Advanced Cancer, Breast Cancer, Advanced Solid Tumors, PI3K Gene Mutation
Conditions
Keywords
PI3K, Solid Tumor, Breast Cancer, OKI-219, trastuzumab, fulvestrant, H1047r, ribociclib, atirmociclib, tucatinib
Brief summary
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.
Interventions
DRUGOKI-219
Oral twice daily
DRUGFulvestrant
Intramuscular injection
DRUGTrastuzumab
Intravenous (IV)
DRUGTucatinib
Oral twice daily
DRUGAtirmociclib
Oral twice daily
DRUGRibociclib
Oral once daily continuous for 21-days followed by 7 days off
Sponsors
OnKure, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Identify maximum tolerated dose (MTD) of OKI-219 in monotherapy | Cycle 1 (First 28 days on treatment) | Frequency of participants experiencing dose-limiting toxicities during the first 28-day cycle |
| Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of SAEs | Through 30 days after last dose, an average of 1 year | Number and type of SAEs experienced by participants during treatment and follow-up |
| Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of Grade 2 or greater treatment emergent adverse events | Through 30 days after last dose, an average of 1 year | Number of treatment-emergent adverse events (TEAEs) equal or greater than Grade 2 experienced during treatment and follow-up |
| Assess rate of dose modifications during treatment with OKI-219 as monotherapy or in combination with other anti-cancer therapies | Through last study dose, an average of 1 year | rate of dose modifications |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: objective response rate (ORR) | Up to approximately 36 months | ORR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) |
| To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: clinical benefit rate (CBR) | Up to approximately 36 months | CBR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) |
| Dose optimization only: to estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: progression free survival (PFS) | Up to approximately 36 months | PFS per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) |
| Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: maximum plasma concentration (Cmax) | Through cycle 6 of treatment (up to 28 weeks) | PK of OKI-219: Cmax |
| To determine the impact of OKI-219 dosing as monotherapy and in combination with other anti-cancer therapies on blood glucose and insulin | Through last study dose, an average of 1 year | Changes in plasma glucose, serum insulin, serum c-peptide levels, and hemoglobin A1c (HbA1c) will be evaluated on treatment compared to baseline. |
| To assess the PDx activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies | Through last study dose, an average of 1 year | PDx activity will be evaluated with serial tumor biopsy samples assessed for PI3K/AKT/mTOR downstream pathway changes. |
| To assess the dose-response impact of OKI-219 as monotherapy and in combination with other anti-cancer therapies on PI3KαH1047R ctDNA levels | Through last study dose, an average of 1 year | Changes in PI3KαH1047R ctDNA on treatment and end of treatment (EOT) compared to baseline. |
| Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: time of maximum plasma concentration (Tmax) | Through cycle 6 of treatment (up to 28 weeks) | PK of OKI-219: Tmax |
| Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: area under the plasma concentration-time curve (AUC) | Through cycle 6 of treatment (up to 28 weeks) | PK of OKI-219: AUC |
| Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: terminal elimination half-life time (t1/2) | Through cycle 6 of treatment (up to 28 weeks) | PK of OKI-219: t1/2 |
Countries
Belgium, France, Italy, South Korea, Spain, United States
Contacts
Primary ContactOnKure, Inc.
Outcome results
None listed