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

OKI-219-101 is a Phase 1a/1b, open-label, multicenter, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and efficacy of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab. Phase 1a (Part A) will investigate escalating doses of OKI-219 monotherapy, and Phase 1b will investigate OKI-219 (at a tolerated dose determined in Part A) in combination with standard dose fulvestrant (Part B) or standard dose trastuzumab (Part C). Participants will continue to receive study treatment until disease progression, intolerable toxicity, or other study treatment withdrawal criteria are met.


Eligibility Criteria:
Inclusion Criteria:

1. Participants with advanced solid tumors with documented evidence of a PI3KαH1047R mutation in tumor tissue and/or blood (ie, ctDNA) obtained during the course of normal clinical care in a Clinical Laboratory Improvement Amendments (CLIA)- or similarly certified laboratory.
2. Cohort-specific disease requirements:

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

      * Participants with advanced solid tumors and no effective standard therapy option or for whom standard-of-care therapy is not available or not appropriate.
      * Participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer, must have received at least 1 prior line of hormonal therapy and at least 1 prior line of cyclin-dependent kinase (CDK)4/6-inhibitor in the advanced or metastatic setting unless contraindicated.
      * Participants with HER2+ locally advanced, unresectable or metastatic breast cancer must have received prior taxane, trastuzumab, pertuzumab, tucatinib, and trastuzumab deruxtecan unless unavailable in the region or contraindicated.
      * Participants with HER2-low breast cancer must have received prior trastuzumab deruxtecan unless unavailable in the region or contraindicated.
      * Participants with colorectal cancer must have Kirsten rat sarcoma viral oncogene 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 therapy in the advanced or metastatic setting and at least 1 prior CDK4/6-inhibitor unless contraindicated or unavailable in the region.
      * Participants must be post-menopausal or agree to ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist started at least 4 weeks prior to the first dose of study drug.
      * Participants with HER2-low breast cancer must have received prior trastuzumab deruxtecan unless unavailable in the region or contraindicated.
      * 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 metastatic breast cancer must have received prior taxane, trastuzumab, pertuzumab, tucatinib, and trastuzumab deruxtecan unless unavailable in the region or contraindicated.
      * 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 surgical biopsy, excluding bone biopsies. If no archival tissue is available, a fresh biopsy must be performed.
6. Adequate organ and marrow function, defined as follows:

   1. Absolute neutrophil count ≥ 1.5 × 10\^9/L;
   2. Platelets ≥ 100,000/μL;
   3. Hemoglobin ≥ 8.0 g/dL;
   4. Total bilirubin within the institutional upper limit of normal (ULN);
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN;
   6. Creatinine clearance calculated using the Cockcroft-Gault formula ≥ 60 mL/min.
7. All prior clinically significant treatment-related toxicities must have resolved to Grade ≤ 1 or baseline (per CTCAE version 5.0) except for alopecia. Participants with stable Grade 2 peripheral neuropathy or endocrinopathies with stable endocrine replacement therapy are eligible. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment (eg, vitiligo or hearing loss) may be eligible after discussion with the Sponsor.
8. Able to swallow and tolerate oral medications.
9. At least 1 measurable lesion based on RECIST version 1.1.

Exclusion Criteria:

1. Treatment with any investigational product or other anticancer therapy (including chemotherapy, 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 protein expression by IHC.
5. Major surgery or wide-field radiation within 28 days or limited field palliative radiation 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 or equivalent 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 of enrollment.
13. Impaired cardiovascular function or clinically significant cardiovascular disease, including any of the following:

    1. History of acute myocardial infarction or acute coronary syndromes in the 6 months prior to enrollment.
    2. Symptomatic congestive heart failure (Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality in the last 6 months except for medically managed atrial fibrillation or paroxysmal supraventricular tachycardia.
    3. Uncontrolled hypertension despite medical management
14. Any medical condition that would impair the administration or absorption of oral agents.
15. History of symptomatic drug-induced pneumonitis.
16. Participants with HIV infection and any of the following:

    1. Cluster of differentiation 4 (CD4) count \< 350 cells/μL;
    2. A history of AIDS with an opportunistic infection within 12 months prior to enrollment;
    3. Not on established antiretroviral therapy for at least 4 weeks prior to enrollment and HIV viral load \> 400 copies/mL.
17. Positive hepatitis B virus (HBV) core antibody unless antigen negative and HBV DNA polymerase chain reaction (PCR) is negative. In the case of participants with positive HBV core antibody with antigen negative and negative HBV DNA PCR, the Investigator should consider the use of prophylaxis for reactivation.
18. Positive hepatitis C virus (HCV) antibody unless PCR negative for HCV RNA with completion of curative antiviral treatment.
19. History or current evidence of congenital long QT syndrome.
20. QTc interval corrected using Fridericia's formula (QTcF) \> 470 msec on screening ECG.
21. Use of any of the following within 1 week prior to the first dose of study drug or ongoing need for these medications throughout the treatment phase:

    1. Proton pump inhibitors (PPIs);
    2. Medications that are moderate or strong inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)2B7;
    3. Sensitive substrates of organic anion transporter (OAT)1, OAT3, breast cancer resistance protein (BCRP), or OATP1B1 with known risk for clinically relevant drug interactions related to transporter inhibition (note: the 1-week washout period prior to the first dose is not necessary for these substrates).