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Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma (PRECISION-NEC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04452292
Recruitment Status : Recruiting
First Posted : June 30, 2020
Last Update Posted : January 14, 2022
Sponsor:
Information provided by (Responsible Party):
Aman Chauhan, University of Kentucky

Tracking Information
First Submitted Date  ICMJE June 24, 2020
First Posted Date  ICMJE June 30, 2020
Last Update Posted Date January 14, 2022
Actual Study Start Date  ICMJE September 14, 2021
Estimated Primary Completion Date July 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2020)
  • Sequencing Rate (Feasibility) [ Time Frame: 2 months ]
    Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit.
  • Molecular Cohort Assignment (Feasibility) [ Time Frame: 2 months ]
    Percentage of patients who were successfully assigned into a molecularly-defined cohort (TP53/RB1 co-mutations or not).
Original Primary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
  • Sequencing Rate (Feasibility) [ Time Frame: 2 months ]
    Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit.
  • Molecular Cohort Assignment (Feasibility) [ Time Frame: 2 months ]
    Percentage of patients who were successfully assigned into a molecularly-definted cohort (TP53/RB1 co-mutations or not).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
  • Progression-Free Survival (PFS) [ Time Frame: 2 years ]
    Duration of time from the first cycle of anticancer therapy to time of progressive disease or death from any cause, whichever occurs first.
  • Complete Response Rate [ Time Frame: 2 years ]
    Percentage of patients experiencing overall complete response (CR).
  • Partial Response Rate [ Time Frame: 2 years ]
    Percentage of patients experiencing overall partial response (PR).
  • Progressive Disease Rate [ Time Frame: 2 years ]
    Percentage of patients experiencing overall progressive disease (PD).
  • Stable Disease Rate [ Time Frame: 2 years ]
    Percentage of patients experiencing overall stable disease (SD).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma
Official Title  ICMJE A Pilot Feasibility Study of Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Large-Cell Neuroendocrine Carcinoma
Intervention  ICMJE
  • Other: Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma
    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.
  • Other: Treatment for Small Cell Lung Cancer
    Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.
Study Arms  ICMJE
  • Active Comparator: No TP53/Rb1 Co-Mutation
    HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).
    Intervention: Other: Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma
  • Experimental: TP53/Rb1 Co-Mutation Present
    HG-LCNEC tumor with the TP53/Rb1 co-mutation.
    Intervention: Other: Treatment for Small Cell Lung Cancer
Publications * Saghaeiannejad Esfahani H, Vela CM, Chauhan A. Prevalence of TP-53/Rb-1 Co-Mutation in Large Cell Neuroendocrine Carcinoma. Front Oncol. 2021 May 31;11:653153. doi: 10.3389/fonc.2021.653153. eCollection 2021.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 25, 2020)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2023
Estimated Primary Completion Date July 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Aman Chauhan, MD 859257-7715 amanchauhan@uky.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04452292
Other Study ID Numbers  ICMJE MCC-20-GI-112-PMC; MULTI-37
KL2TR001996 ( U.S. NIH Grant/Contract )
UL1TR001998 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Aman Chauhan, University of Kentucky
Study Sponsor  ICMJE Aman Chauhan
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Aman Chauhan, MD University of Kentucky
PRS Account University of Kentucky
Verification Date January 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP