Dose-Esc/Exp RMC4630 & Cobi in Relapsed/Refractory Solid Tumors & RMC4630& Osi in EGFR+ Locally Adv/Meta NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) proﬁles of RMC-4630 and cobimetinib in adult participants with relapsed/refractory solid tumors with specific genomic aberrations and to identify the recommended Phase 2 dose (RP2D); and to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) proﬁles of RMC-4630 and osimertinib in adult participants with EGFR mutation-positive locally advanced or metastatic NSCLC.

Detailed Description
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This open-label, phase 1b/2 dose-escalation and dose-expansion study is designed to evaluate the safety and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of RMC-4630 in combination with cobimetinib in participants with relapsed/refractory solid tumors; and of RMC-4630 in combination with osimertinib in adult participants with EGFR mutation-positive locally advanced or metastatic NSCLC.

Official Title
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Ph1b/2 Open-Label,Multicenter Dose-Esc & Dose-Exp Study of Combo RMC4630 & Cobimetinib in Participants w/Relapsed/Refractory Solid Tumors & Ph1b Study of RMC4630 w/Osimertinib in Participants w/EGFR Mutation+,Locally Adv or Meta NSCLC

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: RMC-4630
* Drug: Cobimetinib
* Drug: Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years For RMC-4630 + Cobimetinib only - Participants who have advanced solid tumors that have failed, are intolerant to, or are considered ineligible for standard of care anti-cancer treatments including approved drugs for oncogenic drivers in their tumor type. For RMC-4630 + Osimertinib only - Locally advanced or metastatic EGFR mutant NSCLC not amenable to curative surgery or radiotherapy For RMC-4630 + Cobimetinib only - Participants must have one of the following genotypic aberrations: KRAS mutations and amplifications, BRAF Class 3 mutations, or NF1 LOF mutations For RMC-4630 + Osimertinib only - Evidence of radiological documentation of progression with osimertinib monotherapy or an osimertinib containing regimen. Participants should not be considered a current candidate for 1st generation EGFR TKI's by the investigator. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 Adequate hematological, hepatic, and renal function Capable of giving signed informed consent form (ICF). Willing and able to compile with study requirements and restrictions Life expectancy >12 weeks Female of childbearing potential and males with partners of childbearing potential must comply with effective contraception criteria . Exclusion Criteria: Primary central nervous system (CNS) tumors. Known or suspected leptomeningeal or brain metastases or spinal cord compression. For RMC-4630 + osimertinib arm only - Known or suspected Small cell, squamous, or pleomorphic lung transformations Clinically significant cardiac disease Active, clinically signiﬁcant interstitial lung disease or pneumonitis History or current evidence of retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vein occlusion (RVO), or predisposing factors to RPED or RVO Known HIV infection or active/chronic hepatitis B or C infection. Any other unstable or clinically signiﬁcant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol prior/concomitant therapy Females who are pregnant or breastfeeding

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: Parallel Assignment
Interventional Model Description: This is a dose escalation study followed by dose expansion.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RMC-4630 and Cobimetinib<br>RMC-4630 and Cobimetinib for oral administration | Drug: RMC-4630<br>* RMC-4630 for oral administration<br>Drug: Cobimetinib<br>* Cobimetinib for oral administration<br>* Other names: GDC-0973, XL518;|
| Experimental: RMC-4630 and Osimertinib<br>RMC-4630 and Osimertinib for oral administration | Drug: RMC-4630<br>* RMC-4630 for oral administration<br>Drug: Drug: Osimertinib<br>* Osimertinib for oral administration<br>* Other names: AZD9291;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs). | An adverse event (AE) was defined as any untoward medical occurrence in a participant, temporally associated with the use of a pharmaceutical / an investigational product, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product(s) was also an AE. All AEs and SAEs will be collected from the start of intervention until the safety visit or EOT visit, whichever is later. The number of safety-evaluable participants who experienced at least one treatment-emergent AE was reported per protocol. | AEs were collected from the start of intervention through 30 days post last day of study drug taken. Participants were monitored/assessed for adverse events for a maximum of 17 months which includes a maximum duration of 16 months on treatment. | 
| Number of Participants With Dose Limiting Toxicities (DLTs) | Any toxicities occurring during the DLT observation period (cycle 1) that were considered R/T study treatment, including GR4 AEs; GR3 febrile neutropenia or hemorrhage; GR3 thrombocytopenia with clinically significant bleeding; GR ≥2 pneumonitis; GR3 hypertension or rash which does not improve or remains uncontrolled for >5 or more days despite maximal supportive care; GR3 non hematologic AEs that remain uncontrolled for >72 hours despite maximal supportive care; Concurrent elevation of AST or ALT >3 × ULN & total bilirubin >2 × ULN or international normalized ratio (INR) >1.5 in the absence of cholestasis and other causes; Grade 3 QTcF prolongation based on a triplicate ECG; Ejection fraction <50% with an absolute decrease of >10% from baseline; Retinal vein occlusion any grade; 50% or less dose intensity of RMC4630 and/or cobimetnib or osimertinib due to study drug related toxicity. Refer to protocol for further details. | Cycle 1: Study Day 1 - Study Day 28 (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib | 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 | 
| Tmax | Time to achieve peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib | 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 | 
| Area Under the Curve (AUC) | Area under the plasma concentration time curve of RMC-4630 and cobimetinib or RMC-4630 and osimertinib | 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 | 
| Accumulation Ratio | AUC ratio (C1D15 versus C1D1) of RMC-4630 and cobimetinib or RMC-4630 and osimertinib | 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 | 
| Duration of Response (DOR) | Duration of response of RMC-4630 and cobimetinib or RMC-4630 and osimertinib per RECIST v1.1 | Response assessment occurs from the start of intervention until the date of documented disease progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first. | 
| t1/2 | Elimination half-life of RMC-4630 and cobimetinib or RMC-4630 and osimertinib | 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of participants who achieve a CR or PR per RECIST v1.1. ORR and the corresponding 95% two-sided confidence interval were derived. | Response assessment occurs from the start of intervention until the date of documented disease progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SHP2, PTPN11, NSCLC, KRAS G12, BRAF Class 3, NF1 LOF, KRAS amplification, KRAS mutations, advanced solid tumor, advanced solid malignancies, bladder cancer, carcinoma, non-small-cell lung, neoplasm, squamous cell, carcinoma, squamous cell, esophageal neoplasms carcinoma, bronchogenic, bronchial neoplasms, lung neoplasms, respiratory tract neoplasms, thoracic neoplasms, neoplasms by site, neoplasms, lung diseases, respiratory tract diseases, gastrointestinal cancer, colorectal cancer, skin cancer, ovarian cancer, pancreatic cancer, endometrium/uterus cancer, cervical cancer