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

Shaheen Shagufta

Status and phase

Completed

Phase 2

Conditions

Glucagonoma

Stage III Pancreatic Cancer

Pancreatic Polypeptide Tumor

Insulinoma

Recurrent Islet Cell Carcinoma

Somatostatinoma

Stage IV Pancreatic Cancer

Recurrent Pancreatic Cancer

Gastrinoma

Treatments

Drug: Temozolomide

Biological: Bevacizumab

Drug: Capecitabine

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01525082

SU-10282011-8571 (Other Identifier)

NET0012 (Other Identifier)

NCI-2011-03497 (Registry Identifier)

4593 (Other Identifier)

END0012 (Other Identifier)

IRB-22412

Details and patient eligibility

About

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.

Full description

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.

Enrollment

20 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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)].