| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced and/or metastatic solid tumors |
|
| 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 | 10065252 |
| E.1.2 | Term | Solid tumor |
|
| 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 (Dose Escalation): to define the safety, tolerability, dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of BMS-863233 administered orally to subjects with advanced and/or metastatic solid tumors
- Phase 2 (Cohort Expansion): to describe the preliminary anti-tumor activity of BMS-863233 administered orally to subjects with advanced and/or metastatic colorectal carcinoma, breast carcinoma, or bone/soft tissue sarcoma whose tumors have molecular features that indicate activation of the Cdc7 pathway in pre-treatment tumor tissue specimens |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 and Phase 2:
• To characterize multi-dose pharmacokinetics (PK) of BMS-863233
• To assess the effects of BMS-863233 on heart rate (HR), and PR, QRS and QTcF intervals on electrocardiogram (ECG)
Phase 2:
• To evaluate the pharmacodynamic effect of BMS-863233 on biomarkers that may
include, but are not limited to, markers of Cdc7 pathway activity (eg, Cdc7 and
pMCM2), cell proliferation (eg, Ki67), and apoptosis (eg, cleaved Caspase 3) in
tumor biopsy specimens |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics Blood Sample Amendment Number 01 - Site Specific (version 1.0 dated 16-Mar-09):
The objective of this Amendment is to permit the collection and storage of blood samples for use in future exploratory pharmacogenetic research. Bristol-Myers Squibb will use DNA obtained from the blood sample and health information collected from the main clinical trial, CA198002 to study the association between genetic variation and drug response. Bristol-Myers Squibb may also study the causes and further progression of Advanced and/or Metastatic Solid Tumors by comparing the use the DNA from this study in conjunction with pharmacogenetic research results from other clinical studies to accomplish this objective. |
|
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Target Population
a) Phase 1 (Dose Escalation): Subjects with advanced and/or metastatic solid tumors who are either refractory to or have relapsed from standard therapies, or for whom a standard therapy does not exist
i) For all subjects, a tumor paraffin tissue block or 4-10 unstained slides from the tumor tissue block must be identified for biomarker analyses
b) Phase 2 (Cohort Expansion): Subjects with advanced and/or metastatic colorectal carcinoma, breast carcinoma, or bone/soft tissue sarcoma who are either refractory to or have relapsed from standard therapies, or for whom a standard therapy does not exist. In addition, subjects MUST also have
i) Demonstrated evidence of Cdc7 pathway activity in a pre-treatment tumor biopsy (as evidenced by ≥ 10% of tumor cells positive for Cdc7 and pMcM2 expression by IHC). This evaluation will normally be performed on archived material from a prior tumor biopsy. Tumor paraffin block or 10 unstained slides must be provided for these analyses. If, however, archived tumor material is unavailable or unsuitable for evaluation, then tumor material from a fresh biopsy must be submitted to determine eligibility. In this setting, the material collected via fresh tumor biopsy to determine eligibility will also used to fulfill pre-treatment biopsy requirements and a separate biopsy will not be required.
ii) Accessible tumor tissue that can be biopsied at acceptable clinical risk (as judged by the Investigator) and consent to a pre-treatment and on-treatment fresh tumor biopsy
iii) Measurable disease as assessed by CT or MRI. Subjects must have measurable lesions distinct from those that will be biopsied for determination of protocol eligibility or subsequent biomarker studies
c) Histologic or cytologic diagnosis of the solid tumor (ie, non-hematologic malignancy)
d) Life expectancy of 12 weeks or greater
e) ECOG performance status ≤ 1. (See Appendix 2)
f) Accessible and able to comply with treatment, PK sample collection and required study follow-up
g) Organ and marrow function as follows:
i) Absolute neutrophil count ≥ 1,500 cells/mm³
ii) Platelet count ≥ 100,000 cells/mm³
iii) Hemoglobin ≥ 9.0 g/dL
iv) Total bilirubin ≤ 1.5 times the institutional upper limit of normal (IULN)
v) ALT, AST ≤ 2.5 times the IULN
vi) Creatinine ≤ 1.5 times the IULN, or Cr clearance ≥ 60 mL/min
vii) PT-INR/PTT ≤1.2 times the IULN
3) Age and Sex
a) Men and women, ages 18 years and above
b) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least three months after the study in such a manner that the risk of pregnancy is minimized. Suggested precautions should be used to minimize the risk or pregnancy for at least 3 weeks prior to initiation of dosing, while women are on study, and for at least 12 weeks after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
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 and for up to 12 weeks after the last dose of investigational product.
b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to investigational product administration.
d) Sexually active fertile men not using effective birth control if their partners are WOCBP.
