Clinical Trials /

177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

NCT03805594

Description:

This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in treating patients with castration-resistant prostate cancer that has spread to other places in the body. 177Lu-PSMA-617 carries a radioactive component which attached to the prostate specific membrane antigen (PSMA) receptor found on tumor cells. Its radiation component destroys the tumor cell. 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. Giving 177Lu-PSMA-617 and pembrolizumab may work better at treating prostate cancer.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer
  • Official Title: Immunogenic Priming With PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in Combination With Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: 185511
  • SECONDARY ID: NCI-2018-02993
  • SECONDARY ID: 18-25747
  • SECONDARY ID: 185511
  • SECONDARY ID: P30CA082103
  • NCT ID: NCT03805594

Conditions

  • Castration Levels of Testosterone
  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • Prostate Adenocarcinoma
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
Lutetium Lu 177-PSMA-617177Lu-PSMA-617, Lu177-PSMA-617Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)

Purpose

This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in treating patients with castration-resistant prostate cancer that has spread to other places in the body. 177Lu-PSMA-617 carries a radioactive component which attached to the prostate specific membrane antigen (PSMA) receptor found on tumor cells. Its radiation component destroys the tumor cell. 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. Giving 177Lu-PSMA-617 and pembrolizumab may work better at treating prostate cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase 2 dose and schedule of lutetium Lu 177-PSMA-617
      (177Lu-PSMA-617) in combination with pembrolizumab in patients with metastatic
      castration-resistant prostate carcinoma (mCRPC). (Part A) II. To determine the objective
      response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Part B
      [Dose Expansion])

      SECONDARY OBJECTIVES:

      I. To characterize the safety profile of the combination. II. To determine the median
      duration of response by RECIST 1.1 criteria. III. To determine the proportion of patients who
      experience >= 50% decline from baseline in serum prostate-specific antigen (PSA).

      IV. To determine the median PSA progression-free survival. V. To determine the median time to
      symptomatic skeletal related event. VI. To determine the 6 month radiographic
      progression-free survival rate and median radiographic progression-free survival.

      VII. To determine the median overall survival.

      CORRELATIVE OBJECTIVES:

      I. To assess the lesion-specific response rate by baseline PSMA avidity on gallium Ga
      68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET).

      II. To quantify the change from baseline in T cell repertoire, circulating T cell subsets,
      tumor infiltrating lymphocytes, and tumor PD-L1 expression by immunohistochemistry after one
      priming dose of Lu-PSMA radioligand therapy (RLT).

      III. To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with
      initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes.

      IV. To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of
      disease progression.

      OUTLINE: Patients are assigned sequentially to 1 of 3 treatment schedules.

      SCHEDULE 1: Patients receive lutetium Lu 177-PSMA-617 intravenously (IV) over 20-30 minutes
      on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1.

      SCHEDULE 2: Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab
      IV over 30 minutes on day 1.

      SCHEDULE 3: Starting day -21, patients receive pembrolizumab IV over 30 minutes. Patients
      also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1.

      In all schedules, treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2
      years) in the absence of disease progression or unacceptable toxicity. Patients who achieve
      stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of
      pembrolizumab.

      After completion of study treatment, patients are followed up at 30 and 90 days.
    

Trial Arms

NameTypeDescriptionInterventions
Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)ExperimentalPatients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
  • Lutetium Lu 177-PSMA-617
  • Pembrolizumab
Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)ExperimentalPatients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
  • Lutetium Lu 177-PSMA-617
  • Pembrolizumab
Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)ExperimentalStarting day -21, patients receive pembrolizumab IV over 30 minutes. Patients also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
  • Lutetium Lu 177-PSMA-617
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  The subject is able and willing to comply with study procedures and provide signed and
             dated informed consent

          -  Histologically confirmed prostate adenocarcinoma. De novo small cell neuroendocrine
             prostate cancer will not be allowed due to putative lower PSMA expression in this
             tumor subtype. Treatment-emergent small cell neuroendocrine prostate cancer detected
             in metastatic tumor biopsy is not an exclusion

          -  A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with positive
             lesions defined as those with maximum standardized uptake value (SUVmax) values
             greater than mediastinal blood pool

          -  Progressive metastatic castration-resistant prostate cancer by Prostate Cancer Working
             Group (PCWG)3 criteria at the time of study entry

          -  Castrate level of serum testosterone at study entry (< 50 ng/dL). Patients without
             prior bilateral orchiectomy are required to remain on luteinizing hormone-releasing
             hormone (LHRH) analogue treatment for duration of study

          -  Prior progression on at least one second generation androgen signaling inhibitor
             including abiraterone, apalutamide, and/or enzalutamide

          -  Absolute neutrophil count > 1.5 x 10^9/L

          -  Hemoglobin > 9.0 g/dL

          -  Platelet count > 100,000/microliter

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated glomerular
             filtration rate (GFR) > 50 ml/min by Cockcroft-Gault or 24 hour urine collection

          -  Total bilirubin =< 1.5 x ULN. In patients with known or suspected Gilbert?s disease,
             direct bilirubin =< ULN

          -  Aspartate aminotransferase and alanine aminotransferase =< 2.5 x ULN

          -  No other systemic anti-cancer therapies administered other than LHRH analogue within
             28 days, or 5 half-lives, whichever is shorter, prior to initiation of study
             treatment. Adverse events related to prior anti-cancer treatment must have recovered
             to grade =< 1 with the exclusion of alopecia

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             0 or 1

          -  Patients must use appropriate methods of contraception during study treatment and for
             at least 60 days after last study treatment

