A Study Investigating DNA-damage Response Agents in Molecularly Altered Advanced Cancer

Prior treatment

• Previous therapy with an telangiectasia and rad3 related protein inhibitor.
• Exposure to a small molecule investigational product within 14 days or 5 half-lives.
• Concomitant use of known strong CYP 3A inhibitors and inducers.

Other illness

• Participants with known active infections ((i.e., hepatitis B or C, tuberculosis, or COVID-19).
• Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.

Lab values

• Any of the following cardiac diseases currently or within the last 6 months:
  • Unstable angina pectoris.
  • Congestive heart failure \> Class 2 as defined by the New York Heart Association
  • Acute myocardial infarction.
  • Significant ventricular or supraventricular arrhythmias.
  • Mean resting corrected QT interval (QTc) \> 470 msec obtained from three electrocardiograms (ECGs) in 24 hours using the Fredericia formula.
  • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age.
  • For Cohort B (mCRPC\]), surgery or local prostatic intervention (excluding a prostatic biopsy) within 28 days of Cycle 1 Day 1.

Other

• Participants with symptomatic and/or uncontrolled brain metastases.

• Participants must have a histologically confirmed diagnosis of AST (excluding NSCLC) or mCRPC tumour.
• Participants must have a deleterious or suspected deleterious ATM mutation in tumour or blood (germline or ctDNA). Definitions of qualifying ATM mutations may include deleterious/suspected deleterious, pathogenic/likely pathogenic, disease- or cancer-associated variants, or equivalent wording. Variants of unknown significance, benign or likely benign alterations are not qualifying.
• Participant must have normal organ and bone marrow function measured within 28 days prior to the first dose of study intervention.
• Participants who have no curative treatment options and are deemed appropriate for an investigational study in the opinion of the investigator.
• Availability of archival or fresh tumour specimens for central testing of ATM protein loss using immunohistochemistry and for confirmation of ATM mutation using next generation sequencing.
• Previously received and progressed on at least one novel hormonal agent (eg, abiraterone acetate, apalutamide, and/or enzalutamide) for the treatment of prostate cancer
• Participants with histologically confirmed metastatic castrate resistant prostate cancer.
• Documented prostate cancer progression at study entry while on androgen deprivation or after bilateral orchiectomy as assessed by the investigator.
• Serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within (≤) 28 days before enrolment.