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Neoadjuvant Atezolizumab With or Without Enzalutamide in Localized Prostate Cancer Given Before Radical Prostatectomy

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03821246
Recruitment Status : Recruiting
First Posted : January 29, 2019
Last Update Posted : November 20, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Lawrence Fong, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE January 10, 2019
First Posted Date  ICMJE January 29, 2019
Last Update Posted Date November 20, 2019
Actual Study Start Date  ICMJE January 25, 2019
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2019)
Changes in tumor-infiltrating effector cluster of differentiation 3 (CD3)+ T cells by multiplexed immunohistochemistry (IHC) [ Time Frame: Baseline up to 12 months ]
The proportion of subjects with positive responses will be reported with 95% confidence intervals.
Original Primary Outcome Measures  ICMJE
 (submitted: January 28, 2019)
Changes in tumor-infiltrating effector CD3+ T cells by multiplexed immunohistochemistry (IHC) [ Time Frame: Baseline up to 12 months ]
The proportion of subjects with positive responses will be reported with 95% confidence intervals.
Change History Complete list of historical versions of study NCT03821246 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2019)
  • Incidence of adverse events per National Institutes of Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Up to 12 months ]
    Adverse events will be tabulated.
  • Pathologic complete response (pCR) rate [ Time Frame: Up to 12 months ]
    Defined as defined as the absence of tumor on the gross specimen.Will be reported following standard pathologic review of the radical prostatectomy (RP) specimen. These will be reported in sum [pCR+ minimal residual disease (MRD) rate] and independently.
  • MRD rate [ Time Frame: Up to 12 months ]
    Defined as the sum of the cross-sectional diameter of residual tumors =< 0.5 cm. Will be reported following standard pathologic review of the RP specimen. These will be reported in sum (pCR+MRD rate) and independently.
  • Prostate specific antigen (PSA) response [ Time Frame: Up to 2 months ]
    Defined as >= 50% decline in PSA. The PSA response proportion will be reported for each cohort.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2019)
  • Incidence of adverse events per National Institutes of Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Up to 12 months ]
    Adverse events will be tabulated.
  • Pathologic complete response (pCR) rate [ Time Frame: Up to 12 months ]
    Defined as defined as the absence of tumor on the gross specimen.Will be reported following standard pathologic review of the radical prostatectomy (RP) specimen. These will be reported in sum (pCR+ minimal residual disease [MRD] rate) and independently.
  • MRD rate [ Time Frame: Up to 12 months ]
    Defined as the sum of the cross-sectional diameter of residual tumors =< 0.5 cm. Will be reported following standard pathologic review of the RP specimen. These will be reported in sum (pCR+MRD rate) and independently.
  • Prostate specific antigen (PSA) response [ Time Frame: Up to 2 months ]
    Defined as >= 50% decline in PSA. The PSA response proportion will be reported for each cohort.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Atezolizumab With or Without Enzalutamide in Localized Prostate Cancer Given Before Radical Prostatectomy
Official Title  ICMJE An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy
Brief Summary This phase II trial studies how well atezolizumab works alone or in combination with enzalutamide in treating men with localized prostate cancer before radical prostatectomy. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, may lessen the amount of androgens made by the body. Giving atezolizumab in combination with enzalutamide may work better in treating prostate cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the impact of atezolizumab-based combination therapy on the composition and function of tumor-infiltrating immune cells (TIICS).

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of atezolizumab-based combination therapy in localized prostate cancer (PC).

II. To determine the clinical efficacy of atezolizumab-based combination therapy in localized PC.

EXPLORATORY OBJECTIVES:

I. To characterize changes in the frequency and number of circulating immune cells following atezolizumab-based combination therapy in localized PC.

II. To determine the impact of atezolizumab-based combination therapy on the composition and phenotype of the tumor microenvironment.

III. To determine the impact of atezolizumab-based combination therapy on the circulating and intratumoral T cell repertoire.

IV. To explore the role of novel imaging modalities to understand the immunologic and clinical impact to immunotherapeutic approaches in localized PC.

V. To characterize changes in the gut microbiome associated with each therapeutic combination.

OUTLINE: Patients are assigned sequentially to 1 of 2 groups.

COHORT A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1.

COHORT B: Patients receive atezolizumab as in Cohort A and enzalutamide orally (PO) once daily (QD) on days 1-21.

Two more groups consisting of treatment with atezolizumab in combination with other drugs may be added in the future.

In all cohorts, treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 28 days after treatment, patients undergo radical prostatectomy.

After completion of study treatment, patients are followed up at 14 days, 6 and 12 weeks, and 6 and 12 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostate Adenocarcinoma
Intervention  ICMJE
  • Drug: Atezolizumab
    Given IV
    Other Names:
    • MPDL 3280A
    • MPDL 328OA
    • MPDL-3280A
    • MPDL3280A
    • MPDL328OA
    • RG7446
    • RO5541267
    • Tecentriq
  • Drug: Enzalutamide
    Given PO
    Other Names:
    • ASP9785
    • MDV3100
    • Xtandi
Study Arms  ICMJE
  • Experimental: Cohort A (atezolizumab)
    Patients receive atezolizumab intravenously IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 28 days after treatment, patients undergo radical prostatectomy.
    Intervention: Drug: Atezolizumab
  • Experimental: Cohort B (atezolizumab, enzalutamide)
    Patients receive atezolizumab as in Cohort A and enzalutamide PO QD on days 1-21. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 28 days after treatment, patients undergo radical prostatectomy.
    Interventions:
    • Drug: Atezolizumab
    • Drug: Enzalutamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 19, 2019)
51
Original Estimated Enrollment  ICMJE
 (submitted: January 28, 2019)
68
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the prostate

