Clinical Trials /

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

NCT04592237

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabazitaxel, Carboplatin, and Cetrelimab Followed by Niraparib With or Without Cetrelimab for the Treatment of Aggressive Variant Metastatic Prostate Cancer
  • Official Title: Randomized Phase II Study of Platinum-Taxane-Cetrelimab Induction Followed by Niraparib Plus or Minus Cetrelimab Maintenance in Men With Aggressive Variant Prostate Cancers

Clinical Trial IDs

  • ORG STUDY ID: 2020-0200
  • SECONDARY ID: NCI-2020-07731
  • SECONDARY ID: 2020-0200
  • NCT ID: NCT04592237

Conditions

  • Aggressive Variant Prostate Carcinoma
  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • Metastatic Prostate Neuroendocrine Carcinoma
  • Metastatic Prostate Small Cell Carcinoma
  • Stage IV Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
CabazitaxelJevtana, RPR-116258A, Taxoid XRP6258, XRP-6258Group I (niraparib)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboGroup I (niraparib)
CetrelimabJNJ 63723283, JNJ-63723283, JNJ63723283, WHO 10757Group I (niraparib)
NiraparibMK-4827, MK4827Group I (niraparib)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (niraparib)ExperimentalINDUCTION: 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.
  • Cabazitaxel
  • Carboplatin
  • Cetrelimab
  • Niraparib
Group II (cetrelimab, niraparib)ExperimentalINDUCTION: 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
  • Carboplatin
  • Cetrelimab
  • Niraparib

Eligibility Criteria

        Inclusion Criteria:

          -  Completion of informed consent prior to any study specific procedures

          -  Patients must agree to tissue collection for correlative studies at the specified
             timepoints

          -  Patients must consent to the MD Anderson Immunotherapy Platform laboratory protocol
             PA13-0291

          -  Histologically or cytologically confirmed prostate carcinoma

          -  Presence of metastatic disease documented on imaging studies (bone scan, computed
             tomography [CT] and/or magnetic resonance imaging [MRI] scans)

          -  Patients must meet at least one of the following AVPC criteria:

               -  Histologically proven small cell (neuroendocrine) prostate carcinoma

               -  Exclusive visceral metastases

               -  Predominantly lytic bone metastases identified by plain x-ray or CT scan

               -  Bulky (>= 5 cm in longest dimension) lymphadenopathy or high-grade tumor mass in
                  prostate/pelvis

               -  Low PSA (=< 10 ng/mL) at initial presentation (prior to androgen ablation or at
                  symptomatic progression in the castrate-setting) plus high volume (>= 20) bone
                  metastases

               -  Elevated serum lactate dehydrogenase (LDH) (>= 2 x ULN) or elevated serum
                  carcinoembryonic antigen (CEA) (>= 2 x ULN) in the absence of other etiologies

               -  Short interval (=< 180 days) to castrate-resistant progression following
                  initiation of hormonal therapy

               -  Known loss or mutation (by Clinical Laboratory Improvement Act [CLIA] certified
                  molecular testing, immunohistochemistry [IHC] and/or deoxyribonucleic acid [DNA]
                  sequencing) in at least 2 of Tp53, RB1 and PTEN defined as:

                    -  AVPC determination by immunohistochemistry. As previously described, tumor
                       samples are considered negative (and thus abnormal) for RB1 and PTEN if
                       their labeling index is =< 10% and positive (and thus aberrant) for Tp53 if
                       their labeling index is >= 10%, where the labeling index is defined as the
                       percentage of positive cells, and calculated as the number of positively
                       stained epithelial cells divided by the total number of epithelial cells, at
                       X200 magnification

                    -  AVPC determination by DNA sequencing. As previously described, the TP53, RB1
                       and PTEN genes will be considered aberrant if they contain exonic
                       nonsynonymous missense or stop-gain mutations, frameshift or non frameshift
                       indels (insertions or deletions), and/or copy number losses

          -  Patients must have documented evidence of progressive disease as defined by any of the
             following: a) PSA progression: minimum of 2 rising values (3 measurements) obtained a
             minimum of 7 days apart with the last result being at least >= 1.0 ng/mL; b) New or
             increasing non-bone disease (RECIST); c) Positive bone scan with 2 or more new lesions
             (Prostate Cancer Working Group 3 [PCWG3]); d) Increasing symptoms unequivocally
             attributed to disease progression as judged by the treating physician and the
             principal investigator (PI)

          -  Surgically or ongoing medically castrated, with baseline testosterone levels of =< 50
             ng/dL (=< 2.0 nM)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

          -  Hemoglobin >= 10.0 g/dL (unless due to bone marrow infiltration by tumor, in which
             case hemoglobin > 8 g/dL is allowed) (within 7 days prior to treatment registration).
             Patient may have blood transfusions prior to study enrollment

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (unless due to bone marrow
             infiltration by tumor, in which case ANC > 1,000/mm^3 is allowed) (within 7 days prior
             to treatment registration)

