Lenvatinib + Pembrolizumab for Neuroendocrine Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University of California, San Francisco
Must not be taking: Immunosuppressants, QT prolonging drugs
Disqualifiers: Poorly differentiated NEC, Cardiovascular disease, Active infection, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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).
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, certain medications, especially those that might interact with the trial drugs or affect the QT interval, may need to be adjusted or stopped. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug combination Lenvatinib and Pembrolizumab for treating neuroendocrine cancer?
Research shows that Pembrolizumab, one of the drugs in the combination, has been studied for its effects on neuroendocrine tumors. In some studies, it has shown limited activity, with a few patients experiencing stable disease or partial response, suggesting potential benefits in certain cases.
12345Is the combination of lenvatinib and pembrolizumab safe for humans?
The combination of lenvatinib and pembrolizumab has been studied in various cancers and generally shows a manageable safety profile. Common side effects include high blood pressure, low thyroid hormone levels, diarrhea, nausea, vomiting, loss of appetite, tiredness, and weight loss.
678910What makes the drug combination of lenvatinib and pembrolizumab unique for treating neuroendocrine cancer?
The combination of lenvatinib and pembrolizumab is unique because it targets both the blood vessels that supply the tumor and the immune system's ability to fight cancer, potentially offering a new option for neuroendocrine cancer, which currently has limited treatment choices.
711121314Eligibility Criteria
This trial is for adults with well-differentiated grade 3 neuroendocrine tumors (WD G3 NET), including those in the pancreas, gastrointestinal tract, or lungs with specific characteristics. Participants must have a life expectancy over 3 months and at least one measurable lesion. They should be able to undergo MRI imaging if at UCSF, have good organ function, controlled blood pressure, and agree to use contraception.Inclusion Criteria
At least 1 measurable target lesion according to RECIST 1.1
My cancer progressed after treatment and my Ki67 score is below 30%.
Tumors with ambiguous histology and/or Ki67 >/=55% must be reviewed at the participating site to confirm that they are not poorly differentiated
+9 more
Exclusion Criteria
I have not had coughing up blood or tumor bleeding in the last 3 weeks.
Pregnant women
I don't have any health issues that could affect the study's results.
+19 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive 20 mg once daily of lenvatinib plus 400 mg of pembrolizumab every 6 weeks for up to 18 doses
Up to 24 months
Follow-up
Participants are monitored for safety and effectiveness after treatment, including adverse event monitoring for 30 days and serious adverse events for 90 days
3 months
Long-term Follow-up
Participants are followed for disease status until disease progression, initiation of non-study cancer treatment, or withdrawal of consent
Until disease progression or end of study
Participant Groups
The study tests Lenvatinib combined with Pembrolizumab on patients with WD G3 NETs. It's a Phase II trial across multiple sites without selection based on biomarkers. The effects of treatment are monitored through blood samples, tumor biopsies, and Hyperpolarized 13C-Pyruvate MRI scans that measure changes in the tumor environment.
1Treatment groups
Experimental Treatment
Group I: Lenvatinib Plus PembrolizumabExperimental Treatment3 Interventions
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
Lenvatinib is already approved in United States, European Union, European Union for the following indications:
🇺🇸 Approved in United States as Lenvima for:
- Differentiated Thyroid Cancer
- Renal Cell Carcinoma
- Hepatocellular Carcinoma
- Endometrial Cancer
🇪🇺 Approved in European Union as Lenvima for:
- Thyroid Cancer
- Renal Cell Carcinoma
- Hepatocellular Carcinoma
- Endometrial Cancer
🇪🇺 Approved in European Union as Kisplyx for:
- Renal Cell Carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, San FranciscoSan Francisco, CA
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Who Is Running the Clinical Trial?
University of California, San FranciscoLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. [2021]Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs.
Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. [2021]Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs.
Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. [2021]KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET).
Impacts of pembrolizumab therapy on immune phenotype in patients with high-grade neuroendocrine neoplasms. [2022]High grade neuroendocrine neoplasms (G3 NENs) are rare aggressive tumors with limited treatment options. Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. Baseline tumor samples were assessed for PD-L1 and tumor infiltrating lymphocytes (TIL). Peripheral blood samples drawn pre-treatment, prior to cycle three, and at disease progression were analyzed by flow cytometry. One patient achieved partial response, two had stable disease, and 18 exhibited progressive disease. The partially responding patient did not progress after 392 days, and the median progression-free survival (PFS) was 59 days. Longer PFS correlated independently with higher pre-treatment peripheral blood T-cell counts and lower pre-treatment activation state (CD69 expression) of naïve T cells and NK cells. Peripheral T-cell viability was reduced in patients with greater TILs. Post-treatment, T cells had reduced numbers of CD4+ cells, reduced PD-1 expression, increased activation of effector (CD62L-) cells, and increased expression of TIGIT. Baseline TIGIT expression on peripheral T cells also correlated positively with Ki67 in tumor. Patients with higher baseline T-cell expression of TIM-3 had shorter PFS. Despite limited activity of pembrolizumab, this study highlights the immune phenotype in this rare tumor type before and after treatment. High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.
Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract. [2023]To investigate the efficacy and safety of pembrolizumab in women with recurrent small cell neuroendocrine tumors of the lower genital tract.
Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]The combination of lenvatinib plus pembrolizumab demonstrated a relevant clinical benefit in patients with endometrial carcinoma. The safety profile was consistent with the established profiles of each drug in monotherapy, with the most frequent adverse events being hypertension, an on-target effect, hypothyroidism, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss.
The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. Clinical trial registration: NCT03884101, NCT03713593, NCT03820986, NCT03776136, NCT03797326, NCT03829319, NCT03829332, NCT03976375, NCT04428151, NCT04199104, NCT03898180, NCT04246177 (ClinicalTrials.gov).
Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. [2023]Pembrolizumab plus lenvatinib has shown antitumor activity and acceptable safety in patients with platinum-refractory urothelial carcinoma (UC).
Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. [2021]Both pembrolizumab and lenvatinib demonstrate antitumor activity and safety in cancers. However, whether their combination is safer and more effective than monotherapies remains unknown. A systematic review was performed to assess the safety and efficacy of pembrolizumab plus lenvatinib versus their respective monotherapies in solid cancers.
Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. [2022]Lenvatinib combined with pembrolizumab showed a promising result in an early phase study for hepatocellular carcinoma (HCC). The efficacy and safety of lenvatinib plus pembrolizumab for patients with unresectable HCC (uHCC) beyond the first-line setting were unclear.
Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. [2020]Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study.
Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. [2020]Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study.
Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. [2022]Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy.
A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. [2022]Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors.