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Immune Checkpoint Inhibitors

Pembrolizumab 200mg IV day 1 with Carboplatin AUC 6 IV day 1 or Cisplatin 80mg/m2 day 1 with etoposide 100mg/m2 days 1-3 of 21 day cycle. Repeat 4-6 cycles to be followed by maintenance Pembrolizumab 200mg IV day 1 every 21 days until progression or intolerance for up to 2 years.

Intravenous administration of pembrolizumab in combination with cisplatin or carboplatin and etoposide in first line metastatic or unresectable high grade neuroendocrine carcinoma:

Robert Ramirez, DO

The purpose of this study is to test the efficacy, safety, and tolerability of the combination of chemotherapy treatment, which could be either Cisplatin or carboplatin and etoposide, and the research study drug, Pembrolizumab (also known as MK-3475) in patients with high grade neuroendocrine carcinomas of the gastroenteropancreatic system or lung who are chemotherapy naïve. The chemotherapy treatment you receive will be either Cisplatin or carboplatin and etoposide. the participant's doctor will discuss this choice with you and determined which chemotherapy treatment is best for you.

Combination chemotherapy is the mainstay of treatment for patients with high grade GEPNETs and neuroendocrine carcinomas of the lung.

This study will utilize pembrolizumab, a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus blocks a protective mechanism of cancer cells and thereby allows the immune system to destroy them, in combination with chemotherapy.

Combination chemotherapy and pembrolizumab was recently FDA approved and ongoing trials are utilizing this or similar combination with preliminary data demonstrating a promising safety profile.

Pembrolizumab With Chemotherapy in Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung Neuroendocrine Carcinoma

A Phase II Trial of Pembrolizumab in Combination With Cisplatin or Carboplatin and Etoposide in Chemotherapy naïve Patients With Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung (Excluding Small Cell) Neuroendocrine Carcinoma

Assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Merck Sharp & Dohme LLC

Ochsner Health System

Principal Investigator

Other Dietary Supplements

Lenvatinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Pyruvate

Participants will receive 20 mg once daily of lenvatinib plus 400 mg of pembrolizumab every 6 weeks for up to 18 doses. Eligible participants may also receive a Hyperpolarized 13C-pyruvate (HP 13C) magnetic resonance imaging (MRI) scan

Hyperpolarized 13C-Pyruvate

Phu Lam

Emily Bergsland, MD

This is the first study to be done in a newly described class of neuroendocrine tumors known as well-differentiated grade 3 neuroendocrine tumors (WD G3 NET). First described in the pancreas in 2017, the classification was broadened to include gastrointestinal tract tumors in 2019. Recent data suggest an equivalent subtype exists in the lungs (NEC with carcinoid morphology). WD G3 NETs can occur de novo as well as the result of grade progression over time. This is a single arm, multi-site, Phase II study in biomarker "unselected" participants. This study will also incorporate serial blood samples, tumor biopsies, and special imaging to better understand the impact of therapy on the tumor and microenvironment. Hyperpolarized (HP) 13C-pyruvate magnetic resonance imaging (MRI) - a novel non-radioactive imaging modality able to provide in vivo measurements of the pyruvate-to-lactate conversion rate (kpl).

PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (ORR) of lenvatinib plus pembrolizumab.

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of lenvatinib plus pembrolizumab. II. To evaluate the duration of response (DOR) in patients receiving lenvatinib plus pembrolizumab.

III. To evaluate progression-free survival (PFS) in patients receiving lenvatinib plus pembrolizumab.

EXPLORATORY OBJECTIVES:

I. To evaluate overall survival (OS) in participants receiving lenvatinib plus pembrolizumab.

II. To compare overall response rate (ORR), DOR, and PFS by Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) with the same measures assessed by Response Evaluation Criteria In Solid Tumors version 1.1.

III. To correlate clinical outcomes (ORR, DOR, PFS, OS) with baseline immune cell infiltration, T cell receptor (TCR) repertoires, and programmed death-ligand 1 (PD-L1) staining in pre-treatment biopsies. IV. To assess changes in immune cell infiltration, PD-L1 staining, and TCR repertoires in pre- and post-biopsies.

V. Correlate Ki67proliferative index with outcomes (ORR, DOR, PFS, OS).

IV. To characterize the baseline molecular features (tissue- and blood-based) of G3 NETs treated with lenvatinib and pembrolizumab.

VII. To correlate the molecular features of G3 NET with clinical outcomes (e.g., response/resistance, survival, safety, pharmacodynamic activity) in the setting of treatment with pembrolizumab plus lenvatinib.

VIII. To describe the relationship between baseline tumor growth rate (TGR) and RECIST measurements for all patients.

IX. To examine changes in TGR over time in patients treated with Lenvatinib plus pembrolizumab TGR as assessed by cross-sectional imaging.

X. To investigate the relationship between on-treatment changes in pyruvate-to-lactate conversion rate (kpl) and ORR, PFS, and OS.

XI. To investigate the relationship between baseline tumor proliferative index (as measured by Ki67), metabolic profile (NMR spectroscopy), and pyruvate-to-lactate conversion rate (kpl, as measured by hyperpolarized 13C-pyruvate imaging) and ORR, PFS and OS.

XII. Assessment of baseline heterogeneity of pyruvate-to-lactate conversion rate (kpl) between patients and between tumors within a given participant.

OUTLINE:

There are 2 stages to this study. If at least 2 participants in stage 1 show a demonstrated response, a second stage will open to enroll additional participants. Participants may continue treatment for up to two years of therapy (i.e., 18 doses of pembrolizumab).

After the end of treatment, each participant will be followed for 30 days for adverse event (AE) monitoring. Serious adverse events (SAE) and events of clinical interest (ECI) will be collected for 90 days after the end of treatment or 30 days after the end of treatment if the participant initiates new anticancer therapy, whichever is earlier. Participants who discontinue for reasons other than progressive disease will have post-treatment follow-up for disease status until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. After documented disease progression each participant will be followed by telephone for overall survival and anti-cancer therapy until death, withdrawal of consent, or the end of the study, whichever occurs first.

Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors

A Phase II Study of Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors

ORR is defined as a complete response (CR) or a partial response (PR) according to RECIST version 1.1 criteria. The All Subjects as Treated (ASaT, ITT) population will be used for analysis which consists of all participants who received at least one dose of the study treatment. Participants without at least confirmatory scan will be classified as non-responders. The point estimate and 95% confidence interval will be reported.

Adverse events occurring from the start of treatment until 30 days after the end of treatment will be summarized by maximum toxicity grade. The toxicity grade and classification will be determined using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Duration of Response is defined as the time from the date of first response per RECIST criteria (CR or PR) until the date of disease progression or death. Kaplan-Meier methods will be used to determine the median and 95% confidence interval.

Progression-free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause at 18 weeks as determined by RECIST v1.1. Participants who did not progress or die at the 18 week assessment will be censored on the date of their last evaluable tumor assessment. Kaplan-Meier methods will be used to determine median PFS with a 95% confidence interval

Progression-free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause at as determined by RECIST v1.1. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Kaplan-Meier methods will be used to determine median PFS with a 95% confidence interval

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab With Chemotherapy in Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung Neuroendocrine Carcinoma	NCT03901378	Neuroendocrine ... Large Cell Neur... High Grade Neur...	Pembrolizumab	18 Years -	Ochsner Health System
Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors	NCT05746208	Neuroendocrine ... Well-Differenti... High Grade Neur...	Lenvatinib Pembrolizumab Hyperpolarized ...	18 Years -	University of California, San Francisco
Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors	NCT05746208	Neuroendocrine ... Well-Differenti... High Grade Neur...	Lenvatinib Pembrolizumab Hyperpolarized ...	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for high grade neuroendocrine carcinoma, any site