Study of RP-6306 Alone or in Combination With RP-3500 in Patients With Advanced Solid Tumors

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

Detailed Description
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Phase 1, multi-center, open-label, dose-escalation study to: Evaluate the safety profile and MTD of RP-6306 alone and in combination with RP-3500 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 Assess preliminary anti-tumor activity associated with RP-6306 alone and in combination with RP-3500

Official Title
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Phase 1 Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-6306 Alone or in Combination With RP-3500 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: RP-6306
* Drug: RP-3500


Participation Criteria
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Eligibility Criteria
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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 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. Measurable disease as per RECIST v1.1. 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. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: RP-6306 Single-Agent, Dose Escalation and Food-effect Study<br>Patients receive RP-6306 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified. | Drug: RP-6306<br>* Oral PKMYT1 Inhibitor<br>|
| Experimental: Phase 1: RP-6306 in combination with RP-3500, Dose Escalation Study<br>Patients receive RP-6306 with RP-3500 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified. | Drug: RP-6306<br>* Oral PKMYT1 Inhibitor<br>Drug: RP-3500<br>* Oral ATR Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of RP-6306 in patients with advanced solid tumors as assessed by NCI CTCAE v5.0 |  | Up to 90 days after last administration of study intervention | 
| To define the MTD of RP-6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule |  | Up to 90 days after last administration of study intervention | 
| Safety and Tolerability of RP-6306 in combination with RP-3500 in patients with advanced solid tumors as assessed by NCI CTCAE v5.0 |  | Up to 90 days after last administration of study intervention | 
| To define the MTD of RP-6306 in combination with RP-3500, and determine a recommended Phase 2 dose (RP2D) and preferred schedule |  | Up to 90 days after last administration of study intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the plasma concentrations of RP-6306 monotherapy in the fasted and fed states. |  | through study completion, an average of 1 year | 
| To assess the correlation between RP-6306 dose (mg) and degree of inhibition of phospho-CDK1 signal by immunohistochemistry. |  | for the first 3 months on treatment | 
| To assess the percent of patients with a response to RP-6306 monotherapy per RECIST v1.1 criteria. |  | Through Study Completion, an average of 1 year | 
| To assess the correlation between RP-6306 and RP-3500 dose (mg) and degree of gamma-H2AX induction by immunohistochemistry. |  | for the first 3 months on treatment | 
| To assess the percent of patients with a response to RP-6306 and RP-3500 per RECIST v1.1 criteria. |  | Through Study Completion, an average of 1 year |