Solid Tumor
Conditions
Keywords
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
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.
Detailed description
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.
Interventions
DRUGRMC-4630
RMC-4630 for oral administration
DRUGCobimetinib
Cobimetinib for oral administration
DRUGDrug: Osimertinib
Osimertinib for oral administration
Sponsors
Sanofi
Revolution Medicines, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a dose escalation study followed by dose expansion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs). | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) | 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 | 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 |
| Cmax | 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 |
| t1/2 | 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) | 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. |
| Duration of Response (DOR) | 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 |
| Tmax | 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 |
Countries
South Korea, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) Participants who received intermittent dose of RMC-4630 80mg on D1 and D4 of a 28-day cycle and Cobimetinib 20 mg QD 21 days on and 7 days off of a 28-day cycle. | 8 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) Participants who received intermittent dose of RMC-4630 80mg on D1 and D4 of a 28-day cycle and Cobimetinib 40 mg QD 21 days on and 7 days off of a 28-day cycle. | 6 |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) Participants who received intermittent dose of RMC-4630 140mg on D1 and D4 of a 28-day cycle and Cobimetinib 20 mg QD 21 days on and 7 days off of a 28-day cycle. | 12 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) Participants who received intermittent dose of RMC-4630 140mg on D1 and D2 of a 28-day cycle and Cobimetinib 20 mg QD 21 days on and 7 days off of a 28-day cycle. | 7 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) Participants who received intermittent dose of RMC-4630 140mg on D1 and D2 of a 28-day cycle and Cobimetinib 40 mg D1 and D2 of a 28-day cycle. | 65 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg (D1D2) Participants who received intermittent dose of RMC-4630 140mg on D1 and D2 of a 28-day cycle and Cobimetinib 60 mg D1 and D2 of a 28-day cycle. | 7 |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg QD Participants who received intermittent dose of RMC-4630 100 mg on D1 and D2 of a 28-day cycle and Osimertinib 80 mg QD. | 4 |
| IIntermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg QD Participants who received intermittent dose of RMC-4630 140 mg on D1 and D2 of a 28-day cycle and Osimertinib 80 mg QD. | 4 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 2 | 2 | 9 | 6 | 31 | 6 | 2 | 3 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Other | 1 | 2 | 0 | 0 | 5 | 0 | 0 | 0 |
| Overall Study | Sponsor decision to terminate the study | 1 | 1 | 0 | 1 | 11 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 3 | 0 | 17 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg (D1D2) | Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg QD | IIntermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg QD | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 0 Participants | 15 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 6 Participants | 7 Participants | 50 Participants | 8 Participants | 6 Participants | 2 Participants | 2 Participants | 85 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 5 Participants | 1 Participants | 8 Participants | 1 Participants | 0 Participants | 4 Participants | 2 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 6 Participants | 45 Participants | 7 Participants | 5 Participants | 0 Participants | 1 Participants | 76 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 2 Participants | 34 Participants | 5 Participants | 4 Participants | 2 Participants | 2 Participants | 58 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 5 Participants | 31 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 2 / 6 | 9 / 12 | 6 / 7 | 31 / 65 | 6 / 7 | 2 / 4 | 3 / 4 |
| other Total, other adverse events | 8 / 8 | 6 / 6 | 12 / 12 | 7 / 7 | 64 / 65 | 7 / 7 | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 2 / 8 | 4 / 6 | 3 / 12 | 3 / 7 | 29 / 65 | 3 / 7 | 1 / 4 | 1 / 4 |
Outcome results
Primary
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.
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.
Population: All safety-evaluable participants who experienced at least one treatment-emergent AE.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Number of Participants With Adverse Events (AEs). | 8 Participants |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Number of Participants With Adverse Events (AEs). | 6 Participants |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Number of Participants With Adverse Events (AEs). | 12 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Number of Participants With Adverse Events (AEs). | 7 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Number of Participants With Adverse Events (AEs). | 64 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Number of Participants With Adverse Events (AEs). | 7 Participants |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Number of Participants With Adverse Events (AEs). | 4 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Number of Participants With Adverse Events (AEs). | 4 Participants |
Primary
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.
