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

Purpose

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 other anti-cancer drugs. 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 fulvestrant (Part B), trastuzumab and tucatinib (Part C), atirmociclib (Part D), and ribociclib and fulvestrant (Part E). Participants will continue to receive study treatment until disease progression, intolerable toxicity, or other study treatment withdrawal criteria are met.

Conditions

  • Advanced Cancer
  • Breast Cancer
  • Advanced Solid Tumors
  • PI3K Gene Mutation

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Participants with advanced solid tumors with documented evidence of a PI3KαH1047R mutation in tumor tissue and/or blood (ie, ctDNA). - Eastern Cooperative Oncology Group (ECOG) Performance status score of to 1. - Life expectancy > 12 weeks for Part A and > 6 months for Parts B, C, D, and E in the opinion of the Investigator. - Adequate organ and bone marrow function - Have adequate archival tumor tissue sample available or be approved by the Sponsor for enrollment if no tumor sample is available. - At least 1 measurable lesion based on RECIST version 1.1. Additional Cohort-specific key inclusion criteria: Part A - 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 CDK4/6-inhibitor in the advanced or metastatic setting. - Participants with HER2+ locally advanced, unresectable or metastatic breast cancer, must have received prior taxane, trastuzumab, pertuzumab, and tucatinib. Prior trastuzumab deruxtecan is allowed but not required. - Participants with HER2-low breast cancer must have received prior trastuzumab deruxtecan. - Participants with colorectal cancer must have KRAS wild-type disease. 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. - Participants with HER2-low breast cancer should have received prior trastuzumab deruxtecan Part C ● Participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer must have received prior taxane, trastuzumab, and pertuzumab unless unavailable in the region or contraindicated. Prior trastuzumab deruxtecan is allowed but not required. Part D ● Participants must have HR+/HER2- locally advanced, unresectable or metastatic breast cancer Part E ● Participants must have HR+/HER2- locally advanced, unresectable or metastatic breast cancer.

Exclusion Criteria

  • Treatment with any investigational product or other anticancer therapy within 28 days or 5 half-lives, whichever is shorter, of the start of treatment - Participants with a known KRAS mutation. - Participants with a known deleterious mutation in phosphatase and tensin homolog (PTEN) or negative for PTEN protein expression by IHC. - 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. - Known active central nervous system metastasis, including leptomeningeal disease. - Uncontrolled Type 1 or Type 2 diabetes as defined by HbA1C ≥ 8%. - Concomitant active malignancy or previous malignancy within 2 years of the time of enrollment. - Impaired cardiovascular function or clinically significant cardiovascular disease, - History of symptomatic drug-induced pneumonitis. - Participants with active HIV, Hepatitis B, and Hepatitis C viral infections Additional Cohort-specific key exclusion criteria: Part C: - Grade 2 or higher diarrhea at study entry. - History of chronic liver disease. Part E: ● History of interstitial lung disease.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Phase 1a: Part A Dose Escalation 		OKI-219 Monotherapy Dose Escalation in participants with advanced solid tumors with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
Experimental
Phase 1b: Part B Dose Escalation 		OKI-219 + Fulvestrant Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Fulvestrant
    Intramuscular injection
Experimental
Phase 1b: Part B Dose Optimization 		OKI-219 + Fulvestrant Dose Optimization in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Fulvestrant
    Intramuscular injection
Experimental
Phase 1b: Part C Dose Escalation 		OKI-219 + Tucatinib + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Trastuzumab
    Intravenous (IV)
  • Drug: Tucatinib
    Oral twice daily
Experimental
Phase 1b: Part C Dose Expansion 		OKI-219 + Tucatinib + Trastuzumab Dose Expansion in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Trastuzumab
    Intravenous (IV)
  • Drug: Tucatinib
    Oral twice daily
Experimental
Phase 1b: Part D Dose Escalation 		OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Fulvestrant
    Intramuscular injection
  • Drug: Atirmociclib
    Oral twice daily
Experimental
Phase 1b: Part D Dose Expansion 		OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Fulvestrant
    Intramuscular injection
  • Drug: Atirmociclib
    Oral twice daily
Experimental
Phase 1b: Part E Dose Escalation 		OKI-219 + Fulvestrant + Ribociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Fulvestrant
    Intramuscular injection
  • Drug: Ribociclib
    Oral once daily continuous for 21-days followed by 7 days off
Experimental
Phase 1b: Part E Dose Expansion 		OKI-219 + Fulvestrant + Ribociclib Dose Expansion in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
  • Drug: OKI-219
    Oral twice daily
  • Drug: Fulvestrant
    Intramuscular injection
  • Drug: Ribociclib
    Oral once daily continuous for 21-days followed by 7 days off

Recruiting Locations

Massachusetts General Hospital
Boston 4930956, Massachusetts 6254926 02114
Contact:
Jennifer Petersen
jpetersen3@mgb.org

More Details

Status
Recruiting
Sponsor
OnKure, Inc.

Study Contact

OnKure, Inc.
720-307-2892
info@onkure.com