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Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors | Clinical Trials | Clareo Health

RECRUITINGPHASE2

Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors

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

NCT05746208•University of California, San Francisco

Summary

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).

Detailed Description

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). VI. 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, or two years of therapy whichever comes first). 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.

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•1. Participants must have locally advanced or unresectable histologically or cytologically confirmed WD G3 NET.
•1. pancreas primary.
•2. other primary sites:
•* gastrointestinal site,
•* unknown primary site,
•* lung neuroendocrine carcinoma with carcinoid morphology, or
•* other non-pancreatic primary sites with well-differentiated (WD) morphology and Ki67 \> 20%.
•3. WD G3 NET occurring de novo or in the setting of grade progression allowed (provided WD G3 NET is thought to be the dominant histology at the time of enrollment).
•4. Tumors with ambiguous histology and/or Ki67 \>/=55% must be reviewed at the participating site to confirm that they are not poorly differentiated. Tumors with confirmed ambiguous histology will be considered eligible.
•2. At least 1 measurable target lesion according to RECIST 1.1, including the following criteria.
+84 more criteria

Exclusion Criteria

•1. Has poorly differentiated neuroendocrine carcinoma (e.g., small cell NEC, large cell NEC, Merkel cell carcinoma, prostate neuroendocrine carcinoma) or WD Grades 1 or 2 NET (without evidence of G3 NET).
•2. Uncontrolled blood pressure (BP) (Systolic BP \>=140 mmHg or diastolic BP \>=90 mmHg) despite an optimized regimen of antihypertensive medication.
•3. Significant gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib.
•4. Has pre-existing \>= grade 3 (G3) gastrointestinal or non-gastrointestinal fistula.
•5. Has clinically significant cardiovascular disease within 12 months from the first dose of study intervention, including New York Heart Association (NYHA) Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
•6. Radiographic evidence of major blood vessel invasion/infiltration (e.g., carotid artery) or intratumoral cavitation in the chest (e.g. tumors above the diaphragm).
•The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy. NOTE: Vascular encasement may be allowed in selected cases below the diaphragm; clinical judgement must be employed. Eligible tumors may include:
•1. Portal vein or inferior vena cava involvement by tumor is allowed at the discretion of the investigator (and is distinguished from invasion through the wall of a vessel.
•2. Vascular encasement by tumor below diaphragm is allowed at the discretion of the investigator, Examples of potentially eligible tumors include: mesenteric mass encasing superior mesenteric artery (SMA)/superior mesenteric vein (SMV), splenic vein involvement from a pancreas primary tumor, or lymphadenopathy adjacent to the inferior vena cava, portal vein, or other vessels without a clear plane between the tumor and vessel).
•* Vascular encasement by the tumor in the abdomen, such as a mesenteric mass encasing the SMV/SMA, must be distinguished from invasion through the wall of a vessel and with consideration of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
+6 more criteria

Locations (1)

University of California, San Francisco

San Francisco, California, United States

Key Dates

Start Date

July 17, 2023

Primary Completion Date

January 31, 2028

Completion Date

March 31, 2028

Last Updated

March 17, 2026

Enrollment

ESTIMATED participants

Conditions

Neuroendocrine TumorsWell-Differentiated Neuroendocrine CarcinomaHigh Grade Neuroendocrine Carcinoma, Any Site

Interventions

Lenvatinib

DRUG

Pembrolizumab

DRUG

Hyperpolarized 13C-Pyruvate

DRUG

Contacts

Jennifer Luan

CONTACT

(415) 514-6220 Jennifer.Luan@ucsf.edu

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: March 17, 2026Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors

Inclusion Criteria

Exclusion Criteria

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