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Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Niraparib

Taxane

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

INDUCTION: Patients receive cabazitaxel IV over 60 minutes and carboplatin IV over 60 minutes on day 1. Beginning cycle 2, patients also receive cetrelimab IV over 30-60 minutes on day 1. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive niraparib orally PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

INDUCTION: Patients receive cabazitaxel IV over 60 minutes and carboplatin IV over 60 minutes on day 1. Beginning cycle 2, patients also receive cetrelimab IV over 30-60 minutes on day 1. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive cetrelimab IV over 30 minutes on day 1 and niraparib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabazitaxel

Cetrelimab

Ana Aparicio

This phase II trial studies the effect of cabazitaxel, carboplatin, and cetrelimab followed by niraparib with or without cetrelimab in treating patients with aggressive variant prostate cancer that has spread to other places in the body (metastatic). Chemotherapy drugs, such as cabazitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as niraparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as cetrelimab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving niraparib with or without cetrelimab, after treatment with cabazitaxel, carboplatin, and cetrelimab, may help control aggressive variant prostate cancer.

PRIMARY OBJECTIVES:

I. Estimate the progression free survival of men with aggressive variant prostate carcinoma (AVPC) treated with induction cabazitaxel-carboplatin and cetrelimab followed by maintenance niraparib with or without cetrelimab.

II. Evaluate changes in the density and localization of immune markers and cell subsets in AVPC tumors treated with or without cetrelimab added to cabazitaxel-carboplatin induction and niraparib maintenance, and screen for their association with outcomes.

SECONDARY OBJECTIVES:

I. Determine the percentage of patients that are able to complete the 6 cycles of induction chemoimmunotherapy.

II. Estimate the Response Evaluation Criteria in Solid Tumors (RECIST), prostate specific antigen (PSA) and circulating tumor cells (CTC) responses in men with AVPC treated with induction cabazitaxel-carboplatin and cetrelimab followed by maintenance niraparib with or without cetrelimab.

III. Estimate the overall survival of men with AVPC treated with induction cabazitaxel-carboplatin and cetrelimab followed by maintenance niraparib with or without cetrelimab.

IV. Determine the safety and tolerability of each of the regimens. V. Determine the frequency of PD-L1 expression in tumors treated with cabazitaxel-carboplatin induction and niraparib maintenance and its association with outcomes.

VI. Collect and archive solid and liquid tumor samples from study patients for later hypothesis generating associations.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I:

INDUCTION: Patients receive cabazitaxel intravenously (IV) over 60 minutes and carboplatin IV over 60 minutes on day 1. Beginning cycle 2, patients also receive cetrelimab IV over 30-60 minutes on day 1. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive niraparib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP II:

INDUCTION: Patients receive cabazitaxel IV over 60 minutes and carboplatin IV over 60 minutes on day 1. Beginning cycle 2, patients also receive cetrelimab IV over 30-60 minutes on day 1. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive cetrelimab IV over 30 minutes on day 1 and niraparib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment patients are followed up for 30 to 90 days (after last dose cetrelimab), and then every 6 months thereafter.

Cabazitaxel, Carboplatin, and Cetrelimab Followed by Niraparib With or Without Cetrelimab for the Treatment of Aggressive Variant Metastatic Prostate Cancer

Randomized Phase II Study of Platinum-Taxane-Cetrelimab Induction Followed by Niraparib Plus or Minus Cetrelimab Maintenance in Men With Aggressive Variant Prostate Cancers

Estimated by the methods of Kaplan and Meier. The 2 randomized treatment arms will be compared by a log rank test.

Defined as the proportion of patients with reduction in tumor burden. Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Will be reported separately for induction and for each randomized arm.

Defined as the proportion of patients with reduction in tumor burden. Evaluated by prostate specific antigen (PSA) response criteria. PSA will be considered evaluable for assessment of PSA response if \>= 1.0 ng/ml. Will be reported separately for induction and for each randomized arm.

Defined as the proportion of patients with reduction in tumor burden. Will be reported separately for induction and for each randomized arm.

Toxicity will be scored using Common Terminology Criteria for Adverse Events (CTCAE) version 5 for toxicity and adverse event reporting. Descriptive tables will be provided for adverse events by grade and attribution for the cabazitaxel/carboplatin for all patients, and then separately for patients receiving niraparib maintenance vs niraparib + cetrelimab. The numbers of cycles prior to and post randomization will be reported for each arm.

Janssen Pharmaceutica

M.D. Anderson Cancer Center

Anti-Inflammatory Agents

Prednisone

Nivolumab

Lenograstim

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Subjects with neuroendocrine prostate cancer (NEPC) or aggressive variant prostate cancer (AVPC) will receive a combination of nivolumab, ipilimumab, carboplatin and cabazitaxel for up to 10 cycles of 21 days each. After carboplatin and cabazitaxel are discontinued, a combination of nivolumab and ipilimumab will be administered.

Nivolumab will be administered intravenously at a dose of 360 mg every 3 weeks.

Ipilimumab will be administered intravenously at a dose of 1 mg/kg every 6 weeks.

Carboplatin will be administered intravenously at a dose of AUC 4 mg/ml per minute.

Cabazitaxel will be administered intravenously at a dose of 20 or 25 mg/m2.

AUC 4 mg/ml per minute intravenously every 3 weeks for up to 10 cycles.

Subjects will also receive granulocyte-colony stimulating factor (G-CSF) therapy while receiving carboplatin.

20 or 25 mg/m2 intravenously every 3 weeks for up to 10 cycles.

Subjects will also take prednisone by mouth at a dose of 10 mg daily and receive granulocyte-colony stimulating factor (G-CSF) therapy while receiving cabazitaxel.

Julia Hurrelbrink, RN, BSN

Andrew Armstrong, MD, ScM

The purpose of this study is to evaluate the safety and efficacy of a combination of nivolumab, ipilimumab, cabazitaxel and carboplatin in men with neuroendocrine prostate cancer (NEPC) or other aggressive variants of prostate cancer (AVPC). This study will also investigate biomarkers to gain a better understanding of how the drug combination of nivolumab, ipilimumab, cabazitaxel and carboplatin affects these types of prostate cancer and the immune system. Eligible subjects will receive up to 10 cycles of nivolumab, ipilimumab, carboplatin and cabazitaxel followed by maintenance nivolumab and ipilimumab. Subjects may continue receiving study drugs until cancer progression, severe toxicity, withdrawal of consent, 3 years from the initial dose of study drugs or study termination, whichever occurs earlier. Subjects will be followed for 3 years from the initial dose of study drugs.

A Study of Chemoimmunotherapy for the Treatment of Men With Neuroendocrine or Aggressive Variant Metastatic Prostate Cancer

A Phase II, Single Arm Study of Chemoimmunotherapy for the Treatment of Men With Neuroendocrine or Aggressive Variant Metastatic Prostate Cancer (CHAMP)

Progression-free survival will be determined by immune modified or Prostate Cancer Working Group 3 (PCWG3)-defined RECIST 1.1 radiographic criteria.

Progression-free survival will be determined by immune modified or PCWG3-defined RECIST 1.1 radiographic criteria.

Radiographic progression free survival will be determined by immune modified PCWG3-defined RECIST criteria.

Radiographic response will be determined by immune modified PCWG3-defined RECIST criteria.

The toxicity and safety will be graded using NCI CTCAE v5.0.

Bristol-Myers Squibb

Andrew J. Armstrong, MD

Professor of Medicine

Lutetium Lu 177 dotatate

Radiopharmaceuticals

Patients receive lutetium Lu 177 dotatate IV over 30 minutes. Cycles repeat Q6W for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gallium Ga 68-dotatate IV during screening then undergo PET/CT scan at baseline and collection of blood throughout the trial.

Biospecimen Collection

Computed Tomography

Gallium Ga 68-DOTATATE

Lutetium Lu 177 Dotatate

Positron Emission Tomography

Site Public Contact

Jacek Pinski

Mamta Parikh

Maha H. Hussain

Zin W. Myint

John M. Floberg

Michael A. Carducci

Michael McCormack

Edmund Folefac

John M Floberg

This phase II trial studies how well lutetium Lu 177 dotatate works in treating patients with prostate cancer with neuroendocrine differentiation that has spread to other places in the body (metastatic). Neuroendocrine differentiation refers to cells that have traits of both hormone-producing endocrine cells and nerve cells. These cells release hormones into the blood in response to a signal from the nervous system. Hormones are biological substances that circulate through the bloodstream to control the activity of other organs or cells in the body. Lutetium Lu 177-dotate is a radioactive drug. It binds to a protein called somatostatin receptor, which is found on some neuroendocrine tumor cells. Lutetium Lu 177-dotatate builds up in these cells and gives off radiation that may kill them. It is a type of radioconjugate and a type of somatostatin analog. Treatment with Lutetium Lu 177 dotatate may shrink the tumor in a way that can be measured in patients with metastatic prostate cancer with neuroendocrine differentiation.

PRIMARY OBJECTIVE:

I. Evaluate the objective response rate for patients treated with lutetium Lu 177 dotatate using Prostate Cancer Working Group (PCWG) 3 criteria.

SECONDAY OBJECTIVES:

I. Evaluate the 6-month radiographic progression-free survival of neuroendocrine-differentiated prostate cancer treated with lutetium Lu 177 dotatate.

II. Determine if the change in fludeoxyglucose (FDG)-positron emission tomography (PET) signal from pre-treatment to after 2 doses of lutetium Lu 177 dotatate correlates with objective response rate.

EXPLORATORY OBJECTIVES:

I. Evaluate the potential to perform patient-specific dosimetry of lutetium Lu 177 dotatate using gamma imaging to predict treatment response and renal toxicity.

II. Perform gene expression analysis of circulating tumor cells to identify pre-treatment biomarkers of response and signatures of resistance at the time of progression.

OUTLINE:

Patients receive lutetium Lu 177 dotatate intravenously (IV) over 30 minutes. Cycles repeat every 6 weeks (Q6W) for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gallium Ga 68-dotatate IV during screening then undergo positron emission tomography (PET)/computed tomography (CT) scan at baseline and collection of blood throughout the trial.

Patients are followed up at 6 weeks after last dose lutetium Lu 177 dotatate and then every 3 months for 2 years after removal from study or until death, whichever occurs first.

Testing the Safety and Effectiveness of Radiation-based Treatment (Lutetium Lu 177 Dotatate) for Metastatic Prostate Cancer That Has Neuroendocrine Cells

A Phase II Study of Lutetium Lu 177 Dotatate in Metastatic Prostate Cancer With Neuroendocrine Differentiation

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be summarized using descriptive statistics. Expression levels of candidate markers will be correlated with radiographic time to progression using univariate Cox proportional hazard regression analysis. The Benjamini-Hochberg false discovery rate method will be utilized to control the false discovery rate when evaluating the markers. Machine learning methods will be used to identify signatures of resistance at the time of progression.

Descriptive analyses will be conducted to evaluate the potential to perform patient-specific dosimetry of lutetium Lu 177 dotatate using gamma imaging to predict treatment response and renal toxicity. Imaging outcome parameters will be summarized in terms of means, medians, standard deviations and ranges, stratified by assessment time point (24, 96, and 192 hours post-injection), stratified by response (PD, SD versus CR, PR) and toxicity type/grade.

The objective response rate according to Prostate Cancer Working Group (PCWG) 3 criteria will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR will be reported along with the corresponding two-sided 95% confidence interval. The confidence interval will be adjusted for the two-stage design structure. This analysis will be based on the intent-to-treat population.

Will be determined by PCWG3 criteria. Specifically, progression/response will be determined via RECIST 1.1 criteria using diagnostic computed tomography (CT) scans of the chest/abdomen/pelvis to analyze progressive disease (PD), stable disease (SD), complete response (CR), partial response (PR), and toxicity type/grade. Progression and response will also be assessed by fludeoxyglucose positron emission tomography (18F-FDG PET).

Will be assessed with Quantitative Total Extensible Imaging (QTxI).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cabazitaxel, Carboplatin, and Cetrelimab Followed by Niraparib With or Without Cetrelimab for the Treatment of Aggressive Variant Metastatic Prostate Cancer	NCT04592237	Aggressive Vari... Castration-Resi... Metastatic Pros... Metastatic Pros... Metastatic Pros... Stage IV Prosta...	Cabazitaxel Carboplatin Cetrelimab Niraparib	18 Years -	M.D. Anderson Cancer Center
A Study of Chemoimmunotherapy for the Treatment of Men With Neuroendocrine or Aggressive Variant Metastatic Prostate Cancer	NCT04709276	Metastatic Pros... Metastatic Pros...	Nivolumab Ipilimumab Carboplatin Cabazitaxel	18 Years -	Duke University
Testing the Safety and Effectiveness of Radiation-based Treatment (Lutetium Lu 177 Dotatate) for Metastatic Prostate Cancer That Has Neuroendocrine Cells	NCT05691465	Metastatic Pros... Metastatic Pros... Metastatic Pros... Stage IV Prosta...	Biospecimen Col... Computed Tomogr... Gallium Ga 68-D... Lutetium Lu 177... Positron Emissi...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic prostate neuroendocrine carcinoma