Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

September 26, 2017 updated by: Jordan Berlin, MD, Vanderbilt-Ingram Cancer Center

A Phase 1 Study of Veliparib (ABT-888) in Combination With Capecitabine and Temozolomide in Advanced Well-Differentiated Neuroendocrine Tumors

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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
    • Medullary thyroid carcinoma
    • Neuroendocrine tumors of unknown primary site
  • Patients must have progressed on octreotide therapy and/or radioactive isotopes linked to octreotide or its congeners if they had a positive octreotide scan; patients who have negative or mildly positive octreotide scans are exempt from this requirement
  • Somatostatin analogs can be continued at their tolerated dose in patients with functional symptoms related to underlying disease such as in functional islet cell, insulinomas, glucagonomas etc
  • Patients may have received prior chemotherapy for advanced disease including either capecitabine or temozolomide single agent as long as it did not include combination of capecitabine and temozolomide
  • Patients must have completed prior (non-excluded) anti-cancer therapy (including surgery or chemotherapy or hepatic embolization/chemoembolization or radioactive isotopes i.e. yttrium 90) at least 4 weeks prior to day 1
  • Patients with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease and have not had treatment with steroids within 1 week of study enrollment
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Anticipated life expectancy of greater than 3 months
  • Patients must have measurable disease either primary and/or metastatic masses reproducibly measurable in one or two diameters by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 parameters by CT scan or MRI scan; positron emission tomography (PET) or octreotide scans are useful adjuncts but will not be used to measure response
  • Granulocytes > 1,500/ml
  • Platelets > 100,000/ml
  • Hemoglobin >= 10 g/dl
  • Creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
  • Bilirubin < 1.5 x ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if liver metastases are present)
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of veliparib, capecitabine and temozolomide administration
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients must be able to swallow pills

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
  • Patients who are receiving any other investigational agents
  • Major surgical procedure within 4 weeks of treatment

  • Patients may not have any clinically significant cardiovascular disease including the following:

    • Myocardial infarction or ventricular tachyarrhythmia within 6 months
    • Prolonged QTc > 480 msec at baseline
    • Symptomatic congestive heart failure (CHF) of New York Heart Association (NYHA) functional class >= 3
    • Major conduction abnormality (unless a cardiac pacemaker is present)
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with capecitabine or temozolomide or veliparib

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Capecitabine
Given PO
Drug: Temozolomide
Given PI
Drug: Veliparib
given PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
Up to 28 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Response rate measured as complete response, partial response or stable disease according to RECIST 1.1 criteria
Time Frame: 56 days (2 courses)
56 days (2 courses)
Response duration
Time Frame: Up to 4 weeks
Up to 4 weeks
Progression Free Survival
Time Frame: From start of treatment to time of progression or death, assessed up to 4 weeks
From start of treatment to time of progression or death, assessed up to 4 weeks
Overall Survival
Time Frame: Up to 4 weeks
Up to 4 weeks
Poly-adenosine diphosphate (ADP)-ribosylated (PAR) level
Time Frame: Baseline to day 15 of course 1
Baseline to day 15 of course 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt-Ingram Cancer Center

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Jordan Berlin, M.D., Vanderbilt-Ingram Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

December 1, 2017

Primary Completion (Anticipated)

February 1, 2019

Study Completion (Anticipated)

February 1, 2020

Study Registration Dates

First Submitted

July 10, 2016

First Submitted That Met QC Criteria

July 10, 2016

First Posted (Estimate)

July 13, 2016

Study Record Updates

Last Update Posted (Actual)

September 28, 2017

Last Update Submitted That Met QC Criteria

September 26, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VICC GI 14134
  • NCI-2016-01044 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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