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NCT03989115

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

Completed Phase 1, PHASE2 Results posted Last updated 26 June 2023
What this trial tests

Phase 1, PHASE2 trial testing RMC-4630 in Solid Tumor in 113 participants. Completed in 8 February 2022.

Timeline
2 July 2019
Primary endpoint
8 February 2022
8 February 2022

Quick facts

Lead sponsorRevolution Medicines, Inc.
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment113
Start date2 July 2019
Primary completion8 February 2022
Estimated completion8 February 2022
Sites24 locations across United States, South Korea

Drugs / interventions tested

Conditions studied

Sponsor

Revolution Medicines, Inc. — full company profile →

Who can join

18 and older, any sex, with Solid Tumor. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Adverse Events (AEs). Primary · 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 conditio

GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)8
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)6
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)12
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)7
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)64
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D27
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)4
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)4
Number of Participants With Dose Limiting Toxicities (DLTs) Primary · 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 abs

GroupValue95% CI
Intermittent RMC-4630 (D1D4 or D1D2) + Daily Cobimetinib (QD21/7)1
Intermittent RMC-4630 (D1D2) + Intermittent Cobimetinib (D1D2)0
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)3
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)1
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)0
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D22
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)1
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)2
Cmax Secondary · 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

C1D1
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)214± 45
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)248± 38
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)469± 42
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)430± 61
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)354± 52
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2449± 27
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)242± 57
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)449± 25
C1D15
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)207± 90
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)266± 64
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)465± 37
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)504± 71
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)395± 56
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2469± 20
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)286± 38
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)408± 3
Tmax Secondary · 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

C1D1
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)2.941.00 – 4.13
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)2.001.00 – 2.03
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)1.990.90 – 7.50
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)1.020.98 – 2.00
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)2.000.42 – 8.00
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D21.920.92 – 3.97
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)2.030.98 – 7.55
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)2.951.07 – 4.10
C1D15
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)2.041.00 – 4.07
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)2.080.97 – 4.99
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)3.041.87 – 7.77
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)1.081.00 – 2.12
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)2.000.57 – 23.7
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D21.960.97 – 2.07
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)1.981.88 – 2.00
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)4.074.05 – 4.08
Area Under the Curve (AUC) Secondary · 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

C1D1
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)2570± 34
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)2580± 30
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)5510± 38
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)4610± 39
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)4700± 38
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D24720± 26
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)3360± 28
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)5920± 15
C1D15
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)3220± 91
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)3360± 44
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)6370± 37
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)5580± 45
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)5460± 45
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D25600± 18
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)4230± 35
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)5500± 26
Accumulation Ratio Secondary · 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

GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)1.36± 56
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)1.22± 24
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)1.24± 16
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)1.20± 28
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)1.19± 41
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D21.20± 41
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)1.12± 20
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)0.841± 41
Duration of Response (DOR) Secondary · 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

GroupValue95% CI
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)NA
t1/2 Secondary · 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

C1D1
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)15.712.3 – 20.2
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)16.115.2 – 20.9
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)15.111.7 – 20.6
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)16.215.1 – 35.7
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)17.010.8 – 26.2
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D216.914.9 – 20.1
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)20.114.0 – 26.2
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)16.616.6 – 16.6
C1D15
GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)20.815.0 – 31.2
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)24.519.8 – 29.2
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)15.714.9 – 17.3
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)22.216.5 – 91.7
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)14.45.18 – 18.2
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D218.411.3 – 24.8
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)24.615.2 – 25.2
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)NANA – NA
Overall Response Rate (ORR) Secondary · 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.

GroupValue95% CI
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)00.0 – 45.9
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)00.0 – 45.9
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)00.0 – 36.9
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)00.0 – 45.9
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)1.820.0 – 9.7
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D200.0 – 45.9
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)00.0 – 7.1
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)00.0 – 7.1

Adverse events — posted to ClinicalTrials.gov

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.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)
Serious: 2/8 (25%)
Deaths: 2/8
Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)
Serious: 4/6 (67%)
Deaths: 2/6
Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)
Serious: 3/12 (25%)
Deaths: 9/12
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)
Serious: 3/7 (43%)
Deaths: 6/7
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)
Serious: 29/65 (45%)
Deaths: 31/65
Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2
Serious: 3/7 (43%)
Deaths: 6/7
Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)
Serious: 1/4 (25%)
Deaths: 2/4
Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)
Serious: 1/4 (25%)
Deaths: 3/4

Serious adverse events (46 terms)

