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Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

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ClinicalTrials.gov Identifier: NCT03248570
Recruitment Status : Recruiting
First Posted : August 14, 2017
Last Update Posted : April 5, 2019
Sponsor:
Information provided by (Responsible Party):
Lawrence Fong, University of California, San Francisco

Brief Summary:
This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

Condition or disease Intervention/treatment Phase
Castration Resistant Prostatic Cancer Metastatic Prostate Cancer Drug: Pembrolizumab Drug: Chemotherapy Phase 2

Detailed Description:

This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

All subjects will receive pembrolizumab 200mg intravenously (IV) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study is objective response rate (ORR) according to immune-mediated response criteria (irRC).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

After determination of DNA damage repair status, subjects will be assigned to one of two treatment groups:

  • Group 1 (DNA damage repair proficient group): Twenty-five subjects
  • Group 2 (DNA damage repair deficient group): Twenty-five subjects

All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression or unacceptable toxicity.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Open Label Study of Pembrolizumab in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects
Actual Study Start Date : February 20, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: DNA damage repair proficient group
Twenty-five subjects with mismatch repair (MMR) intact
Drug: Pembrolizumab
All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression or unacceptable toxicity.
Other Names:
  • KEYTRUDA
  • MK-3475

Drug: Chemotherapy
At time of progression, all subjects will also have the option of receiving taxane-based chemotherapy followed by repeat pembrolizumab for those who have a clinical response to chemotherapy. Chemotherapy regimen will be at the discretion of the treating physician, and may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. carboplatin). A minimum of 4 cycles and a maximum of 8 cycles of chemotherapy will be given.

Experimental: DNA damage repair defective group
Twenty-five subjects with defective DNA repair
Drug: Pembrolizumab
All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression or unacceptable toxicity.
Other Names:
  • KEYTRUDA
  • MK-3475

Drug: Chemotherapy
At time of progression, all subjects will also have the option of receiving taxane-based chemotherapy followed by repeat pembrolizumab for those who have a clinical response to chemotherapy. Chemotherapy regimen will be at the discretion of the treating physician, and may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. carboplatin). A minimum of 4 cycles and a maximum of 8 cycles of chemotherapy will be given.




Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: From baseline until complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months ]
    Objective response rate (ORR) in mCRPC subjects with proficient DNA damage repair (Group 1) and defective DNA damage repair (Group 2), using immune-related response criteria (irRC)


Secondary Outcome Measures :
  1. Immune-related progression-free survival (irPFS) [ Time Frame: At 20 weeks and 28 weeks ]
    Compare rate of immune-related progression-free survival (irPFS) using irRC and RECIST v.1.1.

  2. Progression-free survival (PFS) [ Time Frame: At 20 weeks and 28 weeks ]
    Compare rate of progression-free survival (PFS) using irRC and RECIST v.1.1.

  3. Proportion of subjects achieving any prostate specific antigen (PSA) response [ Time Frame: From baseline until complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months ]
    Compare the proportion of subjects achieving any PSA response from baseline in both study groups

  4. Proportion of subjects achieving any PSA decline ≥ 50% [ Time Frame: From baseline until complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months ]
    Proportion of subjects achieving any PSA decline ≥ 50% from baseline in both study groups

  5. Safety of pembrolizumab [ Time Frame: From baseline until 30 days after end of treatment (at complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months) ]
    The safety of pembrolizumab in both study groups by CTCAE v4.0, summarized by maximum toxicity grade for each study group

  6. Time to progression after taxane-based chemotherapy [ Time Frame: From completion of taxane-based chemotherapy to progression, up to 24 months ]
    Time to progression after taxane-based chemotherapy in subjects who initially progress on pembrolizumab, undergo taxane-based chemotherapy, followed by repeat pembrolizumab in both study groups.



Information from the National Library of Medicine

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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:

  1. Histologically documented adenocarcinoma of the prostate.
  2. Metastatic castration resistant prostate cancer with castrate-level testosterone (<50 ng/dL).

    a. Subjects must maintain a castrate-level testosterone during the study.

