First-in-Human Study of the PI3KaH1047R Mutant-Selective Inhibitor OKI-219 as Monotherapy and in Combination with Endocrine Therapy or HER2-targeted Therapy in Patients with Advanced Solid Tumors and Breast Cancer

Cancer Categories

Breast

Karmanos Trial ID

2024-004

NCT ID

NCT06239467

Age Group

Adult

Scope

National

Phase

Phase I

Principal Investigator

Lubina
Arjyal, M.D.
Gastroenterology, Oncology - Medical View Profile

Objective:

Phase 1a Monotherapy Dose Escalation (Part A)

Primary Objectives:

To assess the safety of OKI-219, and to identify the maximum tolerated dose (MTD) and one or more pharmacologically active dose (PAD) levels of OKI-219 as a single agent in participants with advanced solid tumors with the PI3Kα^H1047R mutation

Secondary Objectives:

To characterize additional measures of the safety and tolerability of OKI-219 in participants with advanced solid tumors with the PI3Kα^H1047R mutation
To assess the plasma PK of OKI-219 following single and multiple doses as monotherapy
To assess the effect of food on the PK of OKI-219
To estimate the preliminary antitumor activity of OKI-219 as monotherapy
To assess the dose-response impact of OKI-219 on PI3Kα^H1047R circulating tumor DNA (ctDNA) levels
To determine the impact of OKI-219 dosing on blood glucose and insulin
To assess the PDx activity of OKI-219 and its association with PK, safety, and efficacy

Phase 1b Combination Dose Escalation and Dose Optimization (Parts B and C)

Primary Objectives:

Fulvestrant Combination (Part B)
Phase 1b
To assess the safety of OKI-219 when combined with fulvestrant and identify 2 PAD levels of OKI-219 + fulvestrant to evaluate in the Dose Optimization arms in participants with HR+/HER2–/PI3Kα^H1047Rmutated metastatic breast cancer
Dose Optimization
To compare 2 PAD levels of OKI-219 + a fixed dose of fulvestrant and identify the recommended Phase 2 dose (RP2D) for OKI-219 combined with fulvestrant in participants with HR+/HER2–/PI3Kα^H1047Rmutated metastatic breast cancer
Trastuzumab Combination (Part C)
Phase 1b
To assess the safety of OKI-219 when combined with trastuzumab and identify 2 PAD levels of OKI-219 + trastuzumab to evaluate in the Dose Optimization arms in participants with HR±/HER2+/PI3Kα^H1047Rmutated metastatic breast cancer
Dose Optimization
To compare 2 PAD levels of OKI-219 + a fixed dose of trastuzumab and identify the RP2D for OKI-219 combined with trastuzumab in participants with HR±/HER2+/PI3Kα^H1047R-mutated
metastatic breast cancer

Secondary Objectives:

To characterize additional measures of the safety and tolerability of OKI-219 in combination with fulvestrant or trastuzumab in participants with metastatic breast cancer with the PI3Kα^H1047R mutation
To assess the plasma PK of OKI-219 following single and multiple doses in combination with fulvestrant or trastuzumab
To estimate the preliminary antitumor activity of OKI-219 in combination with fulvestrant or trastuzumab
To assess the dose-response impact of OKI-219 in combination with fulvestrant or trastuzumab on PI3Kα^H1047R ctDNA levels
To determine the impact of OKI-219 dosing in combination with fulvestrant or trastuzumab on blood glucose and insulin
To assess the PDx activity of OKI-219 in combination with fulvestrant or trastuzumab and its association with PK, safety, and efficacy

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Eligibility

Inclusion Criteria:

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.
Cohort-specific disease requirements:

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.

Phase 1a Monotherapy Backfill Additional Criterion (Part A):

Participants must have a tumor amenable to predose, post dose and end-of- treatment tumor biopsy

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.

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%

ECOG PS 0 to 1.
Life expectancy > 12 weeks.
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.
Adequate organ and marrow function, defined as follows:

Absolute neutrophil count ≥ 1.5 × 10^9/L;
Platelets ≥ 100,000/μL;
Hemoglobin ≥ 8.0 g/dL;
Total bilirubin within the institutional upper limit of normal (ULN);
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN;
Creatinine clearance calculated using the Cockcroft-Gault formula ≥ 60 mL/min.

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.
Able to swallow and tolerate oral medications.
At least 1 measurable lesion based on RECIST version 1.1.

Exclusion Criteria:

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.
Prior treatment with the PI3KαH1047R mutant-selective inhibitor LOXO-783.
Participants with a known KRAS mutation.
Participants with a known deleterious mutation in 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.
Treatment with systemic corticosteroids at a dose of > 10 mg of prednisone or equivalent at the time of enrollment.
Uncontrolled Type 1 or Type 2 diabetes.
Known history of Crigler-Najjar syndrome.
Known Gilbert's syndrome.
Participants who are pregnant or nursing.
Concomitant active malignancy or previous malignancy within 2 years of the time of enrollment.
Impaired cardiovascular function or clinically significant cardiovascular disease, including any of the following:

History of acute myocardial infarction or acute coronary syndromes in the 6 months prior to enrollment.
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.
Uncontrolled hypertension despite medical management

Any medical condition that would impair the administration or absorption of oral agents.
History of symptomatic drug-induced pneumonitis.
Participants with HIV infection and any of the following:

Cluster of differentiation 4 (CD4) count < 350 cells/μL;
A history of AIDS with an opportunistic infection within 12 months prior to enrollment;
Not on established antiretroviral therapy for at least 4 weeks prior to enrollment and HIV viral load > 400 copies/mL.

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.
Positive hepatitis C virus (HCV) antibody unless PCR negative for HCV RNA with completion of curative antiviral treatment.
History or current evidence of congenital long QT syndrome.
QTc interval corrected using Fridericia's formula (QTcF) > 470 msec on screening ECG.
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:

Proton pump inhibitors (PPIs);
Medications that are moderate or strong inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)2B7;

Locations

Karmanos Cancer Institute - Detroit Headquarters

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Farmington Hills, MI 48334
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