First-in-Human Study of OKI-219 in Advanced Solid Tumors and Advanced Breast Cancer (PIKture-01)

OnKure

Status and phase: Enrolling; Phase 1

Conditions: Advanced Cancer; Breast Cancer; PI3K Gene Mutation; Advanced Solid Tumors

Treatments: Drug: Ribociclib; Drug: Fulvestrant; Drug: Trastuzumab; Drug: Atirmociclib; Drug: OKI-219; Drug: Tucatinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT06239467

OKI-219-101

Details and patient eligibility

About

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.

Enrollment: 200 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key 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.

Key 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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200 participants in 9 patient groups

Phase 1a: Part A Dose Escalation

Experimental group

Description:

OKI-219 Monotherapy Dose Escalation in participants with advanced solid tumors with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Phase 1b: Part B Dose Escalation

Experimental group

Description:

OKI-219 + Fulvestrant Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Drug: Fulvestrant

Phase 1b: Part B Dose Optimization

Experimental group

Description:

OKI-219 + Fulvestrant Dose Optimization in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Drug: Fulvestrant

Phase 1b: Part C Dose Escalation

Experimental group

Description:

OKI-219 + Tucatinib + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: Tucatinib

Drug: OKI-219

Drug: Trastuzumab

Phase 1b: Part C Dose Expansion

Experimental group

Description:

OKI-219 + Tucatinib + Trastuzumab Dose Expansion in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: Tucatinib

Drug: OKI-219

Drug: Trastuzumab

Phase 1b: Part D Dose Escalation

Experimental group

Description:

OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Drug: Atirmociclib

Drug: Fulvestrant

Phase 1b: Part D Dose Expansion

Experimental group

Description:

OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Drug: Atirmociclib

Drug: Fulvestrant

Phase 1b: Part E Dose Escalation

Experimental group

Description:

OKI-219 + Fulvestrant + Ribociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Drug: Fulvestrant

Drug: Ribociclib

Phase 1b: Part E Dose Expansion

Experimental group

Description:

OKI-219 + Fulvestrant + Ribociclib Dose Expansion in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Treatment:

Drug: OKI-219

Drug: Fulvestrant

Drug: Ribociclib