Clinical Trials /

Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations

NCT03413995

Description:

The aim of this research is to find out if the study drug rucaparib leads to lowering of PSA levels in men with metastatic prostate cancer that has not yet been treated with androgen deprivation therapy (also referred to as metastatic hormone sensitive prostate cancer) and who have an inherited mutation in a gene involved in repairing DNA damage. The research will also examine if rucaparib is safe in individuals with metastatic prostate cancer. Prior research studies have shown that drugs like rucaparib can be of benefit to patients with advanced metastatic prostate cancer who are resistant to androgen deprivation therapy AND who carry a mutation in a DNA repair gene. We are studying if rucaparib will be an effective treatment for these patients earlier in their treatment course (for example, prior to the start of medicines that lower testosterone level). It is unknown whether rucaparib will have the same benefit in men with metastatic prostate cancer carrying a mutation in a DNA repair gene, prior to the use of medicines that lower your testosterone level.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations
  • Official Title: Phase II Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations (TRIUMPH)

Clinical Trial IDs

  • ORG STUDY ID: J17187
  • SECONDARY ID: IRB00156514
  • NCT ID: NCT03413995

Conditions

  • Prostate Cancer Metastatic

Interventions

DrugSynonymsArms
RucaparibRucaparib 600 mg BID, continuous dosing

Purpose

The aim of this research is to find out if the study drug rucaparib leads to lowering of PSA levels in men with metastatic prostate cancer that has not yet been treated with androgen deprivation therapy (also referred to as metastatic hormone sensitive prostate cancer) and who have an inherited mutation in a gene involved in repairing DNA damage. The research will also examine if rucaparib is safe in individuals with metastatic prostate cancer. Prior research studies have shown that drugs like rucaparib can be of benefit to patients with advanced metastatic prostate cancer who are resistant to androgen deprivation therapy AND who carry a mutation in a DNA repair gene. We are studying if rucaparib will be an effective treatment for these patients earlier in their treatment course (for example, prior to the start of medicines that lower testosterone level). It is unknown whether rucaparib will have the same benefit in men with metastatic prostate cancer carrying a mutation in a DNA repair gene, prior to the use of medicines that lower your testosterone level.

Detailed Description

      With respect to germline mutations, a recent study found that the incidence of inherited
      DNA-repair gene alterations in metastatic prostate cancer to be significantly higher (11.8%)
      than in both men with localized prostate cancer (4.6%) and in the general population at large
      (2.7%). Specifically, mutations in 7 genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, RAD51D, GEN1)
      were significantly enriched in patients with metastatic prostate cancer compared to the
      general population. These findings suggest that a subset of men are more likely to develop
      metastatic prostate cancer (i.e. those with germline mutations in DNA-repair genes) and may
      potentially benefit from PARPi therapy.

      The clinical activity of PARPi in patients with DNA-repair mutations and metastatic prostate
      cancer has now been established. Focusing specifically on patients with a germline mutation
      in a pre-specified group of DNA-repair genes, we hypothesize that targeted therapy with PARPi
      should be sufficient to induce a clinical response irrespective of hormonal
      (castration-sensitive or castration-resistant) status. Our hypothesis is based largely on the
      data from Mateo et al showing a clinical response rate of 88% in a heavily pre-treated
      population of mCRPC patients with a DNA repair mutation, with the most pronounced responses
      being in men with germline inactivation.

      For men with mHSPC, this trial would also provide an alternative to ADT. Identification of a
      non-hormonal based therapy is warranted as ADT is associated with a shorter time to
      castration resistance in men harboring a germline DNA repair mutation versus those with
      intact DNA repair. However, given that primary ADT (in mHSPC) is a standard first-line
      therapy, all patients on trial must be ineligible for or decline standard-of-care hormonal
      treatment. For patients with mHSPC who do not respond to PARPi, we will build safety rules
      into the trial design to take patients off study at first signs of progression. Primary ADT
      (mHSPC) would still remain a treatment option upon progression.
    

Trial Arms

NameTypeDescriptionInterventions
Rucaparib 600 mg BID, continuous dosingExperimentalRucaparib 600mg by mouth twice daily, continuous dosing
  • Rucaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Willing and able to provide written informed consent and HIPAA authorization for the
             release of personal health information.

