Clinical Trial of Alpelisb and Tucatinib in Patients With PIK3CA-Mutant HER2+ Metastatic Breast Cancer.

NCT05230810 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 01AB21- PIK3CA
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 4

Brief Summary

Phase IB/II clinical trial of Alpelisb and Tucatinib in patients with PIK3CA-Mutant HER2-positive metastatic breast cancer.

Conditions

HER2-positive Metastatic Breast Cancer

Keywords

ALPELISIB; TUCATINIB; HER2-positive Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Phase Ib Safety and Tolerability of alpelisib and tucatinib combination, summary of all AEs and SAEs on study as evaluated by NCI-CTCAE v 5.0

  MTD of tucatinib and alpelisib in combination, summary of all AEs and SAEs on study as evaluated by NCI-CTCAE v 5.0

  10 Months

• Phase II Efficacy of tucatinib combination evaluated by progression free survival (PFS)

  PFS in the overall study population (the time from allocation to the first documented disease progression by RECIST1.1, or death due to any cause, whichever occurs first)

  20 Months

Secondary Outcomes (6)

• Phase Ib Pharmacokinetic (PK) properties of alpelisib and tucatinib

  10 Months

• Phase Ib Tumor response evaluation

  10 Months

• Phase Ib Duration of Response (DOR)

  10 months

• Phase II Tumor response evaluation

  20 months

• Phase II Incidence, nature and severity of all AEs that occur on or after C1D1 of therapy

  20 months

Study Arms (1)

Ib Safety Cohort /II Expansion Cohort

EXPERIMENTAL

In phase Ib, the tolerability of tucatinib and alpelisib combination will be confirmed and maximum tolerated dose determined. Therapy will be administered in 28 day cycles of tucatinib 300 mg PO BID and alpelisib 250 mg PO daily (dose level 1). Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. Fulvestrant will also be administered in patients with HR+/HER2+ metastatic breast cancer. Once RP2D is determined, the study will be continued to phase II, and new patients will enroll at RP2D. All patients in phase IB part, who are remaining on study at the time of initiation of phase II, will be rolled over to phase II. At that time, their study drug doses will be modified as follows: (1) if a patient is on the drug doses lower than RP2D, doses will not be increased; (2) if a patient is on a higher doses compared to RP2D, doses of study drugs will be changed to RP2D.

Drug: Alpelisib; Drug: Tucatinib; Drug: Fulvestrant

Interventions

Alpelisib DRUG

Orally twice a day

Also known as: Piqray

Ib Safety Cohort /II Expansion Cohort

Tucatinib DRUG

Orally once a day

Also known as: Tukysa

Ib Safety Cohort /II Expansion Cohort

Fulvestrant DRUG

500 mg intramuscularly into the buttocks slowly \*Fulvestrant will be administered only in patients with HR+/HER2+ metastatic breast cancer