  3. Disease progression defined by one or more of the following three criteria:

    1. PSA > 2.0 ng/mL and rising PSA by at least 2 consecutive measurements a minimum of 1-week apart.
    2. Soft tissue progression as defined by RECIST v1.1 criteria
    3. Bone disease progression as defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3)
  4. Have measurable disease based on RECIST v.1.1 and irRC for response assessment.

    a. Must have at least one lesion that is 10mm in longest diameter for a soft tissue lesion or 15mm in short axis for a lymph node.

  5. Have received prior abiraterone and/or enzalutamide.
  6. Be willing and able to provide written informed consent/assent for the trial.
  7. Be ≥ 18 years of age on day of signing informed consent.
  8. Be willing to provide archival tissue from prior biopsy or surgery for prostate cancer, if available.
  9. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  10. Patients must discontinue antiandrogen therapy (i.e. bicalutamide, flutamide, nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline after washout.

    1. Bicalutamide: Washout period at least 6 weeks
    2. Flutamide and nilutamide: Washout period at least 4 weeks
  11. Patients must discontinue therapies for mCRPC, with the exception of Gonadotropin-releasing hormone (GnRH) agent, for 5 half-lives or 28 days, whichever is shorter.

    1. For patients on abiraterone/prednisone, prednisone should be discontinued for at least 7 days before starting study treatment.
    2. Prior chemotherapy is allowed if no progression of disease on chemotherapy.
    3. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitor (e.g. olaparib) is allowed.
    4. Tissue biopsy may be performed during washout period.
  12. Demonstrate adequate organ function as defined as follows, all screening labs should be performed within 10 days of treatment initiation.

    a. Hematological

    i. Absolute neutrophil count (ANC): ≥ 1,500 /microliters (mcL)

    ii. Platelets: ≥ 100,000 / mcL

    iii. Hemoglobin: ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

    b. Renal

    i. 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

    c. Hepatic

    i. Serum total bilirubin: ≤ 1.5 X ULN

    ii. Aspartate Aminotransferase (AST) (SGOT) and Alanine Aminotransferase (ALT) (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

    iii. Albumin: > 2.5 mg/dL

    d. Coagulation

    i. International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or Partial Thromboplastin Time (PTT) is within therapeutic range of intended use of anticoagulants

    ii. Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

  13. Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

  1. Significant liver metastasis or disease-related bone pain requiring scheduled narcotics.
  2. Prior taxane-based chemotherapy with progressive disease on chemotherapy.

    1. Prior docetaxel for metastatic hormone sensitive prostate cancer is allowed, if no progression of disease on docetaxel as defined by RECIST v1.1 and PCWG3.
    2. Prior taxane-based chemotherapy (i.e. docetaxel or cabazitaxel with or without platinum agent) for mCRPC is allowed if no progression of disease on chemotherapy as defined by RECIST v1.1 and PCWG3.
  3. 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.
  4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy >10mg/day or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  5. Has a known history of active Bacillus Tuberculosis (TB).
  6. Hypersensitivity to pembrolizumab or any of its excipients.
  7. 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.
  8. 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.

    1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    2. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  9. 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.
  10. 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.
  11. Has 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 < 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  12. Has known history of, or any evidence of active, non-infectious pneumonitis.
  13. Has an active infection requiring systemic therapy.
  14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  16. Is expecting to father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  17. Has received prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-PD-L1, or anti-PD-L2 agent.
  18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus [HCV] RNA [qualitative] is detected).
  20. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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): NCT03248570


Contacts
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Contact: Paula Dutton 877-827-3222 cancertrials@ucsf.edu
Contact: Lawrence Fong, MD 877-827-3222 cancertrials@ucsf.edu

Locations
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United States, California
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94115
Contact: Lawrence Fong, MD    877-827-3222    cancertrials@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Lawrence Fong, MD University of California, San Francisco

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Responsible Party: Lawrence Fong, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03248570     History of Changes
Other Study ID Numbers: CC 16557
First Posted: August 14, 2017    Key Record Dates
Last Update Posted: April 5, 2019
Last Verified: April 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.: Yes

Additional relevant MeSH terms:
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Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents