Patent Application
20060025437
SNS-595 is novel naphthyridine cytotoxic agent that was previously known as AG-7352 (see e.g., Tsuzuki et al., Tetrahedron-Asymmetry 12: 1793-1799 (2001) and U.S. Pat. No. 5,817,669). The chemical name of SNS-595 is (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazoyl)-1,8-naphthyridine-3-carboxylic acid and has the structure shown below
The present invention relates to pharmaceutical compositions and methods of using SNS-595 to treat cancer.
In one aspect of the present invention, pharmaceutical composition is provided comprising:
Suitable examples of acids include both organic and inorganic acids such as acetic acid, ascorbic acid, benzene-sulfonic acid, ethansulfonic acid, glycolic acid, hydrogen chloride, hydrogen bromide, hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesulfonic acid, proprionic acid, succinic acid, sulfuric acid, trifluoroacetic acid, and toluenesulfonic acid. In one embodiment, the acid is hydrochloric acid, methanesulfonic acid or lactic acid. In another embodiment, the acid is methanesulfonic acid.
In another embodiment, the pharmaceutical composition further comprises a tonicity agent. Suitable examples of a tonicity agent include amino acids (e.g., alanine and glycine), electrolytes (e.g., sodium chloride and potassium chloride), monosaccharides (e.g. glucose or galactose), disaccharides (e.g. sucrose) and hexahydric alcohols (e.g., mannitol and sorbitol). In another embodiment, the tonicity agent is sodium chloride, glucose, mannitol, or sorbitol. In another embodiment, the tonicity agent is a hexahydric alcohol. In another embodiment, the tonicity agent is sorbitol.
SNS-595 is a cytotoxic agent for the treatment of cancer. The types of cancers that can be treated using the inventive methods include but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer (both small cell and non-small cell), lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
In another aspect of the invention, a method of using SNS-595 to treat a human cancer is provided. The method comprises administering to a patient on the basis of body surface area, a dose of 10 mg/m2-150 mg/m2 of SNS-595. Body surface area calculations can be calculated for example, with the Mosteller formula wherein:
BSA(m2)=square root of [(height(cm)×weight(kg)/3600].
In another embodiment, the dose is 10 mg/m2-100 mg/m2. In another embodiment, the dose is 30 mg/m2-75 mg/m2. In another embodiment, the dose is 40 mg/m2-80 mg/m2. In another embodiment, the dose is 50 mg/m2-90 mg/m2. In another embodiment, the dose is 15 mg/m2-80 mg/m2.
In another embodiment the dose is 20 mg/m2-30 mg/m2. In another embodiment the dose is 25 mg/m2-35 mg/m2. In another embodiment the dose is 40 mg/m2-50 mg/m2. In another embodiment the dose is 45 mg/m2-55 mg/m2. In another embodiment the dose is 50 mg/m2-60 mg/m2. In another embodiment the dose is 55 mg/m2-65 mg/m2. In another embodiment the dose is 60 mg/m2-70 mg/m 2. In another embodiment the dose is 65 mg/m2-75 mg/m2. In another embodiment the dose is 70 mg/m2-80 mg/m2. In another embodiment the dose is 75 mg/m2-85 mg/m2. In another embodiment the dose is 80 mg/m2-90 mg/m2. In another embodiment the dose is 85 mg/m2-95 mg/m2. In another embodiment the dose is 90 mg/m2-100 mg/m2.
The administered dose of SNS-595 can be delivered simultaneously (e.g. a single bolus injection) or over a 24-hour period (e.g., continuous infusion over time or divided bolus doses over time) and is repeated until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. See e.g., Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack there of is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
The administered dose of SNS-595 can be expressed in units other than as mg/m2. For example, doses can be expressed as mg/kg. One of ordinary skill in the art would readily know how to convert doses from mg/m2 to mg/kg to given either the height or weight of a subject or both (see e.g., http:///www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 10 mg/m2-150 mg/m2 for a 65 kg human is approximately equal to 0.26 mg/kg-3.95 mg/kg. In another example, a dose of 15 mg/m2-80 mg/m2 for a 65 kg human is approximately equal to 0.39 mg/kg-2.11 mg/kg.
In another aspect of the present invention, SNS-595 is administered according to a dosing schedule. In one embodiment, the method comprises:
In another embodiment, the method comprises administering a dose of 10 mg/m2-100 mg/m2 in steps i) and iii). In yet another embodiment, the method comprises administering a dose of 15 mg/m2-80 mg/m2 in steps i) and iii).
