| 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 |
• Primary Phase 1 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, 4, 8 and 11 of a 21-day cycle in subjects with confirmed solid tumor malignancy.
• Primary Phase 2 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 |
Secondary Phase 1 Objectives:
• To describe the overall safety profile of BMS-753493 administered as a 3 to 5 minute bolus i.v. infusion on Days 1, 4, 8 and 11 of a 21-day cycle;
• To assess the plasma pharmacokinetics (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.
Secondary Phase 2 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
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, (6 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, etc., 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;
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception 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.
Phase 2 includes the above inclusion criteria and the following:
• Subjects with measurable, confirmed, advanced ovarian (including primary
peritoneal), renal cell or breast cancer or non-measurable, confirmed, advanced
ovarian (including primary peritoneal) 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 or breast cancer, up to 4 prior treatment regimens are
permitted.
− 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 unwilling or unable to use an acceptable method to avoid
pregnancy for entire study period as per Investigator’s discretion to avoid
pregnancy throughout study & for up to 4 weeks after study in such a
manner that risk of pregnancy is minimized
b)WOCBP using a contraceptive method deemed inappropriate by Investigator
c)pregnant or breastfeeding Women
d)Women with positive pregnancy test on enrollment or prior to investigational
product administration
e)Sexually active fertile men not using effective birth control if their partners are
WOCBP
2) Medical History and Concurrent Diseases
a)Inability to be venipunctured &/or tolerate venous access
b)Subjects with known symptomatic brain metastasis. Subjects with controlled brain
metastasis will be allowed & steroid therapy may be continued. Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastasis are ruled out by CT or MRI
c)CTCAE Grade 2 or greater neuropathy currently or prior history of Grade 3 or greater neuropathy
d)Psychiatric disorders or other conditions rendering subject incapable of
complying with requirements of protocol
e)Serious intercurrent infections, or nonmalignant medical illnesses that are
uncontrolled or whose control may be jeopardized by complications of this
therapy
f)Uncontrolled or significant cardiovascular disease, including:
i)myocardial infarction within 6 months
ii)uncontrolled angina within 3 months
iii)congestive heart failure within 3 months
iv)diagnosed or suspected congenital LQT syndrome
v)any history of significant arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or torsades de pointes)
vi) prolonged QTcF on screening or Cycle 1 Day 1 pre-dose mean (QTcF
≥450msec)
vii)subjects with pacemaker
viii)2nd degree AV block or any form of BBB
ix)troponin (T or I)> institutional upper limits of normal
x)LVEF< institutional limits of normal as determined by MUGA or
echocardiogram
xi)inadequate cardiac function as defined by a NYHA classification of >Class I;
g)Known MTHFR mutations or known impaired regulation of homocysteine levels;
h)Uncontrolled thyroid disorder, including hypothyroidism, hyperthyroidism,
Grave’s disease or Hashimoto’s disease. Subjects with hypothyroidism who are
on thyroid replacement therapy & whose symptoms of thyroiditis are resolved to
≤Grade 1 before enrollment are eligible
i)Any other sound medical, psychiatric &/or social reason as determined by Investigator
3) Physical and Laboratory Test Findings
a)Inadequate hematologic function with absolute neutrophils <1,500/mm³, platelets
<100,000/mm³ or hemoglobin <10g/dL
b)Inadequate hepatic function with serum bilirubin≥1.5 x upper institutional limits of normal, ALT ≥ 2.5 x upper institutional limits of normal, AST ≥2.5 x upper institutional limits of normal
c)Inadequate renal function defined as calculated creatinine clearance of <60mL/min according to 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 &/or TSH outside of institutional limits of normal
4) History of any significant drug allergy which in Investigator’s discretion would inhibit subject’s participation
5) Prohibited Treatments &/or Therapies
a)Exposure to any investigational drug or placebo within 4 weeks of study drug
administration
b)Use of multi-vitamins 1/or folic acid supplements for 1 week prior to Cycle 1
Day 1 & throughout 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 for anti-emetic purposes &/or continuing therapy for controlled brain metastases
f)Use of known P-gp inhibitors (Prot App 8) is prohibited for 1 week prior to Cycle 1 Day 1 & throughout 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 psychiatric or
physical (eg, infectious disease) illness
Phase 2 includes above exclusion 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 28 days prior to Cycle 1 Day 1, which would make
them ineligible for CA125 assessment
Phase 1 & 2
Eligibility criteria for this study have been carefully considered to ensure safety of
study subjects & to ensure that results of the study can be used. It is imperative that
subjects fully meet all eligibility criteria
|
|
| 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 predose 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 at 0, 5, 30 min, 1, 2, 3, 4, 8 and 24 h on Days 1 and 4 and pre-dose on Days 8 and 11, and pre-dose on
Day 1 of Cycle 2. PK urine samples for BMS-753493 will be collected at 0-2 h and 2-8h 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 of Cycle 1, and pre-dose on Days 8 and 11 of Cycle 1 and pre-dose on Day 1 of Cycle 2. For the subsequent subjects, samples will be collected at 0, 2, 4, 6 and 24 h on Day 1, pre-dose on Day 4, 8 and 11 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 subjects, with the exception of ovarian cancer subjects with elevated CA125, 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 | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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, 4, 8 and 11 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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