condition or laboratory abnormality with an onset date before initial study treatment administration is considered to be pre-existing in nature. Any known pre-existing conditions that are ongoing at time of study entry should be considered medical history.
All events meeting the criteria and definition of an AE or SAE (as defined below under “Adverse Event Characteristics”) occurring from the initial study treatment administration through 100 days following the last dose of the study treatment must be recorded as an adverse event in the patient's source documents and on the CRF regardless of frequency, severity (grade) or assessed relationship to the study treatment or intervention. However, with regards to laboratory and vital sign abnormalities, only those which require protocol treatment to be modified or treatment to be rendered should be reported as AEs
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre-existing condition that occurs after the patient begins study treatment is also considered an adverse event. However, anticipated fluctuations of pre-existing conditions, including the disease under study, that don't represent a clinically significant exacerbation or worsening, need not be reported as AEs.
Adverse Event. An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and which does not necessarily have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an experimental intervention, whether or not related to the intervention.
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures will not be reported as adverse events. However, the medical condition for which the procedure was performed must be reported if it meets the definition of an adverse event unless it is a pre-existing (prior to protocol treatment) condition.
Serious Adverse Event. An adverse event is considered “serious” if, in the view of either the investigator or sponsor-investigator, it results in any of the following outcomes:
Previously planned (prior to signing the informed consent form) surgeries should not be reported as SAEs unless the underlying medical condition has worsened during the course of the study. Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in the patient's medical history at the time of study enrollment should not be considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for example, for the administration of study therapy or other protocol-required procedure) should not be considered SAEs. However, if the preexisting condition worsened during the course of the study, it should be reported as an SAE.
Expected Adverse Events. An adverse event (AE) is considered “expected” if:
Unexpected Adverse Event. An adverse event (AE) is considered “unexpected” if it is not described in the Package Insert, devimistat Investigator's Brochure, in published medical literature, in the protocol, or in the informed consent document.
Adverse Event Characteristics
CTCAE Term. (AE description) and grade: The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be down loaded from the CTEP web site. (http://ctep.cancer.gov)
Attribution of the AE. The investigator or co-investigator is responsible for assignment of attribution.
Serious Adverse Event Reporting Guidelines
Reporting Procedures for Multi-Site Trials. All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of causality to study drug, will be reported to the Principal Investigator and also to the Coordinating Center. All SAEs and UPs must be reported to the Coordinating Center within 24 hours of first awareness of the event. Events should be reported using the Coordinating Center's SAE form as available in the study database. A copy of the SAE form as available in the study database should be sent to the Coordinating Center via fax or email within 24 hours of the site's knowledge of the event.
Follow-up information must also be reported within 24 hours of receipt of the information by the investigator.
All SAEs and UPs will be reported to the IRB per current institutional standards
The Coordinating Center will disseminate information regarding SAEs and UPs to the participating sites within 5 days of review of the information by the Coordinating Center's Principal Investigator (or designee in the event of extended absence) only in the case that the event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study drug. The Coordinating Center will be responsible for reporting of events to the FDA and supporters, as appropriate (outlined below).
Reporting Procedures to Sponsor. All Serious Adverse Events (SAEs) occurring from the initial study treatment administration through 100 days following the last dose of the study treatment will be reported by the Coordinating Center to the study sponsor. Any SAEs occurring after 100 days following the last dose of the study treatment that are believed to be related to study drug will also be reported to the sponsor.
The Coordinating Center will send the initial completed SAE Form within 24 hours of receipt via email to the sponsor.
If only limited information is initially available or an ongoing SAE changes in its intensity or relationship to the study drug, or if new information becomes available, a follow-up report will be generated and sent to the sponsor within 24 hours of receipt.
Reporting Procedures to FDA. In this trial, serious, unexpected adverse events believed to be definitely, probably or possibly related to the study treatment will be reported to the Food and Drug Administration via the MedWatch 3500A Form. The site's Assistance Program will assist the IND Sponsor in reporting SAEs to the FDA that meet the reporting requirements in 21 CFR 312.32. This reporting could include the initial report and follow-up reports when appropriate for the event. SAEs not meeting the expedited reporting requirements will be submitted to the FDA with the IND Annual Report.
Routine Reporting. All other adverse events—such as those that are expected, or are unlikely or definitely not related to the study participation—are to be reported annually as part of regular data submission.
Reporting of Pregnancy. Pregnancies that occur during study participation or within 6 months of last study dose should be reported to the Coordinating Center via e-mail immediately upon site's knowledge of the event.
Reporting of Unanticipated Problems. There are types of incidents, experiences and outcomes that occur during the conduct of human subjects research that represent unanticipated problems but are not considered adverse events. For example, some unanticipated problems involve social or economic harm instead of the physical or psychological harm associated with adverse events. In other cases, unanticipated problems place subjects or others at increased risk of harm, but no harm occurs.
