Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
Primary Purpose
Functional Pancreatic Neuroendocrine Tumor, Malignant Somatostatinoma, Merkel Cell Carcinoma
Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Capecitabine
Temozolomide
Veliparib
Pharmacological Study
Laboratory Biomarker Analysis
Sponsored by
About this trial
This is an interventional treatment trial for Functional Pancreatic Neuroendocrine Tumor
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
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (capecitabine, temozolomide, veliparib)
Arm Description
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
Response rate measured as complete response, partial response or stable disease according to RECIST 1.1 criteria
Response duration
Progression Free Survival
Overall Survival
Poly-adenosine diphosphate (ADP)-ribosylated (PAR) level
Full Information
NCT ID
NCT02831179
First Posted
July 10, 2016
Last Updated
September 26, 2017
Sponsor
Vanderbilt-Ingram Cancer Center
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT02831179
Brief Title
Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
Official Title
A Phase 1 Study of Veliparib (ABT-888) in Combination With Capecitabine and Temozolomide in Advanced Well-Differentiated Neuroendocrine Tumors
Study Type
Interventional
2. Study Status
Record Verification Date
September 2017
Overall Recruitment Status
Withdrawn
Why Stopped
Loss of funding support
Study Start Date
December 2017 (Anticipated)
Primary Completion Date
February 2019 (Anticipated)
Study Completion Date
February 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt-Ingram Cancer Center
Collaborators
National Cancer Institute (NCI)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Functional Pancreatic Neuroendocrine Tumor, Malignant Somatostatinoma, Merkel Cell Carcinoma, Metastatic Adrenal Gland Pheochromocytoma, Metastatic Carcinoid Tumor, Multiple Endocrine Neoplasia Type 1, Multiple Endocrine Neoplasia Type 2A, Multiple Endocrine Neoplasia Type 2B, Neuroendocrine Neoplasm, Non-Functional Pancreatic Neuroendocrine Tumor, Pancreatic Glucagonoma, Pancreatic Insulinoma, Recurrent Adrenal Cortex Carcinoma, Recurrent Adrenal Gland Pheochromocytoma, Recurrent Merkel Cell Carcinoma, Somatostatin-Producing Neuroendocrine Tumor, Stage III Adrenal Cortex Carcinoma, Stage III Thyroid Gland Medullary Carcinoma, Stage IIIA Merkel Cell Carcinoma, Stage IIIB Merkel Cell Carcinoma, Stage IV Adrenal Cortex Carcinoma, Stage IV Merkel Cell Carcinoma, Stage IVA Thyroid Gland Medullary Carcinoma, Stage IVB Thyroid Gland Medullary Carcinoma, Stage IVC Thyroid Gland Medullary Carcinoma, Thymic Carcinoid Tumor, VIP-Producing Neuroendocrine Tumor, Well Differentiated Adrenal Cortex Carcinoma, Zollinger Ellison Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (capecitabine, temozolomide, veliparib)
Arm Type
Experimental
Arm Description
Capecitabine PO BID on days 1-14, temozolomide PO BID on days 10-14 and veliparib PO BID on days 10-14.
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Intervention Description
Given PI
Intervention Type
Drug
Intervention Name(s)
Veliparib
Intervention Description
given PO
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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 Outcome Measure Information:
Title
Response rate measured as complete response, partial response or stable disease according to RECIST 1.1 criteria
Time Frame
56 days (2 courses)
Title
Response duration
Time Frame
Up to 4 weeks
Title
Progression Free Survival
Time Frame
From start of treatment to time of progression or death, assessed up to 4 weeks
Title
Overall Survival
Time Frame
Up to 4 weeks
Title
Poly-adenosine diphosphate (ADP)-ribosylated (PAR) level
Time Frame
Baseline to day 15 of course 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jordan Berlin, M.D.
Organizational Affiliation
Vanderbilt-Ingram Cancer Center
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
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