A Phase 1/2 Open-label Study of Pembrolizumab Combined With PNT-2002 Radioligand Therapy in Patients With Metastatic Renal Cell Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Metastatic Renal Cell Carcinoma
- Sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Enrollment
- 37
- Primary Endpoint
- Objective response rate by RECIST 1.1 criteria
- Status
- Withdrawn
- Last Updated
- 8 months ago
Overview
Brief Summary
This is a multi-center, single arm open label phase 1b/2 study of pembrolizumab in combination with 177Lu-PNT2002 (also known as 177Lu-PSMA I&T) radiopharmaceutical therapy in patients with metastatic clear cell renal cell carcinoma (RCC) who have progressed after prior treatment with anti-programmed cell death protein 1 (PD1) or PD-L1 immune-checkpoint inhibitors (ICIs). The study comprises 2 phases: an open-label Phase 1b dose escalation portion followed by a Phase 2 dose expansion portion. Investigators hypothesize that pembrolizumab in combination with 177Lu-PNT2002 in in patients with metastatic clear cell RCC at a biologically active dose will result in tolerable safety profile and it will lead to improved radiological objective responses in patients who have progressed after prior treatment with standard anti-PD1 or anti- Programmed Cell Death Ligand 1 (PDL1) immune-checkpoint inhibitor containing regimen when compared to historic controls. Patients in both phases will have prostate-specific membrane antigen (PSMA), positron emission tomography (PET) imaging with the radiotracer (F-18)-DCFPyl, to help detect any spread of the cancer.
Detailed Description
In the dose escalation phase, three dose levels of 177Lu-PNT2002 given intravenously every 8 weeks, starting from 3.4 gigabequerel (GBq) in combination with the standard dose of pembrolizumab 400 mg given intravenously every 6 weeks. After determining the maximum tolerated dose (MTD) or the recommended Phase 2 Dose (RP2D), the study will proceed to the dose expansion phase and in this portion of the study, patients will receive 177Lu-PNT-2002 intravenously every 8 weeks at the MTD/RP2D for a maximum of 4 cycles in combination pembrolizumab 400 mg intravenously every 6 weeks for a maximum of 17 cycles. The primary objective of the phase 1b portion of the study is to determine the MTD or RP2D of 177Lu-PNT2002 radiopharmaceutical therapy in combination with pembrolizumab in patients with metastatic clear cell RCC. The primary objective of the phase 2 portion of the study is to evaluate the efficacy of 177Lu-PNT2002 in combination with pembrolizumab in patients with metastatic clear cell RCC who progressed on prior anti PD-1/PDL1 therapy based on objective response rate (ORR) by RECIST 1.1 criteria. Patients in both phases will receive PSMA-PET with (F-18)-DCFPyl at screening, 12 weeks, and 24 weeks. (F-18)-DCFPyl was developed as a diagnostic radiotracer for the detection of prostate cancer and was FDA approved in 2021 for the detection of PSMA positive lesions in men with prostate cancer. However, PSMA is not entirely prostate-specific, as it has been shown to be present on neovascular endothelium of numerous solid tumors, including RCC. Prior studies have demonstrated high sensitivity and specificity of the detection of metastatic clear cell RCC lesions using PET imaging with various PSMA radiotracers, such as (F-18)-DCFPyl. Based on this, the high expression of PSMA in RCC and the synergy of PSMA radiopharmaceuticals with ICIs, such as pembrolizumab, provide a novel treatment strategy in RCC.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of clear cell RCC will be enrolled in this study.
- •Participants must have progressed on treatment with an anti-PD-1/L1 ICI administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
- •Treatment with at least 6 weeks of an approved anti-PD-1/L1 ICI.
- •More than one prior line of anti-PD-1/L1 ICI is allowed.
- •The immediate prior line of therapy is not mandated to be with anti-PD-1/L1 ICI.
- •Postoperative or adjuvant systemic therapy can be counted as a prior ICI therapy as long as recurrence is detected within 6 months of completion of treatment, in which case it will be counted as a prior therapy for metastatic disease.
