Clinical Trials /

Targeting Resistant Prostate Cancer With ATR and PARP Inhibition (TRAP Trial)

NCT03787680

Description:

The purpose of this study is to test the effectiveness (how well the drugs work), safety, and tolerability of the investigational drug combination of olaparib and AZD6738 for all patients with metastatic castration-resistant prostate cancer.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Targeting Resistant Prostate Cancer With ATR and PARP Inhibition (TRAP Trial)
  • Official Title: A Multi-Center Phase II Study Testing the Activity of Olaparib and AZD6738 (ATR Inhibitor) in Metastatic Castration-Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: UMCC 2018.108
  • SECONDARY ID: HUM00152799
  • NCT ID: NCT03787680

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
OlaparibAZD2281Cohort 1 (DRPro)
AZD6738Cohort 1 (DRPro)

Purpose

The purpose of this study is to test the effectiveness (how well the drugs work), safety, and tolerability of the investigational drug combination of olaparib and AZD6738 for all patients with metastatic castration-resistant prostate cancer.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 (DRPro)ExperimentalPatients with metastatic castration-resistant prostate cancer (mCRPC) who are DNA repair proficient (DRPro).
  • Olaparib
  • AZD6738
Cohort 2 (DRDef)ExperimentalPatients with metastatic castration-resistant prostate cancer (mCRPC) who are DNA repair deficient (DRDef).
  • Olaparib
  • AZD6738

Eligibility Criteria

        Inclusion Criteria:

          1. Provision of informed consent prior to any study specific procedures

          2. Male ages 18 years and older at time of signing the informed consent form

          3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 42 days
             prior to registration

          4. Histologic or cytologic proof of prostate adenocarcinoma (excluding small-cell or
             neuroendocrine pathologies)

          5. Metastatic prostate cancer on CT, MRI or Bone scan

          6. Must have disease progression (while testosterone level is under 50 ng/dl) on prior
             therapy prior to study entry defined as one (or more) of the following:

               1. PSA progression defined as continuously rising PSA values measured a minimum of 1
                  week apart with a minimal starting value of 1.0 ng/mL

               2. Progression of bidimensionally measurable soft tissue or nodal metastasis by CT
                  or MRI based on RECIST, v1.1

               3. Progression of bone disease on bone scan as defined by two new lesions per PCWG3

          7. Prior treatment with at least one of the following:

               1. One line of therapy in mCRPC

               2. Second generation anti-androgen (e.g. abiraterone, enzalutamide or apalutamide)
                  within the hormone-sensitive phase of disease AND progression occurs while on
                  therapy

          8. Patients must be withdrawn from prior therapy for ≥3 weeks without PSA decline
             (patients may remain on prior prednisone up to 10 mg total daily exposure at
             provider's discretion).

          9. Agree to undergo a biopsy of at least one metastatic site (if feasible) to determine
             DNA repair status, unless prior metastatic tissue underwent next-generation sequencing
             in a CLIA certified lab. If no site is reachable, or first biopsy
             insufficient/unsuccessful, circulating analysis by Guardant360 panel will be done.

         10. Treated with continuous androgen deprivation therapy (either surgical castration or
             LHRH agonist/antagonist) with documented castrate level of serum testosterone (<50
             ng/dL)

         11. At least 2 weeks since prior palliative radiation or 4 weeks for radiation to >30% of
             the bone marrow or with a wide field of radiation

         12. Patient must have normal organ and bone marrow function measured within 42 days prior
             to registration as defined below

               1. Hemoglobin ≥10 g/dL (with no blood transfusion or erythropoietin use within the
                  past 42 days)

               2. Absolute neutrophil count ≥1.5x109/L

               3. Platelet count ≥100x109/L (with no platelet transfusions within last 42 days)

               4. Total bilirubin <1.5x ULN (unless the patient has documented Gilbert's disease
                  and <2.0x ULN should be used)

               5. AST or ALT ≤ 2.5x ULN, unless liver metastases are present in which case they
                  cannot be ≥5x ULN

               6. Glomerular filtration rate (GFR) ≥51 mL/min, as assessed using the Cockcroft-
                  Gault equation

         13. Estimated life expectancy ≥12 weeks

         14. Subjects must be surgically sterile or using an acceptable method of contraception
             (defined as barrier methods in conjunction with spermicides) for the duration of the
             study (from the time they sign consent) and for 6 months after the last dose of either
             drug to prevent pregnancy in a partner. Female partners of male patients should also
             use a highly effective form of contraception (as described in Appendix C) if they are
             of childbearing potential. Male patients should not donate sperm throughout the period
             of taking olaparib and for 6 months following the last dose of olaparib.

         15. Patient is willing and able to comply with the protocol for the duration of the study,
             including undergoing biopsy (if warranted), treatment, scheduled visits and
             examinations

        Exclusion Criteria:

          1. A diagnosis of ataxia telangiectasia

          2. Prior treatment with a PARP inhibitor (e.g. olaparib, veliparib, niraparib,
             rucaparib), AZD6738 or other DNA-damage response agents

          3. Cytotoxic chemotherapy, first- or second-generation antiandrogen or CYP17 inhibitors
             are not permitted within 21 days or 5 half-lives of registration (whichever is
             longest).

          4. Major surgery < 2 weeks prior to enrolment; patients must have recovered from any
             effects of major surgery

          5. Persistent toxicities (≥CTCAE Grade 2) caused by previous cancer therapy, besides
             Grade 2 alopecia and Grade 2 neuropathy (these are allowed).

          6. Patients with current or prior MDS/AML or with features suggestive of MDS/AML

          7. Any other malignancy which has been active or treated within the past 3 years, with
             the exception of non-melanomatous skin cancer, or Ta bladder cancer

          8. Patients with active brain metastases are excluded because of unknown penetration into
             the CNS. A confirmatory scan for asymptomatic patients is not required. Patients with
             a history of treated central nervous system (CNS) metastases are eligible provided
             they meet all of the following criteria: disease outside the CNS is present, no
             clinical evidence of progression since completion of CNS-directed therapy, minimum 3
             weeks between completion of radiotherapy and registration and recovery from
             significant (Grade ≥ 3) acute toxicity with no ongoing requirement for >10 mg of
             prednisone per day or an equivalent dose of other corticosteroid. Patients with spinal
             cord compression unless considered to have received definitive treatment for this and
             evidence of clinically stable disease for 28 days.

          9. Any of the following cardiac disease currently or within the last 6 months:

               1. Unstable angina pectoris

               2. Congestive heart failure (by New York Heart Association ≥ Class 2) or known
                  reduced LVEF < 55%

               3. Acute myocardial infarction

               4. Conduction abnormality not controlled with pacemaker or medication (e.g. complete
                  left bundle branch block or third-degree heart block)

               5. Significant ventricular or supraventricular arrhythmias (patients with chronic
                  rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
                  are eligible).

               6. Uncontrolled hypertension (Grade 2 or above) requiring clinical intervention

               7. Patients at risk of brain perfusion problems, e.g. TIAs or history of pre-
                  syncope or syncopal episodes unexplained by reversible causes

         10. Mean resting corrected QT interval> 470 msec for females and >450 for men, obtained
             from 3 ECGs 2-5 minutes apart using the Fredericia formula. Absence of any factors
             that increase the risk of QTc prolongation or risk of arrhythmic such as congenital
             long QT syndrome, immediate family history of long QT syndrome or unexplained sudden
             death under 40 year of age. Patients with relative hypotension (<90/60 mmHg) or
             previously known clinically relevant orthostatic hypotension defined as a postural
             hypotension ≥20 mmHg

         11. Concomitant use of known potent cytochrome P (CYP) 3A inhibitors or inducers. The
             required washout period prior to starting study treatment is five half-lives except
             for St-Johns' wort, which is 3 weeks. See Appendix B.

               -  Patient has had prescription or non-prescription drugs or other products known to
                  be CYP3A4 and/or CYP2B6 substrates or CYP3A4 and/or CYP2B6 substrates with a
                  narrow therapeutic index. Exposure of other drugs metabolised by CYP3A4 and/or
                  CYP2B6 may be reduced and additional monitoring may be required. See Appendix B.

               -  The use of herbal supplements or 'folk remedies' (and medications and foods that
                  significantly modulate CYP3A activity) should be discouraged. If deemed
                  necessary, such products may be administered with caution and the reason for use
                  documented in the CRF. Please see Appendix B for further details.

