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

Study Overview
=================
Brief Summary
-----------------
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
-----------------
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.

Official Title
-----------------
Phase I/Ib Study With the Combination of RMC-4630 (SHP2 Inhibitor) and LY3214996 (ERK Inhibitor) in Metastatic KRAS Mutant CRC, PDAC and NSCLC

Conditions
-----------------
Pancreatic Cancer, Colorectal Cancer, Non-small Cell Lung Cancer, KRAS Mutation-Related Tumors

Intervention / Treatment
-----------------
* Drug: RMC-4630
* Drug: LY3214996


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part A: Histological or cytological proof of advanced KRASm NSCLC, CRC or PDAC; PART B: Histological or cytological proof of advanced KRASm PDAC. Age => 18 years; Able and willing to give written informed consent; WHO performance status of 0 or 1 Able and willing to undergo blood sampling for PK and PD analysis; 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; 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; Evaluable disease according to RECIST 1.1 criteria; (PART A and PART B); 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 Adequate organ system function. Exclusion Criteria: 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 Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment; Patients currently using concomitant medication that are strong inhibitors or inducers of CYP3A4; 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. Symptomatic or untreated leptomeningeal disease 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 not permitted to receive antiepileptic drugs or corticosteroids. Patients who have had previous treatment with any targeted drug combination known to interfere RAS/MEK/MAPK pathway components. Toxicities related to prior treatments > grade 1 (excluding alopecia) History of interstitial lung disease or pneumonitis Woman who are breast feeding; Patients who have undergone any major surgery within the last 4 weeks prior to starting study drug or who would not have fully recovered from previous surgery. Radio- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment; except a palliative dose of radiation of 8 Gy, which is allowed up to one week before study start and should not be applied to the target lesion. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients; Patients with a known history of or uncontrolled hepatitis B (HBV) or C (HCV); Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance; Patients with cardiac comorbidities (myocardial infarct within 6 months of study start, NYHA class ≥ III, congestive heart failure or instable angina pectoris), uncontrolled hypertension (systolic blood pressure > 160 mm Hg and/or diastolic pressure > 90 mm Hg), prolonged QT interval(> 440 ms for men, > 460 ms for women) or patients who have had a stroke within 6 months prior to start study. Other severe, acute, or chronic medical or psychiatric condition, laboratory abnormality active infections that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study. Patients with pulmonary embolisms or deep venous thrombosis (DVT) within 3 months prior to start Known hypersensitivity to one of the study drugs or excipients. Baseline diarrhea and/or any condition that would impair absorption of oral agents Patient with a history or findings of central or branch retinal artery or venous occlusion with significant vision loss or other retinal diseases that cause current visual impairment or would likely cause visual impairment over the time period of the study, as assessed by an ophthalmologist.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A: Phase I study - Dose-escalation of RMC-4630 and LY3214996 combination to determine RP2D/MTD. Dose level will be escalated according to standard 3+3 design. Part B: Phase Ib study - To further characterize the safety, tolerability and PK/PD of the RP2D of the RMC-4630 and LY3214996 combination. Expansion cohort in which patients with KRASm PDAC will be treated with the RP2D found in Part A of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Dose-escalation<br>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. | Drug: RMC-4630<br>* SHP2-inhibitor Powder in capsule Administered on day 1 and day 2 of every week<br>* Other names: SAR442720;Drug: LY3214996<br>* ERK inhibitor Powder in capsule Administered every day<br>|
| Experimental: Phase Ib<br>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. | Drug: RMC-4630<br>* SHP2-inhibitor Powder in capsule Administered on day 1 and day 2 of every week<br>* Other names: SAR442720;Drug: LY3214996<br>* ERK inhibitor Powder in capsule Administered every day<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Through study completion, an average of 2 year | 
| 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 | Tumor assessed every 8 weeks through study completion, with an expected average of 4 treatment cycles (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed plasma concentrations of RMC-4630 and LY3214996 | Blood samples are obtained and plasma concentrations of RMC-4630 and LY3214996 are measured using a validated LC-MS/MS method. | 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. | 
| Area under de plasma - time concentration curve of RMC-4630 and LY3214996 | Blood samples are obtained and plasma concentrations of RMC-4630 and LY3214996 are measured using a validated LC-MS/MS method. | Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose. | 
| Elimination half-life of RMC-4630 and LY3214996 (T1/2) | Blood samples are obtained and plasma concentrations of RMC-4630 and LY3214996 are measured using a validated LC-MS/MS method. | Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose. | 
| Total body clearance of RMC-4630 and LY3214996 | Blood samples are obtained and plasma concentrations of RMC-4630 and LY3214996 are measured using a validated LC-MS/MS method. | Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose. | 
| Volume of distribution of RMC-4630 and LY3214996 | Blood samples are obtained and plasma concentrations of RMC-4630 and LY3214996 are measured using a validated LC-MS/MS method. | Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose. | 
| Baseline molecular status of potential predictive markers of tumor response | Baseline molecular status of potential predictive markers of tumor response wil be studied in tumor biopsies taken before treatment, during treatment and (optional) after treatment using the Ampliseq SOCV1panel | 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) | 
| Pharmacodynamic biomarkers of RMC-4630 and LY3214996 | To evaluate pharmacodynamic (PD) biomarkers of the RMC-4630- LY3214996 combination, the expression levels of relevant down-stream proteins are measured in tumor biopsies, using the Ampliseq SOCV1panel. Markers to be assessed include molecular status (mutation/amplification/expression) of markers related to the RAF/MEK/ERK and PI3K/AKT pathway (e.g. BRAF, HRAS, NRAS, KRAS, PIK3CA, PTEN, pS6-RP, c-MET, EGFR, HER-3, pERK, pAKT, pEGFR, and pRSK). | 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) | 
| Potential mechanism of resistance | Potential mechanisms of are studied in tumor biopsies taken before treatment, during treatment and (optional) after treatment using the Ampliseq SOCV1panel | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SHP2, ERK, Combination therapy, KRAS mutation-related tumors