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Veliparib and Combination Chemotherapy in Treating Patients with Metastatic Pancreatic Cancer

Trial Status: Active

This phase I / II trial studies the side effects and best dose of veliparib when given together with combination chemotherapy and to see how well it works in treating patients with pancreatic cancer that has spread to other places in the body. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving veliparib and combination chemotherapy may kill more tumor cells.

Inclusion Criteria

  • Histologically proven pancreatic adenocarcinoma with measurable disease, defined as at least 1 unidimensionally measurable lesion on imaging as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • A known BRCA-associate genetic mutation OR family history suggesting of a breast or ovarian cancer syndrome, as defined by one or more of the following: * Personal or known family history of a deleterious (or indeterminate) mutation in the BRCA1, BRCA2, PALB2, or one of the FANC genes * Personal history of breast cancer and one or more of the following: ** Diagnosed =< 45 years old ** Diagnosed at any age with >= 1 1st, 2nd, or 3rd degree relative with breast cancer =< 50 years old and/or >= 1st, 2nd, or 3rd relative with epithelial ovarian cancer at any age ** Two primary breast cancer with the first diagnosed at =< 50 years old ** Diagnosed =< 60 years old with triple negative breast cancer ** Diagnosed at any age with >= 2 1st, 2nd, or 3rd degree relatives with breast cancer at any age ** Diagnosed at any age with >= 2 1st, 2nd, or 3rd degree relatives with pancreatic cancer or aggressive prostate cancer (Gleason score >= 7) at any age ** 1st, 2nd, or 3rd degree male relative with breast cancer ** Ashkenazi Jewish descent * Personal history of epithelial ovarian cancer * Personal history of male breast cancer * Personal history of pancreatic cancer and >= 2 1st, 2nd, or 3rd degree relatives with breast, epithelial ovarian, pancreatic, or aggressive prostate cancer (Gleason score >= 7) at any age
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Subjects with no brain metastases or a history of previously treated brain metastases who: * Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment * AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intercranial disease * AND have not had treatment with steroids for brain metastases within 1 week of study enrollment
  • Prior therapies: * For patients stratified to the untreated arm: ** Untreated patients should have received zero prior therapies for metastatic disease ** They may have received prior adjuvant chemotherapy and/or radiation therapy, but not within 6 months prior to treatment ** They may have received prior palliative radiation therapy for unresectable disease, but without any systemic chemotherapy, even as a radiosensitizer * For patients in the previously treated arm: ** Previously treated patients may have received any number of prior therapies ** Patients who received prior adjuvant chemotherapy and/or radiation therapy within 6 months of treatment will be considered previously treated *** Patients may have received any prior therapies EXCEPT prior therapy with a PARP inhibitor ** Timing of prior therapies: *** At least 14 days must have passed since all prior anti-cancer therapy, including chemotherapy, biological therapy, or radiation therapy *** However, at least 28 days must have passed since any prior antibody-based therapies (such as, but not limited to cetuximab or bevacizumab) *** Additionally, at least 28 days must have passed since any prior investigational agent *** All patients must have completely recovered from all transient side effects related to prior therapies **** However, any side effects that are expected to be more durable or even permanent (e.g., neurotoxicity or ototoxicity) must have resolved to at least grade 1
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelets >= 75,000/mm^3
  • Hemoglobin >= 9.5 g/dL
  • Serum creatinine =< 1.5 × upper normal limit of institution's normal range OR creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 X the upper normal limit of institution's normal range
  • Bilirubin =< 2.5 X the upper normal limit of institution's normal range
  • 5FU and oxaliplatin are known to be safe to be administered in patients with such abnormal liver function tests
  • ABT-888 is primarily excreted in the urine, and is not even metabolized by the liver; thus such degree of hepatic impairment is not expected to affect the dosing of ABT-888
  • Partial thromboplastin time (PTT) must be =< 2 X upper normal limit of institution's normal range; subjects on anticoagulant (such as coumadin) must have a PTT =< 5 X upper normal limit of institution's normal range
  • International normalized ratio (INR) < 2; subjects on anticoagulant (such as coumadin) must have an international normalized ratio (INR) < 5
  • Subjects with significant fluid retention, including ascites or pleural effusion, may be allowed at the discretion of the Principal Investigator (PI)
  • Life expectancy > 12 weeks
  • Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
  • Men and women enrolled in the protocol must agree to use adequate contraceptive measure when the female (patient, or partner of the male patient) has childbearing potential (the woman is not postmenopausal and has an intact uterus)
  • Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures
  • Patients must have fully recovered from all effects of surgery; patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy; minor procedures requiring “Twilight” sedation such as endoscopies or mediport placement may only require a 24 hour waiting period, but this must be discussed with an investigator

Exclusion Criteria

  • Central nervous system (CNS) metastases which do not meet the criteria outlined in the inclusion criteria
  • Clinically significant peripheral neuropathy at the time of randomization (defined in the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v4.0] as grade 2 or greater neurosensory or neuromotor toxicity)
  • Active severe infection, or known chronic infection with human immunodeficiency virus (HIV), hepatitis B virus; patients with chronic hepatitis C virus may be enrolled if there is no clinical/laboratory evidence of cirrhosis AND the patient’s liver function tests fall within the parameters set
  • Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months
  • Life-threatening visceral disease or other severe concurrent disease
  • Women who are pregnant or breastfeeding
  • Anticipated patient survival under 3 months
  • Regarding prior malignancies: * Patients with a second active malignancy being actively treated at the time of screening with palliative or curative intent with cytotoxic chemotherapy, surgery, or radiation are ineligible * Patients with stage III or stage IV cancers of any type who have completed cytotoxic chemotherapy, surgery, or radiation in the adjuvant setting within 3 years of screening are ineligible ** For these patients, if more than three years have passed from the completion of adjuvant therapy to screening for the current protocol, then the patient is eligible for enrollment * However, patients with stage I or stage II cancers of any type, and who have completed cytotoxic chemotherapy, surgery, or radiation in the adjuvant setting by the time they are screening for the current protocol are eligible for enrollment * Patients who are being treated with adjuvant hormonal therapies, such as anti-estrogens or anti androgens, are eligible for enrollment provided they stop the hormonal therapy prior to starting the study medications * Finally, patients with cervical cancer in situ, in situ carcinoma of the bladder, or non-melanoma carcinoma of the skin that have been removed, are eligible for enrollment at any time * Questions regarding the inclusion of individual subjects should be directed to the principle investigator
  • Clinically significant and uncontrolled major medical condition(s) including but not limited to: * Active uncontrolled infection * Symptomatic congestive heart failure * Unstable angina pectoris or cardiac arrhythmia * 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

District of Columbia

Washington
MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Michael Jon Pishvaian
Phone: 202-444-2144

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of ABT-888 (veliparib) combined with modified fluorouracil (5FU) and oxaliplatin in patients with metastatic pancreatic cancer. (Phase I)

II. To determine the objective response rate of ABT-888 combined with 5FU and oxaliplatin in patients with metastatic pancreatic cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To determine disease control rate (complete response [CR]+partial response [PR]+stable disease [SD] at 6 months) in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

II. To determine progression free survival in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

III. To determine overall survival in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

IV. To determine time to disease progression in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

V. To determine duration of disease control in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

VI. To determine tolerability and safety of the combination in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

VII. To determine degree of neuropathy, as measured by the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG)-neurotoxicity (NTX)-4 (version 4) in patients with metastatic pancreatic cancer treated with ABT-888 combined with 5FU and oxaliplatin.

VIII. To associate the response rate of ABT-888 plus 5FU and oxaliplatin to tumors that have decreased expression of or mutations in breast cancer (BRCA)-1 or -2 or related pathway genes.

IX. To associate the response rate of ABT-888 plus 5FU and oxaliplatin to poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) activity levels in serial tumor samples.

X. To associate the response rate of ABT-888 plus 5FU and oxaliplatin to expression levels of deoxyribonucleic acid (DNA) repair enzymes in tumor tissues

XI. To associate the response rate of ABT-888 plus 5FU and oxaliplatin to pharmacokinetic and pharmacogenomic parameters associated with the metabolism of ABT-888.

XII. To isolate and propagate tumor cell lines obtained from patient samples and circulating tumor cells.

OUTLINE: This is a phase I, dose escalation study of veliparib followed by a phase II study.

Patients receive fluorouracil intravenously (IV) over 46 hours continuously on days 1-3, oxaliplatin IV on day 1, leucovorin calcium IV on day 1, and veliparib orally (PO) twice daily (BID) on days 1-7. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
MedStar Georgetown University Hospital

Principal Investigator
Michael Jon Pishvaian

  • Primary ID 2009-608
  • Secondary IDs NCI-2013-00656
  • Clinicaltrials.gov ID NCT01489865