Immunotherapy in Patients With Metastatic Cancers and CDK12 Mutations

Phase 2

Completed

Conditions: Metastatic Cancer
Solid Tumor
Metastatic Castration Resistant Prostate Cancer

Interventions: Drug: Nivolumab
Drug: Ipilimumab

Registration Number: NCT03570619

Lead Sponsor: University of Michigan Rogel Cancer Center

Brief Summary: This study will attempt to determine the efficacy of checkpoint inhibitor immunotherapy with nivolumab and ipilimumab combination therapy followed by nivolumab monotherapy in patients with metastatic prostate cancer and other tumor solid tumor histologies harboring loss of CDK12 function as well as monotherapy nivolumab treatment in patient with metastatic prostate cancer harboring loss of CDK12 function.

Detailed Description: This study investigates the efficacy of checkpoint inhibitor immunotherapy in patients with metastatic cancer with CDK12 mutations. The study includes three cohorts: Cohort A consists of metastatic prostate cancer patients being treated with combination nivolumab and ipilimumab treatment followed by monotherapy nivolumab treatment. Cohort B consists of other solid tumor patients being treated with combination nivolumab and ipilimumab treatment followed by monotherapy nivolumab treatment. As of an amendment approved 03FEB2021 a third cohort was added, Cohort C, which consists of metastatic prostate cancer patients being treated with monotherapy nivolumab treatment.

As of an amendment approved 21JUN2020 the maximum duration of treatment, as well as the anticipated timing for some of the studies outcome measures, were updated from 52 weeks to 104 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

Inclusion Criteria

Be ≥18 years of age as of date of signing informed consent.
Be willing and able to provide written informed consent for the study.
ECOG Performance Status of 0, 1 or 2 (Eastern Cooperative Oncology Group scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 5 where 0 represents perfect health and 5 represents death.
Subjects must have a histologic or cytologic diagnosis of metastatic adenocarcinoma of the prostate without small cell histology OR another type of metastatic carcinoma.
All subjects, regardless of cancer type, must have a documented CDK12 aberration in tumor tissue.
Subjects with prostate cancer must have documented prostate cancer progression within six months prior to screening with PSA progression defined as a minimum of three rising PSA levels ≥ 1; 1 week between each assessment with a baseline PSA value at screening of ≥ 2 ng/mL.
Subjects with prostate cancer must have ongoing androgen deprivation with total serum testosterone < 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 nmol/L)). If the subject is currently being treated with LHRH agonists (subjects who have not undergone an orchiectomy), this therapy must have been initiated at least 4 weeks prior to registration. This treatment must be continued throughout the study.
Subjects with non-prostate histologies must have RECIST 1.1-measurable cancer on computed tomography (CT) or magnetic resonance imaging (MRI) scans.
Subjects must have recovered to baseline or ≤ grade 1 toxicities related to any prior treatments unless AE(s) are clinically non-significant and/or stable.
Patients must be ≥ 2 weeks from most recent systemic therapy or most recent radiation therapy.
Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to registration.
Female and male subjects of reproductive potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 5 months (for women) and 7 months (for men) after the last dose of study therapy.
Adequate organ and marrow function

Exclusion Criteria

Prior treatment with anti-PD-1/PD-L1 and anti-CTLA-4 is NOT allowed. Prior intravesical BCG therapy is allowed.
Treatment with any investigational agent or on an interventional clinical trial within 28 days prior to registration.
Prior or concurrent malignancy except for: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localized or locally advanced prostate cancer definitively treated without recurrence or with biochemical recurrence only, or any other cancer fully treated or from which the subject has been disease-free for at least 2 years.
Autoimmune diseases such as rheumatoid arthritis. Vitiligo, mild psoriasis (topical therapy only) or hypothyroidism are allowed.
Need for systemic corticosteroids >10mg prednisone daily or equivalent alternative steroid (except physiologic dose for adrenal replacement therapy) or other immunosuppressive agents (such as cyclosporine or methotrexate) Topical and inhaled corticosteroids are allowed if medically needed.
Any history of organ allografts
Any history of HIV, hepatitis B or hepatitis C infection

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Solid Tumors (non-prostate)	Nivolumab	Patients with all other metastatic subtypes will be enrolled in cohort B
Metastatic CRPC	Nivolumab	Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort A.
Metastatic CRPC	Ipilimumab	Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort A.
Solid Tumors (non-prostate)	Ipilimumab	Patients with all other metastatic subtypes will be enrolled in cohort B
Metastatic CRPC with Monotherapy	Nivolumab	Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort C once enrollment to cohort A has been completed.

Primary Outcome Measures

Name	Time	Method
The Proportion of Patients With CDK12 Loss of Function Metastatic CRPC That Respond to Treatment.	Up to 24 months post treatment	The primary objective is overall response rate (ORR) of patients with metastatic CRPC. Response will be defined as a 50% decline in PSA (prostate specific antigen) from baseline as determined by PCWG3 criteria.

Secondary Outcome Measures

Name	Time	Method
Radiographic Progression Free Survival Time (rPFS)	Up to 104 weeks after start of therapy	Radiographic progression-free survival (rPFS) is defined as the duration of time from start of treatment to time of radiographic progression. Progression is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.
The Proportion of Patients That Respond to Treatment in Cohort B.	Up to 104 weeks after start of therapy	Overall response will be defined as patients that achieve either a partial response or complete response using RECIST 1.1 criteria. Complete response (CR) is defined as disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.
Progression Free Survival Time (PFS)	Up to 24 months post treatment	Progression is defined as the duration of time from start of treatment to time of progression. Progression is defined as: Either, Radiographic progression: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions OR, PSA Progression: For rising PSA after an initial decline from baseline, the PSA is recorded from the start of therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is confirmed by a second value 4 or more weeks later, confirming a rising trend. If there is no initial decline from baseline, PSA progression is defined as ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks.
Duration of Therapy (DOT)	Up to 104 weeks after start of therapy	Defined by the time interval from the start of treatment to the day of permanent discontinuation of treatment (including death).
Progression Rate at 6 Months	6 months	Progression is defined as: Either, Radiographic progression: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions OR, PSA Progression: For rising PSA after an initial decline from baseline, the PSA is recorded from the start of therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is confirmed by a second value 4 or more weeks later, confirming a rising trend. If there is no initial decline from baseline, PSA progression is defined as ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks.
Overall Survival Time	Up to 24 months post treatment	Defined as the time from the start of treatment until death from any cause. Patients alive or lost to follow-up at the time of analysis will be censored at their last date of follow-up.
PSA Progression Free Survival Time	Up to 24 months post treatment	PSA Progression: For rising PSA after an initial decline from baseline, the PSA is recorded from the start of therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is confirmed by a second value 4 or more weeks later, confirming a rising trend. If there is no initial decline from baseline, PSA progression is defined as ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks.
Time to PSA Progression	Up to 24 months post treatment	PSA Progression: For rising PSA after an initial decline from baseline, the PSA is recorded from the start of therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is confirmed by a second value 4 or more weeks later, confirming a rising trend. If there is no initial decline from baseline, PSA progression is defined as ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks.

Trial Locations

Locations (8): Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore, Maryland, United States
Siteman Cancer Center at Washington University
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Saint Louis, Missouri, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
University of California San Diego, Moores Cancer Center
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San Diego, California, United States
University of California San Francisco/Helen Diller Family Comprehensive Cancer Center
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San Francisco, California, United States
Karmanos Cancer Institute
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Detroit, Michigan, United States
H. Lee. Moffitt Cancer Center & Research Institute, Inc.
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Tampa, Florida, United States
University of Michigan Rogel Cancer Center
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Ann Arbor, Michigan, United States