Metastatic Cancer, Metastatic Castration Resistant Prostate Cancer, Solid Tumor
Conditions
Keywords
Metastatic Cancer, Metastatic Castration Resistant Prostate Cancer, mCRPC, Immunotherapy, CDK12, Solid Tumor
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.
Interventions
DRUGNivolumab
Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy. Patients in arm Metastatic CRPC will receive therapy with monotherapy nivolumab therapy at flat dose 480 mg IV every 4 weeks for up to 104 weeks of total therapy.
DRUGIpilimumab
Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy.
Sponsors
Memorial Sloan Kettering Cancer Center
University of California, San Francisco
University of Michigan Rogel Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metastatic CRPC Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort A.
Nivolumab: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy.
Patients in arm Metastatic CRPC will receive therapy with monotherapy nivolumab therapy at flat dose 480 mg IV every 4 weeks for up to 104 weeks of total therapy.
Ipilimumab: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy. | 33 |
| Solid Tumors (Non-prostate) Patients with all other metastatic subtypes will be enrolled in cohort B
Nivolumab: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy.
Patients in arm Metastatic CRPC will receive therapy with monotherapy nivolumab therapy at flat dose 480 mg IV every 4 weeks for up to 104 weeks of total therapy.
Ipilimumab: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy. | 8 |
| Metastatic CRPC With Monotherapy Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort C once enrollment to cohort A has been completed.
Nivolumab: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy.
Patients in arm Metastatic CRPC will receive therapy with monotherapy nivolumab therapy at flat dose 480 mg IV every 4 weeks for up to 104 weeks of total therapy. | 15 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 |
| Overall Study | new diagnosis of new malignancy | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Metastatic CRPC | Solid Tumors (Non-prostate) | Metastatic CRPC With Monotherapy | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 2 Participants | 8 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 6 Participants | 7 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 8 Participants | 15 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 0 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 25 Participants | 8 Participants | 12 Participants | 45 Participants |
| Region of Enrollment United States | 33 participants | 8 participants | 15 participants | 56 participants |
| Sex: Female, Male Female | 0 Participants | 8 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 33 Participants | 0 Participants | 15 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 21 / 33 | 3 / 8 | 6 / 15 |
| other Total, other adverse events | 32 / 33 | 7 / 8 | 14 / 15 |
| serious Total, serious adverse events | 16 / 33 | 6 / 8 | 4 / 15 |
Outcome results
Primary
The Proportion of Patients With CDK12 Loss of Function Metastatic CRPC That Respond to 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.
Time frame: Up to 24 months post treatment
Population: only subjects who received at least 1 cycle(s) of therapy, and who have 2 PSA measurements after protocol therapy initiation were considered evaluable for PSA response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metastatic CRPC | The Proportion of Patients With CDK12 Loss of Function Metastatic CRPC That Respond to Treatment. | 2 participants |
| Metastatic CRPC With Monotherapy | The Proportion of Patients With CDK12 Loss of Function Metastatic CRPC That Respond to Treatment. | 0 participants |
Secondary
Duration of Therapy (DOT)
Defined by the time interval from the start of treatment to the day of permanent discontinuation of treatment (including death).
Time frame: Up to 104 weeks after start of therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic CRPC | Duration of Therapy (DOT) | 12 weeks |
| Solid Tumors (Non-prostate) | Duration of Therapy (DOT) | 8.07 weeks |
| Metastatic CRPC With Monotherapy | Duration of Therapy (DOT) | 15.86 weeks |
Secondary
Overall Survival Time
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.
Time frame: Up to 24 months post treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic CRPC | Overall Survival Time | 273 days |
| Solid Tumors (Non-prostate) | Overall Survival Time | NA days |
| Metastatic CRPC With Monotherapy | Overall Survival Time | 421 days |
Secondary
Progression Free Survival Time (PFS)
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.
Time frame: Up to 24 months post treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic CRPC | Progression Free Survival Time (PFS) | 213 days |
| Solid Tumors (Non-prostate) | Progression Free Survival Time (PFS) | NA days |
| Metastatic CRPC With Monotherapy | Progression Free Survival Time (PFS) | 138 days |
Secondary
Progression Rate at 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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metastatic CRPC | Progression Rate at 6 Months | 74 percentage of Participants |
| Solid Tumors (Non-prostate) | Progression Rate at 6 Months | 67 percentage of Participants |
| Metastatic CRPC With Monotherapy | Progression Rate at 6 Months | 71 percentage of Participants |
Secondary
PSA Progression Free Survival Time
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 frame: Up to 24 months post treatment
Population: Only evaluable prostate cancer patients were analyzed as PSA is only collected for prostate cancer participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic CRPC | PSA Progression Free Survival Time | 213 days |
| Metastatic CRPC With Monotherapy | PSA Progression Free Survival Time | 138 days |
Secondary
Radiographic Progression Free Survival Time (rPFS)
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.
Time frame: Up to 104 weeks after start of therapy
Population: numbers updated to include only evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic CRPC | Radiographic Progression Free Survival Time (rPFS) | 166 days |
| Solid Tumors (Non-prostate) | Radiographic Progression Free Survival Time (rPFS) | NA days |
| Metastatic CRPC With Monotherapy | Radiographic Progression Free Survival Time (rPFS) | 110 days |
Secondary
The Proportion of Patients That Respond to Treatment in Cohort B.
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.
Time frame: Up to 104 weeks after start of therapy
Population: Only Cohort B analyzed and only 3 patients were evaluable per RECIST
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metastatic CRPC | The Proportion of Patients That Respond to Treatment in Cohort B. | 0 Participants |
| Solid Tumors (Non-prostate) | The Proportion of Patients That Respond to Treatment in Cohort B. | 1 Participants |
| Metastatic CRPC With Monotherapy | The Proportion of Patients That Respond to Treatment in Cohort B. | 0 Participants |
Secondary
Time to PSA Progression
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 frame: Up to 24 months post treatment
Population: Only evaluable prostate cancer patients were analyzed as PSA is only collected for prostate cancer participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic CRPC | Time to PSA Progression | NA days |
| Metastatic CRPC With Monotherapy | Time to PSA Progression | NA days |