ReactionSystemIntermittent RMC-4630 80mg…Intermittent RMC-4630 80mg…Intermittent RMC-4630 140m…Intermittent RMC-4630 140m…Intermittent RMC-4630 140m…Intermittent RMC-4630 140m…Intermittent RMC-4630 100m…Intermittent RMC-4630 140m…
pneumoniaInfections and infestations
gastrointestinal hemorrhageGastrointestinal disorders
vomitingGastrointestinal disorders
sepsisInfections and infestations
COVID-19 pneumoniaInfections and infestations
pneumonitisRespiratory, thoracic and mediastinal disorders
hypoxiaRespiratory, thoracic and mediastinal disorders
pleural effusionRespiratory, thoracic and mediastinal disorders
pulmonary embolismRespiratory, thoracic and mediastinal disorders
non-cardiac chest painGeneral disorders
anaemiaBlood and lymphatic system disorders
myocardial infarctionCardiac disorders
large intestinal obstructionGastrointestinal disorders
small intestinal obstructionGastrointestinal disorders
abdominal painGastrointestinal disorders
diarrhoeaGastrointestinal disorders
ileus paralyticGastrointestinal disorders
intestinal obstructionGastrointestinal disorders
upper gastrointestinal haemorrhageGastrointestinal disorders
pneumonia legionellaInfections and infestations
haemoptysisRespiratory, thoracic and mediastinal disorders
dyspnoeaRespiratory, thoracic and mediastinal disorders
dehydrationMetabolism and nutrition disorders
hyperkalaemiaMetabolism and nutrition disorders
hypoglycaemiaMetabolism and nutrition disorders
Other adverse events (155 terms — click to expand)

ReactionSystemIntermittent RMC-4630 80mg…Intermittent RMC-4630 80mg…Intermittent RMC-4630 140m…Intermittent RMC-4630 140m…Intermittent RMC-4630 140m…Intermittent RMC-4630 140m…Intermittent RMC-4630 100m…Intermittent RMC-4630 140m…
diarrhoeaGastrointestinal disorders
nauseaGastrointestinal disorders
fatigueGeneral disorders
anaemiaBlood and lymphatic system disorders
oedema peripheralGeneral disorders
dyspnoeaRespiratory, thoracic and mediastinal disorders
visual impairmentEye disorders
constipationGastrointestinal disorders
abdominal painGastrointestinal disorders
decreased appetiteMetabolism and nutrition disorders
vomitingGastrointestinal disorders
pyrexiaGeneral disorders
hypokalaemiaMetabolism and nutrition disorders
aspartate aminotransferase increasedInvestigations
hypoalbuminaemiaMetabolism and nutrition disorders
dizzinessNervous system disorders
platelet count decreasedInvestigations
vision blurredEye disorders
hypoxiaRespiratory, thoracic and mediastinal disorders
abdominal distentionGastrointestinal disorders
dry mouthGastrointestinal disorders
coughRespiratory, thoracic and mediastinal disorders
pleural effusionRespiratory, thoracic and mediastinal disorders
dehydrationMetabolism and nutrition disorders
thrombocytopeniaBlood and lymphatic system disorders
non-cardiac chest painGeneral disorders
weight increasedInvestigations
hypertensionVascular disorders
dyspepsiaGastrointestinal disorders
blood creatine phosphokinase increasedInvestigations
blood alkaline phosphatase increasedInvestigations
blood creatinine increasedInvestigations
headacheNervous system disorders
proteinuriaRenal and urinary disorders
hypotensionVascular disorders
lymphocyte count decreasedInvestigations
hypomagnesaemiaMetabolism and nutrition disorders
hyponatraemiaMetabolism and nutrition disorders
gamma-glutamyltranferase increasedInvestigations
alanine aminotransferase increasedInvestigations

Most-reported serious reactions: pneumonia, gastrointestinal hemorrhage, vomiting, sepsis, COVID-19 pneumonia, pneumonitis, hypoxia, pleural effusion.

Data from ClinicalTrials.gov NCT03989115 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. RAS-targeted therapies: is the undruggable drugged?
    Moore AR, Rosenberg SC, McCormick F, Malek S. · · 2020 · cited 832× · PMID 32528145 · DOI 10.1038/s41573-020-0068-6
  2. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy.
    Yuan J, Dong X, Yap J, Hu J. · · 2020 · cited 388× · PMID 32807225 · DOI 10.1186/s13045-020-00949-4
  3. The current state of the art and future trends in RAS-targeted cancer therapies.
    Punekar SR, Velcheti V, Neel BG, Wong KK. · · 2022 · cited 382× · PMID 36028717 · DOI 10.1038/s41571-022-00671-9
  4. Tumor biomarkers for diagnosis, prognosis and targeted therapy.
    Zhou Y, Tao L, Qiu J, Xu J, et al · · 2024 · cited 379× · PMID 38763973 · DOI 10.1038/s41392-024-01823-2
  5. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants.
    Hofmann MH, Gerlach D, Misale S, Petronczki M, et al · · 2022 · cited 247× · PMID 35046095 · DOI 10.1158/2159-8290.cd-21-1331
  6. Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.
    Xie X, Yu T, Li X, Zhang N, et al · · 2023 · cited 246× · PMID 37669923 · DOI 10.1038/s41392-023-01589-z
  7. Emerging strategies to target RAS signaling in human cancer therapy.
    Chen K, Zhang Y, Qian L, Wang P. · · 2021 · cited 164× · PMID 34301278 · DOI 10.1186/s13045-021-01127-w
  8. Targeting <i>KRAS</i> Mutant Non-Small-Cell Lung Cancer: Past, Present and Future.
    Uras IZ, Moll HP, Casanova E. · · 2020 · cited 109× · PMID 32560574 · DOI 10.3390/ijms21124325

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