Dose-Esc/Exp RMC4630 & Cobi in Relapsed/Refractory Solid Tumors & RMC4630& Osi in EGFR+ Locally Adv/Meta NSCLC
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| ClinicalTrials.gov Identifier: NCT03989115 |
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Recruitment Status :
Completed
First Posted : June 18, 2019
Results First Posted : June 26, 2023
Last Update Posted : June 26, 2023
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Sponsor:
Revolution Medicines, Inc.
Collaborator:
Sanofi
Information provided by (Responsible Party):
Revolution Medicines, Inc.
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Solid Tumor | Drug: RMC-4630 Drug: Cobimetinib Drug: Drug: Osimertinib | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 113 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | This is a dose escalation study followed by dose expansion. |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | July 2, 2019 |
| Actual Primary Completion Date : | February 8, 2022 |
| Actual Study Completion Date : | February 8, 2022 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: RMC-4630 and Cobimetinib
RMC-4630 and Cobimetinib for oral administration
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Drug: RMC-4630
RMC-4630 for oral administration Drug: Cobimetinib Cobimetinib for oral administration
Other Name: GDC-0973, XL518 |
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Experimental: RMC-4630 and Osimertinib
RMC-4630 and Osimertinib for oral administration
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Drug: RMC-4630
RMC-4630 for oral administration Drug: Drug: Osimertinib Osimertinib for oral administration
Other Names:
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Primary Outcome Measures :
- Number of Participants With Adverse Events (AEs). [ Time Frame: 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. ]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.
- Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1: Study Day 1 - Study Day 28 (28 days) ]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.
Secondary Outcome Measures :
- Cmax [ Time Frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 ]Peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
- Tmax [ Time Frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 ]Time to achieve peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
- Area Under the Curve (AUC) [ Time Frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 ]Area under the plasma concentration time curve of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
- Accumulation Ratio [ Time Frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 ]AUC ratio (C1D15 versus C1D1) of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
- Duration of Response (DOR) [ Time Frame: 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. ]Duration of response of RMC-4630 and cobimetinib or RMC-4630 and osimertinib per RECIST v1.1
- t1/2 [ Time Frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15 ]Elimination half-life of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
- Overall Response Rate (ORR) [ Time Frame: 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. ]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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03989115
Locations
Show 24 study locations
Sponsors and Collaborators
Revolution Medicines, Inc.
Sanofi
Investigators
| Study Director: | Revolution Medicines, Inc. | Revolution Medicines, Inc. |
Study Documents (Full-Text)
Documents provided by Revolution Medicines, Inc.:
Documents provided by Revolution Medicines, Inc.:
Study Protocol and Statistical Analysis Plan [PDF] November 20, 2020
| Responsible Party: | Revolution Medicines, Inc. |
| ClinicalTrials.gov Identifier: | NCT03989115 |
| Other Study ID Numbers: |
RMC-4630-02 |
| First Posted: | June 18, 2019 Key Record Dates |
| Results First Posted: | June 26, 2023 |
| Last Update Posted: | June 26, 2023 |
| Last Verified: | February 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Revolution Medicines, Inc.:
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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 |
Additional relevant MeSH terms:
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Neoplasms Osimertinib Tyrosine Kinase Inhibitors Protein Kinase Inhibitors |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |