Safety and Tolerability of Atezolizumab (ATZ) in Combination With Radium-223 Dichloride (R-223-D) in Metastatic Castrate-Resistant Prostate Cancer (CRPC) Progressed Following Treatment With an Androgen Pathway Inhibitor

Roche

Status and phase: Completed; Phase 1

Conditions: Castrate-Resistant Prostate Cancer

Treatments: Drug: Atezolizumab; Drug: Radium-223 Dichloride

Study type: Interventional

Funder types: Industry

Identifiers

NCT02814669

2015-003606-17 (EudraCT Number)

BO30013

Details and patient eligibility

About

This study is designed to assess the safety and tolerability of atezolizumab when given in combination with radium-223 dichloride in participants with metastatic CRPC who have progressed after treatment with an androgen pathway inhibitor. This adaptive design study includes a cohort phase and a potential randomization phase. An initial concurrent dosing evaluation will evaluate the safety and tolerability of a treatment regimen that employs a concurrent start time for atezolizumab and radium-223 dichloride (Cohort 1). If concurrent dosing is found to be safe and tolerable in Cohort 1, additional participants will be enrolled and eligible participants will be randomized in a 1:1:1 ratio to Arms A, B, and C. If concurrent dosing is not tolerated in Cohort 1, new participants will be enrolled in a staggered dosing evaluation: Cohort 2 (28-day radium-223 dichloride run-in, atezolizumab will begin on Day 1 of Cycle 2) and Cohort 3 (56-day radium-223 dichloride run-in, atezolizumab will begin on Day 1 of Cycle 3). If the Cohort 2 schedule is tolerable, then additional participants will be enrolled using this treatment schedule; If the Cohort 2 schedule is not tolerable, subsequent participants will be enrolled in Cohort 3. If the Cohort 3 schedule is tolerable, then additional participants will be enrolled using this treatment schedule. If Cohort 3 schedule is not tolerable, no additional participant will be enrolled in the study.

Enrollment: 45 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy greater than or equal to (>/=) 12 weeks
• Histologically confirmed, castrate-resistant adenocarcinoma of the prostate
• Measurable disease according to RECIST v1.1
• Multiple bone metastases within 12 weeks prior to study drug
• Participants receiving bisphosphonate or denosumab therapy must have been on a stable dose for at least 4 weeks
• Visceral metastasis and/or lymphadenopathy
• Tumors that are amenable to serial biopsy
• Disease progression according to Prostate Cancer Working Group 2 (PCWG2) criteria during or following treatment with at least one second generation androgen pathway inhibitor (for example, enzalutamide, abiraterone) for metastatic prostate cancer
• Adequate hematologic and end-organ function
• One prior taxane-containing regimen for mCRPC, or refusal or ineligibility of a taxane-containing regimen

Exclusion criteria

• History of small-cell or neuroendocrine prostate carcinoma
• Treatment with approved anti-cancer therapy (with the exception of abiraterone) within 3 weeks of study drug. Abiraterone must not be administered within 2 weeks prior to initiation of study treatment
• Participation in another clinical trial/investigation within 28 days prior to study drug
• Brain metastases or active leptomeningeal disease (with the exception of participants with treated epidural disease and no other epidural progression)
• Uncontrolled tumor-related pain
• Uncontrolled hypercalcemia
• Significant cardiovascular disease
• History of autoimmune disease except controlled/treated hypothyroidism, type 1 diabetes mellitus, or certain skin disorders
• Prior allogeneic stem cell or solid organ transplant
• History of pulmonary fibrosis/inflammation, including active tuberculosis
• Human immunodeficiency virus (HIV) or hepatitis B or C
• Prior treatment with cluster of differentiation (CD) 137 agonist, anti-programmed death (PD) 1, or anti-programmed death ligand (PD-L) 1 therapeutic antibody or pathway-targeting agents
• Immunostimulants within 4 weeks or immunosuppressants within 14 days prior to study drug
• Prior radium-223 dichloride or hemibody external radiotherapy
• Systemic strontium-89, samarium-153, rhenium-186, or rhenium-188 for bone metastases within 24 weeks prior to initiation of study treatment
• Spinal compression or structurally unstable bone lesions suggesting impending pathologic fractures based on clinical findings and/or magnetic resonance imaging (MRI)
• Bone marrow dysplasia
• Unmanageable fecal incontinence

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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45 participants in 6 patient groups

Cohort 1: ATZ + R-223-D (Concurrent)

Experimental group

Description:

Participants will receive concurrent radium-223 dichloride and atezolizumab for a single-cycle, 28-day dose limiting toxicity (DLT) assessment. If the combination is initially found to be safe and tolerable, additional participants will be randomized to Arms A, B, and C.

Treatment:

Drug: Radium-223 Dichloride

Drug: Atezolizumab

RT Arm A: ATZ + R-223-D (Concurrent)

Experimental group

Description:

If Cohort 1 regimen is found to be safe, additional participants will be randomized to this arm (randomized treatment \[RT\]) to receive concurrent radium-223 dichloride and atezolizumab.

Treatment:

Drug: Radium-223 Dichloride

Drug: Atezolizumab

RT Arm B: ATZ + R-223-D (Staggered, 28-Day R-223-D Run-In)

Experimental group

Description:

If Cohort 1 regimen is found to be safe, additional participants will be randomized to this arm to receive radium-223 dichloride in Cycle 1 and radium-223 dichloride and atezolizumab from Cycle 2 onward.

Treatment:

Drug: Radium-223 Dichloride

Drug: Atezolizumab

RT Arm C: ATZ + R-223-D (Staggered, 28-Day ATZ Run-In)

Experimental group

Description:

If Cohort 1 regimen is found to be safe, additional participants will be randomized to this arm to receive atezolizumab in Cycle 1 and radium-223 dichloride and atezolizumab from Cycle 2 onward.

Treatment:

Drug: Radium-223 Dichloride

Drug: Atezolizumab

Cohort 2: ATZ + R-223-D (Staggered, 28-Day R-223-D Run-In)

Experimental group

Description:

If Cohort 1 regimen is not tolerable, Arms A, B, and C will not be introduced and additional participants will be enrolled in this cohort to receive radium-223 dichloride in Cycle 1 and radium-223 dichloride and atezolizumab in Cycle 2. If the regimen is found to be safe, additional participants will be enrolled to receive this same treatment (radium-223 dichloride in Cycle 1 and radium-223 dichloride and atezolizumab from Cycle 2 onward). If, at Cycle 2, Cohort 2 regiment is not tolerable, additional participants will be enrolled in Cohort 3.

Treatment:

Drug: Radium-223 Dichloride

Drug: Atezolizumab

Cohort 3: ATZ + R-223-D (Staggered, 56-Day R-223-D Run-In)

Experimental group

Description:

If Cohort 2 regimen is not tolerable, additional participants will be enrolled in this cohort to receive radium-223 dichloride in Cycles 1, 2 and radium-223 dichloride and atezolizumab in Cycle 3. If the regimen is found to be safe, additional participants will be enrolled to receive this same treatment (radium-223 dichloride in Cycles 1, 2 and radium-223 dichloride and atezolizumab from Cycle 3 onward). If, at Cycle 3, Cohort 3 regiment is not tolerable, no additional participants will be enrolled in this study.

Treatment:

Drug: Radium-223 Dichloride

Drug: Atezolizumab