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.
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:
- progression within 12 months of completion or intolerance to prior taxane OR
- refusal of taxane OR
- contraindication to, or lack of fitness for taxane OR
- Investigator assessment that taxane is not clinically indicated or preferred.
- Maintenance of castration status, defined as serum testosterone level of less than 50
ng/dL. Patients must be surgically castrate or maintained on LHRH agonist or
antagonist therapy for the duration of the study period.
- Must have recovered from any treatment-related toxicities to ≤ CTCAE grade 1.
- Patients with ≤ CTCAE grade 2 anorexia, alopecia, neuropathy, and/or fatigue
however, are also permitted to enroll.
- Participants must have adequate organ and marrow function as defined below:
- leukocytes ≥3,000/mcL
- absolute neutrophil count ≥1,500/mcL
- hemoglobin ≥9 g/dL (without transfusion or growth factor in prior 28 days)
- platelets ≥100,000/mcL (without transfusion or growth factor in prior 28 days)
- total bilirubin ≤1.5 × institutional upper limit of normal, unless the subject
has known or suspected Gilbert's syndrome
- AST(SGOT)/ALT(SGPT) ≤1.5 × institutional upper limit of normal
- creatinine clearance ≥30 mL/min/1.73 m2
- Life expectancy of at least 6 months, as determined by a study Investigator.
- Ability to swallow oral medications.
- Ability to understand and willingness to sign an IRB-approved informed consent.
- Additional Inclusion Criteria (Arm C patients)
- Must have documentation (via CLIA approved, CAP certified next generation
sequencing [NGS] assay report) of genomic aberration resulting in CDK12 loss of
function in metastatic tumor tissue.
- Patients whose tumors have not previously undergone NGS are not eligible for
Arm C but are eligible for the randomized unselected cohorts.
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 6.
- Prior treatment with an inhibitor of PD-1, PD-L1, or PD-L2.
- 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.
- Live vaccine within 30 days of registration.
- Active smoking or a history of smoking greater than 20 pack-years (i.e. # packs of
cigarettes smoked per day × # of years patient has smoked > 20).
- Prior history of radiation therapy to thorax (including to lungs/pleura, esophagus,
intrathoracic lymph nodes, C7-L2 vertebrae, or ribs) for any reason and any
duration/dose.
- Any history of interstitial lung disease, pneumonitis or idiopathic pulmonary
fibrosis, regardless of remission or immunosuppression status.
- Any history of lung cancer, regardless of stage or treatment
- Any of the following abnormalities on pre-treatment pulmonary function testing:
- FEV1/FVC < lower limit of normal (LLN) and FEV1 < 75% predicted OR
- FVC < 70% of predicted, regardless of FEV1/FVC ratio OR
- DLCO (corrected for hemoglobin) < 70% of predicted
- Active bacterial or fungal infection, or known detectable viral infection (e.g., Human
Immunodeficiency Virus [HIV] or viral hepatitis).
- Arterial or venous thromboembolic event within the last 3 months.
- Significant infection, medical condition, or social situation which, in the opinion of
the investigator, would preclude participation or limit the patient's ability to
comply with study requirements.
