Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Prostatic Neoplasms

Neoplasm Metastasis

Neoplasms, Second Primary

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Neoplastic Processes

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Immunomodulating Agents

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort A.

Patients with all other metastatic subtypes will be enrolled in cohort B

Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort C once enrollment to cohort A has been completed.

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.

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.

Ajjai Alva, MD

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.

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.

Immunotherapy in Patients With Metastatic Cancers and CDK12 Mutations

IMPACT: Immunotherapy in Patients With Metastatic Cancers and CDK12 Mutations

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.

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.

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 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.

Defined by the time interval from the start of treatment to the day of permanent discontinuation of treatment (including death).

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: 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.

Memorial Sloan Kettering Cancer Center

University of California, San Francisco

University of Michigan Rogel Cancer Center

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.

Metastatic CRPC

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.

Solid Tumors (Non-prostate)

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.

Metastatic CRPC With Monotherapy

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

University of Michigan Cancer Center Admin

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.

The Proportion of Patients With CDK12 Loss of Function Metastatic CRPC That Respond to Treatment.

The Proportion of Patients That Respond to Treatment in Cohort B.

Radiographic Progression Free Survival Time (rPFS)

Progression Free Survival Time (PFS)

Duration of Therapy (DOT)

Time to Progression (TTP)

Overall Survival Time

PSA Progression Free Survival Time

Time to PSA Progression

Overall Study

Behaviors and Mental Disorders

Aggression

Docetaxel

Carboplatin

Olaparib

Tubulin Modulators

Antimitotic Agents

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Vudalimab IV, carboplatin IV, cabazitaxel IV

vudalimab + carboplatin + cabazitaxel

vudalimab + olaparib

vudalimab monotherapy

vudalimab + docetaxel

Vudalimab IV, cabazitaxel or docetaxel IV

vudalimab + cabazitaxel or docetaxel

Jolene Shorr

Ginger Lee

This Phase 2 study will investigate the safety and clinical activity of vudalimab (XmAb20717) alone or in combination with standard of care anticancer therapies in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on prior therapy.

Detailed Description:

This is a Phase 2, open-label, multiple-dose, multiple-arm, parallel assignment study in patients with mCRPC who have progressed on prior therapy. It will enroll subjects into 1 of 5 molecularly defined cohorts based on the results of acceptable, documented prior diagnostic testing:

* Cohort A: Aggressive variant prostate cancer (AVPCa)
* Cohort B: Homologous recombination deficient (HRD)/cyclin-dependent kinase 12 (CDK12) biallelic loss tumors that have progressed on poly-adenosine diphosphate ribose polymerase inhibitors (HRD/CDK12 PARP Progressors) - Closed to Enrollment
* Cohort C: HRD/CDK12 biallelic loss tumors, naive to PARP inhibitors (HRD/CDK12 PARP Naïve) - Closed to Enrollment
* Cohort D: Microsatellite instability-high (MSI-H) or mismatch repair deficient (MMRD), or tumor mutational burden-high (TMB-H) tumors - Closed to Enrollment
* Cohort E: No Targetable Mutations

XmAb®20717 (Vudalimab) Alone or in Combination With Chemotherapy or Targeted Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 2 Multiple-Dose, Multiple-Arm, Parallel Assignment Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of XmAb®20717 Alone or in Combination With Chemotherapy or Targeted Therapies in Selected Subjects With Metastatic Castration-Resistant Prostate Cancer

Xencor, Inc.

Rare Diseases

Turcot Syndrome

Central Nervous System Depressants

Other Dietary Supplements

Pembrolizumab

Antibodies

Androgens

Abiraterone Acetate

Immunoglobulins

Testosterone

Benzocaine

Antibodies, Blocking

Tannic Acid

This is a single-arm, open-label study of the checkpoint inhibitor, pembrolizumab, in Veterans with mCRPC who have progressed on at least 1 prior novel androgen receptor (AR) signaling inhibitor, inclusive of abiraterone acetate, enzalutamide, apalutamide, and darolutamide. In addition to progressive mCRPC, a patient must have a somatic tumor mutation characterized by dMMR or CDK12-/- detected by next generation sequencing (NGS). Patients enrolled in this study will be treated with pembrolizumab at the FDA approved dosage of 200 mg intravenously every 3 weeks (21 days) until disease progression or unacceptable toxicity. During study, patients will maintain a castrate level of testosterone, = 50 ng/dL by ongoing treatment with a GnRH analogue or prior bilateral orchiectomy. Prior to initiating treatment with pembrolizumab, patients will undergo a baseline biopsy of a metastatic lesion. An additional biopsy of a metastatic lesion at the time of progression will be encouraged as well.

Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.

Matthew B Rettig, MD

Tu Le

Matthew B. Rettig, MD

Ramesh Subrahmanyam, PhD

Behzad Mowlazadeh, MD

Mia Aoki, MS

Joshua Meeks, MD

Moumita Sakar, MD

Brittany Pannecouk

Antonio Fojo, MD

Hannah Catan, RN

Daniel Becker, MD

Asha George, MPH

Rhonda Bitting, MD

Muhammad Zahid

Jeanie Eason, RN

Bruce Montgomery, MD

Ronda K Ramsey, MSHS

The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in Veterans with metastatic castration-resistant prostate cancer (mCRPC) characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to PSA progression, maximal PSA response, time to initiation of alternative anti-neoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pre-treatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.

Research Plan:

This is a single-arm, open-label phase II study that examines the response rate of pembrolizumab in metastatic castration-resistant prostate cancer (mCRPC) patients who have either a mismatch repair deficiency (dMMR) or a biallelic inactivation of CDK12 (CDK12-/-). The study will enroll mCRPC patients who have the selected genetic mutation and at least one metastatic lesion that is amendable to biopsy. All patients must have progressed on at least one prior line of mCRPC therapy, such as abiraterone acetate or enzalutamide. Eligible patients will undergo at least 12 weeks (4 cycles) of pembrolizumab (200 mg IV).

Methodology:

Patients with either a mismatch repair deficiency or biallelic inactivation of CDK12 in their tumor are eligible for this study. If the patient has progressed on at least one prior therapy for mCRPC, including abiraterone acetate or enzalutamide, he is eligible to begin genetic screening. Patients with these mutations will be identified primarily through standard of care genetic testing with either archival tissue or blood. Specimens will be sent to VA approved vendors for genetic testing to determine if the patient has the necessary mutations to receive the study drug (pembrolizumab). If eligible, the patient will sign the Main Treatment ICF and proceed with the screening procedures. Once enrolled the patient will undergo a biopsy of a metastatic lesion (baseline biopsy) to identify molecular correlates. If the patient does not have any archival tissue or blood to be used to identify genetic mutations, the biopsy of a metastatic lesion will be used to both identify genetic mutations and to identify molecular correlates.

When the patient has met all the eligibility criteria, he will receive pembrolizumab. Pembrolizumab will be administered at a starting dose of 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. During the treatment, patients will either simultaneously receive a GnRH analogue or undergo a bilateral orchiectomy prior to treatment to maintain a castrate level of testosterone ( 50 ng/dl). At progression, patients will undergo a second biopsy of the same metastatic lesion of the baseline biopsy. The baseline (pre-treatment) and at-progression biopsies will be used for correlative analyses to determine the efficacy of pembrolizumab.

Note: after the testing process is complete, Oncoplex will return any remaining sample back to the Department of Pathology at the West LA VA Medical Center. These specimens will be stored in Dr. Matthew Rettig's biorepository on site for analysis and future research.

Results:

Since this is a new study, the results have not yet been obtained. The primary endpoint of this study is to measure the objective response rate, radiographic progression free survival at 6 months, and decline in PSA of 50% or more 12 weeks of therapy.

Clinical Significance:

There are 230,000 new incidences of prostate cancer and 30,000 deaths from prostate cancer per year in the US. It is the second most common cause of death in American men. Importantly, prostate cancer is diagnosed in more than 12,000 US Veterans each year, representing nearly one third of all cancer diagnoses in Veterans.

Metastatic prostate cancer is incurable, and its treatment is palliative. However, many Veterans with metastatic castration-resistant prostate cancer (mCRPC) progress despite experiencing some clinical benefit from hormonal therapy and chemotherapy. As a result, novel therapies that provide a robust clinical benefit and have a good safety profile are needed for these patients.

Immunotherapies, such as checkpoint inhibitor, for mCRPC patients that have either a mismatch repair deficiency (dMMR) or a biallelic inactivation of CDK12 (CDK12-/-) is an attractive therapy, especially since therapies involving checkpoint inhibitors have exhibited significant improvements in patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and many other cancers. The results of this study will establish the ideal subset of mCRPC patients who will benefit from the study drug. Importantly, the correlative studies will provide critical insight into the mechanisms of primary and acquired resistance that occur despite selection of patients with CDK12-/- or dMMR. This result can inform further selection of patients for checkpoint inhibition, as well as identify other potential therapies that can be co-administered with pembrolizumab to prevent or overcome resistance to checkpoint inhibitors.

Patients with either a mismatch repair deficiency or biallelic inactivation of CDK12 in their tumor are eligible for this study. Patients with these mutations will be identified primarily through standard of care genetic testing with either archival tissue or blood. Once enrolled the patient will undergo a biopsy of a metastatic lesion (baseline biopsy) to identify molecular correlates.

Pembrolizumab will be administered at a starting dose of 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. During the treatment, patients will either simultaneously receive a GnRH analogue or undergo a bilateral orchiectomy prior to treatment to maintain a castrate level of testosterone ( 50 ng/dl). At progression, patients will undergo a second biopsy of the same metastatic lesion of the baseline biopsy. The baseline (pre-treatment) and at-progression biopsies will be used for correlative analyses to determine the efficacy of pembrolizumab.

This study involves the treatment of patients with metastatic castration resistant prostate cancer with Pembrolizumab. Since only men have prostates, our study will be limited to only enrolling male subjects.

A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

A Phase 2 Study of a Checkpoint Inhibitor in Men With Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

None of the biospecimens will be destroyed. Unused specimens will be used for future research to access clinical data indefinitely. Subjects can request to have all of their specimens destroyed at the end of the study. The research blood and tumor tissue specimens will not be marked with any personal identifiers. As soon as they are collected by a study personnel, the samples will be labeled with a code. The key to the code will remain locked in the research office that is only accessed by study personnel. Only coded specimens will be sent to commercial vendors and VA GLAHS in West LA.

The study investigators will perform research testing on their tissue specimens that is independent of the genetic analysis to be performed at commercial vendor. There are no plans to share the results of other testing performed on their specimens. These results are only for research purposes. However, certain exploratory biomarker test results may be shared with the subject.

We will investigate and identify molecular correlates and biomarkers of resistance and sensitivity to pembrolizumab using baseline and at-progression metastatic tumor biopsies. Molecular correlates will be assessed by RNA-seq, exome-seq, selected protein analyses, and multiplexed immunofluorescence for immune cells. Whenever possible, we will attempt to validate tissue based biomarkers in peripheral blood specimens.

Decline in PSA of 50% or more (PSA50) 12 weeks of therapy (ng/mL)

Objective response in measurable disease by immunotherapy response criteria (iRECIST) or radiographic progression free survival (rPFS) after 6 months of therapy.

* Time to PSA progression
* Time to initiation of alternative anti-neoplastic therapy,
* Time to radiographic progression

The overall survival rate measured as time from enrollment until death.

See what the safety and tolerability of Pembrolizumab on patients with prostate cancer is by assessing adverse and serious adverse events that each patient experiences.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy in Patients With Metastatic Cancers and CDK12 Mutations	NCT03570619	Metastatic Cast... Metastatic Canc... Solid Tumor	Nivolumab Ipilimumab	18 Years -	University of Michigan Rogel Cancer Center
XmAb®20717 (Vudalimab) Alone or in Combination With Chemotherapy or Targeted Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer	NCT05005728	Metastatic Cast...	vudalimab + car... vudalimab + ola... vudalimab monot... vudalimab + doc... vudalimab + cab...	18 Years -	Xencor, Inc.
A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation	NCT04104893	Metastatic Cast...	Pembrolizumab	18 Years -	VA Office of Research and Development
A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation	NCT04104893	Metastatic Cast...	Pembrolizumab	18 Years -	VA Office of Research and Development
XmAb®20717 (Vudalimab) Alone or in Combination With Chemotherapy or Targeted Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer	NCT05005728	Metastatic Cast...	vudalimab + car... vudalimab + ola... vudalimab monot... vudalimab + doc... vudalimab + cab...	18 Years -	Xencor, Inc.

Spots Global Cancer Trial Database for cdk12

Every month we try and update this database with for cdk12 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for cdk12

Every month we try and update this database with for cdk12 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for cdk12 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.