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

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.