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Pancreatic CancerPhase 1SHERPANCT04916236

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

A Phase 1 study testing RMC-4630 and LY3214996 in people with Pancreatic Cancer and Colorectal Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
RMC-4630 and LY3214996
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
1 siteNetherlands
Study dates
31 Mar 2022to 30 Jul 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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;
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  • 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.

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • Netherlands Cancer Institute - Antoni van Leeuwenhoek

    Amsterdam, North Holland, 1066 CX

Other trials in Netherlands

About this study

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

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.

Read the 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.

Being tested
RMC-4630, LY3214996
Keywords
SHP2, ERK, Combination therapy, KRAS mutation-related tumors
Medical subject headings
Pancreatic Neoplasms, Colorectal Neoplasms, Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RMC-4630Drug

    Also called SAR442720

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

  • LY3214996Drug

    • ERK inhibitor
    • Powder in capsule
    • Administered every day
Study groups in NCT04916236
Study groupRoleWhat they receive
Phase I - Dose-escalationExperimentalThis 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.
Receives: Drug: RMC-4630; Drug: LY3214996
Phase IbExperimentalThe 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.
Receives: Drug: RMC-4630; Drug: LY3214996

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: Through study completion, an average of 2 year

  2. 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

    Measured: Tumor assessed every 8 weeks through study completion, with an expected average of 4 treatment cycles (each cycle is 28 days)

Secondary outcomes (8)

  1. 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.

    Measured: 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.

  2. 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.

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

  3. 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.

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

  4. 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.

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

  5. 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.

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

  6. 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

    Measured: 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)

  7. 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).

    Measured: 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)

  8. 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

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Jun 2021
  2. Study start31 Mar 2022
  3. Primary completion30 Jul 2024
  4. Study completion30 Jul 2024

Why it stopped: Due to a lack of safety and efficacy.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
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)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04916236
Sponsor's protocol ID
M20SHP
Acronym
SHERPA
Status last verified
Jan 2025
First submitted
6 May 2021
Last updated
24 Jan 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 29808006

  • 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.

    PubMed 36384095

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing RMC-4630 and LY3214996 in people with Pancreatic Cancer and Colorectal Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 24 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Due to a lack of safety and efficacy.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I - Maximum tolerated dose (MTD) (time frame: Through study completion, an average of 2 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04916236, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jan 2025.

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