A Phase II Multi-Center Trial of Abemaciclib With or Without Atezolizumab in Metastatic Castration Resistant Prostate Cancer
Overview
- Phase
- Phase 2
- Intervention
- Abemaciclib
- Conditions
- Prostate Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 19
- Locations
- 1
- Primary Endpoint
- 6-month Progression Free Survival (PFS) Rate
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This trial is testing whether a molecularly targeted chemotherapy drug called abemaciclib and an immunotherapy drug called atezolizumab, alone or in combination, are effective in shrinking or preventing the growth of metastatic prostate cancer. The trial is also testing the safety of the combination of abemaciclib with atezolizumab.
Detailed Description
This is a multi-center, open label Phase II study of patients with metastatic castration resistant prostate cancer (mCRPC) who will be treated with abemaciclib and atezolizumab alone or in combination. The U.S. Food and Drug Administration (FDA) has not approved abemaciclib or atezolizumab alone or in combination for use in prostate cancer. Abemaciclib is an orally administered molecularly targeted chemotherapy drug called a cyclin-dependent kinase inhibitor, which acts to block the ability of cancer cells to divide and thus prevents tumors from growing. In the laboratory setting, this drug is effective in prostate cancer models that have become resistant to standard hormonal treatments, and this drug is currently being studied for its effectiveness in prostate cancer in other clinical trials. Atezolizumab is an intravenously administered drug called an immune checkpoint inhibitor, which acts to activate the immune system to kill cancer cells. Atezolizumab is ineffective on its own in most patients with prostate cancer, but is being tested in combination with other drugs for prostate cancer in other clinical trials. Multiple research groups have demonstrated in laboratory model systems that abemaciclib can may make immune checkpoint inhibitors more effective. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. The study design divides study participants into two separate cohorts. The first cohort is a set of subjects whose tumors are not known to have mutations in the CDK12 gene (the "biomarker unselected cohort") - either because tumor tissue never underwent genetic profiling, or because genetic profiling was performed but did not demonstrate a mutation in the CDK12 gene. In this "biomarker unselected cohort," this study will be testing whether abemaciclib alone or in combination with atezolizumab is an effective treatment strategy. The second cohort of participants is a set of subjects whose tumors are known to have mutations in the CDK12 gene based on genetic profiling of the tumor that occurred prior to enrollment on this study. Prior studies suggest that cancers with mutations in the CDK12 gene can shrink in response to immune checkpoint inhibitors. This study will be testing in study participants whose tumors are known to have mutations in CDK12 whether atezolizumab alone or in combination with abemaciclib is an effective treatment strategy. In addition, the trial is testing the safety of the combination of the two drugs in both cohorts. Participants will receive study treatment for as long as they do not have serious side effects and their disease does not get worse. Participants will be followed after completion of study treatment for up to 24 months It is expected that about 75 people will take part in this research study. Eli Lilly and Company is supporting this research study by providing funding for research and the study drug abemaciclib. Genentech, Inc. is supporting the study by providing the study drug atezolizumab.
Investigators
Atish Choudhury, MD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of metastatic castration resistant prostate cancer (mCRPC), with histologic confirmation of adenocarcinoma of the prostate (without evidence of small cell carcinoma), with progressive disease at the time of study entry by either
- •Sequence of at least 2 rising PSA values at a minimum of 1-week intervals
- •Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG3 for bone, with or without PSA progression
- •Adult males 18 years of age or older.
- •ECOG performance status of 0 or 1
- •Patients must have metastatic disease by bone scintigraphy or other nodal or visceral lesions on CT or MRI with a bone or soft tissue lesion amenable to image-guided percutaneous biopsy, and the patient must be evaluable for disease response by either
- •Baseline PSA ≥ 2.0 ng/mL OR
- •Measurable disease per RECIST 1.1
- •Past progression or intolerance to at least one novel antiandrogen therapy (abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel, seviteronel or equivalent) in either the hormone-sensitive or castration-resistant disease setting.
- •Not a candidate for docetaxel or cabazitaxel chemotherapy due to:
Exclusion Criteria
- •Clinical evidence of, or known and untreated metastatic CNS disease.
- •Concurrent active malignancy.
- •Patients with non-melanomatous skin cancer, cancer not needing active therapy for at least 2 years, cancer for which the treating investigator deems the subject to be in remission, or any prior malignancy that was treated with curative intent (no evidence of disease for at least 3 years) are also permitted to enroll.
- •Patients who have had chemotherapy or radiotherapy within 4 weeks prior to planned cycle 1 day 1 of study treatment.
- •Patients who have received oral anti-neoplastic intervention such as an oral hormonal agent, PARP inhibitor, AR targeted therapy, or oral experimental agent within 14 days prior to planned cycle 1 day 1 of study treatment.
- •Prior treatment with an inhibitor of CDK4 and/or
- •Prior treatment with an inhibitor of PD-1, PD-L1, or PD-L
- •Patients on concurrent therapy with a moderate or strong CYP3A4 inducer or inhibitor which cannot be safely stopped at least five half-lives prior to initiation of therapy with abemaciclib.
- •Evidence of an active autoimmune disease that has required systemic treatment within the last 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- •Patients with conditions requiring replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) are permitted to enroll.
Arms & Interventions
Biomarker-Unselected Abemaciclib Monotherapy (Randomized)
Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Monotherapy : Participants will receive Abemaciclib orally 2x daily
Intervention: Abemaciclib
Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized)
Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Combination Therapy: Participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle
Intervention: Abemaciclib
Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized)
Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Combination Therapy: Participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle
Intervention: Atezolizumab
CDK12 Mutation Atezolizumab Monotherapy (Non-Randomized)
Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Atezolizumab monotherapy will be given to participants 1-5, these participants will receive Atezolizumab intravenously Day 1 of each 21-Day cycle
Intervention: Atezolizumab
CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized)
Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Combination Therapy will be given to participants 6-21, these participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle
Intervention: Abemaciclib
CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized)
Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Combination Therapy will be given to participants 6-21, these participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle
Intervention: Atezolizumab
Outcomes
Primary Outcomes
6-month Progression Free Survival (PFS) Rate
Time Frame: 6 months
The percentage of participants alive and progression-free at 6 months, as assessed by RECIST 1.1 and PCWG3.
Objective Response Rate (ORR)
Time Frame: 6 months
The percentage of evaluable patients who had radiographic response (complete response or partial response) by RECIST 1.1 criteria OR 50% decline in PSA from pretreatment baseline per PCWG3 criteria.
Number of Participants Experiencing Dose Limiting Toxicity (DLT) in Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized) and CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized) Arms
Time Frame: DLTs were collected while participants on treatment. Treatment duration up to 18 months.
DLT was assessed by Bayesian Continuous Toxicity Monitoring in Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized) and CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized) arms.
Secondary Outcomes
- Clinical Benefit Rate (CBR)(From treatment initiation to end of treatment, with follow-up for up to 2 years after treatment discontinuation)
- Duration of Response (DOR)(From the date of first documented CR or PR until disease progression or death, or up to 2 years)
- Duration of Therapy (DOT)(From treatment initiation until treatment discontinuation for any reason)
- Time to Progression (TTP)(From treatment initiation until documented disease progression, or assessed up to 2 years)
- 12-month Overall Survival (OS)(12 months)
- Number of Participants With Maximum Grade Adverse Events by CTCAE v5.0(From treatment initiation through 100 days after last dose for treatment-emergent adverse events, and up to 2 years after last dose)