Combination Therapy of RMC-4630 and LY3214996 in Metastatic KRAS Mutant Cancers

Brief summary public domain (ClinicalTrials.gov)

This is a Phase I/Ib study in which the safety of the combination therapy of RMC-4630 and LY3214996 in the treatment of KRAS mutant cancers will be studied.

Detailed description public domain (ClinicalTrials.gov)

This is a phase I / Ib study in which the safety of the combination therapy of RMC-4630 and LY3214996 in the treatment of KRAS mutant cancers colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma will be studied. The phase I dose-escalation study is designed to identify the recommended phase 2 dose (RP2D) of the combination regimen of RMC-4630 (SHP2-inhibitor) plus LY3214996 (ERK-inhibitor) in patients with KRASm CRC, NSCLC or PDAC. The phase Ib expansion cohort is designed to further characterize the safety of the selected dose from the first stage of the study and to explore the clinical activity of RMC-4630 in combination with LY3214996 in patients with metastatic KRASm PDAC.

Intervention public domain (ClinicalTrials.gov)

Drug: RMC-4630. * SHP2-inhibitor * Powder in capsule * Administered on day 1 and day 2 of every week

Intervention public domain (ClinicalTrials.gov)

Drug: LY3214996. * ERK inhibitor * Powder in capsule * Administered every day

Arm public domain (ClinicalTrials.gov)

Phase I - Dose-escalation (experimental): This is a single-center open-label phase I dose-finding study (3+3 classical design) evaluating the RP2D of RMC-4630 in combination with LY3214996. Based on the safety, tolerability, and PK and PD data from the dose-finding stage of the study, a RP2D will be defined for the expansion phase.

Arm public domain (ClinicalTrials.gov)

Phase Ib (experimental): The phase Ib expansion cohort study is intended to further characterize the safety, tolerability and PK/PD of the selected dose of RMC-4630 in combination with LY3214996 in patients with advanced KRASm PDAC. Furthermore, it will explore the clinical activity of RMC-4630 in combination with LY3214996 in patients with advanced KRASm PDAC.

Primary outcome public domain (ClinicalTrials.gov)

Phase I - Maximum tolerated dose (MTD). Maximum Tolerated Dose (MTD) of the combination of RMC-4630 and LY3214996. Dose escalation will follow 3+3 design. The CTCAE criteria will be used to determine if adverse events and lab abnormalities will be accounted as dose limiting toxicity (DLT) Time frame: Through study completion, an average of 2 year.

Primary outcome public domain (ClinicalTrials.gov)

Phase Ib - Clinical activity of the RMC-4630 and LY3214996 combination in patients with KRASm PDAC. Response and progression evaluated using internationally accepted response criteria and definitions proposed by the RECIST criteria Time frame: Tumor assessed every 8 weeks through study completion, with an expected average of 4 treatment cycles (each cycle is 28 days).

Secondary outcome public domain (ClinicalTrials.gov)

Observed plasma concentrations of RMC-4630 and LY3214996. Time frame: Prior to initial dose on day 1, day 8, day 15, day 22 and 0.5, 1, 2, 4, 8, 24 hours post dose on day 1 and day 15..

Secondary outcome public domain (ClinicalTrials.gov)

Area under de plasma - time concentration curve of RMC-4630 and LY3214996. Time frame: Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose..

Secondary outcome public domain (ClinicalTrials.gov)

Elimination half-life of RMC-4630 and LY3214996 (T1/2). Time frame: Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose..

Secondary outcome public domain (ClinicalTrials.gov)

Total body clearance of RMC-4630 and LY3214996. Time frame: Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose..

Secondary outcome public domain (ClinicalTrials.gov)

Volume of distribution of RMC-4630 and LY3214996. Time frame: Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose..

Secondary outcome public domain (ClinicalTrials.gov)

Baseline molecular status of potential predictive markers of tumor response. Time frame: Before start of treatment, during treatment and (optional) after treatment discontinuation with RMC-4630 and LY3214996 with an expected average of 4 treatment cycles (each cycle is 28 days).

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: 1. Part A: Histological or cytological proof of advanced KRASm NSCLC, CRC or PDAC; PART B: Histological or cytological proof of advanced KRASm PDAC. 2. Age =\> 18 years; 3. Able and willing to give written informed consent; 4. WHO performance status of 0 or 1 5. Able and willing to undergo blood sampling for PK and PD analysis; 6. Able and willing to undergo tumor biopsies prior to start (or have undergone a biopsy within 2 months of inclusion), while on study treatment and upon progression of disease; 7. Life expectancy =\> 3 months and no deterioration or hospitalizations within 2 weeks leading to C1D1, allowing adequate follow up of toxicity evaluation and antitumor activity; 8. Evaluable disease according to RECIST 1.1 criteria; (PART A and PART B); 9. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraceptive methods, as defined in section 5.9.3, through-out the treatment period, and for 4 months after the study treatment 10. Adequate organ system function. Exclusion Criteria: 1. Part A: No excluded genotypes Part B: Excluded genotypes (including co occurring mutations): * NRAS (except G12A/C) * RASQ61 * KRASG13 * BRAF Class 1, 2, or unclassified * PIK3CA * STK11 * KEAP1 2. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment; 3. Patients currently using concomitant medication that are strong inhibitors or inducers of CYP3A4; 4. History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent completely resected second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin. 5. Symptomatic or untreated leptomeningeal disease 6. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 4 weeks) are allowed to enroll. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 24 participants (actual).

Why stopped public domain (ClinicalTrials.gov)

Due to a lack of safety and efficacy.