First-in-Human Study of OKI-219 in Advanced Solid Tumors and Advanced Breast Cancer

Inclusion Criteria:

1. Participants with advanced solid tumors with documented evidence of a PI3KαH1047Rmutation in tumor tissue and/or blood (ie, ctDNA) obtained during the course ofnormal clinical care in a Clinical Laboratory Improvement Amendments (CLIA)- orsimilarly certified laboratory.

2. Cohort-specific disease requirements:

3. Phase 1a Monotherapy Dose Escalation (Part A):

• Participants with advanced solid tumors and no effective standard therapyoption or for whom standard-of-care therapy is not available or notappropriate.
• Participants with HR+/HER2- locally advanced, unresectable or metastaticbreast cancer, must have received at least 1 prior line of hormonaltherapy and at least 1 prior line of cyclin-dependent kinase (CDK)4/6-inhibitor in the advanced or metastatic setting unlesscontraindicated.
• Participants with HER2+ locally advanced, unresectable or metastaticbreast cancer must have received prior taxane, trastuzumab, pertuzumab,tucatinib, and trastuzumab deruxtecan unless unavailable in the region orcontraindicated.
• Participants with HER2-low breast cancer must have received priortrastuzumab deruxtecan unless unavailable in the region orcontraindicated.
• Participants with colorectal cancer must have Kirsten rat sarcoma viraloncogene homolog (KRAS) wild-type disease.

2. Phase 1a Monotherapy Backfill Additional Criterion (Part A):

• Participants must have a tumor amenable to predose, post dose and end-of-treatment tumor biopsy

3. Phase 1b Dose Escalation and Dose Optimization: OKI-219 + fulvestrant (Part B):

• Participants with locally advanced, unresectable or metastatic HR+/HER2-breast cancer must have received at least 1 prior line of hormonal therapyin the advanced or metastatic setting and at least 1 priorCDK4/6-inhibitor unless contraindicated or unavailable in the region.
• Participants must be post-menopausal or agree to ovarian suppression witha gonadotropin-releasing hormone (GnRH) agonist started at least 4 weeksprior to the first dose of study drug.
• Participants with HER2-low breast cancer must have received priortrastuzumab deruxtecan unless unavailable in the region orcontraindicated.
• Candidate for fulvestrant therapy.

4. Phase 1b Dose Escalation and Dose Optimization: OKI-219 + trastuzumab (Part C):

• Participants with HR±/HER2+ locally advanced, unresectable or metastaticbreast cancer must have received prior taxane, trastuzumab, pertuzumab,tucatinib, and trastuzumab deruxtecan unless unavailable in the region orcontraindicated.
• Candidate for trastuzumab therapy.
• Left ventricular ejection fraction (LVEF) > 50%

3. ECOG PS 0 to 1.

4. Life expectancy > 12 weeks.

5. Have adequate archival tumor tissue (block or 10 slides) from a core or surgicalbiopsy, excluding bone biopsies. If no archival tissue is available, a fresh biopsymust be performed.

6. Adequate organ and marrow function, defined as follows:

7. Absolute neutrophil count ≥ 1.5 × 10^9/L;

8. Platelets ≥ 100,000/μL;

9. Hemoglobin ≥ 8.0 g/dL;

10. Total bilirubin within the institutional upper limit of normal (ULN);

11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ×ULN;

12. Creatinine clearance calculated using the Cockcroft-Gault formula ≥ 60 mL/min.

13. All prior clinically significant treatment-related toxicities must have resolved toGrade ≤ 1 or baseline (per CTCAE version 5.0) except for alopecia. Participants withstable Grade 2 peripheral neuropathy or endocrinopathies with stable endocrinereplacement therapy are eligible. Participants with irreversible toxicity that isnot reasonably expected to be exacerbated by study treatment (eg, vitiligo orhearing loss) may be eligible after discussion with the Sponsor.

14. Able to swallow and tolerate oral medications.

15. At least 1 measurable lesion based on RECIST version 1.1.

Exclusion Criteria:

1. Treatment with any investigational product or other anticancer therapy (includingchemotherapy, antibody-drug conjugates, targeted agents, and immunotherapy) within 14 days or 5 half-lives, whichever is shorter, of the first dose of study drug.

2. Prior treatment with the PI3KαH1047R mutant-selective inhibitor LOXO-783.

3. Participants with a known KRAS mutation.

4. Participants with a known deleterious mutation in PTEN or negative for PTEN proteinexpression by IHC.

5. Major surgery or wide-field radiation within 28 days or limited field palliativeradiation within 7 days prior to the first dose of study drug.

6. Known active central nervous system metastasis.

7. Treatment with systemic corticosteroids at a dose of > 10 mg of prednisone orequivalent at the time of enrollment.

8. Uncontrolled Type 1 or Type 2 diabetes.

9. Known history of Crigler-Najjar syndrome.

10. Known Gilbert's syndrome.

11. Participants who are pregnant or nursing.

12. Concomitant active malignancy or previous malignancy within 2 years of the time ofenrollment.

13. Impaired cardiovascular function or clinically significant cardiovascular disease,including any of the following:

14. History of acute myocardial infarction or acute coronary syndromes in the 6months prior to enrollment.

15. Symptomatic congestive heart failure (Grade 2 or higher), history or currentevidence of clinically significant cardiac arrhythmia and/or conductionabnormality in the last 6 months except for medically managed atrialfibrillation or paroxysmal supraventricular tachycardia.

16. Uncontrolled hypertension despite medical management

17. Any medical condition that would impair the administration or absorption of oralagents.

18. History of symptomatic drug-induced pneumonitis.

19. Participants with HIV infection and any of the following:

20. Cluster of differentiation 4 (CD4) count < 350 cells/μL;

21. A history of AIDS with an opportunistic infection within 12 months prior toenrollment;

22. Not on established antiretroviral therapy for at least 4 weeks prior toenrollment and HIV viral load > 400 copies/mL.

23. Positive hepatitis B virus (HBV) core antibody unless antigen negative and HBV DNApolymerase chain reaction (PCR) is negative. In the case of participants withpositive HBV core antibody with antigen negative and negative HBV DNA PCR, theInvestigator should consider the use of prophylaxis for reactivation.

24. Positive hepatitis C virus (HCV) antibody unless PCR negative for HCV RNA withcompletion of curative antiviral treatment.

25. History or current evidence of congenital long QT syndrome.

26. QTc interval corrected using Fridericia's formula (QTcF) > 470 msec on screeningECG.

27. Use of any of the following within 1 week prior to the first dose of study drug orongoing need for these medications throughout the treatment phase:

28. Proton pump inhibitors (PPIs);

29. Medications that are moderate or strong inhibitors or inducers of uridinediphosphate-glucuronosyltransferase (UGT)2B7;

30. Sensitive substrates of organic anion transporter (OAT)1, OAT3, breast cancerresistance protein (BCRP), or OATP1B1 with known risk for clinically relevantdrug interactions related to transporter inhibition (note: the 1-week washoutperiod prior to the first dose is not necessary for these substrates).