A Phase 1/2 Multiple Ascending Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BMS-863233 in Subjects with Advanced and/or Metastatic Solid Tumors
- Conditions
- Advanced and/or metastatic solid tumorsMedDRA version: 9.1Level: LLTClassification code 10065252Term: Solid tumor
- Registration Number
- EUCTR2009-010572-20-FR
- Lead Sponsor
- Bristol-Myers Squibb International Corporation
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 75
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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method