               -  Patients who are sexually active should consider their female partner to be of
                  childbearing potential if she has experienced menarche and is not postmenopausal
                  (defined as amenorrhea > 24 consecutive months) or has not undergone successful
                  surgical sterilization. Even women who use contraceptive hormones (oral,
                  implanted, or injected), an intrauterine device, or barrier methods (diaphragms,
                  condoms, spermicide) should be considered to be of childbearing potential

               -  Patients who have undergone vasectomy themselves should also be considered to be
                  of childbearing potential

               -  Acceptable methods of contraception include continuous total abstinence, or
                  double-barrier method of birth control (e.g. condoms used with spermicide, or
                  condoms used with oral contraceptives). Periodic abstinence and withdrawal are
                  not acceptable methods of contraception

          -  Patients must provide consent to comply to recommended radioprotection precautions
             during study

          -  Patients willing to undergo metastatic tumor biopsy and have at least one metastatic
             lesion safely accessible to tumor biopsy. Bone or soft tissue lesion is allowed

          -  Measurable disease by RECIST 1.1 criteria

        Exclusion Criteria:

          -  Untreated brain metastases at study entry. Patients with previously treated brain
             metastases are eligible provided the following criteria are all met:

               -  Last treatment was > 28 days prior to cycle 1 day 1 (C1D1)

               -  No evidence of new/progressive brain metastases is observed on magnetic resonance
                  imaging (MRI) obtained during screening window

               -  Patient is clinically stable without requirement of steroid treatment for at
                  least 14 days prior to first dose of study treatment

          -  Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or
             antibody-drug conjugate)

          -  Prior treatment with radium-223 or other radioisotope for the treatment of prostate
             cancer

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (=< 2 weeks of radiotherapy) to non-CNS disease

          -  Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. nivolumab,
             ipilimumab)

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to initiation of study treatment.

               -  Note: Participants must have recovered from all adverse events (AEs) due to
                  previous therapies to =< grade 1 or baseline. Participants with =< grade 2
                  neuropathy may be eligible

               -  Note: If participant received major surgery, they must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  study treatment

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment

               -  Note: Participants who have entered the follow-up phase of an investigational
                  study may participate as long as it has been 4 weeks after the last dose of the
                  previous investigational agent

          -  Receipt of chemotherapy applied in the castration-resistant setting. Prior receipt of
             chemotherapy in the hormone-sensitive setting is allowed

          -  Grade >= 2 peripheral neuropathy at the time of study entry

          -  Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients

          -  Has an active autoimmune disease or grade >= 3 pneumonitis that has required systemic
             treatment in the past 2 years (i.e., with use of disease modifying agents,
             corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine,
             insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
             insufficiency) or treatment with drugs (e.g. neomercazol, carbimazole, etc.) that
             function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid
             gland (e.g. in Graves? disease) is not considered a form of systemic treatment of an
             autoimmune disease

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a
             prednisone equivalent dose of > 10 mg daily or other form of immunosuppressive therapy
             within 7 days prior to first dose of study drug

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette?Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

          -  Patients who because of age, general medical or psychiatric condition, or physiologic
             status cannot give valid informed consent

          -  Has clinically significant cardiovascular disease including, but not limited to:

               -  Uncontrolled or any New York Heart Association class 3 or 4 congestive heart
                  failure

               -  Uncontrolled angina, history of myocardial infarction, unstable angina or stroke
                  within 6 months before study entry

               -  Clinically significant arrhythmias not controlled by medication. Chronic rate
                  controlled or paroxysmal atrial fibrillation/flutter is not an exclusion to study
                  participation

          -  Prior external beam radiation involving >= 25% of bone marrow or within 14 days of
             start of protocol therapy

          -  Major surgery within 28 days of study treatment

          -  Has an active infection requiring systemic therapy

          -  Has a known history of human immunodeficiency virus (HIV) (screening not required)

          -  Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
             reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA]
             [qualitative] is detected) infection (screening not required)

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Any condition that, in the opinion of the principal investigator, would impair the
             patient?s ability to comply with study procedures

          -  History of bleeding diathesis and not currently on anti-coagulation therapy that
             cannot be safely discontinued for the tumor biopsy procedure
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (Part A)
Time Frame:Through study completion of Part A of study, estimated 1 year.
Safety Issue:
Description:Will be determined from the aggregate of the safety and efficacy data observed graded by Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Measure:Frequency and severity of adverse events as defined by CTCAE version 4.0
Time Frame:Up to 90 days
Safety Issue:
Description:The incidence and severity of adverse events related to study treatment will be descriptively reported.
Measure:Median duration of response by RECIST 1.1
Time Frame:From date of first scan indicating response until loss of response or progression, or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier product limit method.
Measure:Prostate-specific antigen (PSA) response rate
Time Frame:Baseline up to 2 years
Safety Issue:
Description:The proportion of patients who achieve a greater than 50% decline from baseline PSA drawn on cycle 1 day 1 (C1D1), at any point in the treatment course, will be descriptively reported along with 95% confidence interval.
Measure:Radiographic progression-free survival (rPFS) rate
Time Frame:6 months from date of first dose of study treatment
Safety Issue:
Description:Will be defined by RECIST version 1.1 Prostate Cancer Working Group (PCWG)3 criteria.
Measure:Median PSA progression-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.
Measure:Overall survival
Time Frame:From first date of study therapy to date of death from any cause, assessed up to 2 years
Safety Issue:
Description:Median overall survival and 95% confidence interval will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

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