Phase II Randomized, Prospective Trial of Lutetium Lu 177 Dotatate PRRT Versus Capecitabine and Temozolomide in Well-Differentiated Pancreatic Neuroendocrine Tumors
Overview
- Phase
- Phase 2
- Intervention
- Lutetium Lu 177 Dotatate
- Conditions
- Metastatic Pancreatic Neuroendocrine Tumor
- Sponsor
- Alliance for Clinical Trials in Oncology
- Enrollment
- 31
- Locations
- 171
- Primary Endpoint
- Progression free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This phase II trial compares capecitabine and temozolomide to lutetium Lu 177 dotatate for the treatment of pancreatic neuroendocrine tumors that have spread to other parts of the body (advanced) or are not able to be removed by surgery (unresectable). Chemotherapy drugs, 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. Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and may reduce harm to normal cells. The purpose of this study is to find out whether capecitabine and temozolomide or lutetium Lu 177 dotatate may kill more tumor cells in patients with advanced pancreatic neuroendocrine tumors.
Detailed Description
This phase II trial compares capecitabine and temozolomide to lutetium Lu 177 dotatate for the treatment of pancreatic neuroendocrine tumors that have spread to other parts of the body (advanced) or are not able to be removed by surgery (unresectable). Chemotherapy drugs, 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. Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and may reduce harm to normal cells. The purpose of this study is to find out whether capecitabine and temozolomide or lutetium Lu 177 dotatate may kill more tumor cells in patients with advanced pancreatic neuroendocrine tumors. The primary and secondary objectives of the study: PRIMARY OBJECTIVE: I. To determine the differences in median progression-free survival (PFS) for lutetium Lu 177 dotatate peptide receptor radionuclide therapy (PRRT) when compared to capecitabine and temozolomide (CAPTEM) in patients with locally advanced or metastatic progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs). SECONDARY OBJECTIVES: I. To evaluate and compare the overall survival (OS) of patients receiving lutetium Lu 177 dotatate versus (vs.) CAPTEM. II. To evaluate and compare time to response, time to maximum response, and overall response rates (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 between both arms. III. To evaluate and compare duration of response and time to progression among both arms. IV. To evaluate and compare treatment related toxicities between the arms. V. To compare global health status/quality of life as measured with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 from baseline through 18 months between patients with pNET treated with lutetium Lu 177 dotatate PRRT versus capecitabine and temozolomide. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive lutetium Lu 177 dotatate intravenously (IV) over 30 minutes on day 1. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive capecitabine orally (PO) twice daily (BID) days 1-14 and temozolomide PO once daily (QD) on days 10-14. Treatment repeats every 4 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologic or pathologic documentation: well-differentiated pancreatic neuroendocrine tumor (G1, G2, or well-differentiated G3) confirmed by local histology and/or pathology
- •Functional or nonfunctional tumors are allowed
- •Stage: locally unresectable or metastatic disease
- •Tumor Site: neuroendocrine tumor of pancreatic primary site
- •Radiologic evaluation: tumor must have shown somatostatin receptor (SSTR) positivity on 68Ga-DOTATATE PET or other SSTR-PET scan in the 12 months prior to registration; however, documentation of SSTR positivity in the 6 months prior to registration is preferred. SSTR positivity is defined as uptake greater than background liver in all measurable lesions
- •Patients are eligible if they meet one of the following criteria:
- •Previously untreated patients with grade 2 or 3 disease AND with symptoms of either disease bulk causing pain, anorexia, early satiety, large effusions/ascites, abdominal pain, abdominal fullness due to hepatomegaly, dyspnea) OR incompletely controlled symptoms of hormone excess despite somatostatin analogue (SSA) and supportive care (including but not limited to: diarrhea, hypercalcemia, hypoglycemia, hyperglycemia, flushing, Cushing's syndrome). Patient may have been started on SSA for up to 2 months for attempted symptom control without disease progression prior to registration
- •Patients previously treated with SSA only and with disease progression by RECIST in prior 12 months
- •Patients previously treated with SSA and one or more prior systemic therapy must have received prior anti-vascular endothelial growth factor (VEGF) pathway therapy inhibitor OR have contraindication to anti-VEGF therapy (including but not limited to: uncontrolled hypertension \[systolic blood pressure \[SBP\] \> 150 and/or diastolic blood pressure \[DBP\] \> 90 despite medical management\], stage IIB or greater heart disease, angina pectoris, prior arterial \[ATE\] and venous thromboembolic \[VTE\] events in the past 6 months, gastrointestinal \[GI\] bleed in the last 6 months) and disease progression by RECIST in prior 12 months
- •Patients previously treated with more than 2 lines of therapy, not including anti VEGF therapy, but with NET related symptoms as outlined in first bullet (pain, anorexia, early satiety, large effusions/ascites, abdominal pain, abdominal fullness due to hepatomegaly, anorexia, early satiety, dyspnea) OR incompletely controlled symptoms of hormone excess despite somatostatin analogue (SSA) and supportive care (including but not limited to: diarrhea, hypercalcemia, hypoglycemia, hyperglycemia, flushing, Cushing's syndrome).
