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Completed

NCT Number: NCT03989115

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

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.

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Key information

Conditions

Solid Tumor Adnexal Diseases Bronchial Diseases Bronchial Neoplasms Carcinoma Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell Cardiovascular Abnormalities Cardiovascular Diseases Colonic Diseases Colorectal Neoplasms Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases Craniofacial Abnormalities Digestive System Diseases Digestive System Neoplasms Endocrine Gland Neoplasms Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Gastrointestinal Diseases Gastrointestinal Neoplasms Genital Diseases Genital Diseases, Female Genital Neoplasms, Female Gonadal Disorders Heart Defects, Congenital Heart Diseases Intestinal Diseases Intestinal Neoplasms Lung Diseases Lung Neoplasms Male Urogenital Diseases Musculoskeletal Abnormalities Musculoskeletal Diseases Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Neoplasms, Squamous Cell Noonan Syndrome Ovarian Diseases Ovarian Neoplasms Pancreatic Diseases Pancreatic Neoplasms Rectal Diseases Respiratory Tract Diseases Respiratory Tract Neoplasms Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases Thoracic Neoplasms Urinary Bladder Diseases Urinary Bladder Neoplasms Urogenital Diseases Urogenital Neoplasms Urologic Diseases Urologic Neoplasms Uterine Cervical Diseases Uterine Cervical Neoplasms Uterine Diseases Uterine Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Severance Hospital Yonsei University Health System, Seoul, Seoul Teugbyeolsi, South Korea

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

RMC-4630

Drug

RMC-4630 for oral administration

Cobimetinib

Drug

Cobimetinib for oral administration

Other names: GDC-0973, XL518

Drug: Osimertinib

Drug

Osimertinib for oral administration

Other names: Tagrisso, AZD9291

Primary outcomes

  1. 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.

  2. 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 outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

Sponsors and collaborators

Lead sponsor

Revolution Medicines, Inc.

Industry

Collaborators

  • Sanofi

Registry information

Official study 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

Important dates

Study start
2019
Primary completion
2022
Study completion
2022
First posted
Jun 18, 2019
Registry last updated
Jun 26, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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