Informations générales (source: ClinicalTrials.gov)
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 (PIKture-01)
Interventional
Phase 1
OnKure, Inc. (Voir sur ClinicalTrials)
février 2024
août 2027
05 avril 2025
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.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Djedjiga Oudni | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Antoine Lacassagne - 06189 - Nice - France | Jennifer Oudard | Contact (sur clinicalTrials) | |||
| Centre de Lutte Contre le Cancer CLCC - Centre Georges Francois Leclerc (CGFL) - 21079 - Dijon - France | Peggy Philippe | Contact (sur clinicalTrials) | |||
| Centre Leon Berard - 69008 - Lyon - France | Amelie Vey | Contact (sur clinicalTrials) | |||
| Centre Oscar Lambret - 59020 - Lille - France | Amelie Decourcelle | Contact (sur clinicalTrials) | |||
Critères
Tous
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.
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.
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).