Comparing Capecitabine And Temozolomide In Combination To Lutetium Lu 177 Dotatate In Patients With Advanced Pancreatic Neuroendocrine Tumors

Study Overview

Comparing Capecitabine and Temozolomide in Combination to Lutetium Lu 177 Dotatate in Patients With Advanced Pancreatic Neuroendocrine Tumors

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.

Metastatic Pancreatic Neuroendocrine Tumor
Unresectable Pancreatic Neuroendocrine Carcinoma

DRUG: Lutetium Lu 177 Dotatate
DRUG: Capecitabine
DRUG: Temozolomide
OTHER: Quality-of-Life Assessment
OTHER: Questionnaire Administration

A022001
NCI-2021-14404 (REGISTRY Identifier) (REGISTRY: NCI Clinical Trial Reporting Program)
U10CA180821 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2022-02-10	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-03-28
First Submitted that Met QC Criteria 2022-02-10	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-04-02
First Posted (ACTUAL) 2022-02-21	Results First Posted N/A	Last Verified 2025-03

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 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.	DRUG: Lutetium Lu 177 Dotatate Given IV OTHER: Quality-of-Life Assessment Ancillary studies OTHER: Questionnaire Administration Ancillary studies
EXPERIMENTAL: 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.	DRUG: Capecitabine Given PO DRUG: Temozolomide Given PO OTHER: Quality-of-Life Assessment Ancillary studies

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: 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.

DRUG: Lutetium Lu 177 Dotatate

Given IV

OTHER: Quality-of-Life Assessment

Ancillary studies

OTHER: Questionnaire Administration

Ancillary studies

EXPERIMENTAL: 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.

DRUG: Capecitabine

Given PO

DRUG: Temozolomide

Given PO

OTHER: Quality-of-Life Assessment

Ancillary studies

Primary Outcome Measures	Measure Description	Time Frame
Progression free survival (PFS)	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.	Up to 8 years from randomization

Secondary Outcome Measures	Measure Description	Time Frame
Progression Free Survival (PFS) at 2 years	Kaplan-Meier methodology will be used to estimate the PFS rate at 2 years.	At 2 years from randomization
Progression Free Survival (PFS) at 3 years	Kaplan-Meier methodology will be used to estimate the PFS rate at 3 years.	At 3 years from randomization
Time to progression (TTP)	Kaplan-Meier methodology will be used to estimate the median time to progression (TTP).	Up to 8 years from randomization
Overall survival (OS)	Kaplan-Meier methodology will be used to estimate the median overall survival (OS). OS is defined as randomization to the time of death due to any cause (or censored at the time of last contact for surviving patients and those lost to follow-up).	Up to 8 years from study registration
Objective response rate (ORR)	The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. Response rates (including complete and partial response) will be tested using Fisher's exact test.	Up to 8 years from randomization
Time-to response	Kaplan-Meier methodology will be used to estimate the median time-to-response. Time-to-response will be defined as the time from randomization to the first tumor response, for those patients having achieved an objective response.	Up to 8 years from randomization
Duration of response	Kaplan-Meier methodology will be used to estimate the median duration of response. Duration of response will be defined as the time from first assessment with documented response (PR or CR) to the time of progression and/or death. Patients who are still responding as of their last evaluation will be censored at the time point. If we observed documented deaths without progression, we will further evaluate this endpoint with death without progression treated as a competing risk.	Up to 8 years from randomization
Incidence of adverse events	Patients will be evaluated for adverse events using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported.	Up to 8 years from randomization
Change in Overall Health Question (Q29) from the EORTC QLQ-C30 questionnaire	To evaluate between-arm differences in patient-reported global health status from baseline through 18 months, the area under the curve will be calculated as a summary statistic for each arm based on estimates from a mixed model for patient-reported global health status/quality of life as assessed by the EORTC QLQ-C30 at baseline, 3, 6, 12, and 18 months.	At baseline up to 18 months
Change in Overall Quality of Life Question (Q30) from the EORTC QLQ-C30 questionnaire	To evaluate between-arm differences in patient-reported quality of life from baseline through 18 months, the area under the curve will be calculated as a summary statistic for each arm based on estimates from a mixed model for patient-reported global health status/quality of life as assessed by the EORTC QLQ-C30 at baseline, 3, 6, 12, and 18 months.	At baseline up to 18 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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).
Any patient with disease progression by RECIST criteria in < 4 months
Patients must have measurable disease per RECIST v1.1 by computer tomography (CT) scan or magnetic imaging (MRI). Any lesions which have undergone percutaneous therapies or radiotherapy after starting protocol therapy should not be considered measurable unless the lesion has clearly progressed since the procedure.

Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as >= 1 cm with CT or MRI (or shortest diameter >= 1.5 cm for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly non- measurable including: leptomeningeal disease, bone metastases, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung.
Prior treatment with tyrosine kinase inhibitors (TKIs) such as mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, temsirolimus, etc.) or VEGF pathway inhibitors (e.g. sunitinib, pazopanib, cabozantinib, bevacizumab, etc.) are allowed
Prior treatment with hepatic intra-arterial embolic therapies is allowed if there is recovery from all toxicities, measurable lesions do not include embolized liver unless there has been clear subsequent progression, all measurable lesions are somatostatin receptor avid, and treatment completed at least 2 months prior to registration
Prior treatment with cryoablation or thermal/radiofrequency ablation of metastases is allowed if there is recovery from all toxicities, measurable lesions do not include treated metastases, and treatment completed at least 2 months prior to registration
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 9.0 g/dL
Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 30 mL/min (calculated by the Cockcroft-Gault equation)
Total bilirubin =< 1.5 x ULN (in patients with liver metastases or known Gilbert's syndrome, total bilirubin must be =< 3.0 x ULN)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN
Albumin >= 3.0 g/dL
Concurrent somatostatin analog use while on protocol therapy is allowed provided that the patient:

Has a functional tumor (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing's syndrome)
Has been on a stable dose of somatostatin analog therapy for at least three months
Has previously demonstrated radiographic disease progression while on somatostatin analog therapy. For subjects receiving lutetium Lu 177 dotatate, there should be a minimum of 14 days between long-acting somatostatin analogue and lutetium Lu 177 dotatate dosing. Short-acting somatostatin analogs should not be administered within 24 hours of lutetium Lu 177 dotatate dosing. Following lutetium Lu 177 dotatate dosing, long-acting somatostatin analogs may be administered between 4 and 24 hours after each dose

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

STUDY_CHAIR: Timothy J. b, MD, Mayo Clinic

Publications

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