Patent Application
20160331717
This application claims the benefit of priority to European Application No. 15305720.3 filed May 13, 2015, the disclosure of which is incorporated herein in its entirety.
The present invention concerns the use of cabazitaxel for treating cancer in patients with hepatic impairment. It also concerns a method of managing the risk of hepatic impairment to allow an effective and safe use of cabazitaxel in the treatment of cancer.
Cabazitaxel is a semi-synthetic derivative of the natural taxoids 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and tumor cell proliferation. Unlike other taxane compounds, this agent is active in tumor models poorly or not sensitive to chemotherapy, including taxanes. In addition, cabazitaxel penetrates the blood-brain barrier.
Cabazitaxel has been developed and is registered under the trademark Jevtana® for the treatment of patients with hormone refractory metastatic prostate cancer (HRPC) previously treated with a docetaxel containing regimen, in combination with prednisone or prednisolone. The recommended dose is 25 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone or prednisolone 10 mg administered daily throughout cabazitaxel treatment. It is available in vials of concentrate (sterile concentrate) and solvent for solution for infusion (60 mg).
It has been observed that the use of cabazitaxel for the treatment of cancer, for example for the treatment of prostate cancer, may provoke some adverse reactions which may be fatal for the patients, notably for patients presenting hepatic impairment.
In the prescribing information as published for Jevtana in the US at its date of launch in June 2010, the following warnings and precautions for use were given: “No dedicated hepatic impairment trial for JEVTANA has been conducted. Patients with impaired hepatic function (total bilirubin ≧1×ULN, or AST and/or ALT≧1.5×ULN) were excluded from the randomized clinical trial. Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase cabazitaxel concentrations. Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as JEVTANA. JEVTANA should not be given to patients with hepatic impairment (total bilirubin ≧1×ULN, or AST and/or ALT≧1.5×ULN).” A similar wording is included in the prescribing information for Jevtana in all the countries where the product is marketed.
Thus there is a need to find a safe treatment for cancer patients presenting hepatic impairment.
The invention answers that need by providing safe dosage regimens of cabazitaxel or recommendation not to use cabazitaxel depending on the degree of hepatic impairment in the treatment of cancer in patients with varying degrees of hepatic impairment.
The present invention relates to the compound having the following formula (I):
which may be in base form or in the form of a hydrate or a solvate,
for its use as a medicament in the treatment of cancer in patients with hepatic impairment where the administered standard dose of 25 mg/m2 of cabazitaxel is reduced or where the administration of cabazitaxel is stopped or to be avoided.
The present invention also relates to a method for treating cancer in a patient with hepatic impairment in need of treatment, said method comprising administering a reduced dose of the compound of formula (I) as defined above, which may be in base form or in the form of a hydrate or a solvate, to said patient, wherein said reduced dose is less than the standard dose of 25 mg/m2 of cabazitaxel.
The present invention also relates to a method of managing the risk of hepatic impairment, to allow an effective and safe use of the compound of formula (I) as defined above, in the treatment of patients treated for cancer, said method comprising the following steps:
The present invention relates to patients with hepatic impairment that may be mild, moderate or severe.
In one aspect of the invention, the cancer to be treated may be a solid tumor. In another aspect, the cancer may be an advanced, measurable or non-measurable, non-hematological cancer. In another aspect, the cancer may be one that is either refractory to standard therapy or for which no standard therapy exists. The cancer may be for example a castration resistant or hormone-refractory metastatic prostate cancer.
In one aspect of the invention, the compound of formula (I) is in the form of an acetone solvate. This acetone solvate may contain between 5% and 8%, and preferably between 5% and 7%, by weight of acetone.
In some aspects of the invention, cabazitaxel may be administered by intravenous infusion at a dose of between 15 and 25 mg/m2, this administration cycle of the antitumour agent being repeated at an interval of 3 weeks between each cabazitaxel administration, which interval may be prolonged by 1 to 2 weeks depending on the tolerance to the preceding cabazitaxel administration.
