Clinical Trials /

Atezolizumab With or Without Tocilizumab in Treating Men With Prostate Cancer Before Radical Prostatectomy

NCT03821246

Description:

This phase II trial studies how well atezolizumab works alone or in combination with tocilizumab 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. IL-6 is expressed by prostate cancer and within the tumor microenvironment and shown to enhance prostate cancer and disease progression. Treatment with an anti-IL-6 antibody such as tocilizumab may inhibit cancer progression. Giving atezolizumab in combination with tocilizumab may work better in treating prostate cancer.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab With or Without Tocilizumab in Treating Men With Prostate Cancer Before Radical Prostatectomy
  • Official Title: An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy

Clinical Trial IDs

  • ORG STUDY ID: 18702
  • SECONDARY ID: NCI-2018-02805
  • NCT ID: NCT03821246

Conditions

  • Prostate Adenocarcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqCohort A (atezolizumab)
TocilizumabActemraCohort B (atezolizumab, tocilizumab)

Purpose

This phase II trial studies how well atezolizumab works alone or in combination with tocilizumab 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. IL-6 is expressed by prostate cancer and within the tumor microenvironment and shown to enhance prostate cancer and disease progression. Treatment with an anti-IL-6 antibody such as tocilizumab may inhibit cancer progression. Giving atezolizumab in combination with tocilizumab 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 one cycle of atezolizumab intravenously (IV) over 30-60 minutes on
      day 1 of a 14 day cycle prior to radical prostatectomy (RP).

      COHORT B: Patients will receive 1 cycle of neoadjuvant atezolizumab and tocilizumab prior to
      RP; atezolizumab will be administered in an identical fashion as Cohort A. Tocilizumab will
      be administered at a dose of 6 mg/kg.

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

      RP will occur 21 days (+/- 7 days) following treatments on Cycle 1 Day 1. No further study
      therapy will be administered following RP

      Following RP, subjects will be followed at 6 weeks, 3 months, 6 months, and 12 months (from
      date of RP), or until disease progression, whichever occurs sooner
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A (atezolizumab)ExperimentalPatients receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
  • Atezolizumab
Cohort B (atezolizumab, tocilizumab)ExperimentalSubjects will receive one (1) cycle of neoadjuvant atezolizumab and one (1) cycle of tocilizumab, 6mg/kg will be administered IV on day 1 of a 14 day IV prior to RP; atezolizumab will be administered in an identical fashion as Cohort A. RP will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
  • Atezolizumab
  • Tocilizumab

Eligibility Criteria

        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
             x institutional ULN

          -  Alanine aminotransferase (ALT) [serum glutamate pyruvate transaminase (SGPT)] =< 2 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)

          -  Serum creatinine <=1.6 mg/dL (141 μmol/L) in female patients and ≤1.9 mg/dL (168
             μmol/L) in male patients . Patients with serum creatinine values exceeding limits may
             be eligible for the study if their estimated glomerular filtration rates (GFR) are >30

          -  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

               -  Appropriately treated Stage I uterine cancer

               -  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

          -  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

          -  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 differentiation 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 of the study drugs of their excipients

          -  Previous treatment with any cell-depleting therapies, including investigational agents
             or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3,
             anti-CD19 and anti-CD20.

          -  Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6
             months of baseline.

          -  Previous treatment with tocilizumab (an exception to this criterion may be granted for
             single dose exposure upon application to the Sponsor-Investigator on a case-by-case
             basis).

          -  Any previous treatment with alkylating agents such as chlorambucil, or with total
             lymphoid irradiation.

          -  History of severe allergic or anaphylactic reactions to human, humanized or murine
             monoclonal antibodies.

          -  Evidence of serious uncontrolled concomitant, nervous system, pulmonary, renal,
             hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal
             disease (including complicated diverticulitis, ulcerative colitis, or Crohn's
             disease.)

          -  Any history of recent serious bacterial, viral, fungal, or other opportunistic
             infections.

          -  Primary or secondary immunodeficiency (history of or currently active) unless related
             to primary disease under investigation.

          -  Any medical or psychological condition that in the opinion of the principal
             investigator would interfere with safe completion of the trial.

          -  Pregnant women or nursing (breast feeding) mothers.

          -  Patients with lack of peripheral venous access

          -  Known active infection or history of recurrent bacterial, viral, fungal, mycobacterial
             or other infections, including, but not limited to, Tuberculosis (TB) (i.e., has signs
             and symptoms of TB) and atypical mycobacterial disease, hepatitis B and C, and herpes
             zoster, but excluding fungal infections of nail beds
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of subjects who demonstrate a positive response to neoadjuvant atezolizumab and atezolizumab-based combination therapy for each Cohort of the study
Time Frame:Up to 12 months
Safety Issue:
Description:A positive response is defined as a ≥40% increase in the number of infiltrating CD3+ T cells between the pre-treatment biopsy at baseline and the post-treatment RP specimen. Thus, a negative response is a <40% increase. The primary endpoint will include all enrolled subjects who receive at least 1 dose of study treatment and undergo RP. Analysis of the primary endpoint will be performed for each cohort independently

Secondary Outcome Measures

Measure:Number of treatment-related of adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:The number of treatment-related adverse events will be reported and classified per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Measure:Sum of Pathologic complete response (pCR) and Minimal residual disease (MRD) rate
Time Frame:Up to 12 months
Safety Issue:
Description: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+ MRD) rate] and independently.
Measure:Rate of Pathologic complete response (pCR) rate
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Rate of Minimal residual disease (MRD)
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Prostate specific antigen (PSA) response
Time Frame:Up to 12 months
Safety Issue:
Description:Defined as >= 50% decline in PSA. The PSA response proportion will be reported for each cohort.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Lawrence Fong

Last Updated

June 5, 2020