Study of RP-3500, Camonsertib, in Advanced Solid Tumors

Study Overview
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Brief Summary
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The primary purpose of this study is to define the maximum tolerated dose (MTD) and determine a recommended Phase 2 dose (RP2D) and schedule of orally-administered RP-3500 (camonsertib) alone or in combination with talazoparib, a PARP inhibitor, or Gemcitabine in patients with advanced solid tumors with ATR inhibitor-sensitizing mutations. This study will also evaluate the safety and tolerability of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine, examine both the pharmacokinetics (PK)and pharmacodynamics (PD)and investigate its anti-tumor activity in solid tumors.

Detailed Description
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This is a first-in-human, Phase 1/2a, multi-center, open-label, dose-escalation and expansion study to: Evaluate the safety profile and MTD of RP-3500 (camonsertib) when administered orally, alone and in combination with talazoparib or gemcitabine, to establish the dose and schedule recommended for the Phase 2 Characterize the PK profile of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine Identify anti-tumor activity associated with RP-3500 (camonsertib) given alone or in combination with talazoparib or gemcitabine Examine biomarker responses and establish a correlation with RP-3500 (camonsertib) exposure and clinical outcomes. The initial cohorts will test RP-3500 (camonsertib) as monotherapy. Additional cohorts will enroll with RP-3500 (camonsertib) in combination with talazoparib or gemcitabine. After the RP2D and schedule is determined, expansion cohort(s) for RP-3500 (camonsertib) will be enrolled to study the anti-tumor effect, and further examine the safety and PK of RP-3500 (camonsertib) at the RP2D

Official Title
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Phase 1/2a Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-3500 Alone or in Combination With Talazoparib or Gemcitabine in Advanced Solid Tumors With ATR Inhibitor Sensitizing Mutations (TRESR Study)

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: RP-3500 (camonsertib)
* Drug: Talazoparib
* Drug: Gemcitabine Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent, according to local guidelines, signed and dated by the patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses. Male or female and ≥ 18 years-of-age at the time of signature of the consent. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Histologically confirmed solid tumors resistant or refractory to standard treatment and/or patients who are intolerant to standard therapy. Measurable disease as per RECIST v1.1 Existing biomarker profile (tumor tissue or plasma) reported from a local test obtained in a certified lab per institutional guidelines: Available tumor tissue Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments. Ability to swallow and retain oral medications. Acceptable organ function at screening Acceptable blood counts at screening Negative pregnancy test (serum or urine) for females of childbearing potential at Screening and prior to first study drug. Resolution of all toxicities of prior treatment or surgery. Male patients with female partners of childbearing potential and females of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study and for at least 6 months following last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 6 months following last dose of study drug. Exclusion Criteria: Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 14 days prior to first dose of study drug. History or current condition (such as transfusion dependent anemia or thrombocytopenia), 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. Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor. Known hypersensitivity to any of the ingredients of RP-3500 (camonsertib). Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the patient's safety. Uncontrolled, symptomatic brain metastases. Uncontrolled high blood pressure Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. Moderate or severe hepatic impairment (ie, Child-Pugh class B or C). History or presence of an abnormal ECG that is clinically significant in the investigator's opinion. History of ventricular dysrhythmias or risk factors such as structural heart disease, coronary heart disease (clinically significant electrolyte abnormalities or family history of sudden unexplained death or long QT syndrome Current treatment with medications that are well-known to prolong the QT interval History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: Dose Escalation, expansion and phase 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RP-3500 (camonsertib) alone<br>Phase 1: Multiple doses of RP-3500 (camonsertib) for oral administration alone | Drug: RP-3500 (camonsertib)<br>* Oral ATR inhibitor<br>|
| Experimental: Expansion cohorts with RP-3500 (camonsertib)<br>Phase 2: Expansion cohorts with RP-3500 (camonsertib) | Drug: RP-3500 (camonsertib)<br>* Oral ATR inhibitor<br>|
| Experimental: RP-3500 (camonsertib) with Talazoparib or Gemcitabine<br>Phase 1: Multiple doses of RP-3500 (camonsertib) for oral administration in combination with talazoparib or gemcitabine | Drug: RP-3500 (camonsertib)<br>* Oral ATR inhibitor<br>Drug: Talazoparib<br>* Oral PARP inhibitor<br>Drug: Gemcitabine Injection<br>* Gemcitabine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the Maximum Tolerated Dose (MTD) which will then be used to inform and determine the Recommended Phase 2 Dose (RP2D) and schedule alone or in combination with talazoparib or gemcitabine |  | Up to 90 days after last administration of study intervention | 
| Frequency of Dose limiting Toxicities (DLTs) |  | At the end of cycle 1 (each cycle is 21 days or 28 days) | 
| Safety and tolerability | Grade and frequency of adverse events and serious adverse events | Up to 90 days after last administration of study intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess preliminary anti-tumor activity with Overall Response Rate in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1) or confirmed response in CA-125 or PSA per GCIG or PSWG criteria. | Overall response rate | About 1 year | 
| Assess preliminary anti-tumor activity with Overall Response Rate in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1) | Objective response rate (ORR) | About 1 year | 
| Assess CR+PR+SD (≥ 4 months) based on RECIST v1.1, confirmed CA-125 response by GCIG criteria, or PSA response based on PCWG3 | Clinical Benefit Rate | About 1 year | 
| Assess preliminary anti-tumor activity with Duration of Response (DOR) in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1). | Duration of response (DOR) | About 1 year | 
| Characterize the pharmacokinetic profile of RP-3500 (camonsertib) | Area-under-the-curve (AUC 0-inf) | Through Study Day 152 | 
| Peak plasma concentration | Cmax | Through Study Day 152 | 
| To assess PK parameters of RP-3500 (camonsertib) monotherapy in fasted and fed states | Comparison of geometric mean ratios (GMR) | Through Study Day 152 | 
| Pharmacodynamic biomarkers of DNA damage (e.g. gH2AX) will be measured by immunohistochemistry and the percentage of positive cells will be compared between the pre and post treatment biopsies to evaluate target engagement | Tumor tissue samples will be collected pre and post dosing | Through Study Day -28 to Day 66 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult