Phase Ib Trial of the KRAS G12C Inhibitor Adagrasib (MRTX849) in Combination With the PARP Inhibitor Olaparib in Patients With KRAS G12C Mutated Advanced Solid Tumors, With a Focus on Gynecological, Breast, Pancreatic and KEAP1 Mutated Non-small Cell Lung Cancers

Inclusion Criteria:

• Participants must be ≥ 18 years old and must fulfil all the following inclusioncriteria to be eligible for enrollment into the study.

1. Dose escalation cohort: Histologically confirmed diagnosis of a solid tumormalignancy with a KRAS G12C mutation. Participants are eligible based ondetection of these mutations in tumor tissue or plasma circulating tumor DNA (ctDNA) with a minimum VAF of 1%.

2. Dose expansion cohort 1: Histologically confirmed diagnosis advanced pancreaticcancer with KRAS G12C mutation. Participants must have progressed on at least 1prior line of standard systemic therapy and must be eligible based on detectionof KRAS G12C mutation in tumor tissue or ctDNA with a minimum VAF of 1%.

3. Dose expansion cohort 2: Histologically confirmed diagnosis of advanced breastcancer with KRAS G12C mutation. Participants must have progressed on at least 1prior line of standard systemic therapy and must be eligible based on detectionof KRAS G12C mutation in tumor tissue or ctDNA with a minimum VAF of 1%.

4. Dose expansion cohort 3: Histologically confirmed diagnosis of advanced uterineor epithelial ovarian cancer with KRAS G12C mutation. Participants must haveprogressed on at least 1 prior line of standard systemic therapy and must beeligible based on detection of KRAS G12C mutation in tumor tissue or ctDNA witha minimum VAF of 1%.

5. Dose expansion cohort 4: Histologically confirmed diagnosis of NSCLC with KRASG12C and KEAP1 co-mutations. Participants must have progressed on at least 1prior line of standard systemic therapy and must be eligible based on detectionof KRAS G12C and KEAP1 co-mutations in tumor tissue or plasma circulating tumorDNA (ctDNA) with a minimum VAF of 1%.

6. Unresectable or metastatic disease and for which standard curative orpalliative measures do not exist or are no longer effective.

7. Participants must have evaluable or measurable disease per RECIST v1.1 for thedose escalation cohort and must have measurable disease per RECIST v1.1 fordose expansion cohorts 1-4.

8. Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial.

9. Life expectancy of at least 3 months.

10. Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or,investigational agent) and radiation therapy discontinued at least 2 weeksbefore first dose date.

11. Eastern Cooperative Oncology Group (ECOG) performance status in 0 or 1 (seeAppendix 1).

12. Laboratory values within the screening period:

13. Absolute neutrophil count ≥ 1.5 x 109/L

14. Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)

15. Hemoglobin ≥ 10 g/dL, in the absence of transfusions for at least 28 days

16. Total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) (if associated withliver metastases or Gilbert's disease, ≤ 3 x ULN)

17. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN (if associated with liver metastases, ≤ 5 x ULN)

18. Creatinine clearance ≥51mL/min calculated using a validated predictionequation:Estimated GFR= (140-age(years)∙ Weight (Kg)∙F)/(serum creatine (mgdL)∙72),where F=0.85 for females and F=1 for males.

19. The effects of adagrasib on the developing human fetus are unknown. For thisreason and because the therapeutic agents used in this trial are known to beteratogenic, women and men, who are sexually active and of childbearingpotential, must agree to use two highly effective forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry,for the duration of study participation, and for 6 months following terminationof the study treatment (MDA Policy CLN 1114). This includes all femaleparticipants, between the onset of menses between 18 and 55 years, unless thepatient presents with an applicable exclusionary factor which may be one of thefollowing: (i) Postmenopausal (no menses in greater than or equal to 12consecutive months); (ii) History of hysterectomy or bilateralsalpingo-oophorectomy; (iii) Ovarian failure (Follicle Stimulating Hormone andEstradiol in menopausal range, who have received Whole Pelvic RadiationTherapy); (iv) History of bilateral tubal ligation or another surgicalsterilization procedure; (v) radiation-induced oophorectomy with last menses atleast 1 year ago; and (vi) chemotherapy-induced menopause with at least 1 yearinterval since last menses. Approved methods of birth control are as follows:Hormonal contraception (i.e. birth control pills, injection, implant,transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation orhysterectomy, Subject/Partner post vasectomy, Implantable or injectablecontraceptives, and condoms plus spermicide. Not engaging in sexual activityfor the total duration of the trial and the drug washout period is anacceptable practice; however periodic abstinence, the rhythm method, and thewithdrawal method are not acceptable methods of birth control. Should a womanbecome pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physicianimmediately.