In one aspect of the invention, the administration of the compound of formula (I) is repeated as a new cycle every 3 weeks.
In one aspect of the invention, the reduced and recommended dose for patients with mild hepatic impairment is 20 mg/m2.
In one aspect of the invention, the reduced and maximum tolerated dose for patients with moderate hepatic impairment is 15 mg/m2.
In one aspect of the invention, the administration of cabazitaxel in patients with mild hepatic impairment may have to be stopped.
In one aspect of the invention, the administration of cabazitaxel in patients with severe hepatic impairment is contraindicated and thus has to be avoided.
The term “patient,” as used herein, includes both human and animals. In one embodiment, a patient is a human.
The term “hepatic impairment” as used herein, is an abnormal hepatic function that is to say a reduced liver function.
A normal hepatic function is defined as a total bilirubin level ≦upper limit of normal [ULN] and by an aspartate aminotransferase level [AST]≦ULN.
Abnormal hepatic functions are:
The term “cabazitaxel” corresponds to the compound belonging to the taxoid family of formula (I):
The chemical name of cabazitaxel is 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7, 101-dimethoxy-9-oxo-11-taxen-13α-yl (2R,3S)-3-tert-butoxycarbonyl-amino-2-hydroxy-3-phenylpropionate. Cabazitaxel is synonymously known as (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate.
This compound and a preparative method thereof is described in WO 96/30355, EP 0 817 779 B1 and U.S. Pat. No. 5,847,170, which are hereby incorporated herein by reference. Cabazitaxel may be administered in base form (cf. above formula), or in the form of a hydrate. It may also be a solvate, i.e. a molecular complex characterized by the incorporation of the crystallization solvent into the crystal of the molecule of the active principle (see in this respect page 1276 of J. Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetone solvate, and, more particularly, may be the solvate described in WO 2005/028462. It may be an acetone solvate of cabazitaxel containing between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means content of acetone/content of acetone+cabazitaxel×100). An average value of the acetone content is 7%, which approximately represents the acetone stoichiometry, which is 6.5% for a solvate containing one molecule of acetone. The procedure described below allows the preparation of an acetone solvate of cabazitaxel:
940 ml of purified water are added at 20±5° C. (room temperature) to a solution of 207 g of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate at about 92% by weight in about 2 litres of acetone, followed by seeding with a suspension of 2 g of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate isolated from acetone/water in a mixture of 20 ml of water and 20 ml of acetone. The resulting mixture is stirred for about 10 to 22 hours, and 1.5 litres of purified water are added over 4 to 5 hours. This mixture is stirred for 60 to 90 minutes, and the suspension is then filtered under reduced pressure. The cake is washed on the filter with a solution prepared from 450 ml of acetone and 550 ml of purified water, and then oven-dried at 55° C. under reduced pressure (0.7 kPa) for 4 hours. 197 g of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate acetone containing 0.1% water and 7.2% acetone (theoretical amount: 6.5% for a stoichiometric solvate) are obtained.
One aspect of the present invention relates to the compound having the following formula (I):
which may be in base form or in the form of a hydrate or a solvate,
for its use as a medicament in the treatment of cancer in patients with hepatic impairment where the administered standard dose of 25 mg/m2 of cabazitaxel is reduced or where the administration of cabazitaxel is stopped or to be avoided.
The present invention also relates to a method for treating cancer in a patient with hepatic impairment, said method comprising the administration of the compound of formula (I) as defined above, which may be in base form or in the form of a hydrate or a solvate, where the administered standard dose of 25 mg/m2 of cabazitaxel is reduced or where the administration of cabazitaxel is stopped or to be avoided.
The present invention also relates to a method of managing the risk of hepatic impairment, to allow an effective and safe use of the compound of formula (I) as defined above, in the treatment of patients treated for cancer, said method comprising the following steps:
The present invention relates to patients with hepatic impairment that may be mild, moderate or severe.
In one aspect of the invention, the cancer to be treated may be a solid tumor. In another aspect, the cancer may be an advanced, measurable or non-measurable, non-hematological cancer. In another aspect, the cancer may be one that is either refractory to standard therapy or for which no standard therapy exists. The cancer may be for example a castration resistant or hormone-refractory metastatic prostate cancer.
One aspect of the invention is a method of treating castration resistant or hormone-refractory metastatic prostate cancer in a patient in need thereof, said method comprising administering a reduced dose of the compound of formula (I) as defined above, which may be in base form or in the form of a hydrate or a solvate, to said patient, wherein said patient has hepatic impairment and wherein said reduced dose is less than the standard dose of 25 mg/m2 of cabazitaxel.
In one aspect of the invention, the compound of formula (I) is in the form of an acetone solvate. This acetone solvate may contain between 5% and 8%, and preferably between 5% and 7%, by weight of acetone.
In some aspects of the invention, cabazitaxel may be administered by intravenous infusion at a dose of between 15 and 25 mg/m2, this administration cycle of the antitumour agent being repeated at an interval of 3 weeks between each cabazitaxel administration, which interval may be prolonged by 1 to 2 weeks depending on the tolerance to the preceding cabazitaxel administration.
In one aspect of the invention, the administration of the compound of formula (I) is repeated as a new cycle every 3 weeks.
In one aspect of the invention, the reduced and recommended dose for patients with mild hepatic impairment is 20 mg/m2.
In one aspect of the invention, the reduced and maximum tolerated dose for patients with moderate hepatic impairment is 15 mg/m2.
In one aspect of the invention, the administration of cabazitaxel in patients with mild hepatic impairment may have to be stopped.
In one aspect of the invention, the administration of cabazitaxel in patients with severe hepatic impairment is contraindicated and thus has to be avoided.
Cabazitaxel may be administered parenterally, such as via intravenous administration. A galenical form of cabazitaxel suitable for administration by intravenous infusion is that in which the cabazitaxel is dissolved in water in the presence of excipients chosen from surfactants, cosolvents, glucose or sodium chloride, etc. For example, a galenical form of cabazitaxel may be prepared by diluting a premix solution of cabazitaxel contained in a sterile vial (80 mg of cabazitaxel+2 ml of solvent+Polysorbate 80) with a sterile vial containing a solution of 6 ml of water and ethanol (13% by weight of 95% ethanol) in order to obtain 8 ml of a solution ready to be rediluted in a perfusion bag. The concentration of cabazitaxel in this ready-to-redilute solution is about 10 mg/ml. The perfusion is then prepared by injecting the appropriate amount of this ready-to-redilute solution into the perfusion bag containing water and glucose (about 5%) or sodium chloride (about 0.9%).
The present invention is based on the monitoring of the patient concerning the hepatic impairment as mentioned above. Indeed, if the patient to be treated experiences any of these hepatic impairments before or during the administration cycle, then the cancer treatment has to be adapted or discontinued. If the hepatic impairment is resolved, the cancer treatment may be continued. Depending on the patient's conditions, the cancer treatment may also be stopped.
Cabazitaxel is administered repeatedly according to a protocol that depends on the patient to be treated (age, weight, treatment history, etc.), which can be determined by a skilled physician. In one aspect of the invention, cabazitaxel is administered by perfusion to the patient according to an intermittent program with an interval between each administration of 3 weeks, which may be prolonged by 1 to 2 weeks depending on the tolerance to the preceding administration.
