| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1 Primary Objective:
• To determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and recommended Phase 2 dose of BMS-753493 administered as a 3 to 5 minute bolus i.v. infusion on Days 1 through 4 of a 21-day cycle in subjects with confirmed solid tumor malignancy.
Phase 2 Primary Objective:
• To assess efficacy of BMS-753493 in subjects with advanced ovarian, renal or breast cancer as measured by the tumor response rate according to RECIST criteria or CA125 levels. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 Secondary Objectives:
• To describe the overall safety profile of BMS-753493 administered as a 3 to 5
minute bolus i.v. infusion on Days 1 through 4 of a 21-day cycle;
• To assess the PK of BMS-753493 and BMS-748285;
• To evaluate the impact of BMS-753493 and BMS-748285 on QTcF;
• To describe any preliminary evidence of anti-tumor activity of BMS-753493 for all
treated subjects.
Phase 2 Secondary Objectives:
• To describe any association between anti-tumor activity and FR status as assessed
by IHC;
• To further characterize safety and tolerability of BMS-753493 in subjects with
advanced ovarian, renal or breast cancer;
• To assess the response duration and progression-free survival (PFS);
• To evaluate the impact of BMS-753493 and BMS-748285 on QTcF;
• To assess the PK of BMS-753493 and BMS-748285. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1:
1) Signed Written Informed Consent
a) The signed informed consent form.
2) Target population
a) Histologically or cytologically confirmed diagnosis of solid tumor malignancy which
has progressed on standard therapy or for whom no standard therapy is known;
i) Minimum availability of 10 archived tumor tissue slides, or subject’s
willingness and ability to undergo tumor biopsy collection for IHC analysis; either available within 28 days or greater from Cycle 1 Day 1;
b) Measurable or non-measurable disease as defined by RECIST criteria;
c) Adequate recovery from recent surgery and radiation therapy. At least one week
must have elapsed from the time of a minor surgery and at least 3 weeks for major
surgery and radiation therapy;
d) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (see Protocol Appendix 3);
e) Available for treatment and follow-up. Subjects enrolled in this trial must be
treated at the participating center;
f) At least four weeks must have elapsed from the last dose of carboplatin,
immunotherapy or chemotherapy, (six weeks for nitrosoureas, or mitomycin C),
prior to beginning protocol therapy. Hormonal anti-cancer agents and
nontraditional cytotoxic agents, such as trastuzumab, gefitinib, erlotinib,
cetuximab, bevacizumab, are not considered chemotherapy regimens when
administered alone, and at least 4 weeks must have elapsed from the last dose of
this class of agents before study drug administration. Subjects must have
recovered to baseline or Grade 1 from the toxicities resulting from previous
therapies.
3) Age and Sex
a) Men and women, ages 18 and greater;
Phase 2 includes the above inclusion criteria and the following:
Subjects with measurable, confirmed, advanced ovarian (including primary peritoneal or fallopian tube), renal cell or breast cancer or non-measurable, confirmed, advanced ovarian (including primary peritoneal or fallopian tube) cancer with CA125 ≥ 2x ULN, which has progressed on standard therapy or for whom no standard therapy is known, in place of:
− Histologically or cytologically confirmed diagnosis of solid tumor malignancy which has progressed on standard therapy or for whom no standard therapy is known.
• IHC will be utilized to select subjects prospectively for assignment to the FR+
and FR- groups.
• For subjects with renal cell cancer, up to 3 prior treatment regimens are permitted,
and for subjects with ovarian cancer up to 4 prior treatment regimens are permitted. For subjects with breast cancer, up to 4 prior cytotoxic treatment regimens, with no more than 3 in the advanced disease setting, are permitted. Hormonal therapies are not included in these counts of previous treatment regimens.
− If a treatment is stopped and restarted after a disease recurrence, that will be
counted as 2 regimens. |
|
| E.4 | Principal exclusion criteria |
Phase 1
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period as per the Investigator’s discretion to avoid
pregnancy throughout the study and for up to 4 weeks after the study in such a
manner that the risk of pregnancy is minimized.
b) WOCBP using a contraceptive method deemed inappropriate by the Investigator.
c) Women who are pregnant or breastfeeding
Phase 1
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period as per the Investigator’s discretion to avoid
pregnancy throughout the study and for up to 4 weeks after the study in such a
manner that the risk of pregnancy is minimized.
b) WOCBP using a contraceptive method deemed inappropriate by the Investigator.
c) Women who are pregnant or breastfeeding
on thyroid replacement therapy and whose symptoms of thyroiditis are resolved to
≤ Grade 1 before enrollment are eligible;
i) Any other sound medical, psychiatric and/or social reason as determined by the
Investigator.
3) Physical and Laboratory Test Findings
a) Inadequate hematologic function with absolute neutrophils <1,500/mm3, platelets
<100,000/mm3, or hemoglobin <10 g/dL;
b) Inadequate hepatic function with serum bilirubin ≥1.5 times the upper
institutional limits of normal, ALT ≥ 2.5 times the upper institutional limits of
normal, AST ≥ 2.5 times the upper institutional limits of normal;
c) Inadequate renal function defined as a calculated creatinine clearance of < 60
mL/min according to the Cockcroft-Gault formula:
i) In men: [eGFRCG(mL/min)]=(140 - age) x weight (kg) / (72 x serum
creatinine concentration in mg/dL)
ii) In women, multiply this result by 0.85
d) Inadequate thyroid function with free T4 and/or TSH outside of the institutional
limits of normal unless approved by Medical Monitor.
4) Allergies and Adverse Drug Reactions
a) History of any significant drug allergy which in the Investigator’s discretion
would inhibit the subject’s participation.
5) Prohibited Treatments and/or Therapies
a) Exposure to any investigational drug or placebo within 4 weeks of study drug
administration;
b) Use of multi-vitamins and/or folic acid supplements for 1 week prior to Cycle 1
Day 1 and throughout the course of the trial;
c) Other concurrent chemotherapy hormonal therapy, immunotherapy regimens or
radiation therapy, standard or investigational;
d) Prior radiation must not have included ≥25% of major bone marrow containing
areas (pelvis, lumbar spine);
e) Use of steroids except in the following instances, in which the use of steroids is allowed:
• for anti-emetic purposes.
• continuing therapy for controlled brain metastases.
• chronic steroid use in the context of a disease requiring such use .
• for appetite stimulation.
• Treatment of a hypersensitivity reaction and as subsequent premedication for the
prevention of same
• Premedication prior to CT scan requiring IV contrast dye in subjects with IV contrast
dye allergy
• Other uses of steroids may be allowed with prior approval from the Medical Monitor
f) The use of known P-gp-inhibitors (Prot. App. 8) is prohibited for 1 week prior to
Cycle 1 Day 1 and throughout the course of the trial.
6) Other
a) Inability to provide an archived tumor sample (10 slides) for analysis within 28
days of study drug administration;
b) Prisoners or involuntarily incarcerated subjects;
c) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
Phase 2 includes above excl. criteria & following:
• Subjects with non-measurable advanced ovarian cancer subjects must not have
received mouse antibodies or have had medical or surgical interference with her
peritoneum or pleura during the 28 days prior to Cycle 1 Day 1, which would
make them ineligible for CA125 assessment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety Outcome Measures:
All subjects who receive BMS-753493 will be evaluated for safety. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, clinical laboratory tests, electrocardiograms, pulmonary function tests, and multigated radionuclide angiography (MUGA) scans or echocardiograms. Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. ECG assessments will be collected at screening (single ECG) pre-dose (triplicate ECGs) and at multiple timepoints (triplicate ECGs) post-dose on Cycle 1 Day 1 at timepoints corresponding to the PK collection, pre-dose and at the end of infusion on Cycle 1 Day 4 and pre-dose on Cycle 2 Day 1. The effect of
BMS-753493 on QTcF will be assessed in both the Phase 1 and Phase 2 portions of the study.
• Efficacy Outcome Measures:
Tumor response information will be obtained for all subjects treated with at least 1 dose of BMS-753493 and who undergo requisite baseline and on-treatment disease assessments and have at least one post-treatment assessment. Tumor response assessment in subjects with measurable disease will be done according to the RECIST criteria. For subjects with ovarian cancer and elevated CA125 levels at baseline, the effect of BMS-753493 on CA125 will be assessed.
• Pharmacokinetic Measures: Phase 1:
Pharmacokinetic samples will be collected in Cycle 1 only at 0, 5, 30 min, 1, 2, 3, 4, 8 and 24 h on Days 1 and 4 and predose on Day 3. PK urine samples for BMS-753493 will be collected at 0-2 h and 2-8 h intervals on Day 1 Cycle 1. AUC(0-8h), AUC(INF), %AUCe, T1/2, MRT, CL, CLR and Vss will be derived from BMS-753493 plasma/urine concentration versus time data, and Cmax, Tmax, AUC(0-24h), AUC(INF), %AUCe and T1/2 will be derived from BMS-748285 plasma concentration versus time data.
• Pharmacokinetic Measures: Phase 2:
Pharmacokinetic samples will be collected in the first 12 subjects at 0, 5, 30 min, 1, 2, 3, 4, 8 and 24 h on Days 1 and 4 and pre-dose on Day 3. For the subsequent subjects, samples will be collected at 0, 2, 4, 6 and 24 h on Days 1 and 4 during Cycle 1. AUC(0-8h), AUC(INF), %AUCe, T1/2, MRT, CL, and Vss will be derived from BMS-753493 plasma concentration versus time data, and Cmax, Tmax, AUC(0-24h), AUC(INF), %AUCe and T1/2 will be derived from BMS-748285 plasma concentration versus time data.
• Pharmacodynamic Measures:
In Phase 1 and Phase 2, subjects with ovarian cancer will have serum CA125 levels monitored at baseline and at each treatment cycle. In Phase 2, all breast cancer subjects will be evaluated by FDGPET scan at baseline and after 2 cycles of therapy. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Dose Ranging + Effectiveness (usual care setting) |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Subjects may continue treatment with BMS-753493 as a 3 to 5 minute bolus i.v. infusion on Days 1 through 4 of a 21-day cycle as long as they continue to meet retreatment criteria or until disease progression, unacceptable toxicity or subject refusal. The study will end 30 days after the last subject completes the last cycle and final follow-up of adverse events. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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