Pembrolizumab with Liver-Directed or Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors and Liver Metastases
- Conditions
- Neuroendocrine NeoplasmMetastatic Malignant Neoplasm in the Liver
- Interventions
- Procedure: Arterial EmbolizationDevice: Yttrium-90 Microsphere RadioembolizationBiological: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate
- Registration Number
- NCT03457948
- Lead Sponsor
- Nicholas Fidelman, MD
- 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.
- Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate safety profile of pembrolizumab in combination with Peptide Receptor Radionuclide Therapy (PRRT), transarterial embolization, and radioembolization.
II. To evaluate the best observed overall response rate (ORR) in lesion(s) not targeted for liver-directed therapy (abscopal effect) to pembrolizumab plus liver-directed therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for patients with metastatic well-differentiated (WD) neuroendocrine tumors (NET)s (WD-NETs).
III. To evaluate the best observed ORR to pembrolizumab plus peptide receptor radionuclide therapy (PRRT) according to RECIST 1.1 for patients with metastatic grade 2 and 3 WD-NET (Ki-67 \> 10%).
SECONDARY OBJECTIVES:
I. To evaluate duration of response (DOR) in patients receiving pembrolizumab in combination with liver-directed therapies or PRRT.
II. To evaluate progression free survival (PFS) in subjects treated with pembrolizumab in combination with liver-directed therapies or PRRT.
III. Best observed radiographic ORR per modified RECIST (mRECIST) in lesions targeted for liver-directed therapy.
IV. Duration of response in lesions targeted for liver-directed therapy by mRECIST.
EXPLORATORY OBJECTIVES:
I. To compare ORR, DOR, and PFS based on immune-related (ir)RECIST with the same measures assessed by RECIST 1.1.
II. To correlate clinical outcomes (ORR, DOR, PFS) with baseline immune cell infiltration and PD-L1 staining in cycle 1 and cycle 5 tumor biopsies.
III. To assess the level of PD-L1 expression in tumor tissue prior to liver-directed therapy (prior to PRRT) and 5 weeks following liver-directed therapy (following PRRT).
IV. To assess T cell infiltration on the pre-177Lu-DOTATATE (pre-PRRT) and on the on-treatment tumor tissue biopsies.
V. To assess baseline circulating T cell receptor (TCR) repertories and changes in TCR repertories with treatment, and correlate baseline and turnover of repertories to clinical outcomes.
VI. To analyze the relationship between baseline tumor proliferative index (as measured by Ki67) and response to therapy.
OUTLINE: Patients originally assigned to 1 of 3 groups. As of 09/15/2022, Groups 2 and 3 are closed to enrollment.
GROUP I (PRRT): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. PRRT using 177Lu-DOTATATE(Lutathera®) will be offered to patients with somatostatin receptor positive (SSTR+) tumors with Ki-67 index \> 20% (well-differentiated grade 3). Patients may have any number of liver and/or extrahepatic lesions with liver parenchyma replacement by tumor \< 75%. 200±20 millicurie (mCi) of 177Lu-DOTATATE will be administered intravenously per treatment on outpatient basis. Patients will receive a total of four treatments of 177Lu-DOTATATE, administered every 8±1 weeks. Patients with partial response (PR) or stable disease (SD) by RECIST v. 1.1 after cycle 4 of pembrolizumab who were treated with PRRT (group 1) would continue to receive systemic IV administrations of 177Lu-DOTATATE every 8 +/-1 weeks for up to four (4) treatments. After completion of four (4) PRRT treatments, pembrolizumab may be administered alone for up to 35 cycles
CLOSED - GROUP II (TRANSARTERIAL EMBOLIZATION (TAE)): 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 TAE over 2-3 hours, 3-7 days following the first dose of pembrolizumab.
CLOSED - GROUP III (RADIOEMBOLIZATION (RE)): 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 RE 3-15 days following the first dose of pembrolizumab.
After completion of study treatment, patients are followed up at 30 days and then every 3-6 months thereafter.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 32
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED) Pembrolizumab 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. Group II [pembrolizumab, TAE] (CLOSED) Arterial Embolization 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. Group I [pembrolizumab, 177Lu DOTATATE] Pembrolizumab 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. Group II [pembrolizumab, TAE] (CLOSED) Pembrolizumab 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. Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED) Yttrium-90 Microsphere Radioembolization 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. Group I [pembrolizumab, 177Lu DOTATATE] Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate 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.
- Primary Outcome Measures
Name Time Method Proportion of participants with an overall response At 12 weeks 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.
Number of treatment-related adverse events (Group 1) Up to 30 days after the end of treatment 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.
- Secondary Outcome Measures
Name Time Method Immune-related progression free survival (irPFS) Up to 3 years Immune-related progression free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause, whichever occurs first, as determined by immune-related-RECIST (irRC). Kaplan-Meier methods will be used to estimate irPFS with 95% confidence interval for each group separately.
Duration of response (DOR) Up to 3 years Kaplan-Meier method will be used to summarize DOR for participants with a documented complete response or partial response per RECIST v.1.1 criteria. . Median DOR and its 95% confidence interval will be obtained for each of the three liver-directed therapies and PRRT groups separately.
Number of treatment-related adverse events (Groups 2 & 3) Up to 30 days after the end of treatment 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.
Median Progression free survival (PFS) Up to 3 years Progression free survival is defined as the time from the first day of study treatment with protocol therapy to the date of documented tumor progression or death due to any cause, whichever occurs first, as determined by RECIST v1.1. Kaplan-Meier methods will be used to estimate PFS with 95% confidence interval for each group separately.
Trial Locations
- Locations (1)
University of California, San Francisco
🇺🇸San Francisco, California, United States