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

A Multi-Center Phase II Study Testing the Activity of Olaparib and AZD6738 (ATR Inhibitor) in Metastatic Castration-Resistant Prostate Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Olaparib; Drug: AZD6738

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospital
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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 Patients must be withdrawn from prior therapy for ≥3 weeks (patients may remain on prior prednisone up to 10 mg total daily exposure at provider's discretion) at planned time of treatment start.
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 or known germline loss of BRCA1, BRCA2 or ATM. If no site is reachable, or first biopsy insufficient/unsuccessful, circulating tumor DNA may be obtained.
10. Treated with continuous androgen deprivation therapy (either surgical castration or LHRH agonist/antagonist) with documented castrate level of serum testosterone (<50 ng/dL). A stable dose of bisphosphonate or denosumab for bone metastases should be continued as long as started at least 5 days prior to C1D1 planned start day.
11. At the time of planned treatment start (C1D1), at least 21 or more days will have elapsed from palliative radiation (with the exception of radiation to >30% of bone marrow or with a wide field of radiation, this requires 28 or more days).

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 ≥16 weeks
14. Male patients who are sexually active must be willing to use barrier contraception for the duration of the study and for 1 week after the last study drug administration, with all sexual partners. Male patients must use a condom during treatment and for 6 months after the last dose of study drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential and must not donate sperm for 6 months after the last dose of study drug. Female partners of male patients should also use a highly effective form of contraception (per protocol) for 6 months after the last dose of study drug(s) if they are of childbearing potential. True abstinence is an acceptable form of contraception and must be documented as such.
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 (e.g. cisplatin or carboplatin)
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) of planned treatment start. For clarity, enzalutamide requires 5 weeks washout.
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. If a patient must remain on steroids, they must have started the steady dose at least 28 days prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days prior to study treatment.

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 urgent (for example, adjusting medications within 24 hours) 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 >450, 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 or moderate cytochrome P (CYP) 3A inhibitors (e.g. itraconazole, ciprofloxacin, diltiazem) require 2-week washout prior to planned C1D1. Concomitant use of strong or moderate CYP3A inducers (e.g. phenobarbital, enzalutamide, modafinil require 5-week washout for enzalutamide or phenobarbital and 3 week washout for all others, per protocol.
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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (DRPro); Patients with metastatic castration-resistant prostate cancer (mCRPC) who are DNA repair proficient (DRPro).	Drug: Olaparib; 300 mg by mouth twice a day for days 1-28 of a 28-day cycle.; Other Names: AZD2281; ceralasertib; Drug: AZD6738; 160 mg by mouth daily for days 1-7 of a 28-day cycle.
Experimental: Cohort 2 (DRDef); Patients with metastatic castration-resistant prostate cancer (mCRPC) who are DNA repair deficient (DRDef).	Drug: Olaparib; 300 mg by mouth twice a day for days 1-28 of a 28-day cycle.; Other Names: AZD2281; ceralasertib; Drug: AZD6738; 160 mg by mouth daily for days 1-7 of a 28-day cycle.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of response (Complete Response [CR] or Partial Response [PR]) in DNA repair deficient (DRDef) patients	Evaluated per radiographic response according to RECIST v1.1 or PSA (≥50% decline).	Up to 30 days after study completion (an average of 1 year for study completion)
Progression-free survival (PFS) in DRPro patients	Duration of time from start of treatment to time of progression (based only on radiographic progression or clinical decline/death).	Up to 30 days after study completion (an average of 1 year for study completion)
Progression-free survival (PFS) in DRDef patients	Duration of time from start of treatment to time of progression (based only on radiographic progression or clinical decline/death).	Up to 30 days after study completion (an average of 1 year for study completion)
Radiographic response rate in DRPro patients	Evaluated according to RECIST v1.1.	Up to 30 days after study completion (an average of 1 year for study completion)
Radiographic response rate in DRDef patients	Evaluated according to RECIST v1.1.	Up to 30 days after study completion (an average of 1 year for study completion)
PSA progression-free survival in DRPro patients	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.	Up to 30 days after study completion (an average of 1 year for study completion)
PSA progression-free survival in DRDef patients	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.	Up to 30 days after study completion (an average of 1 year for study completion)
PSA response rate in DRPro patients	Rate of achieving PSA response rate of ≤ 0.2 ng/ml, 50% decline, or 90% decline from entry PSA and confirmed 4 weeks later	Up to 30 days after study completion (an average of 1 year for study completion)
PSA response rate in DRDef patients	Rate of achieving PSA response rate of ≤ 0.2 ng/ml, 50% decline, or 90% decline from entry PSA and confirmed 4 weeks later	Up to 30 days after study completion (an average of 1 year for study completion)
Duration of combined radiographic and PSA response in DRPro patients	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.	Up to 30 days after study completion (an average of 1 year for study completion)
Duration of combined radiographic and PSA response in DRDef patients	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.	Up to 30 days after study completion (an average of 1 year for study completion)
Adverse Events	NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	Up to 30 days after study completion (an average of 1 year for study completion)
Incidence of Myelodysplastic Syndrome (MDS), acute myeloid leukemia (AML) and new primary malignancy		Up to 5 years after study completion (an average of 1 year for study completion)

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Zachery Reichert, M.D., University of Michigan Rogel Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2019
• Primary Completion (Actual): January 26, 2023
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 24, 2018
• First Submitted That Met QC Criteria: December 24, 2018
• First Posted (Actual): December 26, 2018

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: UMCC 2018.108; HUM00152799 (Other Identifier: University of Michigan)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No