Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

A Phase 2 Study of Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

The purpose of this research is to evaluate the effectiveness and safety of a combination of capecitabine, temozolomide and bevacizumab in the treatment of advanced pancreatic neuroendocrine tumors.

PRIMARY OBJECTIVES:

• Estimate if the combination of capecitabine and temozolomide with bevacizumab for metastatic or unresectable neuroendocrine tumors will improve response rate (RR) by 62% over historical controls (null RR of 40% to true RR 65%).
• Assess the toxicities using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

SECONDARY OBJECTIVES:

• Evaluate progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis.
• Assess O6-methyl guanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) at baseline by central pathology (path) review.
• Assess serum hormone marker levels.
• Evaluate computed tomography (CT) Perfusion as a tool to predict early therapeutic response. (Optional)
• Bank serum for future correlative analyses.

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30 to 90 minutes on days 1 and 15, capecitabine orally (PO) twice daily (BID) on days 1 to 14, and temozolomide PO once daily (QD) on days 10 to 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity, with assessment for treatment effect every 3 cycles.

After completion of study treatment, patients are followed up patients are followed long-term for survival.

INCLUSION CRITERIA

• Histologically-confirmed pancreatic neuroendocrine tumors that are moderately- or well-differentiated
• Metastatic or unresectable disease
• If prior surgical resection > 5 years before the development of metastatic disease, a separate (recent) histological or cytological confirmation of metastatic disease is required
• If there is substantial clinical ambiguity regarding the nature or source of apparent metastases, clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease
• The site of previous radiotherapy, if the only site of disease, has evidence of progressive disease
• If prior sunitinib and everolimus has been administered, a 2-week wash-out period is required prior to 1st dose on this study
• If prior liver-directed therapies (ie, chemoembolization, radioembolization), target lesions in the liver have demonstrated growth since the liver-directed treatment
• If prior peptide receptor radionuclide therapy (PRRT), target lesions in the liver have demonstrated growth since the liver-directed treatment
• Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial thromboembolic disease.
• Primary or metastatic tumor lesion measurable in at least 1 dimension, within 4 weeks prior to entry of study.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• ≥ 18 years of age.
• Laboratory values as follows, ≤ 2 weeks prior to randomization:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L (≥ 1500/mm³)
• Platelets (PLT) ≥ 100 x 10e9/L (≥ 100,000/mm³)
• Hemoglobin (Hgb) ≥ 9 g/dL
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
• Serum bilirubin ≤ 1.5 x ULN
• Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present). Note: endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous stenting may be used to normalize the liver function tests
• Urine dipstick or urinalysis for protein, value must be 0, trace, or 1+ protein to enroll. EXCEPTION: if ≥ 2+ must check 24-hour urine protein and must be < 1 g
• Life expectancy ≥ 12 weeks
• Ability to give written informed consent according to local guidelines
• If any prior therapy-related toxicities, must have recovered from all

EXCLUSION CRITERIA Disease-Specific Exclusions

• Prior bevacizumab; fluoropyrimidines (eg, capecitabine or 5-fluorouracil, 5FU); or temozolomide
• Poorly-differentiated or high-grade pancreatic neuroendocrine tumors
• Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to enrollment
• Diagnosis of another malignancy, unless > 3 years earlier and has been disease-free for > 6 months following the completion of curative intent therapy, specific eligibility exceptions as follows:
• Curatively-resected non-melanomatous skin cancer
• Curatively-treated cervical carcinoma in situ
• Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values, if hormonal therapy has been initiated or a radical prostatectomy has been performed
• Other primary solid tumor curatively treated with no known active disease present and no treatment administered for > 3 years
• Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment
• Known hypersensitivity to capecitabine, temozolomide, or any component of the formulation
• Known deficiency of dihydropyrimidine dehydrogenase Bevacizumab-specific Exclusions
• Inadequately-controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)
• Prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to Day 1
• History of stroke or transient ischemic attack within 6 months prior to Day 1
• Known central nervous system (CNS) metastases
• Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
• History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior to Day 1
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Known hypersensitivity to any component of bevacizumab General Medical Exclusions
• Inability to comply with study and/or follow-up procedures
• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study
• Pregnant or lactating/breast feeding
• Lack of effective contraception men or women of child-bearing potential
• Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
• Known history of HIV, HBV, or HCV
• Current, ongoing treatment with full-dose warfarin. However, patients may be on stable doses of a low-molecular weight heparin are allowed [eg, (enoxaparin (Lovenox)].