- •Metastatic or locally advanced inoperable clear cell RCC.
- •Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline.
- •Evidence of positive PSMA avid lesions as per (F-18)-DCFPyL PSMA PET scan at screening. Positive lesions on PSMA-PET are defined as those with maximum standardized uptake value (SUVmax) values greater than liver as assessed by the local site investigator radiologist.
- •At least 70% of all the following lesions must PSMA-PET positive:
Exclusion Criteria
- •Renal cell carcinoma with non-clear cell histology.
- •Prior exposure to radioligand therapy or radioisotope therapy.
- •Treatment with RCC standard of care anti-cancer therapy within 14 days prior to initiation of study treatment
- •Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- •PSMA targeted imaging within 2 weeks prior to screening.
- •Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-central nervous system diseases permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.
- •Must have recovered from any grade 3 or higher reversible toxicity to prior anti cancer therapy treatments.
- •Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
- •Has a diagnosis of immunodeficiency (e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV) 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 additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen (PSA) \<10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
Arms & Interventions
177Lu-PNT2002 3.4 GBq
177Lu-PNT2002 administered at 3.4 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 megabecquerel (MBq) (9 mCi) at screening, week 12 and week 24.
Intervention: Pembrolizumab
177Lu-PNT2002 3.4 GBq
177Lu-PNT2002 administered at 3.4 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 megabecquerel (MBq) (9 mCi) at screening, week 12 and week 24.
Intervention: 177Lu-PNT2002
177Lu-PNT2002 3.4 GBq
177Lu-PNT2002 administered at 3.4 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 megabecquerel (MBq) (9 mCi) at screening, week 12 and week 24.
Intervention: (F-18)-DCFPyL
177Lu-PNT2002 5.1 GBq
177Lu-PNT2002 administered at 5.1 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: Pembrolizumab
177Lu-PNT2002 5.1 GBq
177Lu-PNT2002 administered at 5.1 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: 177Lu-PNT2002
177Lu-PNT2002 5.1 GBq
177Lu-PNT2002 administered at 5.1 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: (F-18)-DCFPyL
177Lu-PNT2002 6.8 GBq
177Lu-PNT2002 administered at 6.8 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: Pembrolizumab
177Lu-PNT2002 6.8 GBq
177Lu-PNT2002 administered at 6.8 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: 177Lu-PNT2002
177Lu-PNT2002 6.8 GBq
177Lu-PNT2002 administered at 6.8 GBq intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: (F-18)-DCFPyL
Dose Expansion
177Lu-PNT2002 administered at the maximum tolerated dose (determined by the 3 dose levels in the dose escalation phase of the study) intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: Pembrolizumab
Dose Expansion
177Lu-PNT2002 administered at the maximum tolerated dose (determined by the 3 dose levels in the dose escalation phase of the study) intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: 177Lu-PNT2002
Dose Expansion
177Lu-PNT2002 administered at the maximum tolerated dose (determined by the 3 dose levels in the dose escalation phase of the study) intravenously (IV) every 8 weeks combined with the standard dose of pembrolizumab 400 mg IV every 6 weeks. 18F-DCFPyL administered as a single bolus intravenous radioactive dose injection of 333 MBq (9 mCi) at screening, week 12 and week 24.
Intervention: (F-18)-DCFPyL
Outcomes
Primary Outcomes
Objective response rate by RECIST 1.1 criteria
Time Frame: 3 years post therapy initiation
Proportion of patients with an objective response, defined as Complete Response or Partial Response by RECIST 1.1. Dose expansion phase of the trial.
Safety assessed by the incidence of dose limiting toxicities.
Time Frame: Day 28
Number of incidences of dose limiting toxicities during days 1 to 28 of cycle 1.
Secondary Outcomes
- Disease control rates(3 years post therapy initiation)
- Progression free survival(4 years post therapy initiation)
- Safety as assessed by number of participants experiencing adverse events(2 years post therapy initiation)
- Duration of response to study therapy(3 years post therapy initiation)
- Overall survival rate(4 years post therapy initiation)