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

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).