Pembrolizumab With Liver-Directed or Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors and Liver Metastases

NCT03457948 | Active Not Recruiting Phase 2 DMC FDA Drug FDA Device

• 2 other identifiers: 17705NCI-2018-00227
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This pilot phase II trial studies how effective pembrolizumab and liver-directed therapy or peptide receptor radionuclide therapy are at treating patients with well-differentiated neuroendocrine tumors and symptomatic and/or progressive tumors that have spread to the liver (liver metastases). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Liver-directed therapies such as radiofrequency ablation, transarterial embolization, yttrium-90 microsphere radioembolization, and cryoablation may help activate the immune system in order to shrink tumors that are not being directly targeted. Peptide receptor radionuclide therapy is a form of targeted treatment that is performed by the use of a small molecule, which carries a radioactive component attached to a peptide. Once injected into the body, this small molecule binds to some specific sites on tumor cells called receptors and emit medium energy radiation that can destroy cells. Because this radionuclide is attached to the peptide, which binds receptors on tumor lesions, the radiation can preferably be targeted to the tumor cells in order to destroy them. Giving pembrolizumab in combination with liver-directed therapy or peptide receptor radionuclide therapy may work better than pembrolizumab alone.

Conditions

Metastatic Malignant Neoplasm in the Liver; Neuroendocrine Neoplasm

Outcome Measures

Primary Outcomes (2)

• Proportion of participants with an overall response

  The All Subjects as Treated (ASaT, ITT) population will be used for the analysis of ORR. The primary efficacy endpoint will be best observed Overall Response Rate (ORR) by RECIST 1.1 (investigator reported). ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). The point estimate and 95% confidence interval of overall response rate will be obtained for each of the three groups separately.

  At 12 weeks

• Number of treatment-related adverse events (Group 1)

  Adverse events occurring from the start of treatment until 30 days after the end of treatment will be summarized by maximum toxicity grade. All treatment related adverse events will be graded using NCI CTCAE v5.0. Safety analysis will include a tabulation of all toxicities by grade. The frequency of toxicities will be tabulated separately for each cohort.

  Up to 30 days after the end of treatment

Secondary Outcomes (4)

• Duration of response (DOR)

  Up to 3 years

• Number of treatment-related adverse events (Groups 2 & 3)

  Up to 30 days after the end of treatment

• Median Progression free survival (PFS)

  Up to 3 years

• Immune-related progression free survival (irPFS)

  Up to 3 years

Study Arms (3)

Group I [pembrolizumab, 177Lu DOTATATE]

EXPERIMENTAL

Patients will be treated with pembrolizumab and intravenous peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate (177Lu-DOTATATE, Lutathera®) for up to four (4) sessions. Patients with somatostatin receptor positive (SSTR+) tumors with Ki-67 index \> 20% (well-differentiated grade 3) and any number of liver and/or extrahepatic lesions with liver parenchyma replacement by tumor \< 75%. Patients who achieve progressive or stable disease response after cycle 4 may receive an additional 4 cycles of pembrolizumab and lutetium Lu-177 DOTATATE in the absence of disease progression or unacceptable toxicity and pembrolizumab for up to 35 cycles.

Biological: Pembrolizumab; Biological: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate

Group II [pembrolizumab, TAE] (CLOSED)

EXPERIMENTAL

Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest being no larger than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo Arterial Embolization (TAE) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.

Procedure: Arterial Embolization; Biological: Pembrolizumab

Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED)

EXPERIMENTAL

Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest measuring more than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo yttrium-90 microsphere Radio Embolization (RE) 3-15 days following the first dose of pembrolizumab.

Biological: Pembrolizumab; Device: Yttrium-90 Microsphere Radioembolization

Interventions

Arterial Embolization PROCEDURE

Undergo TAE

Also known as: TAE, Transarterial Embolization

Group II [pembrolizumab, TAE] (CLOSED)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Group I [pembrolizumab, 177Lu DOTATATE]; Group II [pembrolizumab, TAE] (CLOSED); Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED)

Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate BIOLOGICAL

Given IV

Also known as: Lutathera, 177Lu-DOTATATE

Group I [pembrolizumab, 177Lu DOTATATE]

Yttrium-90 Microsphere Radioembolization DEVICE

Undergo yttrium-90 microsphere RE

Also known as: Yttrium Y 90 Microsphere Therapy, Yttrium-90 Radioembolization, Yttrium-90 Microsphere RE

Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED)

Eligibility Criteria

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

You may qualify if:

• Be willing and able to provide written informed consent for the trial.
• Be \>= 18 years of age on day of signing informed consent.
• Have a histologically proven well-differentiated neuroendocrine tumor (WHO grade 1, grade 2, or morphologically and/or clinically well-differentiated grade 3) of any primary site, including unknown primary site.
• a. For group 1, only well-differentiated grade 2 or 3 tumors with Ki-67 index \> 10% that demonstrate somatostatin receptor expression on DOTA or In-111 Octreoscans will be allowed.
• Radiographic, biochemical, or clinical evidence of tumor progression over a period of up to 12 months in at least one site.
• Group 1: At least one symptomatic and/or progressive somatostatin receptor positive (SSTR+) lesion over a period of up to 12 months, or have at least one measurable lesion based on RECIST v. 1.1.
• Groups 2-3: At least one symptomatic and/or progressive liver lesion over a period of up to 12 months, or have at least two measurable lesions in the liver or at least one measurable lesion in the liver and another measurable lesion elsewhere, based on RECIST v. 1.1.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Have a life expectancy of greater than 3 months.
• Demonstrate adequate organ function.
• Absolute neutrophil count (ANC) \>=1,500 /microliters (mcL).
• Platelet count \>75,000/mcL.
• Hemoglobin \> 9 g/dL (For group 1 only. There is no hemoglobin cut-off level for groups 2-3).
• Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also be used in place of creatinine or CrCl) \<=1.5 X upper limit of normal (ULN) OR \>=60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN.
• Serum total bilirubin \<= 1.5 X ULN OR Direct bilirubin \<= ULN for subjects with total bilirubin levels \> 1.5 ULN.

You may not qualify if:

• Has had prior thermal ablation, embolotherapy, radioembolization, or external beam radiation within 30 days of initiation of study therapy.
• Has had prior peptide receptor radionuclide therapy (group 1 only).
• Has had biliary tract intervention that resulted in compromise to the Ampulla of Vater or a biliary-enteric anastomosis (groups 2-3 only).
• Has greater than 75% liver parenchyma replacement by tumor (determined by radiologist investigator).
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of active Tuberculosis (TB) (Bacillus Tuberculosis).
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., \<=Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., \<=Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with \<= Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Concurrent somatostatin analog therapy is allowed.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

Sponsors & Collaborators

• Nicholas Fidelman, MD: lead
• Merck Sharp & Dohme LLC: collaborator
• BTG International Inc.: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

pembrolizumab; lutetium Lu 177 dotatate

Condition Hierarchy (Ancestors)

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

Study Officials

• Nicholas Fidelman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Clinical Radiology

Study Record Dates

• First Submitted: February 27, 2018
• First Posted: March 8, 2018
• Study Start: August 27, 2018
• Primary Completion: July 31, 2025
• Study Completion (Estimated): May 31, 2026
• Last Updated: September 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)