Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma

Study Overview
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Brief Summary
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PRECISION-NEC is a single-center, open-label, pilot feasibility study of molecularly defined subtypes of metastatic high-grade neuroendocrine carcinoma (HG-NEC). The hypothesis is that HG-NEC (excluding small cell carcinoma) can be segregated based on mutational analysis and that next generation sequencing (NGS)-based assignment of therapy is feasible and will potentially improve the outcomes.

Detailed Description
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Neuroendocrine tumors vary widely in both disease site and grade, ranging from low grade, relatively benign carcinoid tumors to aggressive and rapidly fatal high-grade neuroendocrine carcinomas. High-grade neuroendocrine carcinomas (HG-NECs) can originate anywhere in the body, and are highly aggressive, with dismal 5-year overall survival rates. The lung and gastrointestinal tract (small bowel, colon, rectum, or pancreas) form the majority of these HG-NECs sites. HG-NECs are classified into three subtypes based on histopathology, specifically, as small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma (LCNEC), or poorly differentiated neuroendocrine carcinoma. There is a lack of consensus for upfront systemic regimens for HG-NECs and as such, treatment is often per physician preference. Most often, HG-NECs are treated with platinum-based chemotherapeutic regimens, with marked heterogeneity in response. It is well established that small cell neuroendocrine carcinomas are characterized by a co-mutation for TP53 and RB1, and are exceptionally platinum-sensitive. However less is known about LCNECs. LCNEC was first introduced in 1991 by Travis et. al as a new type of lung cancer. The 2015 World Health Organization Classification categorized LCNEC under neuroendocrine tumors, along with typical carcinoma, atypical carcinoma and the more undifferentiated tumor represented by small cell lung cancer. Prior to 2015, LCNEC was classified under a general category of large cell carcinoma, however as pathologists studied this entity in detail, it was evident that LCNEC has a distinct clinicopathological identity. Histopathologically, these tumors are characterized by high mitotic rate (more than 10 mitosis per high power field), extensive necrosis, and neuroendocrine features, specifically the presence of chromogranin A, neuron specific enolase and synaptophysin. LCNEC is a rare and aggressive disease with a paucity of data regarding disease progression. Precise incidence and prevalence is unknown. From 2003-2012, the Dutch Cancer Registry reported 952 histologically confirmed new cases of pulmonary LCNECs. Among these cases, 383 patients presented with advanced disease, primarily metastases to liver, bone, or brain. The prognosis is poor with overall 5-year survival for metastatic disease less than 5%, which is similar to small cell lung cancer (SCLC), although some studies suggest that the prognosis for early-stage LCNEC might be slightly better and similar to non-small cell lung cancer (NSCLC). Molecular profiling of small-cell neuroendocrine carcinomas is well established and validated, indicating universally expressed co-mutation for TP53 and RB1. Recently there have been attempts to define genomic profiles of LCNEC. The development of a 241-gene panel on pulmonary tumors, next-generation sequencing allows LCNECs to be further defined. Based on specific genetic signatures, Rekhtman and colleagues sub-classified 45 LCNECs into two major cohorts: 1) small cell-like (TP53/RB1 co-mutated; n=18) and 2) non-small cell-like (n=25), as well as one minor cohort (carcinoid-like n=2). Similarly, molecular profiling of gastrointestinal high-grade neuroendocrine carcinomas (GI-NECs) indicate that they can also be dichotomously categorized by the presence or absence of co-mutations for TP53 and RB1. Treatment regimens for small cell neuroendocrine carcinoma are well established, based on clinical trials conducted in SCLC. In contrast, current guidelines regarding optimal treatment for large-cell and poorly differentiated neuroendocrine carcinomas are nonexistent, driven by the paucity of data on these rare and highly fatal tumors. Additionally, the World Health Organization (WHO) recently defined a new subtype of high-grade neuroendocrine carcinoma, mixed neuroendocrine neoplasm (MINEN), which features characteristics found in large-cell carcinomas and in other tumor types, including adenocarcinomas for example. To date, there are no prospective randomized clinical trials examining front line therapies for metastatic HG-NECs, based on mutational profiles. This study will utilize recent genomic profiles of high-grade large cell neuroendocrine carcinomas to guide and inform clinicians of optimal treatments.

Official Title
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A Pilot Feasibility Study of Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma

Conditions
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Large-Cell Neuroendocrine Carcinoma

Intervention / Treatment
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* Other: Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma
* Other: Treatment for Small Cell Lung Cancer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed high grade neuroendocrine carcinoma that is metastatic and/or not resectable Adequate tissue available for genomic sequencing ECOG status less than or equal to 2 Able to consent Patient received up to two cycles of chemotherapy prior to enrollment Adequate bone marrow function Adequate hepatic function Adequate renal function Exclusion Criteria: Small cell carcinoma Psychiatric illness or social situations that limit compliance Pregnant and nursing women Patients who have completed more than two cycles of chemotherapy Patients with resectable cancer or eligible for curative therapy Patients with an actionable mutation for with guidelines recommend up-front therapy with targeted agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: No TP53/Rb1 Co-Mutation<br>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like). | Other: Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma<br>* Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.<br>|
| Experimental: TP53/Rb1 Co-Mutation Present<br>HG-LCNEC tumor with the TP53/Rb1 co-mutation. | Other: Treatment for Small Cell Lung Cancer<br>* Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequencing Rate (Feasibility) | Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit. | 2 months | 
| Molecular Cohort Assignment (Feasibility) | Percentage of patients who were successfully assigned into a molecularly-defined cohort (TP53/RB1 co-mutations or not). | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Duration of time from the first cycle of anticancer therapy to time of progressive disease or death from any cause, whichever occurs first. | 2 years | 
| Complete Response Rate | Percentage of patients experiencing overall complete response (CR). | 2 years | 
| Partial Response Rate | Percentage of patients experiencing overall partial response (PR). | 2 years | 
| Progressive Disease Rate | Percentage of patients experiencing overall progressive disease (PD). | 2 years | 
| Stable Disease Rate | Percentage of patients experiencing overall stable disease (SD). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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poorly differentiated neuroendocrine carcinoma, NGS, TP53/Rb1, co-mutation, molecular subtype