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

NCT ID: NCT04916236

Last Updated: 2025-01-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-31
• Study Completion Date: 2024-07-30

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase I - Dose-escalation

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.

Group Type: EXPERIMENTAL

RMC-4630

Intervention Type: DRUG

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

LY3214996

Intervention Type: DRUG

• ERK inhibitor
• Powder in capsule
• Administered every day

Phase Ib

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.

Group Type: EXPERIMENTAL

RMC-4630

Intervention Type: DRUG

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

LY3214996

Intervention Type: DRUG

• ERK inhibitor
• Powder in capsule
• Administered every day

Interventions

RMC-4630

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

Intervention Type: DRUG

LY3214996

• ERK inhibitor
• Powder in capsule
• Administered every day

Intervention Type: DRUG

Other Intervention Names

SAR442720

Eligibility Criteria

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 not permitted to receive antiepileptic drugs or corticosteroids.

7. Patients who have had previous treatment with any targeted drug combination known to interfere RAS/MEK/MAPK pathway components.

8. Toxicities related to prior treatments > grade 1 (excluding alopecia)

9. History of interstitial lung disease or pneumonitis

10. Woman who are breast feeding;

11. 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.

12. 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.

13. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;

14. Patients with a known history of or uncontrolled hepatitis B (HBV) or C (HCV);

15. Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance;

16. 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.

17. 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.

18. Patients with pulmonary embolisms or deep venous thrombosis (DVT) within 3 months prior to start

19. Known hypersensitivity to one of the study drugs or excipients.

20. Baseline diarrhea and/or any condition that would impair absorption of oral agents

21. 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lustgarten Foundation

OTHER

Sponsor Role: collaborator

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emile Voest, MD, PhD

Role: STUDY_DIRECTOR

Netherlands Cancer Institute - Antoni van Leeuwenhoek

Locations

Netherlands Cancer Institute - Antoni van Leeuwenhoek

Amsterdam, North Holland, Netherlands

Countries

Netherlands

References

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.

Reference Type: RESULT

PMID: 29808006 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36384095 (View on PubMed)

Other Identifiers

M20SHP

Identifier Type: -

Identifier Source: org_study_id