2) Target Disease Exceptions
a) Subjects with known or suspected brain metastasis, primary brain tumors, or brain as the only site of disease
i) Subjects with controlled brain metastasis will be allowed
ii) Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases or are ruled out by CT or MRI.
b) Subjects with a history of prior malignancy with the exception of non-melanoma skin cancer, carcinoma in situ of the cervix, or other malignancy diagnosed > 5 years ago that has undergone potentially curative therapy with no evidence of disease for the last ≥ 5 years and is that is deemed by the investigator to be a low risk for recurrence
c) Subjects with a history of CNS disease must have abnormalities ruled out on a skull CT/MRI study during screening
3) Medical History and Concurrent Diseases
a) Inability to swallow oral medication
b) Evidence of active infection, requiring parenteral anti-bacterial, anti-viral or antifungal therapy ≤7 days prior to administration of study medication
c) Evidence of HIV or Hepatitis C, or active Hepatitis B or Hepatitis A infection
d) Subjects who have received ≥50 Gy radiation dose to ≥30% of their estimated bone marrow distribution (See Appendix 3 for a description of active bone marrow in the adult)
e) History of clinically significant cardiac disease, including a history (personal or family) of congenital long QT syndrome
f) Grade ≥ 2 QTc prolongation at baseline (≥ 470 msec by Bazett formula) confirmed by a repeat ECG
g) History of myocardial infraction or uncontrolled angina within 12 months prior to administration of study drug
f) History of stroke, TIA or other CNS ischemic event
g) History of seizure disorder
h) Current or recent (within 3 months) gastrointestinal disease that could potentially
impact the ability of the subject to swallow and/or absorb study drug
i) Presence of underlying medical condition that could adversely affect the ability of the subject to comply with study procedures and/or study therapy
4) Allergies and Adverse Drug Reactions
a) History of allergies to BMS-863233 or related compounds
5) Prohibited Treatments and/or Therapies
a) Exposure to any investigational agent within 4 weeks of study drug administration
b) For subjects enrolled in Phase 2 (cohort expansion), prior exposure to other Cdc7 inhibitors is also prohibited
c) Concurrent treatment with anticoagulants, including coumadin, heparin or low molecular weight heparins, and anti-platelet agents. A wash-out period of 2 weeks or 5 half-lives of the drug (whichever is longer) is required prior to first dose of BMS-863233
i) Prophylactic anticoagulation for venous access devices will be permitted provided that the PT/INR is ≤ 1.2 times the IULN.
d) Prior chemotherapy or radiotherapy within 4 weeks of study drug administration
(6 weeks for nitrosoureas and mitomycin C). For biologics (eg, monoclonal antibodies such as cetuximab) and extended-release formulations, a washout interval of 5 half-lives is required
d) Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation therapy standard or investigational, with the following exceptions: palliative radiation therapy to a limited field, if it is not the sole site of measurable
and/or assessable disease, is allowed after cycle 1 with prior approval of the Sponsor/Medical Monitor
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
c) Subjects who are mentally incompetent |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety Outcome Measures: All subjects who receive BMS-863233 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, and clinical laboratory tests. The incidence of observed adverse events will be tabulated and reviewed for potential significance and clinical importance. Toxicity will be evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0.
• ECG Evaluations: Heart rate, PR, QRS, and QTcF intervals will be determined on ECGs. A single 12-lead ECG will be collected at screening, at the end of treatment, and at the off-study follow up visits. Serial ECGs will be collected during cycle 1 on Days 1 and 14 of dosing. Based on the review of findings during dose escalation and with agreement between the Investigators and Sponsor, ECG assessments during Phase 2 (cohort expansion) may be limited to predose and at the time of maximum drug concentration of BMS-863233 on Days 1 and 14 of cycle 1.
• Pharmacokinetic Measures: PK parameters including Cmax, Cmin, Tmax, AUC(TAU), THalf, CL/F, and accumulation index will be derived from plasma concentration versus time data for BMS-863233.
• Efficacy Measures: Tumor response will be determined for all subjects with measurable disease as defined by the RECIST criteria. Radiological assessment of the tumor status will be made during screening, and then every 8 weeks (i.e. prior to Day 1 of every other cycle beginning cycle 3), or more frequently if indicated.
• Imaging Biomarker Measures: In Phase 2 (cohort expansion), metabolic responses will be assessed by FDG-PET prior to treatment, and in subjects with metabolically active lesions, between Days 10 and 14 of cycle 1.
• Predictive and Pharmacodynamic Measures: In Phase 2 (cohort expansion), pre-treatment tumor material (from archived material, or a fresh tumor biopsy if archived material is unsuitable or unavailable) will be evaluated for Cdc7 pathway activity (eg, Cdc7 and pMCM2 levels) to determine eligibility. Pre-treatment and on-treatment (prior to scheduled daily dose on Day 8 ± 1 day in Cycle 1) fresh tumor biopsies will be examined for biomarkers that may include, but not limited to, markers of Cdc7 pathway activity (eg, Cdc7, and pMCM2), cell proliferation (eg, Ki67), and apoptosis (eg, cleaved Caspase 3). Additional evaluations may also be performed to identify potential predictive biomarkers of response to BMS-863233.
• Exploratory Measures: Blood samples collected for pharmacokinetic analysis of BMS-863233 during the study will also be assayed for the glucuronide metabolite of BMS-863233 (and/or other metabolites as feasible) using a non-validated bioanalytical assay. |
|
| 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 | Yes |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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
|
| The last visit for each subject will be defined as the follow up visit which is no less than 30 days after the subject’s end-of-treatment visit. If a subject discontinues from treatment due to toxicity, the last visit of the study will be defined as 30 days after the date the Investigator documents the study related toxicity has either resolved to baseline, stabilized, or been deemed irreversible. The end of the trial will occur 30 days after the last subject discontinues from the study. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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