Also known as: Faslodex,

Ib Safety Cohort /II Expansion Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women and men ≥ 18 years old are eligible to enroll
• ECOG performance status 0-1
• Life expectancy of more than 6 months, in the opinion of the investigator
• Histologically confirmed diagnosis of HER2+ locally advanced unresectable or metastatic breast cancer. HER2 positivity is defined by fluorescence in situ hybridization (FISH) and/or 3+ staining by IHC according to the latest ASCO/CAP guidelines.
• Documented presence of activating mutation in PIK3CA in the tumor, based on the analysis of solid or liquid biopsy by an assay approved for clinical decision makingby an FDA-approved test (examples include FoundationOne Liquid®; Guardant360®, Therrascreen® PIK3CA).
• Known ER and PR status of the tumor defined by IHC according to the latest ASCO/CAP guidelines
• Patients with HR-/HER2+ or HR+/HER2+ breast cancer may enroll
• HR+/HER2+ patients should be men or post-menopausal women; premenopausal women with HR+/HER2+ breast cancer are eligible if on ovarian suppression, or agreeable to mandatory ovarian suppression
• HR+/HER2+ patients should be agreeable to concomitant treatment with fulvestrant per study protocol. Prior therapy with fulvestrant is allowed.
• Patients should have received at least two FDA-approved HER2-targeted agents at any time in the course of their disease. Note: 1 line of therapy containing EGFR or HER2-tyrosine kinase inhibitors (for example, neratinib, tucatinib, lapatinib, afatinib, pyrotinib, etc.) in the metastatic setting is allowed
• Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria (appendix C). Bone only disease is allowed.
• Based on screening contrast brain MRI, patients must have one of the following:
• \. No evidence of brain metastases 2. Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions \> 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment 3. Previously treated brain metastases
• a. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator b. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met: i. Time since WBRT is ≥ 21 days prior to first dose of treatment, time since surgical resection of CNS metastases is ≥ 14 days prior to the first dose of study treatment, or time since SRS is ≥ 7 days prior to first dose of treatment.
• ii. Other sites of disease evaluable by RECIST 1.1 or RANO-BM are present c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions. 13. Adequate organ and marrow function as defined below:

You may not qualify if:

• Patients with contraindications to undergo contrast MRI imaging of the brain are excluded from the study
• Pregnancy or breast feeding
• Any systemic anti-cancer therapy (including hormonal therapy or investigational agents) or surgery in \<14 days prior to the first dose of study treatment WBRT in \<21 days, SBRT for CNS disease in \<7 days, or palliative radiation to extracranial sites in \<14 days prior to the first dose of study treatment5.
• Based on screening brain MRI, patients must not have any of the following:
• \. Previous treatment with alpelisib or other PI3K, mTOR or AKT inhibitor of more than 30 days duration.
• \. An established diagnosis of diabetes mellitus type I, or uncontrolled diabetes mellitus type II 9. History of acute pancreatitis within 1 year of screening, or a past medical history of chronic pancreatitis 10. History of severe cutaneous hypersensitivity reactions (Steven Johnson syndrome, erythema multiforme or toxic epidermal necrolysis) 11. Active bacterial, fungal or viral infections requiring treatment with IV antibiotic, IV anti-fungal, or IV anti-viral drugs 12. Known active hepatitis B (HBV) or, active hepatitis C (HCV) or human immunodeficiency virus (HIV) infections. Note: pretesting is not required. Patients with history of treated and cured HCV infection may enroll if they have documented undetectable viral load.
• \. Known HIV infection with CD4+ T-cell (CD4+) counts \< 350 cells/μL. Note: pretesting is not required. Patients with known HIV infection and CD4+ T-cell (CD4+) counts ≥ 350 cells/μL may enroll.
• \. Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications 15. Use of prohibited medications listed in the Appendix D (strong CYP3A4 inducers or inhibitors, and strong CYP2C8 inducers or inhibitors) within 3 elimination half-lives prior to initiation of study treatments 16. Myocardial infarction, severe/unstable angina, percutaneous transluminal coronary angioplasty/stenting (PTCA), or coronary artery bypass graft (CABG) within 6 month of the first dose of the study treatment 17. Clinically significant cardio-vascular disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension (defined as persistent systolic blood pressure \> 160 mm Hg and/or diastolic blood pressure \> 100 mm Hg on antihypertensive medications), or any history of symptomatic congestive heart failure (CHF) 18. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the subject inappropriate for entry into the study.

Sponsors & Collaborators

• Criterium, Inc.: lead
• Novartis: collaborator
• Seagen Inc.: collaborator

Study Sites (4)

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Cancer Care & Hematology-Fort Collins

Fort Collins, Colorado, 80528, United States

Location

Louisiana State University Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Interventions

Alpelisib; tucatinib; Fulvestrant

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Elena Shagisultanova, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2021
• First Posted: February 9, 2022
• Study Start: August 25, 2022
• Primary Completion: March 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: March 16, 2026

Record last verified: 2026-03

Locations

US (4)