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) that may represent an unanticipated problem, the investigator should assess whether the incident, experience, or outcome represents an unanticipated problem. The incident, experience or outcomes is considered unanticipated if it meets all of the following criteria:
If the investigator determines that the incident, experience, or outcome represents an unanticipated problem, the investigator must report it to the IRB within 14 calendar days of the study team becoming aware of the problem.
Safety Report Reconciliation. The sponsor will reconcile the clinical database SAE reports transmitted to the sponsor. Frequency of reconciliation should be every 3 months and prior to the database lock or final data summary. The sponsor will email, upon request from the Investigator, the GPV&E reconciliation report. The data elements listed on the GPV&E reconciliation report will be used for identification purposes. If the Investigator determines a report was not transmitted to the sponsor, the report should be sent immediately.
Study Design/Study Endpoints. This protocol will enroll patients with advanced, unresectable BTC to receive gemcitabine, cisplatin and devimistat in a limited Phase 1b study to confirm the safety profile of the combination therapy and the recommended Phase 2 dose (RP2D). The primary endpoint for the phase 1b portion is the occurrence/lack thereof of dose-limiting toxicity (DLT, defined above) during the first 21-day cycle of combination therapy. After determining the combination RP2D additional patients will be enrolled in the phase 2 portion of the study and randomized 2:1 to treatment arms A (combination regimen at RP2D) and B (gemcitabine and cisplatin alone), respectively. We will stratify the randomization by locally advanced versus metastatic disease. The primary endpoint for the phase 2 study is the ORR (PR+CR) per RECIST v1.1 criteria during active study treatment. Secondary endpoints include PFS and OS. The statistical comparison will not be between treatment groups; rather between the experimental treatment arm (A) and historical ORR levels. We will use the estimated ORR for the limited-sized control arm (B) to confirm the control arm has similar response rate as the historical ORR value.
Phase 1B. We will implement a limited phase 1b trial to assure that the dose levels suggested for this combination are safe. Because toxicity across the combined agents is expected to be mildly additive and not synergistic, and in light of the poor prognosis for these patients, we are willing to tolerate up to but not exceeding 35% DLT toxicity proportion during the first cycle (21-days) of therapy. To investigate this, we will enroll up to 20 patients with dose allocation using the Time-to-Event (TiTE) (Cheung, Y. K. and R. Chappell, “Sequential designs for phase I clinical trials with late-onset toxicities,” Biometrics, 2000, 56(4), 1177-1182; O'Quigley, J., M. Pepe and L. Fisher, “Continual reassessment method: a practical design for phase 1 clinical trials in cancer,” Biometrics, 1990, 46(1), 33-48). This method assumes a model for the time to occurrence of toxic responses as a function of the dose. The time-to-event modification allows information from all patients treated (even those with only partial observation) to contribute information for calculating the dose-toxicity relationship. This method is flexible with regard to the number of patients treated at each dose level, patients may be continuously recruited without recruitment pauses subject to the trial's explicit accrual rules, given patients are assigned to a dose level deemed safe at the time of her/his enrollment. The dose toxicity relationship is estimated using all toxicity data observed when each new patient is scheduled to begin treatment. Population for estimation: Every patient enrolled and receiving at least one dose of devimistat will be considered evaluable for estimation of the probability of DLT. If a patient withdraws for any reason during the first cycle of therapy, not primarily or secondarily associated with toxicity, that patient's follow-up will be used in the ongoing estimation of the probability of toxicity; however, such a patient would be replaced when calculating the maximum trial size. Patients stopping treatment early due to or secondary to toxicity will be considered to have had a DLT event (see DLT definition above).
DLT target rate to determine MTD/RP2D. The highest probability of DLT at a dose level acceptable during the first cycle of therapy is 35%. The dose level with estimated probability closest to, but not exceeding the DLT target rate will be considered the RP2D.
Criterion for dose escalation. The dose level will be assigned to each new patient according to the estimates from the TiTE-CRM algorithm. Whenever a patient presents for enrollment on this trial, the probability of DLT will be estimated for each dose level, based upon the initial expectations and the incidence of DLT events in patients already treated on trial weighted by the percentage of the acute DLT observation period observed. The level that has an estimated toxicity closest to the target rate for DLT will be assigned, subject to the following:
Patients will be recruited and treated on this trial as naturally available. Accrual is estimated to be approximately 2 patients per month. The operating characteristics of this Phase 1B trial were evaluated through simulation using estimate for the true probability of DLT at each dose level under 3 scenarios (n=1,000 simulated trials per scenario). In the first scenario, the true probability of DLT at each dose level is as we had expected a posteriori; the second scenario we have moderately underestimated the true probabilities of DLT for higher dose levels; the third scenario the additive effect of devimistat upon the observed toxicity from the chemotherapy regimen is negligible and not dose dependent. The dose level nearest to but not exceeding our target rate is bolded for each scenario.
