Study of Cabozantinib With Lu-177 in Patients With Somatostatin Receptor 2 Positive Neuroendocrine Tumors

NCT05249114 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: 2022000050
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The phase I objective of this study is to establish the maximal tolerated dose (MTD) of cabozantinib in 20 mg, 40 mg and 60 mg dose escalation cohorts in combination with Lu-177 dotatate at a standard dose of 7.4 GBq in four (4) 8-week cycles followed by continuation cabozantinib.

Conditions

Neuroendocrine Tumors

Keywords

Phase 1b; Cabozantinib; Lu-177; Lutathera; SSTR2; Gastrointestinal

Outcome Measures

Primary Outcomes (1)

• Establish the maximal tolerated dose of cabozantinib in combination with Lu-177 dotatae at a standard dose of 7.4 GBg in four 8-week cycles followed by continuation of cabozantinib.

  The phase I objective of this study is to establish the maximal tolerated dose (MTD) of cabozantinib in 20 mg, 40 mg and 60 mg dose escalation cohorts in combination with Lu-177 dotatate at a standard dose of 7.4 GBq in four (4) 8-week cycles followed by continuation cabozantinib. Due to overlapping toxicities of cabozantinib and Lu-177 dotatate and to allow more incremental dose escalation of cabozantinib, alternating day dosing of 40mg/20mg and 60mg/40mg cohorts are incorporated into the schema. This is expected to reduce the risk of overlapping toxicities while still achieving radio-sensitizing anti-angiogenic, multi-targeted therapy in combination with the beta-emitting radiation from lutetium 177 synergistic due to the prolonged half-life of cabozantinib.

  Up to 2 years

Secondary Outcomes (1)

• Establish objective response rate as measured by RECIST 1.1

  Up to 2 years post study completion

Study Arms (5)

Cohort 1

EXPERIMENTAL

Cabozantinib 20 mg daily with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 20 mg qd.

Drug: Cabozantinib; Drug: Lu-177

Cohort 2

EXPERIMENTAL

Cabozantinib 40 mg qod alternating with 20 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.

Drug: Cabozantinib; Drug: Lu-177

Cohort 3

EXPERIMENTAL

Cabozantinib 40 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.

Drug: Cabozantinib; Drug: Lu-177

Cohort 4

EXPERIMENTAL

Cabozantinib 60 mg qod alternating with 40 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd.

Drug: Cabozantinib; Drug: Lu-177

Cohort 5

EXPERIMENTAL

Cabozantinib 60 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd until disease progression.

Drug: Cabozantinib; Drug: Lu-177

Interventions

Cabozantinib DRUG

Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate equivalent to 20 mg and 60 mg of cabozantinib and contain microcrystalline cellulose, lactose anhydrous, hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and Opadry yellow. The 60 mg tablets are oval and the 20 mg tablets are round. Doses of 40 mg will comprise two 20-mg tablets.

Also known as: Cabometyx

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Lu-177 DRUG

Currently, the only FDA-approved PRRT consists of dotatate, a somatostatin analogue, radiolabeled with Lutetium-177 (Lu177), a beta-minus emitter (brand name Lutathera). Lu177 induces cell death via DNA strand breaks, caspase-3 apoptosis, and interfering with DNA-PK expression (which is associated with DNA repair). PRRT with Lu-177 DOTATATE is a targeted, intravenous therapy inducing DNA damage by delivering ionizing radiation to somatostatin receptor positive tumors.

Also known as: Lutathera

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with unresectable, progressive, histologically well-differentiated neuroendocrine tumors of the fore-, mid-, or hindgut, including pancreas, or those with an unknown primary with target lesions overexpressing somatostatin receptors (Krenning 2, 3 or 4) on a SSTR PET.
• Patients must have previously received one or more lines of systemic therapy including somatostatin analogue therapy.
• Prior PRRT therapy is permitted up to a maximum of 4 standard doses. Enrollment of R-PRRT patients is permitted after initially 3 PRRT-naïve patients have been enrolled on protocol and if the minimum progression free survival (PFS) with initial PRRT therapy was ≥ 18 months from day 1, cycle 1 of PRRT to progression.
• ECOG 0-2.
• Recovery to baseline or ≤ Grade 1 (CTCAE v5.0) from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• Minimum 18 years or older.
• Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
• Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor support.
• White blood cell count ≥ 2500/µL.
• Platelets ≥ 100,000/µL without transfusion.
• Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with documented bone metastases.
• Total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's disease ≤ 3 x ULN).
• Serum albumin ≥ 2.8 g/dl
• (PT)/INR or partial thromboplastin time (PTT) test \< 1.3 x the laboratory ULN

You may not qualify if:

• Prior therapy with cabozantinib.
• Tumors with poorly differentiated or small cell histology.
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Participants must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible participants must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• a. Cardiovascular disorders: i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
• ii. Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment.
• iii. Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose of study treatment.
• Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
• i. The participant has evidence of tumor invading into the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), active diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.

Sponsors & Collaborators

• Providence Health & Services: lead
• Exelixis: collaborator
• Advanced Accelerator Applications: collaborator

Study Sites (1)

Providence Portland Cancer Institute - Franz Clinic

Portland, Oregon, 97213, United States

Location

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

cabozantinib; Lutetium-177; lutetium Lu 177 dotatate

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Study Officials

• Hagen Kennecke, MD

  Providence Health & Services

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2022
• First Posted: February 21, 2022
• Study Start: December 28, 2022
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2029
• Last Updated: April 13, 2026

Record last verified: 2026-04

Locations

US (1)