In the above methods, if the waiting period were 6 days, then the initial dose of SNS-595 is administered on Day 1 (step i); the waiting period is six days (step ii); and the following dose of SNS-595 is administered on Day 8 (step iii). Other exemplary time periods include 2 days, 3 days, 13 days, 20 days, and 27 days. In another embodiment, the waiting period is at least 2 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 6 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 6 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 20 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 20 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 27 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 27 days and steps ii) through iii) are repeated at least five times.
In another embodiment, the dosing method comprises administering a weekly dose of SNS-595 to a subject. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every two weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every three weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every four weeks.
In another embodiment, the dosing method comprises a cycle wherein the cycle comprises administering a dose of SNS-595 to a subject once a week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. In another embodiment, the period where no SNS-595 is administered is two weeks. In another embodiment, the period where no SNS-595 is administered is three weeks.
In another aspect of the invention, a method of treating a solid tumor is provided. The method comprises:
In another aspect of the invention, another method of treating solid tumors is provided. The method comprises administering a dose of 15 mg/m2-40 mg/m2 of SNS-595 to a patient once a week wherein the one-week period comprises a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, the dose is 15 mg/m2-35 mg/m2. In another embodiment, the dose is 20 mg/m2-30 mg/m2. In another embodiment, the dose is 20 mg/m2-25 mg/m2.
In another aspect of the invention, another method of treating solid tumors is provided. The method comprises method comprises administering a dose of 15 mg/m2-40 mg/m2 of SNS-595 to a patient once a week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. In another embodiment, the dose is 15 mg/m2-35 mg/m2. In another embodiment, the dose is 20 mg/m2-30 mg/m2. In another embodiment, the dose is 20 mg/m2-25 mg/m2.
In another aspect of the invention, another method of treating solid tumors is provided. The method comprises administering a dose of 35 mg/m2-80 mg/m2 of SNS-595 to a patient once in a three-week period wherein the three week period comprises a treatment cycle and the treatment cycle is repeated at least twice.
In patients who are considered heavily pretreated (“heavily pretreated patients”), the method comprises administering a dose of 35 mg/m2-60 mg/m2 of SNS-595 to a patient once in a three week period wherein the three week period comprises a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, the method for treating a heavily pretreated patient comprises, administering a dose of 40 mg/m2-50 mg/m2. In another embodiment, the method for treating a heavily pretreated patient, comprises administering a dose of 45 mg/m2-50 mg/m2. A heavily pretreated patient is defined as described by Tolcher et al., J. Clin. Oncol. 19: 2937-2947 (2001) and is a patient who has been treated previously with more than six courses of an alkylating agent-containing chemotherapy regimen, more than two courses of carboplatin or mitomycin C, any prior nitrosourea-containing regimen, irradiation to 25% of the bone-marrow containing areas, high-dose chemotherapy requiring hematopoietic stem-cell reinfusions, or widespread metastases to bone.
Patients, who have not been treated previously for their solid tumors or have been treated but are not considered heavily pretreated, are minimally pretreated (“minimally pretreated patients”). For treating minimally pretreated patients, the method comprises administering a dose of 45 mg/m2-80 mg/m2 of SNS-595 to a patient once in a three week period wherein the three week period comprises a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, the method for treating a minimally pretreated patient comprises, administering a dose of 50 mg/m2-75 mg/m2. In another embodiment, the method for treating a minimally pretreated patient, comprises administering a dose of 55 mg/m2-70 mg/m2. In another embodiment, the method for treating a minimally pretreated patient, comprises administering a dose of 55 mg/m2-65 mg/m2.
In another aspect of the invention, a method of treating a hematologic cancer such as leukemias and lymphomas is provided. The method comprises:
In one embodiment, the waiting period is six days. In another embodiment, the waiting period is two days. In another embodiment, the waiting period is three days.
In another aspect of the invention, another method of treating a hematologic cancer is provided. The method comprises administering a dose of 20 mg/m2-40 mg/m2. In another embodiment, the dose is 25 mg/m2-30 mg/m2. In another embodiment, the dose is 30 mg/m2-35 mg/m2. In another embodiment, the dose is 35 mg/m2-40 mg/m2.
In another aspect of the invention, another method of treating a hematologic cancer is provided. The method comprises administering a dose of 10 mg/m2-20 mg/m2 twice a week wherein the one-week period is a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, the dose is 10 mg/m2-15 mg/m2. In another embodiment, the dose is 15 mg/m2-20 mg/m2.
