An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy

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33
participants needed

68
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Lawrence Fong

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Updated on 27 October 2022

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prostatectomy

cancer

androgens

testosterone

neutrophil count

tumor cells

testosterone level

Summary

This phase II trial studies how well atezolizumab works alone or in combination with etrumadenant or 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 etrumadenant or tocilizumab may work better in treating prostate cancer.

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 etrumadenant (AB928) prior to RP; atezolizumab will be administered in an identical fashion as Cohort A. Etrumadenant will be administered at a dose of 150 mg once daily, until 48 hours prior to RP.

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

Details

Condition	Prostate Adenocarcinoma, Prostate Cancer, Localized Prostate Cancer
Treatment	Tocilizumab, Enzalutamide, Atezolizumab, Emactuzumab, Etrumadenant
Clinical Study Identifier	NCT03821246
Sponsor	Lawrence Fong
Last Modified on	27 October 2022

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Eligibility		Yes	No	Not Sure
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 PI has determined
	that it is safe to do so
	Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
	Availability of a representative tumor specimen that is suitable for the planned study analyses, as determined by the Principal Investigator
	Hemoglobin >= 9 g/dL
	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. Refer to Section 6.3 for additional information on tumor specimens collected at screening
	Absolute lymphocyte count >= 500/uL
	\- Participants must not have been transfused within 2 weeks prior to screening to meet this criterion
	Subjects have not received any prior systemic or locally directed therapy for PC (see
	Platelets >= 100,000/uL without transfusion
	Absolute neutrophil count >= 1,500/microliter (uL) without granulocyte colonystimulating factor support
	exclusion criteria)
	Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (known Gilbert disease: < 3 x ULN)
	Age >= 18 years
	Alkaline phosphatase < 2 x institutional ULN
	Requirements for organ and marrow function
	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
	Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) =< 2 x institutional ULN
	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
	Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 2 x institutional ULN
	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
	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
	For patients receiving therapeutic anticoagulation: stable anticoagulant regimen > 3
	months
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]
	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
	Not a candidate for radical prostatectomy as determined by treating urologic oncology
	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
	surgeon
	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
	Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen, with a Glycated hemoglobin (hemoglobin A1C) < 7.0 are eligible for the study. All subjects with controlled type 2 diabetes mellitus are eligible for the study
	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 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
	Active or history of autoimmune disease or immune deficiency, including, but not
	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
	limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
	erythematosus, rheumatoid arthritis, inflammatory bowel disease
	Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2) or systemic steroid therapy > 10 mg prednisone (or equivalent) daily
	antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's
	Asthma requiring systemic corticosteroids > 10 mg prednisone (or equivalent) daily. Inhaled corticosteroids for the treatment of asthma are permitted
	syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following
	exceptions
	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
	Major surgical procedure (including joint surgery) 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
	Prior allogeneic stem cell or solid organ transplantation
	Treatment with investigational therapy within 28 days prior to initiation of study treatment
	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
	History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
	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
	obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or any
	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
	Prior treatment with adenosine-axis inhibitors, 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
	evidence of active, non-infectious pneumonitis requiring corticosteroids
	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
	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
	Significant cardiovascular disease, such as New York Heart Association class III or
	Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline
	greater cardiac disease, myocardial infarction, or cerebrovascular accident
	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)
	within 3 months prior to initiation of study treatment, unstable arrhythmia
	Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation
	Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-cluster of differentiation 4 (CD4), anti-cluster of differentiation 5 (CD5), anti-cluster of differentiation 3 (CD3), anti-Cluster of Differentiation 19 (CD19) and anti-Cluster of Differentiation 20 (CD20)
	or unstable angina
	History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
	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
	Placement of central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted
	Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial
	Severe infection within 4 weeks prior to initiation of study treatment, including, but
	Pregnant women or nursing (breast feeding) mothers
	not limited to, hospitalization for complications of infection, bacteremia, or
	Patients with lack of peripheral venous access
	severe pneumonia
	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. Note: Because IL-6 inhibition may interfere with the normal immune response to new antigen, patients should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of therapy with tocilizumab to maximize vaccine response
	Treatment with known P-glycoprotein (P-gp) substrates with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
	Treatment with known breast cancer resistance protein (BCRP) substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
	History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
	or fusion proteins
	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)
	Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation
	Additional Exclusion Criteria for Cohort B (atezolizumab + etrumadenant)
	Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (eg,clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin,and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
	Additional Exclusion Criteria for Cohort C (atezolizumab + tocilizumab)
	Known active infection or history of recurrent bacterial, viral, fungal, mycobacterial or other infections, including, but not limited to, 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

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An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy