Clinical Trials /

ATR Kinase Inhibitor M6620 and Carboplatin With or Without Docetaxel in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

NCT03517969

Description:

This phase II trial studies how well ATR kinase inhibitor M6620 and carboplatin with or without docetaxel works in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and docetaxel, 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. Giving ATR kinase inhibitor M6620, carboplatin and docetaxel may work better in treating patients with metastatic castration-resistant prostate cancer.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ATR Kinase Inhibitor M6620 and Carboplatin With or Without Docetaxel in Treating Patients With Metastatic Castration-Resistant Prostate Cancer
  • Official Title: A Phase 2 Study of M6620 in Combination With Carboplatin Compared With Docetaxel in Combination With Carboplatin in Metastatic Castration-Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-00790
  • SECONDARY ID: NCI-2018-00790
  • SECONDARY ID: 10191
  • SECONDARY ID: 10191
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT03517969

Conditions

  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • Stage IV Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor M6620M 6620, M6620, VX-970Arm B (carboplatin, ATR kinase inhibitor M6620)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (docetaxel, carboplatin)
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateArm A (docetaxel, carboplatin)

Purpose

This phase II trial studies how well ATR kinase inhibitor M6620 and carboplatin with or without docetaxel works in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and docetaxel, 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. Giving ATR kinase inhibitor M6620, carboplatin and docetaxel may work better in treating patients with metastatic castration-resistant prostate cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the difference in response rate (either achievement of prostate specific antigen
      [PSA] reduction of greater than 50% or radiographic response by Response Evaluation Criteria
      in Solid Tumors [RECIST] 1.1) of the combination of M6620 (ATR kinase inhibitor M6620) and
      carboplatin as compared to the combination of docetaxel and carboplatin.

      SECONDARY OBJECTIVES:

      I. To assess the difference in time to PSA progression by Prostate Cancer Working Group
      (PCWG)2 criteria of the combination of M6620 and carboplatin as compared to the combination
      of docetaxel and carboplatin.

      II. To describe radiographic progression-free survival and progression-free survival by PCWG3
      criteria in both arms of the study.

      III. Assess the relationship with homologous recombination deficiency (HRD) detected from
      baseline tumor biopsy with response to the combination of M6620 and carboplatin and the
      combination of docetaxel and carboplatin.

      IV. To describe the safety and adverse events from the combination of M6620+carboplatin as
      well the combination of docetaxel+carboplatin.

      EXPLORATORY OBJECTIVES:

      I. Comparison of overall survival in the two arms of the study. II. Explore response rate,
      time to PSA progression, radiographic progression-free survival, and progression-free
      survival by PCWG3 criteria in patients who initially receive docetaxel+carboplatin after
      crossover to M6620+carboplatin.

      III. To assess the relationship with homologous recombination deficiency (HRD) detected from
      baseline circulating free deoxyribonucleic acid (DNA) (cfDNA) with response to the
      combination of M6620 and carboplatin and the combination of docetaxel and carboplatin, and
      describe alterations seen in cfDNA (and optional tumor biopsy) at end of study.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      ARM A (docetaxel, carboplatin): Patients receive docetaxel intravenously (IV) over 60 minutes
      and carboplatin IV over 30 minutes on day 1 or carboplatin alone on day 1. Cycles repeat
      every 21 days in the absence of disease progression or unacceptable toxicity. Patients have
      PSA progression or radiographic progression may crossover to Arm B.

      ARM B (carboplatin, ATR kinase inhibitor M6620): Patients receive carboplatin IV over 30
      minutes on day 1 and ATR kinase inhibitor M6620 IV over 60-90 minutes on days 2 and 9. Cycles
      repeat every 21 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up between 30-42 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (docetaxel, carboplatin)ExperimentalPatients receive docetaxel IV over 60 minutes and carboplatin IV over 30 minutes, or carboplatin alone on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who have PSA progression or radiographic progression may crossover to Arm B.
  • Carboplatin
  • Docetaxel
Arm B (carboplatin, ATR kinase inhibitor M6620)ExperimentalPatients receive carboplatin IV over 30 minutes on day 1 and ATR kinase inhibitor M6620 IV over 60-90 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor M6620
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed prostate cancer

          -  Patients must have metastatic disease by bone scan or other nodal or visceral lesions
             on computed tomography (CT) or magnetic resonance imaging (MRI) and a castrate level
             of testosterone (< 50 ng/dL) and evaluable for disease response by either

               -  Baseline PSA >= 2.0 ng/mL OR

               -  Measurable disease per RECIST 1.1

               -  NOTE: Subjects must maintain a castrate state; if they have not had an
                  orchiectomy, they must continue to receive luteinizing hormone-releasing hormone
                  (LHRH) or gonadotropin-releasing hormone (GnRH) agonists or antagonists unless
                  intolerant

          -  At least 2 prior treatments for castration resistant prostate cancer as follows:

               -  Past progression or intolerance to at least one secondary hormonal therapy
                  (abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel,
                  seviteronel or equivalent)

               -  Past progression or intolerance to taxane-based chemotherapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal, unless the subject has
             known or suspected Gilbert's syndrome

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal or =< 5 x if presence of liver metastases

          -  Creatinine clearance >= 40 mL/min/1.73 m^2

          -  Prior treatment with mTOR inhibitors, cytostatic tyrosine kinase inhibitor (TKI), or
             biologic therapies allowed

          -  Prior treatment with PARP inhibitors permitted

          -  Patients with allergy or intolerance to docetaxel, grade 2 neuropathy or ECOG
             performance status (PS) = 2 are allowed on study, but if randomized to Arm A will
             receive carboplatin as a single agent (AUC 5) rather than docetaxel+carboplatin; they
             must be fit for carboplatin chemotherapy as determined by the treating investigator

          -  Willing to undergo core biopsy of a recurrent/metastatic lesion adequate for next
             generation sequencing (NGS) after trial registration but prior to cycle 1 day 1 of
             therapy; confirmation of adequacy of this biopsy material for NGS is NOT required for
             initiation of therapy

          -  The effects of M6620, carboplatin and docetaxel on the developing human fetus are
             unknown; for this reason and because DNA-damage response inhibitors and
             chemotherapeutic agents are known to be teratogenic, men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study participation; should a woman become pregnant or
             suspect she is pregnant while her partner is participating in this study, she should
             inform her treating physician immediately; men treated or enrolled on this protocol
             must also agree to use adequate contraception prior to the study, for the duration of
             study participation, and 6 months after completion of carboplatin and M6620
             administration

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to planned cycle 1 day 1 of study treatment;
             patients on an oral anti-neoplastic such as an oral hormonal agent, PARP inhibitor or
             oral experimental agent should discontinue >= 14 days prior to planned cycle 1 day 1
             of study treatment

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1), except for grade 2 anorexia, alopecia,
             neuropathy, and fatigue, for which resolution is not required

          -  Patients who are receiving any other investigational agents

          -  Patients with known brain metastases or leptomeningeal disease should be excluded from
             this clinical trial because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M6620 or carboplatin; (patients with allergy to docetaxel will be
             allowed on study, but docetaxel will be excluded from their treatment regimen)

          -  Subjects receiving treatment with ototoxic or nephrotoxic medications that cannot be
             discontinued at least 7 days before first dose of carboplatin and for the duration of
             the study; inadvertent or short-term use on study will not cause a subject to be
             ineligible; if a short course of therapy with nephrotoxic or ototoxic medication is
             anticipated and required, carboplatin should be discontinued until 7 days after this
             course is completed

               -  M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration
                  with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
                  clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or inducers of
                  CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort)
                  should be avoided; because the lists of these agents are constantly changing, it
                  is important to regularly consult a frequently-updated medical reference for a
                  list of drugs to avoid or minimize use of; (patient Drug Information Handout and
                  Wallet Card) should be provided to patients; as part of the enrollment/informed
                  consent procedures, the patient will be counseled on the risk of interactions
                  with other agents, and what to do if new medications need to be prescribed or if
                  the patient is considering a new over-the-counter medicine or herbal product

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant and nursing women are excluded from this study because they do not develop
             prostate cancer

          -  Human immunodeficiency (HIV)-positive participants with detectable viral load and/or
             CD4 count =< 300 are ineligible due to increased risk of lethal infections when
             treated with marrow-suppressive therapy; HIV-positive patients with undetectable viral
             loads and CD4 counts > 300, and not on interacting antiretroviral therapy may be
             eligible after discussing with the principal investigator

          -  Prior treatment with platinum-containing regimen or ATR inhibitor for prostate cancer
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate (complete response + partial response)
Time Frame:Up to 2 years
Safety Issue:
Description:Defined by radiographic response by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 or prostate specific antigen [PSA] response of > 50%). Will be conducted using the Cochran-Mantel-Haenszel (CMH) test, with one-sided p-value of =< 0.05 considered significant.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From the time of randomization up to 2 years
Safety Issue:
Description:Assessed by Prostate Cancer Working Group (PCWG)3. PFS to be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval.
Measure:Time to PSA progression
Time Frame:From the time of randomization up to 2 years
Safety Issue:
Description:Assessed by PCWG2. PSA progression will be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval. Comparison of time to PSA progression between arms will be conducted using the log-rank test.
Measure:Radiographic progression-free survival (rPFS)
Time Frame:From the time of randomization up to 2 years
Safety Issue:
Description:Assessed by RECIST 1.1. rPFS will be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized according to treatment arm. For toxicity reporting, all adverse events will be graded and analyzed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Type of adverse events, intensity (grading), and attribution will be provided in a listing. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized. Laboratory test results will be classified according to the CTCAE version 5.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 25, 2019