In another aspect of the present invention, a method is provided supportive care to patients being treated with SNS-595. The method comprises:
In another embodiment, the dose is 10 mg/m2-100 mg/m2. In yet another embodiment, the dose is 15 mg/m2-80 mg/m2. The supportive care agent is any substance that prevents or manages an adverse effect from SNS-595 treatment and is administered according to the appropriate dosing regimen for that substance. For example, different supportive care agents for treating nausea have different dosing regimen. While some are administered prophylactically, others are co-administered with SNS-595 while still others are administered after the administration of SNS-595. Illustrative examples of supportive care agents their doses and dosing regimens are found in The Physician's Desk Reference.
In one embodiment, the supportive care agent is an antiemetic. Illustrative examples of antiemetics include but are not limited to phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NK, receptor antagonists. Examples of phenothiazine antiemetics include prochlorperazine and trimethobenzamide. An example of a butyophenone antiemetic is haloperidol. An example of a benzodiazapine antiemetic is lorazepam. An example of a corticosteroid antiemetic is dexamethasone. Examples of a serotonin antagonist antiemetic include ondansetron, granisetron, and dolasetron. An example of a cannabinoid antiemetic is dronabinol. An example of an NK1 receptor antagonist is aprepitant.
In another embodiment, the antiemetic is prochlorperazine. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is 10 mg. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg before the administration of SNS-595. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg every four to six hours as needed after the administration of SNS-595.
In another embodiment, the antiemetic is dexamethazone. In another embodiment, the antiemetic is dexamethazone and the therapeutically effective amount is at least 4 mg. In another embodiment, the antiemetic is dexamethazone and the therapeutically effective amount is an oral dose of 4 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethazone and the therapeutically effective amount is an oral dose of 8 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethazone and the therapeutically effective amount is an intravenous dose of between about 10 mg and about 20 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethazone and the therapeutically effective amount is an oral dose of 4 mg every six to twelve hours as needed after the administration of SNS-595.
In another embodiment, the antiemetic is lorazepam. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is 1 mg. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an intravenous dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg every four to six hours as needed after the administration of SNS-595.
In another embodiment, the antiemetic is dolasetron. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is 100 mg. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an oral dose of 100 mg before the administration of SNS-595. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an intravenous dose of 100 mg before the administration of SNS-595.
In another embodiment, the antiemetic is ondansetron. In another embodiment, the antiemetic is ondansetron and the therapeutically effective amount is at least 10 mg. In another embodiment, the antiemetic is ondansetron and the therapeutically effective amount is an intravenous dose of 10 mg before the administration of SNS-595. In another embodiment, the antiemetic is ondansetron and the therapeutically effective amount is an intravenous dose of 32 mg before the administration of SNS-595.
In another embodiment, the antiemetic is granisetron. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is 10 μg/kg. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is an intravenous dose of 10 μg/kg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is at least 1 mg. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is an oral dose of 2 mg before the administration of SNS-595.
In another embodiment, the antiemetic is aprepitant. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is at least 80 mg. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is an oral dose of 125 mg before the administration of SNS-595. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is a daily oral dose of 80 mg for at least two days after the administration of SNS-595.
In another embodiment, the supportive care agent is a hematopoietic agent. A hematopoietic agent is a molecule that stimulates hematopoiesis. Illustrative examples of hematopoietic agents include but are not limited to granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin and erythropoiesis stimulating protein, and derivatives thereof. Examples of G-CSF include but are not limited to filgrastim and its derivatives including pegfilgrastim. An example of GM-CSF includes sargramostim. An example of erythropoietin is epoetin alfa. An example of erythropoiesis stimulating protein is darbepoetin alfa.
In another embodiment, the hematopoietic agent is G-CSF. In another embodiment, the hematopoietic agent is filgrastim. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is at least 4 μg/kg. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount of is a daily dose of at least 4 μg/kg for at least 7 days after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 μg/kg and about 8 μg/kg for at least 7 days starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 μg/kg and about 10 μg/kg for at least 14 days starting from the third day after the administration of SNS-595.
In another embodiment, the hematopoietic agent is pegfilgrastim. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is 6 mg. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is a daily subcutaneous dose of 6 mg after the administration of SNS-595. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is 100 μg/kg. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is a daily dose of 100 μg/kg after the administration of SNS-595.
In another embodiment, the hematopoietic agent is GM-CSF. In another embodiment, the hematopoietic agent is sargramostim. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is 250 μg/m2. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2 as needed starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2 as needed starting from the tenth day after the administration of SNS-595.
In another embodiment, the hematopoietic agent is erythropoietin. In another embodiment, the hematopoietic agent is epoetin alfa. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is at least 150 units/kg. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 150 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 300 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is 40,000 units. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is a weekly dose of 40,000 units after the administration of SNS-595.