Time frame: Cycle 1: Study Day 1 - Study Day 28 (28 days)
Population: DLT-evaluable population was defined as the following: All treated participants in the dose escalation phase who completed the DLT period and received at least 75% of planned dose of RMC-4630 and cobimetinib or RMC-4630 and Osimertinib (ie, not have missed ≥3 doses of RMC-4630 and cobimetinib on the D1D2 intermittent schedule or ≥6 doses of cobimetinib on the 21 on/7 off schedule, or ≥8 doses for reasons other than toxicity) within the DLT observation period (i.e Cycle 1)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Number of Participants With Dose Limiting Toxicities (DLTs) | 3 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
Secondary
Accumulation Ratio
AUC ratio (C1D15 versus C1D1) of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
Time frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Accumulation Ratio | 1.36 ratio | Geometric Coefficient of Variation 56 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Accumulation Ratio | 1.22 ratio | Geometric Coefficient of Variation 24 |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Accumulation Ratio | 1.24 ratio | Geometric Coefficient of Variation 16 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Accumulation Ratio | 1.20 ratio | Geometric Coefficient of Variation 28 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Accumulation Ratio | 1.19 ratio | Geometric Coefficient of Variation 41 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Accumulation Ratio | 1.20 ratio | Geometric Coefficient of Variation 41 |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Accumulation Ratio | 1.12 ratio | Geometric Coefficient of Variation 20 |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Accumulation Ratio | 0.841 ratio | Geometric Coefficient of Variation 41 |
Secondary
Area Under the Curve (AUC)
Area under the plasma concentration time curve of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
Time frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Area Under the Curve (AUC) | C1D1 | 2570 ng/mL x h | Geometric Coefficient of Variation 34 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Area Under the Curve (AUC) | C1D15 | 3220 ng/mL x h | Geometric Coefficient of Variation 91 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Area Under the Curve (AUC) | C1D1 | 2580 ng/mL x h | Geometric Coefficient of Variation 30 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Area Under the Curve (AUC) | C1D15 | 3360 ng/mL x h | Geometric Coefficient of Variation 44 |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Area Under the Curve (AUC) | C1D1 | 5510 ng/mL x h | Geometric Coefficient of Variation 38 |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Area Under the Curve (AUC) | C1D15 | 6370 ng/mL x h | Geometric Coefficient of Variation 37 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Area Under the Curve (AUC) | C1D1 | 4610 ng/mL x h | Geometric Coefficient of Variation 39 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Area Under the Curve (AUC) | C1D15 | 5580 ng/mL x h | Geometric Coefficient of Variation 45 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Area Under the Curve (AUC) | C1D1 | 4700 ng/mL x h | Geometric Coefficient of Variation 38 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Area Under the Curve (AUC) | C1D15 | 5460 ng/mL x h | Geometric Coefficient of Variation 45 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Area Under the Curve (AUC) | C1D1 | 4720 ng/mL x h | Geometric Coefficient of Variation 26 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Area Under the Curve (AUC) | C1D15 | 5600 ng/mL x h | Geometric Coefficient of Variation 18 |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Area Under the Curve (AUC) | C1D15 | 4230 ng/mL x h | Geometric Coefficient of Variation 35 |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Area Under the Curve (AUC) | C1D1 | 3360 ng/mL x h | Geometric Coefficient of Variation 28 |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Area Under the Curve (AUC) | C1D1 | 5920 ng/mL x h | Geometric Coefficient of Variation 15 |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Area Under the Curve (AUC) | C1D15 | 5500 ng/mL x h | Geometric Coefficient of Variation 26 |
Secondary
Cmax
Peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
