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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03805594
Recruitment Status : Suspended (Drug availability)
First Posted : January 15, 2019
Last Update Posted : November 5, 2019
Sponsor:
Collaborators:
Prostate Cancer Foundation
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Rahul Aggarwal, University of California, San Francisco

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Metastatic Prostate Carcinoma Prostate Adenocarcinoma Stage IV Prostate Cancer Stage IVA Prostate Cancer Stage IVB Prostate Cancer Drug: Lutetium Lu 177-PSMA-617 Biological: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 10, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
Patients 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.
Drug: Lutetium Lu 177-PSMA-617
Given IV
Other Names:
  • 177Lu-PSMA-617
  • Lu177-PSMA-617

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Experimental: Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)
Patients 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.
Drug: Lutetium Lu 177-PSMA-617
Given IV
Other Names:
  • 177Lu-PSMA-617
  • Lu177-PSMA-617

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Experimental: Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)
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. 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.
Drug: Lutetium Lu 177-PSMA-617
Given IV
Other Names:
  • 177Lu-PSMA-617
  • Lu177-PSMA-617

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




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

  2. Objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Part B) [ Time Frame: From the start of treatment until disease progression or recurrence, where the reference for progressive disease is the smallest measurements recorded from start of treatment, assessed up to 2 years ]
    Defined as the best response (complete response or partial response). The proportion of patients with objective response will be descriptively reported with 95% confidence interval.


Secondary Outcome Measures :
  1. Frequency and severity of adverse events as defined by CTCAE version 4.0 [ Time Frame: Up to 90 days ]
    The incidence and severity of adverse events related to study treatment will be descriptively reported.

  2. 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 ]
    Will be estimated using Kaplan-Meier product limit method.

  3. Prostate-specific antigen (PSA) response rate [ Time Frame: Baseline up to 2 years ]
    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.

  4. Radiographic progression-free survival (rPFS) rate [ Time Frame: 6 months from date of first dose of study treatment ]
    Will be defined by RECIST version 1.1 Prostate Cancer Working Group (PCWG)3 criteria.

  5. Median PSA progression-free survival [ Time Frame: Up to 2 years ]
    Will be estimated using the Kaplan-Meier method.

  6. Overall survival [ Time Frame: From first date of study therapy to date of death from any cause, assessed up to 2 years ]
    Median overall survival and 95% confidence interval will be estimated using the Kaplan-Meier method.


Other Outcome Measures:
  1. Lesion-specific response rate by baseline PSMA avidity on gallium Ga 68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET) [ Time Frame: Baseline up to 2 years ]
    The median baseline uptake on Ga-PSMA-11 PET between responding versus non-responding lesions will be compared using Mann-Whitney test.

  2. Percent change in T cell repertoire, circulating T cell subsets, tumor infiltrating lymphocytes (TILs), and tumor PD-L1 expression by immunohistochemistry [ Time Frame: Baseline up to 2 years ]
    The percent change from baseline in these parameters will be reported using descriptive statistics (e.g. median, range, standard deviation).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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, darolutamide, 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 exception of any grade alopecia and grade ≤ 2 neuropathy.
  • 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 enrollment on clinical study investigating Lu-PSMA-based radioligand therapy
  • 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-central nervous system (CNS) disease
  • Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. nivolumab, ipilimumab)
  • 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 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. neomercazole, 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) >= grade 2 pneumonitis that required steroids within the past 2 years or has current >= grade1 pneumonitis at the time of study enrollment.
  • 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

    *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.

  • 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 (HCV) (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection (screening not required)
  • Has a known history of active Bacillus tuberculosis (TB)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03805594


Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94115
Sponsors and Collaborators
University of California, San Francisco
Prostate Cancer Foundation
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rahul Aggarwal, MD University of California, San Francisco

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Responsible Party: Rahul Aggarwal, Associate Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03805594    
Other Study ID Numbers: 185511
NCI-2018-02993 ( Registry Identifier: NCI Clinical Trial Reporting Program (CTRP) )
R01CA229354 ( U.S. NIH Grant/Contract )
First Posted: January 15, 2019    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma
Prostatic Neoplasms
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents