A Phase 1 Study of Veliparib (ABT-888) in Combination With Capecitabine and Temozolomide in Advanced Well-Differentiated Neuroendocrine Tumors
Overview
- Phase
- Phase 1
- Intervention
- Capecitabine
- Conditions
- Functional Pancreatic Neuroendocrine Tumor
- Sponsor
- Vanderbilt-Ingram Cancer Center
- Primary Endpoint
- Maximum tolerated dose determined by dose limiting toxicities defined as any toxicity in the first course evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
- Status
- Withdrawn
- Last Updated
- 8 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of veliparib when given together with capecitabine and temozolomide in treating patients with neuroendocrine tumor that has spread to other places in the body and usually cannot be cured or controlled with treatment, has returned after a period of improvement, and cannot be removed by surgery. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of veliparib (ABT-888) in combination with capecitabine and temozolomide in patients with advanced well-differentiated neuroendocrine tumors. SECONDARY OBJECTIVES: 2. To determine the safety profile of the combination of capecitabine, temozolomide and veliparib in patients with advanced well-differentiated neuroendocrine tumors (NET). 3. To evaluate the antitumor activity of the combination of capecitabine, temozolomide and veliparib in advanced well-differentiated NET patients 4. To determine progression-free survival (PFS) of the combination of capecitabine, temozolomide, and veliparib in advanced well-differentiated NET patients IV. To evaluate the association between pharmacodynamic biomarkers and response in patients with advanced well-differentiated NET patients. OUTLINE: This is a dose-escalation study of veliparib. Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14. Courses repeat every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.
Investigators
Jordan Berlin, MD
Professor of Medicine
Vanderbilt-Ingram Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Pathologically confirmed metastatic unresectable well differentiated (low grade and intermediate grade) neuroendocrine tumors (Ki-67 \< 20% and mitotic rate \< 2 per 10 high power field) that demonstrate progressive disease (by serial computed tomography \[CT\] or magnetic resonance imaging \[MRI\] scans) in past 12 months including
- •Carcinoid tumors originating anywhere in the body including the gastrointestinal (GI) tract or bronchial tree or thymus
- •Pancreatic neuroendocrine tumors (including functional and non-functional islet cell, insulinomas and glucagonomas)
- •Pheochromocytomas
- •Gastrinomas (Zollinger-Ellison syndrome)
- •Multiple endocrine neoplasia (MEN type I/II),
- •Adrenal carcinomas with NET markers by immunohistochemistry (IHC) or serum
- •Somatostatinoma
- •VIPoma (vasoactive intestinal peptide)
- •Merkel cell tumors
Exclusion Criteria
- •Prior chemotherapy with combination of capecitabine (or 5-flourouracil \[5-FU\]) "and" temozolomide (or dacarbazine \[DTIC\]) will be excluded; patients can have had prior therapies up to 3 prior chemotherapy regimens such as streptozocin, anthracyclines, irinotecan, etoposide, or a platinum agent including single agent capecitabine (or 5FU) or temozolomide (or DTIC).
- •History of severe hypersensitivity reaction to capecitabine, 5-FU, temozolomide or DTIC will be excluded (i.e. anaphylaxis or anaphylactoid reactions)
- •Patients who have active or uncontrolled infection or serious medical or psychiatric illness preventing informed consent or on intensive treatment
- •Patients with brain metastases are excluded
- •Patients with uncontrolled seizures or any neurological conditions resulting in increased risk for seizures are not eligible for study entry
- •Patients with documented central nervous system (CNS) ischemia and/or infarction, whether symptomatic or discovered incidentally without clinical symptoms, will be excluded from study participation
- •Patients with a history of the arterial or venous thromboembolism within =\< 12 months of study entry are not eligible
- •Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are excluded from the study
- •Patients with another active malignancy within the past five years except for carcinoma in situ of cervix or in situ carcinoma of the bladder or non-melanomatous carcinoma of the skin
- •Clinically significant and uncontrolled major medical conditions including but not limited to: active uncontrolled infection, psychiatric illness/ social situation that would limit compliance with study requirements; any medical condition, which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities
Arms & Interventions
Treatment (capecitabine, temozolomide, veliparib)
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Intervention: Capecitabine
Treatment (capecitabine, temozolomide, veliparib)
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Intervention: Temozolomide
Treatment (capecitabine, temozolomide, veliparib)
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Intervention: Veliparib
Treatment (capecitabine, temozolomide, veliparib)
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Intervention: Pharmacological Study
Treatment (capecitabine, temozolomide, veliparib)
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Intervention: Laboratory Biomarker Analysis
Outcomes
Primary Outcomes
Maximum tolerated dose determined by dose limiting toxicities defined as any toxicity in the first course evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame: Up to 28 days
Secondary Outcomes
- Progression Free Survival(From start of treatment to time of progression or death, assessed up to 4 weeks)
- Poly-adenosine diphosphate (ADP)-ribosylated (PAR) level(Baseline to day 15 of course 1)
- Response rate measured as complete response, partial response or stable disease according to RECIST 1.1 criteria(56 days (2 courses))
- Response duration(Up to 4 weeks)
- Overall Survival(Up to 4 weeks)