Refractory Advanced diGestive Neuroendocrine Carcinomas Treated With tARlatamab

Overview

Neuroendocrine neoplasms (NENs) comprise a heterogeneous family of neoplasms arising from the neuroendocrine cells localized in endocrine glands or from the diffuse neuroendocrine cells such as in the digestive or lung tract. Treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NEC) is primarily based on chemotherapy regimens, primarily platinum, which achieve limited benefit and a median overall survival of approximately 12 months. Currently, new treatments that activate the immune system to stimulate antitumor responses and prolong survival in patients with NECs are being investigated. Given the high levels of DLL3 expression on the cell surface of neuroendocrine tumor cells and its minimal, primarily cytoplasmic, localization in normal tissues, DLL3 is a promising target for the development of T-cell-directed therapies in NECs. Tarlatamab is a HLE BiTE molecule that combines the binding specificities for DLL3 and CD3, which could activate the immune system to fight NEC cells. The main hypothesis is that treatment with tarlatamab, a bispecific anti-DLL3 and anti-CD3 conjugate, either as a single agent or in combination with standard second-line chemotherapy (FOLFIRI) scheme could be an effective treatment option for patients with advanced neuroendocrine carcinomas of the digestive system or unknown primary origin.

1. RACIONAL Neuroendocrine carcinomas (NECs) are aggressive neoplasms located primarily in the gastroenteropancreatic (GEP) tract or of unknown origin. They are uncommon tumors with an estimated incidence per year that ranges from 5 to 7 cases per 100,000 people. The reported incidence has substantially increased over the last decades, at least partially due to improved diagnostic techniques and clinical awareness. Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NEC) is primarily based on chemotherapy regimens, primarily platinum-based, which achieve limited benefit and a median overall survival of approximately 12 months. Dual blockade of PD-1 and CTLA-4 has demonstrated efficacy in several tumor types and achieved prolonged survival in a subset of pretreated patients with Grade 3 GEP-NEN. Therefore, activating the immune system to stimulate antitumor responses and prolong survival in patients with NECs is a feasible strategy to explore. Given the high levels of DLL3 expression on the cell surface of neuroendocrine tumor cells and its minimal, primarily cytoplasmic, localization in normal tissues, DLL3 is a promising target for the development of T-cell-directed therapies in NECs. Tarlatamab is a HLE BiTE molecule that combines the binding specificities for DLL3 and CD3, which could activate the immune system to fight NEC cells. Tarlatamab is currently approved for the treatment of patients with small cell lung cancer. 2. HYPOTHESIS The main hypothesis is that treatment with tarlatamab, a bispecific anti-DLL3 and anti-CD3 conjugate, either as a single agent or in combination with standard second-line chemotherapy (FOLFIRI) scheme could be an effective treatment option for patients with advanced neuroendocrine carcinomas of the digestive system or unknown primary origin. 3. OBJECTIVES The main objectives: 1. To find the best tarlatamab-based treatment. 2. To evaluate the efficacy of tarlatamab, either as a single agent or in combination with the FOLFIRI regimen, in patients with NECs, assessed in terms of overall survival (OS). Secondary objectives 1. To evaluate the clinical efficacy results of tarlatamab for patients with NEC. 2. To assess the correlation of risk factors with the efficacy of tarlatamab treatment. 3. To assess the quality of life (QoL) of patients with NEC treated with tarlatamab. 4. To assess the safety of the planned treatment regimen. 5. To determine molecular or clinical predictive biomarkers of response to tarlatamab 4\. ENDPOINTS Primary Endpoint for First Part The primary endpoint for the first part of this study will be the Progression-free Survival (PFS) rate, defined as the percentage of patients without progression as defined by RECIST V1.1 criteria or death. PFS rate will be calculated for each treatment arm separately once 38 PFS events are reported in the first 54 patients included (27 per treatment arm). Primary Endpoint for Second Part The primary endpoint will be the 12-months Overall Survival (OS) rate, defined as the percentage of patients alive after 12 months from the first dose of study treatment. OS will consider death from any cause as an event. Patients alive and free of events at the date of the analysis will be censored at their last known contact. OS will be calculated for each treatment arm separately. Secondary efficacy endpoints -Objective response rate (ORR) according to RECIST V1.1 criteria (Appendix 3) -Disease control rate (DCR). * Duration of the response (DoR). * Progression free survival (PFS). * Overall survival (OS). * Health-related quality of life (HRQoL), assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3. Secondary safety endpoints \- Frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0 \- Frequency of AEs leading to treatment discontinuation. Secondary translational endpoints -Blood biomarkers -Correlation between clinical and molecular determinants and efficacy of tarlatamab 5\. STUDY DESIGN The RAGNAR trial is a two-arm, randomized clinical trial of tarlatamab, either as monotherapy or in combination with standard first-line chemotherapy in patients with NECs. During the first part, patients will be randomized to tarlatamab or tarlatamab plus FOLFIRI. In the second part of the trial, the study will continue enrollment and treat all patients with the regimen chosen in the initial two-arm phase. An initial safety evaluation is planned for the first six patients enrolled in the FOLFIRI + tarlatamab arm to determine if the combination is well tolerated. Clinic visits will occur on C1D1, C1D8, C1D15, and every 2 weeks ±3 days beginning in cycle 2. Response assessment by computed tomography (CT) or magnetic resonance imaging (MRI) following Response Evaluation Criteria in Solid Tumors (RECIST 1.1) will be performed prior to treatment initiation (baseline), every 8 weeks (+/- 1 week), and every 12 weeks (+/- 2 weeks) thereafter until disease progression, patient withdrawal, initiation of a new line of therapy, or death. Quality of life will be assessed at the baseline and safety visit. Approximately 87 patients are expected to participate in the study in approximately 10 hospitals in Spain and 10 in France. 6\. STUDY POPULATION Patient with histologically confirmed NEC (Ki-67 \>20% or mitotic rate \>20 per 10 HPF) of GEP or unknown origin, age ≥18 years, male or female, with unresectable locally advanced or metastatic disease, on second-line treatment after progression to: i) first-line platinum-based chemotherapy, ii) first-line combination chemotherapy with immunotherapy. Patients must have DLL3-positive tumors, measurable disease per RECIST 1.1, and adequate organ function. 7\. TREATMENT Patients will be randomized 1:1 to receive: arm A) Tarlatamab or Arm B) Tarlatamab plus FOLFIRI. After the observation of 38 PFS events, an interim analysis will be performed to identify the treatment arm with better PFS and safety outcomes. The decision on which arm should be continued for the second part of the trial will be done taking into account both, PFS and safety profile. The decision will be taken by a scientific committee composed of 4 oncologists. At the time of the interim analysis is expected to have included approximately 54 patients (27 per treatment arm). 8\. ETHICAL CONSIDERATIONS The development of new strategies to treat NEC is an unmet need. Patients with NEC have limited therapeutic options, and clinical trials are recommended. The risks observed with tarlatamab in previous clinical studies are acceptable considering the poor prognosis of patients with NEC and are similar to those described with other treatments. To mitigate these risks, the protocol already includes a gradual intrapatient dose escalation during the first cycle, starting from a low dose of tarlatamab (1 mg). The protocol also considers close monitoring of patients on the day of administration to monitor the potential occurrence of hypersensitivity reactions, CRS, and ICANS. The protocol establishes premedication for the prevention of the most common AEs, including hydration, treatment with dexamethasone or equivalent corticosteroids, and antiemetics for patients treated with FOLFIRI. In addition, the protocol establishes an initial safety cohort composed of the first six patients included in the FOLFIRI + tarlatamab group to determine whether the combination is well tolerated.