Metastatic Pancreatic Neuroendocrine Tumor Clinical Trial
Official title:
Phase II Randomized, Prospective Trial of Lutetium Lu 177 Dotatate PRRT Versus Capecitabine and Temozolomide in Well-Differentiated 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.
| Status | Recruiting |
| Enrollment | 198 |
| Est. completion date | October 2033 |
| Est. primary completion date | March 31, 2028 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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). - 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 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 |
| Country | Name | City | State |
|---|---|---|---|
| United States | Hickman Cancer Center | Adrian | Michigan |
| United States | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland |
| United States | Advocate Good Shepherd Hospital | Barrington | Illinois |
| United States | Nebraska Medicine-Bellevue | Bellevue | Nebraska |
| United States | Tower Cancer Research Foundation | Beverly Hills | California |
| United States | Illinois CancerCare-Bloomington | Bloomington | Illinois |
| United States | Prisma Health Cancer Institute - Spartanburg | Boiling Springs | South Carolina |
| United States | Boston Medical Center | Boston | Massachusetts |
| United States | Montefiore Medical Center - Moses Campus | Bronx | New York |
| United States | Montefiore Medical Center-Einstein Campus | Bronx | New York |
| United States | Montefiore Medical Center-Weiler Hospital | Bronx | New York |
| United States | Aurora Cancer Care-Southern Lakes VLCC | Burlington | Wisconsin |
| United States | Illinois CancerCare-Canton | Canton | Illinois |
| United States | Saint Francis Medical Center | Cape Girardeau | Missouri |
| United States | Southeast Cancer Center | Cape Girardeau | Missouri |
| United States | Memorial Hospital of Carbondale | Carbondale | Illinois |
| United States | SIH Cancer Institute | Carterville | Illinois |
| United States | Illinois CancerCare-Carthage | Carthage | Illinois |
| United States | Centralia Oncology Clinic | Centralia | Illinois |
| United States | Advocate Illinois Masonic Medical Center | Chicago | Illinois |
| United States | Northwestern University | Chicago | Illinois |
| United States | University of Chicago Comprehensive Cancer Center | Chicago | Illinois |
| United States | University of Illinois | Chicago | Illinois |
| United States | Marshfield Clinic-Chippewa Center | Chippewa Falls | Wisconsin |
| United States | Baptist Memorial Hospital and Cancer Center-Collierville | Collierville | Tennessee |
| United States | AMG Crystal Lake - Oncology | Crystal Lake | Illinois |
| United States | Aurora Saint Luke's South Shore | Cudahy | Wisconsin |
| United States | Cancer Care Specialists of Illinois - Decatur | Decatur | Illinois |
| United States | Decatur Memorial Hospital | Decatur | Illinois |
| United States | Northwestern Medicine Cancer Center Kishwaukee | DeKalb | Illinois |
| United States | Smilow Cancer Hospital-Derby Care Center | Derby | Connecticut |
| United States | Illinois CancerCare-Dixon | Dixon | Illinois |
| United States | Advocate Good Samaritan Hospital | Downers Grove | Illinois |
| United States | Epic Care-Dublin | Dublin | California |
| United States | Prisma Health Cancer Institute - Easley | Easley | South Carolina |
| United States | Marshfield Medical Center-EC Cancer Center | Eau Claire | Wisconsin |
| United States | Crossroads Cancer Center | Effingham | Illinois |
| United States | Advocate Sherman Hospital | Elgin | Illinois |
| United States | Bay Area Breast Surgeons Inc | Emeryville | California |
| United States | Epic Care Partners in Cancer Care | Emeryville | California |
| United States | Saint Vincent Hospital | Erie | Pennsylvania |
| United States | Illinois CancerCare-Eureka | Eureka | Illinois |
| United States | Smilow Cancer Hospital Care Center-Fairfield | Fairfield | Connecticut |
| United States | Parkland Health Center - Farmington | Farmington | Missouri |
| United States | Illinois CancerCare-Galesburg | Galesburg | Illinois |
| United States | Western Illinois Cancer Treatment Center | Galesburg | Illinois |
| United States | Northwestern Medicine Cancer Center Delnor | Geneva | Illinois |
| United States | Aurora Health Care Germantown Health Center | Germantown | Wisconsin |
| United States | Smilow Cancer Hospital Care Center at Glastonbury | Glastonbury | Connecticut |
| United States | Aurora Cancer Care-Grafton | Grafton | Wisconsin |
| United States | Aurora BayCare Medical Center | Green Bay | Wisconsin |
| United States | Aurora Health Center - Greenfield | Greenfield | Wisconsin |
| United States | Prisma Health Cancer Institute - Butternut | Greenville | South Carolina |
| United States | Prisma Health Cancer Institute - Eastside | Greenville | South Carolina |
| United States | Prisma Health Cancer Institute - Faris | Greenville | South Carolina |
| United States | Prisma Health Greenville Memorial Hospital | Greenville | South Carolina |
| United States | Smilow Cancer Hospital Care Center at Greenwich | Greenwich | Connecticut |
| United States | Prisma Health Cancer Institute - Greer | Greer | South Carolina |
| United States | Smilow Cancer Hospital Care Center - Guilford | Guilford | Connecticut |
| United States | Smilow Cancer Hospital Care Center at Saint Francis | Hartford | Connecticut |
| United States | Advocate South Suburban Hospital | Hazel Crest | Illinois |
| United States | Mayo Clinic in Florida | Jacksonville | Florida |
| United States | Capital Region Southwest Campus | Jefferson City | Missouri |
| United States | Jefferson Hospital | Jefferson Hills | Pennsylvania |
| United States | Aurora Cancer Care-Kenosha South | Kenosha | Wisconsin |
| United States | Illinois CancerCare-Kewanee Clinic | Kewanee | Illinois |
| United States | Marshfield Clinic - Ladysmith Center | Ladysmith | Wisconsin |
| United States | Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center | Lebanon | New Hampshire |
| United States | AMG Libertyville - Oncology | Libertyville | Illinois |
| United States | Condell Memorial Hospital | Libertyville | Illinois |
| United States | Cancer Partners of Nebraska - Pine Lake | Lincoln | Nebraska |
| United States | Southeast Nebraska Cancer Center - 68th Street Place | Lincoln | Nebraska |
| United States | Cedars Sinai Medical Center | Los Angeles | California |
| United States | Illinois CancerCare-Macomb | Macomb | Illinois |
| United States | Aurora Bay Area Medical Group-Marinette | Marinette | Wisconsin |
| United States | Marshfield Medical Center-Marshfield | Marshfield | Wisconsin |
| United States | Contra Costa Regional Medical Center | Martinez | California |
| United States | Toledo Clinic Cancer Centers-Maumee | Maumee | Ohio |
| United States | Baptist Memorial Hospital and Cancer Center-Memphis | Memphis | Tennessee |
| United States | Aurora Cancer Care-Milwaukee | Milwaukee | Wisconsin |
| United States | Aurora Saint Luke's Medical Center | Milwaukee | Wisconsin |
| United States | Aurora Sinai Medical Center | Milwaukee | Wisconsin |
| United States | Medical College of Wisconsin | Milwaukee | Wisconsin |
| United States | Marshfield Clinic-Minocqua Center | Minocqua | Wisconsin |
| United States | Toledo Clinic Cancer Centers-Monroe | Monroe | Michigan |
| United States | Forbes Hospital | Monroeville | Pennsylvania |
| United States | Yale University | New Haven | Connecticut |
| United States | UC Comprehensive Cancer Center at Silver Cross | New Lenox | Illinois |
| United States | Mount Sinai Hospital | New York | New York |
| United States | Yale-New Haven Hospital North Haven Medical Center | North Haven | Connecticut |
| United States | Cancer Care Center of O'Fallon | O'Fallon | Illinois |
| United States | Advocate Christ Medical Center | Oak Lawn | Illinois |
| United States | Advocate Outpatient Center - Oak Lawn | Oak Lawn | Illinois |
| United States | Bay Area Tumor Institute | Oakland | California |
| United States | Nebraska Medicine-Village Pointe | Omaha | Nebraska |
| United States | University of Nebraska Medical Center | Omaha | Nebraska |
| United States | Smilow Cancer Hospital-Orange Care Center | Orange | Connecticut |
| United States | Northwestern Medicine Orland Park | Orland Park | Illinois |
| United States | University of Chicago Medicine-Orland Park | Orland Park | Illinois |
| United States | Vince Lombardi Cancer Clinic - Oshkosh | Oshkosh | Wisconsin |
| United States | Illinois CancerCare-Ottawa Clinic | Ottawa | Illinois |
| United States | Advocate Lutheran General Hospital | Park Ridge | Illinois |
| United States | Illinois CancerCare-Pekin | Pekin | Illinois |
| United States | Illinois CancerCare-Peoria | Peoria | Illinois |
| United States | Methodist Medical Center of Illinois | Peoria | Illinois |
| United States | Illinois CancerCare-Peru | Peru | Illinois |
| United States | Valley Radiation Oncology | Peru | Illinois |
| United States | Mayo Clinic Hospital in Arizona | Phoenix | Arizona |
| United States | Allegheny General Hospital | Pittsburgh | Pennsylvania |
| United States | West Penn Hospital | Pittsburgh | Pennsylvania |
| United States | Illinois CancerCare-Princeton | Princeton | Illinois |
| United States | Aurora Cancer Care-Racine | Racine | Wisconsin |
| United States | Marshfield Medical Center-Rice Lake | Rice Lake | Wisconsin |
| United States | Mayo Clinic in Rochester | Rochester | Minnesota |
| United States | Missouri Baptist Medical Center | Saint Louis | Missouri |
| United States | Sainte Genevieve County Memorial Hospital | Sainte Genevieve | Missouri |
| United States | Huntsman Cancer Institute/University of Utah | Salt Lake City | Utah |
| United States | Prisma Health Cancer Institute - Seneca | Seneca | South Carolina |
| United States | Vince Lombardi Cancer Clinic-Sheboygan | Sheboygan | Wisconsin |
| United States | Sanford Cancer Center Oncology Clinic | Sioux Falls | South Dakota |
| United States | Sanford USD Medical Center - Sioux Falls | Sioux Falls | South Dakota |
| United States | Baptist Memorial Hospital and Cancer Center-Desoto | Southhaven | Mississippi |
| United States | Memorial Medical Center | Springfield | Illinois |
| United States | Southern Illinois University School of Medicine | Springfield | Illinois |
| United States | Springfield Clinic | Springfield | Illinois |
| United States | Smilow Cancer Hospital Care Center at Long Ridge | Stamford | Connecticut |
| United States | Marshfield Medical Center-River Region at Stevens Point | Stevens Point | Wisconsin |
| United States | Missouri Baptist Sullivan Hospital | Sullivan | Missouri |
| United States | Aurora Medical Center in Summit | Summit | Wisconsin |
| United States | BJC Outpatient Center at Sunset Hills | Sunset Hills | Missouri |
| United States | State University of New York Upstate Medical University | Syracuse | New York |
| United States | Toledo Clinic Cancer Centers-Toledo | Toledo | Ohio |
| United States | Torrance Memorial Physician Network - Cancer Care | Torrance | California |
| United States | Smilow Cancer Hospital-Torrington Care Center | Torrington | Connecticut |
| United States | Smilow Cancer Hospital Care Center-Trumbull | Trumbull | Connecticut |
| United States | Vince Lombardi Cancer Clinic-Two Rivers | Two Rivers | Wisconsin |
| United States | Epic Care Cyberknife Center | Walnut Creek | California |
| United States | Northwestern Medicine Cancer Center Warrenville | Warrenville | Illinois |
| United States | Illinois CancerCare - Washington | Washington | Illinois |
| United States | Sibley Memorial Hospital | Washington | District of Columbia |
| United States | Smilow Cancer Hospital-Waterbury Care Center | Waterbury | Connecticut |
| United States | Smilow Cancer Hospital Care Center - Waterford | Waterford | Connecticut |
| United States | Marshfield Clinic-Wausau Center | Wausau | Wisconsin |
| United States | Aurora Cancer Care-Milwaukee West | Wauwatosa | Wisconsin |
| United States | Aurora West Allis Medical Center | West Allis | Wisconsin |
| United States | Smilow Cancer Hospital Care Center - Westerly | Westerly | Rhode Island |
| United States | Marshfield Medical Center - Weston | Weston | Wisconsin |
| United States | Wexford Health and Wellness Pavilion | Wexford | Pennsylvania |
| United States | Marshfield Clinic - Wisconsin Rapids Center | Wisconsin Rapids | Wisconsin |
| United States | Sanford Cancer Center Worthington | Worthington | Minnesota |
| Lead Sponsor | Collaborator |
|---|---|
| Alliance for Clinical Trials in Oncology | National Cancer Institute (NCI) |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | 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 | |
| Secondary | 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 | |
| Secondary | Time to progression (TTP) | Kaplan-Meier methodology will be used to estimate the median time to progression (TTP). | Up to 8 years from randomization | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 |
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