         12. As judged by the Investigator, any evidence of severe or uncontrolled systemic
             diseases that places the patient at unacceptable risk of toxicity or non-compliance.
             Examples include, but are not limited to, active bleeding diatheses, renal transplant,
             uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome,
             extensive bilateral lung disease on High Resolution CT scan, severe Parkinson's
             disease, active inflammatory bowel disease, psychiatric condition, immunocompromised
             patients or active infection including any patient known to have hepatitis B,
             hepatitis C and human immunodeficiency virus (HIV) or requiring systemic antibiotics,
             antifungals or antiviral drugs. Screening for chronic conditions is not required

         13. A known hypersensitivity to olaparib, AZD6738 or any excipient of the product or any
             contraindication to the combination anti-cancer agent as per local prescribing
             information

         14. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with the absorption of the study
             medication, refractory nausea and vomiting, chronic gastrointestinal diseases or
             previous significant bowel resection, with clinically significant sequelae that would
             preclude adequate absorption of AZD6738

         15. Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT).

         16. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable, for timing refer to inclusion
             criteria no.12)

         17. Involvement in the planning and/or conduct of the study

         18. Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and
             requirements.

         19. Previous enrolment in the present study.

         20. Has received a live vaccination with 2 weeks of enrollment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of response (Complete Response [CR] or Partial Response [PR]) in DNA repair proficient (DRPro) patients
Time Frame:Up to 30 days after study completion (an average of 1 year)
Safety Issue:
Description:Evaluated per radiographic response according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or by Prostate Specific Antigen (PSA) (≥50% decline).

Secondary Outcome Measures

Measure:Rate of response (Complete Response [CR] or Partial Response [PR]) in DNA repair deficient (DRDef) patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Evaluated per radiographic response according to RECIST v1.1 or PSA (≥50% decline).
Measure:Progression-free survival (PFS) in DRPro patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Duration of time from start of treatment to time of progression (based only on radiographic progression or clinical decline/death).
Measure:Progression-free survival (PFS) in DRDef patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Duration of time from start of treatment to time of progression (based only on radiographic progression or clinical decline/death).
Measure:Radiographic response rate in DRPro patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Evaluated according to RECIST v1.1.
Measure:Radiographic response rate in DRDef patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Evaluated according to RECIST v1.1.
Measure:PSA progression-free survival in DRPro patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Composite of survival and duration of PSA control as defined by time from start of therapy to first PSA increase ≥ 25% and ≥2 ng/ml above the nadir and confirmed by a second value at or beyond 4 weeks later.
Measure:PSA progression-free survival in DRDef patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Composite of survival and duration of PSA control as defined by time from start of therapy to first PSA increase ≥ 25% and ≥2 ng/ml above the nadir and confirmed by a second value at or beyond 4 weeks later.
Measure:PSA response rate in DRPro patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Rate of achieving PSA response rate of ≤ 0.2 ng/ml, 50% decline, or 90% decline from entry PSA and confirmed 4 weeks later
Measure:PSA response rate in DRDef patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Rate of achieving PSA response rate of ≤ 0.2 ng/ml, 50% decline, or 90% decline from entry PSA and confirmed 4 weeks later
Measure:Duration of combined radiographic and PSA response in DRPro patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Time from first documented response (RECIST v1.1 CR/PR or PSA decline ≥50%) until death, recurrent or progressive disease (based on RECIST v1.1) or first PSA increase ≥ 25% and ≥2 ng/ml above the PSA nadir.
Measure:Duration of combined radiographic and PSA response in DRDef patients
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:Time from first documented response (RECIST v1.1 CR/PR or PSA decline ≥50%) until death, recurrent or progressive disease (based on RECIST v1.1) or first PSA increase ≥ 25% and ≥2 ng/ml above the PSA nadir.
Measure:Adverse Events
Time Frame:Up to 30 days after study completion (an average of 1 year for study completion)
Safety Issue:
Description:NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Measure:Incidence of Myelodysplastic Syndrome (MDS), acute myeloid leukemia (AML) and new primary malignancy
Time Frame:Up to 5 years after study completion (an average of 1 year for study completion)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Michigan Rogel Cancer Center

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