Time frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Cmax | C1D1 | 214 ng/mL | Geometric Coefficient of Variation 45 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Cmax | C1D15 | 207 ng/mL | Geometric Coefficient of Variation 90 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Cmax | C1D1 | 248 ng/mL | Geometric Coefficient of Variation 38 |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Cmax | C1D15 | 266 ng/mL | Geometric Coefficient of Variation 64 |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Cmax | C1D1 | 469 ng/mL | Geometric Coefficient of Variation 42 |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Cmax | C1D15 | 465 ng/mL | Geometric Coefficient of Variation 37 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Cmax | C1D1 | 430 ng/mL | Geometric Coefficient of Variation 61 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Cmax | C1D15 | 504 ng/mL | Geometric Coefficient of Variation 71 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Cmax | C1D1 | 354 ng/mL | Geometric Coefficient of Variation 52 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Cmax | C1D15 | 395 ng/mL | Geometric Coefficient of Variation 56 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Cmax | C1D15 | 469 ng/mL | Geometric Coefficient of Variation 20 |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Cmax | C1D1 | 449 ng/mL | Geometric Coefficient of Variation 27 |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Cmax | C1D15 | 286 ng/mL | Geometric Coefficient of Variation 38 |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Cmax | C1D1 | 242 ng/mL | Geometric Coefficient of Variation 57 |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Cmax | C1D1 | 449 ng/mL | Geometric Coefficient of Variation 25 |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Cmax | C1D15 | 408 ng/mL | Geometric Coefficient of Variation 3 |
Secondary
Duration of Response (DOR)
Duration of response of RMC-4630 and cobimetinib or RMC-4630 and osimertinib per RECIST v1.1
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.
Population: There were insufficient number of participants with events to calculate.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Duration of Response (DOR) | NA day(s) |
Secondary
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Overall Response Rate (ORR) | 0 % of participants |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Overall Response Rate (ORR) | 0 % of participants |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Overall Response Rate (ORR) | 0 % of participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Overall Response Rate (ORR) | 0 % of participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Overall Response Rate (ORR) | 1.82 % of participants |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Overall Response Rate (ORR) | 0 % of participants |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Overall Response Rate (ORR) | 0 % of participants |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Overall Response Rate (ORR) | 0 % of participants |
Secondary
t1/2
Elimination half-life of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
Time frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | t1/2 | C1D1 | 15.7 h |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | t1/2 | C1D15 | 20.8 h |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | t1/2 | C1D1 | 16.1 h |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | t1/2 | C1D15 | 24.5 h |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | t1/2 | C1D1 | 15.1 h |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | t1/2 | C1D15 | 15.7 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | t1/2 | C1D1 | 16.2 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | t1/2 | C1D15 | 22.2 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | t1/2 | C1D1 | 17.0 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | t1/2 | C1D15 | 14.4 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | t1/2 | C1D1 | 16.9 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | t1/2 | C1D15 | 18.4 h |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | t1/2 | C1D15 | 24.6 h |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | t1/2 | C1D1 | 20.1 h |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | t1/2 | C1D1 | 16.6 h |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | t1/2 | C1D15 | NA h |
Secondary
Tmax
Time to achieve peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib
Time frame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Tmax | C1D1 | 2.94 h |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7) | Tmax | C1D15 | 2.04 h |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Tmax | C1D1 | 2.00 h |
| Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7) | Tmax | C1D15 | 2.08 h |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Tmax | C1D1 | 1.99 h |
| Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7) | Tmax | C1D15 | 3.04 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Tmax | C1D1 | 1.02 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7) | Tmax | C1D15 | 1.08 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Tmax | C1D1 | 2.00 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2) | Tmax | C1D15 | 2.00 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Tmax | C1D1 | 1.92 h |
| Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2 | Tmax | C1D15 | 1.96 h |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Tmax | C1D15 | 1.98 h |
| Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD) | Tmax | C1D1 | 2.03 h |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Tmax | C1D1 | 2.95 h |
| Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD) | Tmax | C1D15 | 4.07 h |