Exclusion Criteria
- •Patients with poorly differentiated neuroendocrine carcinoma (large cell histology or small cell histology) are not eligible
- •No prior temozolomide, dacarbazine, capecitabine, 5-FU, or any PRRT for treatment of the pNET
- •Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects
- •\* Therefore, for women of childbearing potential only, a negative pregnancy test done =\< 14 days prior to registration is required
- •No known brain metastases unless adequately treated, demonstrated to be stable, and off all treatment (including steroids) for at least 2 months prior to registration
- •No uncontrolled congestive heart failure (New York Heart Association \[NYHA\] II, III, IV).
- •No significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may pose a risk to patient safety
- •No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy or are on adjuvant hormonal therapy and are free of disease for \>= 3 years
- •No known medical condition causing an inability to swallow and no known impairment of gastrointestinal function that may significantly alter the absorption of an oral agent
Arms & Interventions
Arm I (lutetium Lu 177 dotatate)
Patients receive lutetium Lu 177 dotatate IV over 30 minutes on day 1. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Lutetium Lu 177 Dotatate
Arm I (lutetium Lu 177 dotatate)
Patients receive lutetium Lu 177 dotatate IV over 30 minutes on day 1. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Arm I (lutetium Lu 177 dotatate)
Patients receive lutetium Lu 177 dotatate IV over 30 minutes on day 1. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration
Arm II (capecitabin, temozolomide)
Patients receive capecitabine PO BID days 1-14 and temozolomide PO QD on days 10-14. Treatment repeats every 4 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Capecitabine
Arm II (capecitabin, temozolomide)
Patients receive capecitabine PO BID days 1-14 and temozolomide PO QD on days 10-14. Treatment repeats every 4 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Temozolomide
Arm II (capecitabin, temozolomide)
Patients receive capecitabine PO BID days 1-14 and temozolomide PO QD on days 10-14. Treatment repeats every 4 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Outcomes
Primary Outcomes
Progression free survival (PFS)
Time Frame: Up to 8 years from randomization
Progression free survival (PFS) will be compared between the two treatment arms using Kaplan-Meier methods. The hazard ratio (HR) and median PFSwill be estimated along with corresponding 95% confidence intervals.
Secondary Outcomes
- Progression Free Survival (PFS) at 3 years(At 3 years from randomization)
- Time to progression (TTP)(Up to 8 years from randomization)
- Overall survival (OS)(Up to 8 years from study registration)
- Time-to response(Up to 8 years from randomization)
- Change in Overall Quality of Life Question (Q30) from the EORTC QLQ-C30 questionnaire(At baseline up to 18 months)
- Progression Free Survival (PFS) at 2 years(At 2 years from randomization)
- Objective response rate (ORR)(Up to 8 years from randomization)
- Change in Overall Health Question (Q29) from the EORTC QLQ-C30 questionnaire(At baseline up to 18 months)
- Duration of response(Up to 8 years from randomization)
- Incidence of adverse events(Up to 8 years from randomization)