          -  Males aged 18 years of age and above

          -  Histological or cytologic proof of adenocarcinoma of the prostate

          -  Germline mutation in one or more homologous recombination DNA-repair genes (BRCA1,
             BRCA2, ATM, CHEK2, NBN, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC,
             FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM) as documented by a clinical
             CLIA-grade, genetic test (including but not limited to Invitae, Color Genomics, etc)

          -  All patients must be ineligible for or have declined androgen deprivation therapy
             (ADT)-based systemic treatment

          -  Absolute PSA ≥2.0 ng/ml at screening.

          -  Radiographic evidence of metastatic disease by CT scan and bone scan, performed within
             the prior 8 weeks.

          -  Serum testosterone ≥ 100 ng/dl.

          -  Participants must have normal organ and bone marrow function measured within 28 days
             prior to administration of study treatment as defined below:

               -  Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
                  / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT))

          -  Participants must have creatinine clearance estimated using the Cockcroft-Gault
             equation of ≥51 mL/min:

               -  Estimated creatinine clearance = (140-age [years]) x weight (kg) serum creatinine
                  (mg/dL) x 72

          -  ECOG Performance Status <2

          -  Participants must have a life expectancy ≥ 12 months.

          -  Male participants and their partners, who are sexually active and of childbearing
             potential, must agree to the use of two highly effective forms of contraception in
             combination [see appendix E for acceptable methods], throughout the period of taking
             study treatment and for 6 months after last dose of study drug to prevent pregnancy in
             a partner.

        Exclusion Criteria:

          -  Current active second malignancy (history of non-melanoma skin cancers and superficial
             bladder cancers are allowed)

          -  Prior ADT in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary
             is allowed; prior ADT for biochemical recurrence is also allowed, as long as no ADT
             has been administered in past 6 months and testosterone has recovered (>100 ng/dl).
             The total duration of prior ADT should not exceed 24 months.

          -  Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide),
             or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months is
             not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is
             allowed, as long as subject has been stable on medication for past 6 months.

          -  Presence of visceral (i.e. lung or liver) metastases >3cm in long-axis dimension.

          -  Pain due to bone metastases requiring narcotic analgesics.

          -  Prior treatment with intravenous chemotherapy.

          -  Use of any prohibited concomitant medications (Appendix B: Medications With the
             Potential for Drug-Drug Interactions) within the prior 2 weeks.

          -  Involvement in the planning and/or conduct of the study (applies to both Clovis
             Oncology staff and/or staff at the study site)

          -  Previous enrollment in the present study

          -  Participation in another clinical study with an investigational product during the
             last 1 month.

          -  Any previous treatment with a PARP inhibitor, including rucaparib.

          -  Resting ECG with QTc > 480 msec on 2 or more time points within a 24 hour period or
             family history of long QT syndrome

          -  Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
             caused by previous cancer therapy, excluding alopecia.

          -  Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of MDS/AML.

          -  Major surgery within 2 weeks of starting study treatment, and patients must have
             recovered from any effects of any major surgery.

          -  Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant
             systemic disease or active, uncontrolled infection. Examples include, but are not
             limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial
             infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
             disease, or any psychiatric disorder that prohibits obtaining informed consent.

          -  Unable to swallow orally administered medication or gastrointestinal disorders likely
             to interfere with absorption of the study medication.

          -  Immunocompromised patients, e.g., patients who are known to be serologically positive
             for HIV. Known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting
             the infection through blood or other body fluids

          -  Known hypersensitivity to rucaparib or any of the excipients of the product.

          -  Whole blood transfusions in the last 30 days prior to entry to the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response Rate(PSA)to rucaparib for pts with met. hormone sensitive prostate ca harboring germline mutation in homologous recombination DNA repair gene. Measured by decline in PSA to 50% of baseline, confirmed w/second measurement at least 4 weeks apart.
Time Frame:4 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:2 years
Safety Issue:
Description:
Measure:PSA progression-free survival, defined as a time from initiation of rucaparib therapy until PSA increase of 25 %, confirmed with another measurement at least 3 weeks later
Time Frame:6 months
Safety Issue:
Description:
Measure:Progression-free survival, defined as time from initiation of rucaparib therapy to radiographic or clinical progression or death, whichever comes first.
Time Frame:2 years
Safety Issue:
Description:
Measure:Objective response rate, defined as the proportion of patients achieving a complete or partial response in target lesions found on radiographic scans
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center

Trial Keywords

  • metastatic hormone sensitive

Last Updated

January 26, 2018