In another embodiment, the hematopoietic agent is erythropoiesis stimulating protein. In another embodiment, the hematopoietic agent is darbepoetin alfa. In another embodiment, the hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is between about 1.5 μg/kg and about 4.5 μg/kg. In another embodiment, the hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is a weekly dose of between about 1.5 μg/kg and about 4.5 μg/kg
All cited references are incorporated herein by reference.
Pharmaceutical Composition Suitable for Injection or Intravenous Infusion
Acidic compositions (<pH 4) provided the appropriate balance of increased solubility of SNS-595 and desirable pharmaceutical properties (e.g. increased patient comfort by causing less irritation at the delivery site). An illustrative example of a suitable composition comprises: 10 mg SNS-595 per mL of aqueous solution of 4.5% sorbitol that is adjusted to pH 2.5 with methanesulfonic acid. One protocol for making such a solution includes the following for making a 100 mg/10 mL presentation: 100 mg of SNS-595 and 450 mg D-sorbitol are added to distilled water; the volume is brought up to a volume of 10 mL; and the pH of the resulting solution is adjusted to 2.5 with methanesulfonic acid. The resulting composition is also suitable for lyophilization. The lyophilized form is then reconstituted with sterile water to the appropriate concentration prior to use.
Pharmacokinetics of SNS-595 in Cancer Patients
SNS-595 was administered to enrolled patients for up to six cycles. A cycle is defined as a three-week period, with SNS-595 administered on the first day of each cycle (day 0), followed by at least 21 days of observation. SNS-595 was administered to cohorts of at least 3 patients and dose escalation occurred by sequential cohort. Doses of SNS-595 were linear with AUC ∞ and its pharmacokinetic properties were remarkably consistent among patients in the same cohort.
Clinical Trial Data
SNS-595 was administered to patients with advanced solid cancers every 3 weeks as an IV fusion over 10 minutes without premedication. Cohorts of 3-6 patients were accrued to does based on a modified Fibonacci sequence. Forty patients (24 male and 16 female; median age=0.5 yrs, range 33-76) were treated in seven cohorts at doses starting at 3 mg/m2 and advancing to 75 mg/m2. Twenty five of these patients were heavily pretreated and five teen were minimally pretreated. Tumor types included ovarian (n=8), lung (n=7), colorectal (n=5), adenocarcinoma of unknown primary (n=4), renal (n=3), arcoma (n=3), pancreas (n=2), melanoma (n=2), breast (n=1), bladder (n=1), cholangiocarcinoma (n=1), Müllerian (n=1), neuroendocrine (n=1) and peritoneal (n=1).
Median ECOG (European Cooperative Oncology Group) performance status was 1 (range 0.2). For the heavily pretreated patients, the dose limiting toxicity (DLT) consisting of Grade 4 neutropenia for greater than 7 days was observed at 60 mg/m2. For minimally pretreated patients, one dose limiting toxicity has been seen at a dose of 75 mg/m2.
Non-hematologic toxicities were generally mild (grade ½), without dose-limiting gastro-intestinal or neurotoxicity. Pharmacokinetic parameters were evaluated in 36 patients (21 heavily pretreated and 15 minimally pretreated) after a single dose of 3 to 75 mg/m2. Clearance (CL), volume of distribution, and terminal half-life (T½) remained unchanged across all patients up to 48 mg/m2. In minimally pretreated patients, PK parameters remained unchanged up to 75 mg/m2. CL was 2.2 L/hr/m2 (range of 1.0-3.8 L/hr/m2), the volume of distribution was 53 L/m2 (range of 31-76 L/m2), and the T½ was approximately 20 hr (range of 13-49 hr). Exposure was similar for both heavily and minimally pretreated patients and increased linearly with doses up to 48 mg/m2. Exposure for minimally pretreated patients continued to increase linearly up to 75 Mg/m2, whereas heavily pretreated patients showed a greater than dose linear AUC (area under the curve) at the 60 mg/m2 dose level. Ten of 36 evaluable patients achieved stabilization of disease for greater than 4 cycles.
This application is a continuation-in-part of application Ser. No. 11/080,283, filed Mar. 14, 2005, which claims priority under 35 USC § 119, to U.S. Provisional Application Ser. No. 60/553,578 filed Mar. 15, 2004, the entire disclosures of which are hereby expressly incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60553578 | Mar 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11080283 | Mar 2005 | US |
| Child | 11218387 | Sep 2005 | US |
