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

Phase 1

Recruiting

• Conditions: Advanced Cancer; Breast Cancer
• Interventions: Drug: OKI-219; Drug: Fulvestrant; Drug: Trastuzumab

• Registration Number: NCT06239467
• Lead Sponsor: OnKure, Inc.

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 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-01-12
• Study First Submitted QC: 2024-01-25
• Study First Posted: 2024-02-02
• Study Start: 2024-02-26
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-04
• Last Update Posted: 2025-03-06
• Primary Completion: 2026-06-01
• Study Completion: 2027-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 150

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1b: Part B Dose Escalation	OKI-219	OKI-219 + Fulvestrant Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1a: Part A Dose Escalation	OKI-219	OKI-219 Monotherapy Dose Escalation in participants with advanced solid tumors with the PI3Kα1047R mutation
Phase 1b: Part B Dose Optimization	OKI-219	OKI-219 + Fulvestrant Dose Optimization in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1b: Part C Dose Escalation	OKI-219	OKI-219 + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1b: Part C Dose Optimization	OKI-219	OKI-219 + Trastuzumab Dose Optimization in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1b: Part B Dose Escalation	Fulvestrant	OKI-219 + Fulvestrant Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1b: Part B Dose Optimization	Fulvestrant	OKI-219 + Fulvestrant Dose Optimization in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1b: Part C Dose Escalation	Trastuzumab	OKI-219 + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
Phase 1b: Part C Dose Optimization	Trastuzumab	OKI-219 + Trastuzumab Dose Optimization in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation

Primary Outcome Measures

Name	Time	Method
Identify maximum tolerated dose (MTD) in monotherapy or in combination with fulvestrant or trastuzumab	Cycle 1 (First 28 or 21 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 fulvestrant or trastuzumab: 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 fulvestrant or trastuzumab: 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 fulvestrant or trastuzumab	Through last study dose, an average of 1 year	rate of dose modifications

Secondary Outcome Measures

Name	Time	Method
To assess the PDx activity of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab	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.
Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with fulvestrant or trastuzumab: maximum plasma concentration (Cmax)	Through cycle 6 of treatment (up to 28 weeks)	PK of OKI-219: Cmax
Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with fulvestrant or trastuzumab: 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 fulvestrant or trastuzumab: 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 fulvestrant or trastuzumab: terminal elimination half-life time (t1/2)	Through cycle 6 of treatment (up to 28 weeks)	PK of OKI-219: t1/2
To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab: 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 fulvestrant or trastuzumab: 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 fulvestrant or trastuzumab: 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)
To assess the dose-response impact of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab 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.
To determine the impact of OKI-219 dosing as monotherapy and in combination with fulvestrant or trastuzumab 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.

Trial Locations

Locations (31)

California Cancer Associates for Research and Excellence; 🇺🇸 Encinitas, California, United States

University of California San Diego UCSD; 🇺🇸 La Jolla, California, United States

UCLA Jonsson Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Regents of the University of Colorado; 🇺🇸 Aurora, Colorado, United States

Sarah Cannon Research Institute at HealthONE; 🇺🇸 Denver, Colorado, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Karmanos Cancer Insitute; 🇺🇸 Detroit, Michigan, United States

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

Stony Brook University; 🇺🇸 Stony Brook, New York, United States

SCRI Oncology Partners - Nashville; 🇺🇸 Nashville, Tennessee, United States

NEXT Oncology Virginia; 🇺🇸 Fairfax, Virginia, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

Institut Jules Bordet; 🇧🇪 Anderlecht, Belgium

UZ Leuven - Campus Gasthuisberg; 🇧🇪 Leuven, Belgium

GZA Hopsitals Campus Sint-Augustinus; 🇧🇪 Wilrijk, Belgium

Centre de Lutte Contre le Cancer CLCC - Centre Georges Francois Leclerc (CGFL); 🇫🇷 Dijon, France

Centre Oscar Lambret; 🇫🇷 Lille, France

Centre Leon Berard; 🇫🇷 Lyon, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Institut Gustave Roussy; 🇫🇷 Villejuif, France

Ospedale San Gerardo-ASST Monza; 🇮🇹 Monza, Italy

Istituto Clinico Humanitas; 🇮🇹 Rozzano, Italy

Gachon University Gil Medical Center; 🇰🇷 Incheon, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital; 🇰🇷 Seoul, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

NEXT Oncology Phase I Unit / IOB- Hospital Quironsalud Barcelona; 🇪🇸 Barcelona, Spain

Hospital Beata Maria Ana; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

START - Madrid; 🇪🇸 Madrid, Spain