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

NCT04916236 | Terminated Phase 1 DMC

• 1 other identifier: M20SHP
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

SHP2; ERK; Combination therapy; KRAS mutation-related tumors

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (8)

• Observed plasma concentrations of RMC-4630 and LY3214996

  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

  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)

  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

  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

  Prior to initial dose on day 1, day 15, and 0.5, 1, 2, 4, 8, 24 hours post dose.

Study Arms (2)

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.

Drug: RMC-4630; Drug: LY3214996

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.

Drug: RMC-4630; Drug: LY3214996

Interventions

RMC-4630 DRUG

* SHP2-inhibitor * Powder in capsule * Administered on day 1 and day 2 of every week

Also known as: SAR442720

Phase I - Dose-escalation; Phase Ib

LY3214996 DRUG

* ERK inhibitor * Powder in capsule * Administered every day

Phase I - Dose-escalation; Phase Ib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Lustgarten Foundation: collaborator

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Related Publications (2)

• Mainardi S, Mulero-Sanchez A, Prahallad A, Germano G, Bosma A, Krimpenfort P, Lieftink C, Steinberg JD, de Wit N, Goncalves-Ribeiro S, Nadal E, Bardelli A, Villanueva A, Bernards R. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med. 2018 Jul;24(7):961-967. doi: 10.1038/s41591-018-0023-9. Epub 2018 May 28.

  PMID: 29808006 RESULT

• Frank KJ, Mulero-Sanchez A, Berninger A, Ruiz-Canas L, Bosma A, Gorgulu K, Wu N, Diakopoulos KN, Kaya-Aksoy E, Ruess DA, Kabacaoglu D, Schmidt F, Kohlmann L, van Tellingen O, Thijssen B, van de Ven M, Proost N, Kossatz S, Weber WA, Sainz B Jr, Bernards R, Algul H, Lesina M, Mainardi S. Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer. Cell Rep Med. 2022 Nov 15;3(11):100815. doi: 10.1016/j.xcrm.2022.100815.

  PMID: 36384095 DERIVED

MeSH Terms

Conditions

Pancreatic Neoplasms; Colorectal Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

LY3214996

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Emile Voest, MD, PhD

  Netherlands Cancer Institute - Antoni van Leeuwenhoek

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 6, 2021
• First Posted: June 7, 2021
• Study Start: March 31, 2022
• Primary Completion: July 30, 2024
• Study Completion: July 30, 2024
• Last Updated: January 24, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)