Clinical trial NCT06239467: First-in-Human Study of OKI-219 in Advanced Solid Tumors and Advanced Breast Cancer
Official title: PIKture-01: First-in-Human Study of the PI3KαH1047R Mutant-Selective Inhibitor OKI-219 as Monotherapy in Participants With Advanced Solid Tumors and in Combination With Endocrine Therapy or HER2-Targeted Therapy in Participants With Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Cancer
Breast Cancer
Keywords: PI3K
Solid Tumor
Breast Cancer
OKI-219
trastuzumab
fulvestrant
Lead sponsor: OnKure, Inc.
Sponsor class: INDUSTRY
First posted: 2024-02-02
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Identify maximum tolerated dose (MTD) in monotherapy or in combination with fulvestrant or trastuzumab
timeFrame: Cycle 1 (First 28 or 21 days on treatment)
measure: Assess safety of OKI-219 as monotherapy or in combination with fulvestrant or trastuzumab: incidence of SAEs
timeFrame: Through 30 days after last dose, an average of 1 year
measure: Assess safety of OKI-219 as monotherapy or in combination with fulvestrant or trastuzumab: incidence of Grade 2 or greater treatment emergent adverse events
timeFrame: Through 30 days after last dose, an average of 1 year
measure: Assess rate of dose modifications during treatment with OKI-219 as monotherapy or in combination with fulvestrant or trastuzumab
timeFrame: Through last study dose, an average of 1 year
Secondary outcomes:
measure: 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)
timeFrame: Through cycle 6 of treatment (up to 28 weeks)
measure: 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)
timeFrame: Through cycle 6 of treatment (up to 28 weeks)
measure: 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)
timeFrame: Through cycle 6 of treatment (up to 28 weeks)
measure: 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)
timeFrame: Through cycle 6 of treatment (up to 28 weeks)
measure: To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab: objective response rate (ORR)
timeFrame: Up to approximately 36 months
measure: To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab: clinical benefit rate (CBR)
timeFrame: Up to approximately 36 months
measure: 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)
timeFrame: Up to approximately 36 months
measure: To assess the dose-response impact of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab on PI3KαH1047R ctDNA levels
timeFrame: Through last study dose, an average of 1 year
measure: To determine the impact of OKI-219 dosing as monotherapy and in combination with fulvestrant or trastuzumab on blood glucose and insulin
timeFrame: Through last study dose, an average of 1 year
measure: To assess the PDx activity of OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab
timeFrame: Through last study dose, an average of 1 year
Other outcomes:
Locations:
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: La Jolla
country: United States
facility: University of California San Diego UCSD
state: California
city: Los Angeles
country: United States
facility: UCLA Jonsson Comprehensive Cancer Center
state: California
city: Newport Beach
country: United States
facility: Hoag - Huntington Beach
state: California
city: Aurora
country: United States
facility: Regents of the University of Colorado
state: Colorado
city: Denver
country: United States
facility: Sarah Cannon Research Institute at HealthONE
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Insitute
state: Michigan
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Stony Brook
country: United States
facility: Stony Brook University
state: New York
city: Nashville
country: United States
facility: SCRI Oncology Partners - Nashville
state: Tennessee
city: Fairfax
country: United States
facility: NEXT Oncology Virginia
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg
city: Wilrijk
country: Belgium
facility: GZA Hopsitals Campus Sint-Augustinus
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer CLCC - Centre Georges Francois Leclerc (CGFL)
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Pierre Benite
country: France
facility: Hopital Lyon Sud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Monza
country: Italy
facility: Ospedale San Gerardo-ASST Monza
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Barcelona
country: Spain
facility: NEXT Oncology Phase I Unit / IOB- Hospital Quironsalud Barcelona
city: Madrid
country: Spain
facility: Hospital Beata Maria Ana
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: START - Madrid
Study officials:
References: