Phase 1b/2 Study of ATR InhibiTor RP-3500 and PARP Inhibitor Combinations in Patients With Molecularly Selected Cancers (ATTACC)

This is a first-in-human Phase 1b/2, multi-center, open-label, dose-escalation and expansion study to:

• Evaluate the safety profile and MTD of RP-3500 when administered orally in combination with Niraparib or Olaparib to establish the recommended Phase 2 dose and schedule.
• Characterize the PK profile of RP-3500 in combination with Niraparib or Olaparib
• Assess anti-tumor activity associated with RP-3500 in combination with Niraparib or Olaparib
• Examine biomarker responses and establish a correlation with RP-3500 treatment in combination with Niraparib or Olaparib.

After the RP2D and schedule is determined, expansion cohort(s) for RP-3500 in combination with Niraparib or Olaparib will be enrolled to study the anti-tumor effect, and further examine the safety, PK, and pharmacodynamic (PD).

Inclusion Criteria:

• Male or female and ≥18 years-of-age at the time of signature of the informed consent
• Confirmed advanced solid tumors resistant or refractory to standard treatment
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
• Measurable disease as per RECIST v1.1
• Next generation sequencing (NGS) report obtained in CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarkers.
• Submission of available tumor tissue or willingness to have a biopsy performed if safe and feasible
• Acceptable hematologic and organ function at screening
• Negative pregnancy test for women of childbearing potential at Screening and prior to first study drug.
• Ability to swallow and retain oral medications.

Exclusion Criteria:

• Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor.
• Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 10 days or 5 half-lives (whichever is longer), prior to first dose of study drug.
• Use of radiotherapy (except for palliative reasons) within 7 days prior to first dose of study drug.
• History or current condition, therapy, or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment.
• No other anticancer therapy is to be permitted while the patient is receiving study treatment.
• Major surgery ≤28 days or minor surgical procedures ≤7 days prior to first study treatment dose.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled high blood pressure
• History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis
• Presence of other known active invasive cancers.
• Pregnant or breastfeeding women.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the study protocol and/or follow-up procedures outlined in the protocol.