          -  White blood cells (WBC) > 3 x 10^9/L (unless due to bone marrow infiltration by tumor,
             in which case WBC > 2 x 10^9/L is allowed) (within 7 days prior to treatment
             registration)

          -  No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
             on peripheral blood smear (within 7 days prior to treatment registration)

          -  Platelet count >= 100 x 10^9/L (unless due to bone marrow infiltration by tumor, in
             which case platelet > 50,000/mm^3 is allowed) (within 7 days prior to treatment
             registration)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except for
             patients with known Gilbert's disease) (within 7 days prior to treatment registration)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
             institutional upper limit of normal (unless liver metastases are present in which case
             it must be =< 5 x ULN) (within 7 days prior to treatment registration)

          -  Calculated creatinine clearance (Cockcroft-Gault equation) >= 30 mL/min (within 7 days
             prior to treatment registration)

          -  Able to swallow study drugs whole as a tablet/capsule

          -  Patients who have partners of childbearing potential (e.g. female that has not been
             surgically sterilized or who are not amenorrheic for >= 12 months) must be willing to
             use a method of birth control in addition to adequate barrier protection as determined
             to be acceptable by the investigator during the study and for 3 months after last dose
             of niraparib administration and 5 months after the last dose of cetrelimab. In
             addition men should not donate sperm during this period. Please note that the efficacy
             of hormonal contraception may be decreased if administered with niraparib

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up

        Exclusion Criteria:

          -  Any prior treatment for castration-resistant prostate cancer (CRPC) with carboplatin,
             cisplatin, cabazitaxel, PARP-inhibitor or an anti-PD1 or anti-PDL1 inhibitor

          -  Patients who have received more than one line of chemotherapy. Any number of prior
             hormonal or targeted therapies are allowed

          -  Patients who have not recovered from adverse events secondary to systemic therapy
             (except for luteinizing hormone-releasing hormone [LHRH] agonist or antagonist
             treatment for prostate cancer, and bisphosphonates or RANK ligand inhibitors for bone
             strengthening), major surgery or radiotherapy for the treatment of prostate cancer to
             a grade =< 2

          -  Any unresolved toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade
             >= 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is
             not reasonably expected to be exacerbated by the investigational product may be
             included (e.g., hearing loss, peripherally neuropathy)

          -  History or current diagnosis of MDS/AML

          -  Active uncontrolled infection (patients completing a course of antibiotic or antiviral
             therapy whose infection is deemed to be controlled may be allowed on study after
             discussion with the PI; the PI will serve as the final arbiter regarding eligibility)

          -  Active or symptomatic viral hepatitis or chronic liver disease

          -  A history of pneumonitis or extensive bilateral lung disease of non-malignant etiology

          -  A malignancy (other than the one treated in this study) which has a >= 30% probability
             of recurrence within 24 months (except for adequately treated non-melanoma skin
             cancer, curatively treated in-situ cancer of the cervix or Ta urothelial carcinomas)

          -  Any underlying medical or psychiatric condition, which in the opinion of the
             investigator, will make the administration of study drug hazardous or obscure the
             interpretation of adverse events. Examples include, but are not limited to,
             uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction,
             superior vena cava syndrome, extensive bilateral lung disease on high resolution
             computed tomography (HRCT) scan, uncontrolled seizures, history of allogeneic organ
             transplant, history of primary immunodeficiency or any psychiatric disorder that
             prohibits obtaining informed consent

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study medication

          -  Patients with symptomatic uncontrolled brain metastases or spinal cord compressions. A
             scan to confirm the absence of brain metastases is not required. The patient can
             receive a stable dose of corticosteroids before and during the study as long as these
             were started at least 28 days prior to treatment

          -  Patients with a known hypersensitivity to niraparib, carboplatin, cabazitaxel or an
             anti-PD1 or anti-PDL1 inhibitor

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of cetrelimab, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid or steroids as pre-medication for
             hypersensitivity reactions (e.g. CT scan premedication)

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               -  Patients with celiac disease controlled by diet alone

          -  Receipt of live attenuated vaccination within 30 days of receiving cetrelimab

          -  Prisoners or subjects who are involuntarily incarcerated

          -  Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (e.g. infectious disease) illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:Time from randomization until documented disease progression, start of new therapy for prostate cancer in the absence of progression, or death in the absence of progression, whichever comes first, assessed up to 5 years
Safety Issue:
Description:Estimated by the methods of Kaplan and Meier. The 2 randomized treatment arms will be compared by a log rank test.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Time from randomization until death or last contact, assessed up to 5 years
Safety Issue:
Description:Estimated by the methods of Kaplan and Meier. The 2 randomized treatment arms will be compared by a log rank test.
Measure:Response rate
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Response rate
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Response rate by circulating tumor cells
Time Frame:Up to 5 years
Safety Issue:
Description:Defined as the proportion of patients with reduction in tumor burden. Will be reported separately for induction and for each randomized arm.
Measure:Incidence of adverse events
Time Frame:Up to 30 days after last administration of study drug
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

November 9, 2020