In some aspects of the invention, the patient to be treated has prostate cancer that is resistant to hormone therapy (i.e., hormone refractory) and has previously been treated with docetaxel. In some aspects, the patient has prostate cancer that progressed during or after treatment with docetaxel. In some aspects, the patient was previously treated with at least 225 mg/m2 cumulative dose of docetaxel. In a particular aspect, the patient showed progression of their disease in the six months following hormone therapy or during docetaxel treatment or after docetaxel treatment. In another particular aspect, the patient showed progression of their disease in the three months following hormone therapy or after docetaxel treatment.
In some aspects of the invention, cabazitaxel is administered to a patient with castration resistant or hormone-refractory metastatic prostate cancer in combination with a corticoid, such as prednisone or prednisolone. The corticoid is preferably administered at a daily dose of 10 mg orally.
In some aspects, the treatment does not include patients for whom:
The present invention also relates to a method of providing the compound of formula (I) as defined above, which may be in base form or in the form of a hydrate or a solvate, wherein said compound is provided along with information indicating that it is useful for treating patients with cancer, for example castration resistant or hormone-refractory metastatic prostate cancer, said patients being at risk of developing hepatic impairment.
According to an embodiment, the information comprises printed matter, preferably a label, that advises that the compound of formula (I) is useful for treating patients suffering from cancer, for example castration resistant or hormone-refractory metastatic prostate cancer, said patients being at risk of developing hepatic impairment.
The present invention also relates to a method of promoting the use of the compound of formula (I) as defined above, the method comprising the step of conveying to a recipient at least one message selected from the group consisting of:
(a) the reduced and recommended dose for patients with mild hepatic impairment is 20 mg/m2.
(b) the reduced and maximum tolerated dose for patients with moderate hepatic impairment is 15 mg/m2.
(c) the administration of cabazitaxel in patients with mild hepatic impairment may have to be stopped.
(d) the administration of cabazitaxel in patients with severe hepatic impairment has to be avoided.
The present invention also relates to a method of promoting the use of the compound of formula (I) as defined above, the method comprising the step of conveying to a recipient at least one message selected from the group consisting of:
(a) Patients with mild hepatic impairment (total bilirubin >1 to 1.5×Upper Limit of Normal (ULN) or AST>1.5×ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety;
(b) Limited efficacy data for cabazitaxel at 15 mg/m 2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to <3×ULN) are available to recommend this dose in this population;
(c) cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3×ULN).
The present invention also relates to a method of promoting the use of the compound of formula (I) as defined above, the method comprising the step of conveying to a recipient at least one message selected from the group consisting of:
(a) Patients with mild hepatic impairment (total bilirubin >1 to ≦1.5×Upper Limit of Normal (ULN) or AST>1.5×ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety;
(b) In patients with moderate hepatic impairment (total bilirubin >1.5 to ≦3.0×ULN), the maximum tolerated dose (MTD) is 15 mg/m2. If the treatment is envisaged in patients with moderate hepatic impairment the dose of cabazitaxel should not exceed 15 mg/m2. However, limited efficacy data are available at this dose;
(c) Cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3×ULN.
The present invention also relates to an article of manufacture comprising:
The article of manufacture as defined above may comprise a label or package insert contained within the packaging material indicating at least one message selected from the group consisting of:
(a) the reduced and recommended dose for patients with mild hepatic impairment is 20 mg/m2.
(b) the reduced and maximum tolerated dose for patients with moderate hepatic impairment is 15 mg/m2.
(c) the administration of cabazitaxel in patients with mild hepatic impairment may have to be stopped.
(d) the administration of cabazitaxel in patients with severe hepatic impairment is contraindicated.
The article of manufacture as defined above may comprise a label or package insert contained within the packaging material indicating at least one message selected from the group consisting of:
(a) Patients with mild hepatic impairment (total bilirubin >1 to 1.5×Upper Limit of Normal (ULN) or AST>1.5×ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety;
(b) Limited efficacy data for cabazitaxel at 15 mg/m 2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to <3×ULN) o10 are available to recommend this dose in this population;
(c) cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3×ULN).
The article of manufacture as defined above may comprise a label or package insert contained within the packaging material indicating at least one message selected from the group consisting of:
(a) Patients with mild hepatic impairment (total bilirubin >1 to ≦1.5×Upper Limit of Normal (ULN) or AST>1.5×ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety;
(b) In patients with moderate hepatic impairment (total bilirubin >1.5 to ≦3.0×ULN), the maximum tolerated dose (MTD) is 15 mg/m2. If the treatment is envisaged in patients with moderate hepatic impairment the dose of cabazitaxel should not exceed 15 mg/m2. However, limited efficacy data are available at this dose;
(c) Cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3×ULN.
The present invention also relates to a package comprising the compound of formula (I) as defined above and a label, said label comprising one or more messages that:
a) the reduced and recommended dose for patients with mild hepatic impairment is 20 mg/m2.
(b) the reduced and maximum tolerated dose for patients with moderate hepatic impairment is 15 mg/m2.
(c) the administration of cabazitaxel in patients with mild hepatic impairment may have to be stopped.
(d) the administration of cabazitaxel in patients with severe hepatic impairment is contraindicated.
The present invention also relates to a package comprising the compound of formula (I) as defined above and a label, said label comprising one or more messages that:
(a) Patients with mild hepatic impairment (total bilirubin >1 to 1.5×Upper Limit of Normal (ULN) or AST>1.5×ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety;
(b) Limited efficacy data for cabazitaxel at 15 mg/m2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to <3×ULN) are available to recommend this dose in this population;
(c) cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3×ULN).
The present invention also relates to a package comprising the compound of formula (I) as defined above and a label, said label comprising one or more messages that:
(a) Patients with mild hepatic impairment (total bilirubin >1 to ≦1.5×Upper Limit of Normal (ULN) or AST>1.5×ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety;
(b) In patients with moderate hepatic impairment (total bilirubin >1.5 to ≦3.0×ULN), the maximum tolerated dose (MTD) is 15 mg/m2. If the treatment is envisaged in patients with moderate hepatic impairment the dose of cabazitaxel should not exceed 15 mg/m2. However, limited efficacy data are available at this dose;
(c) Cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3×ULN.
In the package of the invention, the compound of formula (I) may be in the form of an acetone solvate.
Study Title: Phase I safety and pharmacokinetic study of XRP6258 (cabazitaxel) in advanced solid tumor patients with varying degrees of hepatic impairment (POP6792)
Objectives
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Inclusion Criteria:
Exclusion Criteria:
Dose Regimen:
Cabazitaxel is administered on Day 1 of each 3-week cycle. Patients received cabazitaxel administered by IV infusion over 1 hour at the dose specified for each cohort. The actual amount of cabazitaxel administered was adjusted at each cycle based on body surface area (BSA) to a maximum BSA of 2.1 m2 (i.e., patients with a BSA over 2.1 m2 will receive the same amount of cabazitaxel as those with a BSA of 2.1 m).
Required IV premedication included: antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg or other antihistamines); steroid (dexamethasone 8 mg or equivalent steroid). H2 antagonist (ranitidine or other H2 antagonist with the exception of cimetidine).
These premedications were administered by IV infusion, at least 30 minutes prior to each dose of cabazitaxel.
New cycles of therapy did not begin until the absolute neutrophil count (ANC)≧1,500/mm3, platelet count ≧75,000/mm3, hemoglobin ≧9.0 g/dL, INR≦1.3, serum creatinine ≦1.5 mg/dL or ≦1.5 ULN, and non-hematologic toxicities (except alopecia, asthenia, local reactions, and other toxicities that are uncomfortable but do not cause serious morbidity to patients) have recovered to either Grade ≦1 or baseline grades.
A maximum of 2 weeks treatment delay was allowed between treatment cycles. Patients discontinued study treatment if treatment delay exceeds 2 weeks.