0.30
0.35
0.23
Reviewing the operating characteristics suggest that when the true probability of DLT is as expected (simulation scenario #1), the trial design will treat nearly 10 patients at the target level dose and selects that dose correctly as the MTD/RP2D dose in over 70% of simulated trials. Similarly, if toxicity is not increased by adding devimistat to SoC chemotherapy (simulation scenario #3), the design treats nearly 12 patients at the target level dose and selects that dose as the MTD/RP2D in approximately 80% of simulated trials. In the event that we have underestimated toxicity a posteriori and the probability of DLT increases more sharply with increasing dose of devimistat, the design will pick a dose at or below the target level in the majority of simulated trials more likely to pick lower dose levels or stop early.
Phase 2. Upon completion of the 20 patient Phase 1b portion of the trial, an MTD/RP2D will have been determined or all dose levels for the combination deemed excessively toxic. After the MTD/RP2D is determined, additional patients will be enrolled and randomized in a 2 (Arm A: devimistat+gemcitabine+cisplatin) to 1 (Arm B: gemcitabine+cisplatin) manner during the phase 2 portion of this trial to assess efficacy as measured by the ORR. Historical data suggest the ORR for Arm B in this patient population is 25% (Valle, Wasan et al. 2010). We suggest that the combination therapy at the MTD/RP2D would be successful by increasing the ORR to 43%. In order to have at least 80% power to detect such a difference significantly, with at most 5% type one error (using a one-sided test of proportions), 50 patients receiving the combination therapy at the MTD/RP2D are necessary.
The operating characteristics presented above for the Phase 1B portion of the trial suggest that 10-12 patients will have been treated at the MTD/RP2D and those patients will be included in the Phase 2 efficacy assessment. Therefore, the Phase 2 portion of the trial will randomize approximately 48 to 58 patients in order to assure 50 patients in the devimistat treated group. Approximately 16 to 20 patients will be assigned to Arm B/standard of care regimen.
The comparison of interest will be between the observed ORR in those receiving combination therapy versus the historical estimate. Patients randomized to Arm B will help suggest whether the historical estimate for ORR is a reasonable null hypothesis for comparison. If the ORR estimated for the control group is higher than the historical value, it may suggest increasing the null hypothesis value for comparison. In order to operationalize this comparison, we will implement a Bayesian approach to estimate the probability of ORR (CR+PR) for the control patients. Given that the historical estimates published by Valle, et. al 2010 is −25% for the 160 patients treated in that phase 3 trial, we will formalize that probability using a beta distribution b (40,120), which is a unimodal distribution, with mean 0.25 with precision proportional to the sample size, 160. We will then collect binary outcome data for the control patients (yes/no ORR) which allows the posterior distribution (prior data+trial's experience for control patients) to be described also as a beta distribution. If after adding the trial's control data it is suggested that the probability that the ORR is greater than 25% is more than 0.7 (70%), we will increase the estimate for the null hypothesis in the primary outcome comparison to be the probability estimated from the mean of the posterior distribution. The following table lists the number of control patients with an overall response based upon the number of control patients treated (may range from 16 to 20) for biologically reasonable ORR rates above 25%.
Data Analyses Plans. We will report the estimate probability of DLT with 95% Bayesian Credible Intervals for each dose level as estimated by the TiTE-CRM algorithm at the completion of the Phase 1. The probability of DLT will be updated using the experience of the Phase 2 patients at the MTD/RP2D as well.
We will record ORR as a yes/no outcome for each patient for the period of active study treatment and report the estimate and exact 95% binomial confidence intervals. We will estimate PFS and OS using the product-limit method of Kaplan and Meier. Follow-up time will be defined as time from date of first study treatment until the date of radiological or clinical progression (leading to withdrawal from the study), or death from any cause, whichever comes first for PFS and for only death from any cause for OS. For patients without events, we will censor the follow-up time at the date of last disease evaluation at the time of analysis. We will report estimates for the median and 75th percentiles with 95% confidence intervals. We will summarize additional safety data (e.g., laboratory safety parameters, vital signs, concomitant medications and new physical examination findings) descriptively by reporting counts and percentages, with exact binomial confidence intervals where appropriate. ORR will be determined as per the RECISTv1.1 guidelines. We will report adverse events per the NCI CTCAE v5.0.
The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
This application claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 63/108,934, filed Nov. 3, 2020, the contents of which are hereby incorporated by reference in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/057829 | 11/3/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63108934 | Nov 2020 | US |
