Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04452292 |
| Other study ID # |
MCC-20-GI-112-PMC; MULTI-37 |
| Secondary ID |
KL2TR001996UL1TR |
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 14, 2021 |
| Est. completion date |
March 14, 2023 |
Study information
| Verified date |
April 2023 |
| Source |
University of Kentucky |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
