None listed
Conditions
Interventions
Patients wil receive RMC-4630 (On day 1 and day 2 every week) and LY3214996 
(daily). In addition, biopsies are taken before start treatment, during 
treatment and (optional) after disease progression. Furthermore, 
pharmacokinetic sampling will be performed on day 1 and day 15 of the first 
cycle. Adiitionally, every first day of a new cycle (28 days) a sample will be 
taken to determine RMC-4630 and LY3214996 concentrations.
Sponsors
Antoni van Leeuwenhoek Ziekenhuis
Eligibility
Age
18 Years to 99 Years
Inclusion 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 PDAC. 2. Age: 18 years and older; 3. Able and willing to give written informed consent; 4. WHO performance status of 0, 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, allowing adequate follow up of toxicity evaluation and antitumor activity; 8. Evaluable disease (PART A and PART B) 9. Women of childbearing potential must have an negative serum pregnancy test within 14 days prior to registration and agree to use effective contraceptive thoughout the treatment period, and for 4 months after the first of study treatment 10. Adequate organ system function
Exclusion criteria
Exclusion criteria: - Part A: No excluded genotypes - Part B: Excluded genotypes (including co occurring mutations): o NRAS (except G12A/C) o RASQ61 o KRASG13 o BRAF Class 1, 2, or unclassified o PIK3CA o STK11 o KEAP1 - Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment; - 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. - Patients who have had previous treatment with any targeted drug combination known to interfere RAS/MEK/MAPK pathway components. - Woman who are pregnant or breast feeding; - Unreliable contraceptive methods. - 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. - Patients with cardiac comorbidities, uncontrolled hypertension, prolonged QT interval or patients who have had a stroke within 3 months prior to start study. - Known hypersensitivity to one of the study drugs or excipients. - Baseline diarrhea and/or any condition that would impair absorption of oral agents - Toxicities related to prior treatments > grade 1 (excluding alopecia)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PART A: Incidence of dose-limiting toxicities (DLTs) PART B: Progression free survival (PFS), Overall survival (OS) and duration of response (DOR) per RECIST version 1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary parameters: - Incidence and severity of adverse events - Plasma concentrations of RMC-4630, LY3214996 and relevant metabolites Exploratory parameters: - Baseline molecular status (mutation/amplification/expression) of potential predictive markers of tumor response. - Expression levels of relevant downstream proteins including pRSK, DUSP4, pSHP2, pS6-RP, and PTEN - Gene alteration (baseline, relapse) in tumor tissue | — |
Contacts
Public Contactn.a.
n.a.
Outcome results
None listed