    • Subjects with small cell or neuroendocrine PC are not eligible
  • Eligible for radical prostatectomy as determined by urologic oncology surgeon, and subject consents to proceeding with radical prostatectomy

    • Deemed by urologic oncology surgeon to be appropriate for a "window-of-opportunity" study
  • Only patients with high-risk disease are eligible for the safety lead-in for each cohort. Patients with intermediate-risk disease will be included after interim analyses is complete for the corresponding cohort and the principal investigator (PI) has determined that it is safe to do so
  • Availability of a representative tumor specimen that is suitable for the planned study analyses, as determined by the principal investigator

    • A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, serial sections should be submitted along with an associated pathology report prior to study treatment. If only 10-14 slides are available, the patient may still be eligible for the study, after principal investigator approval has been obtained
    • If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, tumor tissue must be obtained from a biopsy performed at screening
  • Subjects have not received any prior systemic or locally directed therapy for PC (see exclusion criteria)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Hemoglobin >= 9 g/dL
  • Absolute neutrophil count >= 1,500/microliter (uL)
  • Absolute lymphocyte count >= 500/uL
  • Platelets >= 100,000/uL without transfusion
  • Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (known Gilbert disease: < 3 x ULN)
  • Alkaline phosphatase < 2 x institutional ULN
  • Aspartate aminotransferase (AST) [serum glutamic-oxaloacetic transaminase (SGOT)] =< 2.5 x institutional ULN
  • Alanine aminotransferase (ALT) [serum glutamate pyruvate transaminase (SGPT)] =< 2.5 x institutional ULN
  • International normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 x institutional ULN for subjects not receiving therapeutic anticoagulation
  • Creatinine clearance >= 30 mL/min (calculated using the Cockcroft-Gault formula)
  • Testosterone level > 150 ng/dL
  • Contraception: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm as defined below:

    • With female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the last dose of study treatment. Men must refrain from donating sperm during the same period
    • With pregnant female partners: men must remain abstinent or use a condom during the treatment period and for 4 months after the last dose of study treatment to avoid exposing the embryo
    • Abstinence: the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
  • For patients receiving therapeutic anticoagulation: stable anticoagulant regimen > 3 months.
  • Ability to understand a written informed consent document, and the willingness to sign it
  • Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria:

  • Evidence of metastatic disease as determined by standard staging scans

    • Staging scans should be performed per urologic standard of care for patients undergoing radical prostatectomy [per American Urological Association (AUA)/National Comprehensive Cancer Network (NCCN) guidelines]
  • Not a candidate for radical prostatectomy as determined by treating urologic oncology surgeon
  • Any prior systemic therapy for PC, including antiandrogens, androgen deprivation therapy [gonadotropin-releasing hormone (GnRH) agonist or antagonist], chemotherapy, targeted therapy, immunotherapy, OR radiopharmaceuticals

    • Subjects who are on finasteride or dutasteride must discontinue therapy and undergo a washout period of 6 weeks to become eligible for the study. Screening procedures should begin following the washout period
  • Prior radiotherapy for PC
  • Any history of prior malignancy, except:

    • Non-melanoma skin cancer treated with curative intent
    • Carcinoma-in-situ (CIS) treated with curative intent, without evidence of recurrence or disease progression for 3 years
    • All other cancer: treated with curative intent and without evidence of disease on standard of care follow-up for 5 years
  • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:

    • Subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement therapy, with a stable dose > 3 months, are eligible for the study
    • Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen, with a hemoglobin A1C < 7.0 are eligible for the study. All subjects with controlled type 2 diabetes mellitus are eligible for the study
    • Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded from the study) are eligible for the study provided all of the following conditions are met:

      • Rash covers < 10% of body surface area
      • Disease is well controlled at baseline and requires only low-potency topical steroids
      • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or any evidence of active, non-infectious pneumonitis requiring corticosteroids
  • History of prior positive human immunodeficiency virus (HIV) test
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (chronic or acute)

    • Subjects with a past or resolved HBV infection are eligible for this study
    • HCV positivity is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening; the HCV RNA test will only be performed for subjects who have a positive HCV antibody test
  • Active tuberculosis
  • Significant cardiovascular disease, such as New York Heart Association class III or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
  • Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2) or systemic steroid therapy > 10 mg prednisone (or equivalent) daily
  • Asthma requiring systemic corticosteroids > 10 mg prednisone (or equivalent) daily. Inhaled corticosteroids for the treatment of asthma are permitted
  • Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
  • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

    • Patients who receive prophylactic antibiotics for transrectal ultrasound guided prostate biopsy are eligible for the study as long as the last dose of antibiotics was taken >= 14 days prior to first dose of study treatment
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
  • Prior allogeneic stem cell or solid organ transplantation
  • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study or within 5 months after the last dose of atezolizumab
  • Treatment with investigational therapy within 28 days prior to initiation of study treatment
  • Prior treatment with cluster of differention 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), ant-PD-1, and anti-PD-L1 therapeutic antibodies
  • Treatment with systemic immunostimulatory agents [including, but not limited to, interferon and interleukin 2 (IL-2)] within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment
  • Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)- agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions:

    • Patients who receive acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study
    • Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma (=< 10 mg prednisone or equivalent), or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency (=< 10 mg prednisone or equivalent) are eligible for the study
  • History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
  • Known allergy or hypersensitivity to any component of the formulations of enzalutamide, and any other drug being combined with atezolizumab in this study
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lawrence Fong, MD 415-514-3160 Lawrence.Fong@ucsf.edu
Contact: Andy Chon 415-476-2351 Andrew.Chon@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03821246
Other Study ID Numbers  ICMJE 18702
NCI-2018-02805 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Lawrence Fong, University of California, San Francisco
Study Sponsor  ICMJE Lawrence Fong
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Principal Investigator: Lawrence Fong, MD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP