Lenvatinib Plus Pembrolizumab in Well Differentiated G3 Neuroendocrine Tumors

Recruiting now · Phase 2

Conditions studied: Neuroendocrine Tumors, Well-Differentiated Neuroendocrine Carcinoma, High Grade Neuroendocrine Carcinoma, Any Site

In brief

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).

Key facts

Study ID

NCT05746208

Run by

University of California, San Francisco

People needed

29

Starts

2023-07-17

Expected to finish

2028-03-31

Last updated by the study team

2026-03-17

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Participants must have locally advanced or unresectable histologically or cytologically confirmed WD G3 NET.
• pancreas primary.
• 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%.
• 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).
• 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.
• At least 1 measurable target lesion according to RECIST 1.1, including the following criteria.
• non-nodal lesion that measures >=1.0 cm in the longest diameter.
• lymph node (LN) lesion that measures as >=1.5 cm in the short axis.
• the lesion is suitable for repeat measurement using computed tomography (CT) / magnetic resonance imaging (MRI) (CT/MRI).
• lesions previously treated with radiation or other locoregional therapy are considered measurable if progression has been demonstrated in such lesions.
• in the setting of grade progression, every attempt should be made to select measurable target lesions that are thought to represent G3 disease (based on biopsy results, tumor growth rate, or other features).
• Eligibility for HP 13C MR (applicable only to UCSF patients who meet the requirements below)- up to 10 patients (if machine is functional, available and scheduling allows):
• At least 1 lesion that is deemed suitable for imaging by HP 13C MR by the investigators (ideally separate from the biopsy site, if planned).
• No contraindications to MRI.
• No prior local therapy to the target lesions (s) -unless clear progression in the lesions(s).
• NOTE: University of California, San Francisco (UCSF) patients who do not meet this requirement will still be allowed to participate if they otherwise meet all eligibility requirements (this criterion should be recorded as "NA" on the eligibility checklist). In other words, the inability to complete HP 13C MR imaging will not preclude study participation)
• Radiographic evidence of progressive disease within 6 months.
• a. Required unless 1L in the setting of clinically significant tumor burden and/or tumor with unfavorable biology (e.g. Ki67 >/=55%, rapid growth rate, fluorodeoxyglucose (FDG)-avid tumor, and/or negative Somatostatin receptor (SSTR)-based Positron Emission Tomography (PET) imaging)
• Age >=18 years.
• a. Because no dosing or adverse event data are currently available on the use of lenvatinib plus pembrolizumab in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group (ECOG) performance status <= 1.

You may not qualify if…

• 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).
• Uncontrolled blood pressure (BP) (Systolic BP >=140 mmHg or diastolic BP >=90 mmHg) despite an optimized regimen of antihypertensive medication.
• Significant gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib.
• Has pre-existing >= grade 3 (G3) gastrointestinal or non-gastrointestinal fistula.
• 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
• 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:
• 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.
• 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.
• Active hemoptysis or tumor bleeding (bright red blood of at least 0.5 teaspoons) within 3 weeks prior to the first dose of study drug.
• Hypersensitivity (>=G3) or known intolerance to lenvatinib or pembrolizumab or any of its excipients.
• Serious non-healing wound, ulcer, or bone fracture.
• Bleeding or thrombotic disorders or participants at risk for severe hemorrhage.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Individuals with new or progressive asymptomatic small (<1 cm) brain metastases are eligible if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first cycle of therapy.
• Participants with previously treated brain metastases (e.g., whole brain radiation therapy, surgery, or radiosurgery) may participate provided they are radiologically stable (i.e., without evidence of progression by imaging) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to the first dose of study intervention.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
• a.Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by a local health authority.
• Has a known history of hepatitis B (defined as hepatitis B surface antigen (HBsAg) reactive) or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for hepatitis B (HBV) and hepatitis C is required unless mandated by a local health authority.
• Participants with controlled hepatitis C are eligible (no detectable HCV RNA qualitative) provided anti-viral therapy completed at least 4 weeks prior to enrollment.

Where it is running

• University of California, San Francisco — San Francisco, California, United States (enrolling)

Full record on ClinicalTrials.gov

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