TRINITY TRIAL; Trial Of PRRT Plus CAPTEM Vs CAPTEM Alone In Well Differentiated GEP NETS

The TRINITY Trial is a Phase III, randomized, controlled, open-label clinical trial designed to evaluate the efficacy and safety of combining peptide receptor radionuclide therapy (PRRT) with standard-of-care chemotherapy (CAPTEM) compared with CAPTEM chemotherapy alone in patients with well-differentiated Grade 3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Gastroenteropancreatic neuroendocrine tumors comprise a heterogeneous group of neoplasms with variable biological behavior and treatment response. The World Health Organization classification recognizes well-differentiated Grade 3 neuroendocrine tumors as a distinct subgroup based on a Ki-67 proliferation index greater than 20%, differentiating them from poorly differentiated neuroendocrine carcinomas. Patients with metastatic or unresectable well-differentiated Grade 3 GEP-NETs represent a clinically challenging population because robust prospective evidence guiding the optimal sequencing or combination of systemic therapies remains limited.

CAPTEM, a combination of capecitabine and temozolomide, is an established chemotherapy regimen used in the management of neuroendocrine tumors. Capecitabine is an oral prodrug that is converted to 5-fluorouracil and exerts antitumor activity through inhibition of thymidylate synthase and disruption of DNA synthesis. Temozolomide is an oral alkylating agent that causes DNA damage. The combination provides a complementary pharmacological approach and has demonstrated activity in advanced neuroendocrine tumors, including well-differentiated Grade 3 disease.

PRRT is a targeted radionuclide treatment that uses a radiolabeled somatostatin analogue to selectively deliver therapeutic radiation to tumor cells expressing somatostatin receptors (SSTR). Lutetium-177 (^177Lu)-DOTATATE is administered intravenously and binds to somatostatin receptors expressed on neuroendocrine tumor cells, resulting in delivery of beta-particle radiation to the targeted tumor tissue. The study population is selected for appropriate SSTR expression and FDG avidity to identify tumors for which PRRT is considered clinically relevant. The combination of PRRT with chemotherapy is also referred to as peptide receptor chemoradionuclide therapy (PRCRT).

The rationale for the TRINITY Trial is based on the established clinical activity of both CAPTEM and PRRT and the reported clinical experience with their combination in neuroendocrine tumors. Although both approaches are used as standard treatment strategies in appropriate patients, there is a need for prospective randomized evidence directly comparing CAPTEM alone with the combination of PRRT and CAPTEM specifically in well-differentiated Grade 3 GEP-NETs. The trial is therefore designed to provide comparative evidence regarding disease control, survival, treatment-related toxicity, and patient-reported quality of life.

The study is being conducted at Adavanced Centre for Treatment, Education and Research in Cancer, Kharghar and Tata Memorial Hospital. Patients considered for participation are evaluated through the multidisciplinary neuroendocrine tumor clinic and relevant gastrointestinal, hepatopancreatobiliary, and oncology disease management groups. Potentially eligible patients are assessed clinically and undergo the investigations required for confirmation of study eligibility and baseline characterization. After confirmation of eligibility and completion of the informed consent process, participants are randomized to one of two treatment groups.

Randomization is performed in a 1:1 ratio using a centralized, web-based randomization system. Permuted block randomization with block sizes of 2 and 4 is used, with stratification according to the primary tumor site, namely pancreatic versus small-intestinal primary tumor. The allocation sequence is generated by an independent statistician. As this is an open-label study, participants, treating physicians, data managers, and statistical analysts are not masked to treatment assignment.

Participants randomized to Arm A receive CAPTEM alone. Capecitabine is administered orally at a dose of 1500 mg/m² twice daily for 14 days, followed by a 2-week rest period. Temozolomide is administered orally on Days 10 through 14 at a dose of 20 mg/m² once daily for 5 days. The protocol permits a maximum of 12 CAPTEM cycles. Capecitabine tablets are administered orally and are swallowed whole with water, according to the administration instructions specified in the protocol. Treatment-related toxicities are monitored clinically and through laboratory investigations, with appropriate management according to clinical requirements and the study protocol.

Participants randomized to Arm B receive PRRT with ^177Lu-DOTATATE in combination with CAPTEM. ^177Lu-DOTATATE is administered intravenously at a standard dose in the range of 180-200 mCi per PRRT session. Four standard PRRT sessions are planned, with an interval of approximately 6-8 weeks between sessions. A gap of approximately 1-2 weeks is maintained between PRRT and CAPTEM administration. The treatment sequence consists of one PRRT session followed by two CAPTEM cycles, with subsequent PRRT and CAPTEM administrations continuing according to the protocol-defined schedule. CAPTEM dosing in the combination arm follows the same regimen used in Arm A.

Additional PRRT may be considered in selected participants who demonstrate partial response following completion of the initial four PRRT sessions, in accordance with established practice standards and clinical assessment. The protocol permits up to a maximum of eight PRRT sessions and up to 12 CAPTEM cycles. Decisions regarding continuation or additional treatment are based on clinical assessment, disease status, treatment tolerance, and the protocol-defined treatment framework.

PRRT administration is conducted in designated radioisotope therapy facilities at Tata Memorial Hospital and ACTREC. Appropriate radiation safety procedures are followed during administration and post-treatment monitoring. Following administration of ^177Lu-DOTATATE, radiation exposure is monitored at regular intervals, and participants remain in the designated isolation/radiation safety facility until the measured exposure rate satisfies the applicable institutional discharge criteria. Post-therapy imaging is performed to assess localization of the administered radiopharmaceutical. Planar imaging is obtained within 24 hours before discharge, and additional imaging may be performed at approximately 48 and 96-168 hours for dosimetric assessment of radiation distribution to tumor and non-target organs, as per institutional practice.

After completion of post-therapy assessment, participants are discharged with treatment and follow-up documentation and advice as specified by the Nuclear Medicine team. Radiation safety procedures are implemented in accordance with institutional requirements. In the event of a medical emergency, appropriate medical care takes priority and radiation precautions are not intended to delay necessary emergency treatment.

Throughout active treatment, participants undergo clinical and laboratory monitoring for treatment tolerance, disease status, and adverse events. Laboratory monitoring includes hematological, renal, hepatic, and electrolyte parameters as clinically appropriate. Adverse events are documented and graded according to the toxicity grading system specified in the protocol. Particular attention is given to clinically significant and severe treatment-related toxicities, including hematological, gastrointestinal, hepatic, renal, and other treatment-associated toxicities. Serious adverse events are documented and reported according to applicable institutional and regulatory requirements.

Tumor assessment is performed using anatomical and functional imaging. FDG PET/CT and Ga-68 DOTA PET/CT are incorporated into the disease assessment strategy because the study population is characterized by both somatostatin receptor expression and FDG uptake. Imaging is performed at protocol-defined intervals and is used to assess disease status and treatment response. In participants receiving PRRT, additional FDG PET/CT and Ga-68 DOTA PET/CT assessments are performed approximately 3-4 weeks after the second and fourth PRRT sessions. Response is evaluated using RECIST 1.1 criteria along with the functional imaging information obtained during follow-up.

Participants continue to be followed after completion of protocol-directed treatment. Clinical follow-up is conducted on an outpatient basis approximately every three months during the first two years and every six months thereafter until disease progression or death. Imaging assessments are performed approximately every 3-4 months during the first two years and subsequently every 6-7 months until progression or death, in accordance with the study protocol and standard institutional follow-up practices. The PRRT-containing arm has additional imaging following the specified PRRT sessions as described above.

Health-related quality of life is assessed using validated European Organisation for Research and Treatment of Cancer questionnaires, including the EORTC QLQ-C30 and the disease-specific EORTC QLQ-GINET21. These questionnaires are administered at protocol-defined time points to evaluate patient-reported health status, symptoms, functioning, and quality-of-life parameters during treatment and follow-up.

The primary efficacy analysis evaluates progression-free survival between the two randomized treatment groups. Progression-free survival is assessed from the relevant baseline/time point until documented disease progression or death, according to the protocol-defined assessment methodology. Disease response and disease control are assessed using the protocol-specified response criteria and imaging schedule. Overall survival is assessed during longitudinal follow-up. Safety analyses include the incidence and severity of adverse events, with particular evaluation of severe treatment-related toxicity.

The planned sample size is 123 participants. The sample size calculation is based on the primary objective of assessing the difference in one-year progression-free survival between the CAPTEM-alone and PRRT-plus-CAPTEM groups. The protocol assumes a one-year PFS rate of 42% for the CAPTEM-alone arm and an anticipated one-year PFS rate of 62% with the addition of PRRT. The study is designed to observe approximately 90 events, considering an accrual period of four years, a follow-up period of one year, a two-sided alpha of 5%, statistical power of 80%, and a 10% dropout rate. The sample size was calculated using a log-rank test with PASS Version 21.0.3.

For efficacy analyses, patients lost to follow-up before the first post-baseline assessment are excluded from the primary efficacy analysis, and no imputation is planned for missing efficacy data. Safety analyses include all observed safety information from participants who receive at least one dose of protocol treatment, whether CAPTEM, PRRT, or both. Adverse events are summarized according to system organ class, severity/grade, and attribution. The proportion of participants experiencing Grade 3 or higher adverse events is reported with exact 95% confidence intervals, together with descriptive summaries of safety outcomes. Serious adverse events are evaluated and reported separately.

Study data are monitored throughout trial conduct. The Principal Investigator monitors study data and completion on a monthly basis. Annual study continuation reports are prepared and submitted to the Institutional Ethics Committee. An independent monitoring committee associated with the Data and Safety Monitoring Committee reviews trial conduct and study data in accordance with the institutional protocol.

The study is intended to establish prospective randomized evidence regarding the comparative use of CAPTEM alone versus PRRT combined with CAPTEM in well-differentiated Grade 3 GEP-NETs. By incorporating efficacy, safety, longitudinal survival follow-up, imaging-based disease assessment, and patient-reported quality-of-life evaluation, the trial aims to provide a comprehensive assessment of the clinical impact of adding PRRT to standard CAPTEM chemotherapy in this patient population.