20. Men treated or enrolled on this protocol must also agree to use adequatecontraception and avoid donating sperm prior to the study, for the duration ofstudy participation, and 6 months after completion of the trial.

21. Prior treatment with a therapy targeting PARP or KRAS G12C mutation ispermitted.

22. Ability to understand and the willingness to sign a written informed consentdocument.

23. Willing to comply with clinical trial instructions and requirements.

Exclusion Criteria:

• Participants presenting with any of the following will not be included in the study:

1. Active brain metastases. Patients are eligible if brain metastases areadequately treated and patients are neurologically stable (which is assessed ina case-by-case by the treating physician based on the likelihood of centralnervous system (CNS) activity - except for residual signs or symptoms relatedto the CNS treatment- and by the lack of corticosteroid dosing or by having astable or decreasing dose of ≤ 10 mg daily prednisone, or equivalent) for atleast 2 weeks prior to enrollment.

2. Participants with carcinomatous meningitis.

3. Participants with myelodysplastic syndrome/acute myeloid leukemia or withfeatures suggestive of MDS/AML.

4. Participants who have not recovered from adverse events due to prioranti-cancer therapy (i.e., have residual toxicities > Grade 1), excludingalopecia.

5. History of significant hemoptysis or hemorrhage within 4 weeks of the firstdose date.

6. Undergone major surgery within 4 weeks of first dose date, or not recoveredfrom any major surgery that occurred >2 weeks before starting study treatment.

7. Undergone allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT).

8. History of intestinal disease, inflammatory bowel disease, major gastricsurgery, or other gastrointestinal conditions (e.g., uncontrolled nausea,vomiting, malabsorption syndrome) likely to alter absorption of study treatmentor result in inability to swallow oral medications.

9. Any of the following cardiac abnormalities:

10. Unstable angina pectoris or myocardial infarction within 6 months prior toenrollment

11. Congestive heart failure NYHA ≥ Class 3 within 6 months prior toenrollment

12. Left ventricular ejection fraction (LVEF) < 50%

13. QTc > 480 milliseconds or medical or immediate family history ofcongenital Long QT Syndrome

14. Symptomatic or uncontrolled atrial fibrillation or other arrhythmia within 6 prior to enrollment

15. History of uncontrolled ventricular arrhythmia, recent (within 6 months)myocardial infarction

16. History of stroke or transient ischemic attack within 6 months prior toenrollment.

17. Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitorslisted in Section 5.5 and Appendix 4, Table 23. The required washout periodprior to starting study treatment is 2 weeks.

18. Concomitant use of known strong or moderate CYP3A inducers listed in Section 5.5 and Appendix 4, Table 23. The required washout period prior to startingstudy treatment is 5 weeks.

19. Use of a medication with any of the following characteristics, which cannot beswitched to an alternative treatment prior to study entry:

20. Substrate of P-gp with narrow therapeutic index

21. Strong inhibitor of BCRP

22. Proton pump inhibitor

23. Known risk of QT prolongation or Torsades de Pointes

24. Any substances listed in Section 6.3

25. Known or suspected presence of another malignancy, unless curatively treated,with no evidence of disease for ≥5 years with the exception of adequatelytreated non-melanoma skin cancer, curatively treated in situ cancer of thecervix, ductal carcinoma in situ (DCIS), Stage 1-grade 1 endometrial carcinoma.

26. Known history of human immunodeficiency virus (HIV) infection or acute orchronicHepatitis B or C infection. Note that the following are permitted:

27. Participants treated for hepatitis C with no detectable viral load;

28. Patients treated for HIV with no detectable viral load for at least 1month prior to enrollment while on a stable regimen of agents that are notstrong inhibitors of CYP3A4

29. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documentedwithin the 28-day screening period prior start of study drug.

30. Breast-feeding or planning to breast feed during the study or within 6 monthsafter study treatment.

31. Any serious illness, uncontrolled inter-current illness, psychiatric illness,active or uncontrolled infection, or other medical history, includinglaboratory results, which, in the Investigator's opinion, would be likely tointerfere with the participant's participation in the study, or with theinterpretation of the results.

32. History of uncontrolled ventricular arrhythmia, recent (within 6 months)myocardial infarction, uncontrolled major seizure disorder, unstable spinalcord compression, superior vena cava syndrome, extensive interstitial bilaterallung disease on High Resolution Computed Tomography (HRCT) scan

33. Participants with a known hypersensitivity to olaparib or any of the excipientsof the product

34. Patients that received live virus and live bacterial vaccines within 3 days oftrial enrollment.