Study of RP-6306 Alone or in Combination with RP-3500 or Debio 0123 in Patients with Advanced Solid Tumors

The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.

Phase 1/1b, multi-center, open-label, dose-escalation study to:

* Evaluate the safety profile and MTD of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 when administered orally to establish the recommended Phase 2 dose and schedule
* Characterize the PK and pharmacodynamics of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123
* Assess preliminary anti-tumor activity associated with RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123

Eligibility Criteria:
Inclusion Criteria:

* Male or female and ≥12 years-of-age at the time of informed consent.
* Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, (or 2 for module 1) for patients \>16 years of age.
* Locally advanced or metastatic resistant or refractory solid tumors.
* Patients \<18 years of age must weigh at least 40 kg.
* Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible
* Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker.
* CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH
* FBXW7 deleterious mutations identified by either a tumor or plasma NGS test
* PPP2R1A deleterious mutations identified by either a tumor or plasma NGS test
* Measurable disease as per RECIST v1.1. For certain modules, patients with prostate cancer or ovarian cancer that have non-measurable disease but have elevated tumor markers (PSA or CA-125, respectively) can also be eligible
* Ability to swallow and retain oral medications.
* Acceptable hematologic and organ function at screening.
* Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
* Resolution of all toxicities of prior therapy or surgical procedures.
* Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.

Exclusion Criteria:

* Chemotherapy or small molecule antineoplastic agent given within 21 days or \<5 half-lives, whichever is shorter, 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.
* Patients who are pregnant or breastfeeding.
* Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
* Major surgery within 4 weeks prior to first dose of RP-6306.
* Uncontrolled, symptomatic brain metastases.
* Uncontrolled hypertension.
* Certain prior anti-cancer therapy
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.