Patients continued on treatment until they experience unacceptable toxicities/AEs, disease progression, withdraw their consent, the investigator decided to withdraw the patient, or study cutoff date, whichever occurs first.
The cutoff date for full data collection was when the last patient has completed cycle 1 treatment and the subsequent 30 days follow up. However, if patients were still receiving treatment after the cutoff date, SAEs and investigational medicinal product (IMP) administration continued to be captured and communicated to the sponsor.
Cohort 3 has been initiated after at least 3 patients of Cohort 2 completed the first cycle of treatment with no dose-limiting toxicities (DLTs) being observed. Similarly, Cohort 4 began after 3 patients complete the first cycle of Cohort 3, providing no DLT has occurred.
Dose Escalation Schedule for Cohort 2:
Dose Escalation Schedule for Cohort 3:
Dose Escalation Schedule for Cohort 4:
The starting dose in Cohort 4 could be 5 or 10 mg/m2, was decided by the study committee based on the safety and PK information from the first 3 patients in Cohort 3.
Dose Escalation Criteria:
For each cohort, the dose escalation criteria as described in the table below had to be met at each dose level following Cycle 1 in order to enroll and treat additional patients at the next dose level. For Cohorts 2, 3 and 4, a 1 week gap was required between the treatment of each patient for the first 3 patients in each dose level to allow safety evaluation.
Dose-Limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD):
To be considered a DLT, the clinical adverse event (AE) or laboratory abnormality should be drug-related as assessed by the investigator.
Liver DLTs in patients with hepatic dysfunction (Cohorts 2, 3 and 4) were defined as an increase in total and direct bilirubin and/or transaminase levels to 3 times the baseline value. In addition, a treatment delay due to cabazitaxel related toxicity of 2 weeks between cycles was considered a DLT.
All other DLTs were defined [according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 grading scale] during the first treatment cycle, as follows:
Non-hematological toxicity Grade 3 or 4 except:
Hematological toxicity defined as:
If 1 DLT occurs in the first cycle, 3 additional patients were included at the same dose level. The MAD of Cohort 2, 3 and 4 was reached at the dose level when at least 2 patients develop a DLT during the first cycle.
Patients who were not treated, or were withdrawn during the first 3 weeks of treatment, for reasons other than DLT and before the MAD is determined, were replaced.
Maximal Tolerated Dose: The MTD was defined as the highest dose at which 0 of the first 3 patients, or 1 of 6 patients experienced a DLT during the first cycle of cabazitaxel to a maximum dose of 25 mg/m2. The MTD was one dose below the MAD. If the MAD reached at 5 or 10 mg/m2 (Cohorts 3 and 4), then no patients were further enrolled as the MTD could not be established. There was no dose recommendation for such patient population.
Prophylactic and therapeutic use of hematopoietic growth factors was not permitted during the first cycle of study treatment unless a hematological DLT is encountered.
Safety Data
Vital signs, medical history, physical examinations, Eastern Cooperative Oncology Group (ECOG) performance status (PS), electrocardiogram (ECG), and laboratory safety tests (including hematology, serum chemistries, and urinalysis) were obtained prior to study drug administration and at designated intervals throughout the study. Treatment-emergent AEs (TEAEs) were collected during the study and up to 30 days after the end of study treatment. Any serious adverse events (SAEs) considered related to the study medication were collected regardless of when they occur. Adverse events were graded according to the NCI CTCAE v. 4.0).
However, if patients were still receiving treatment after the cutoff date, SAEs and IMP administration continued to be captured.
Real time PK information has been used to inform the dose selection in the next dose level for Cohort 3 and 4 and in the starting dose of Cohort 4 along with safety information.
TEAEs leading to permanent study treatment discontinuation were reported in more than 1 patient in any Cohort/dose level.
likely this is due to a lower than normal CL/BSA value for Cohort 1.
| Number | Date | Country | Kind |
|---|---|---|---|
| 15305720.3 | May 2015 | EP | regional |
