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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT05230810
Recruitment Status : Recruiting
First Posted : February 9, 2022
Last Update Posted : January 3, 2023
Seagen Inc.
Information provided by (Responsible Party):
Criterium, Inc.

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

Condition or disease Intervention/treatment Phase
HER2-positive Metastatic Breast Cancer Drug: Alpelisib Drug: Tucatinib Drug: Fulvestrant Phase 1 Phase 2

Detailed Description:
This study is a multicenter, single arm, open-label, run-in phase Ib safety cohort with immediate roll over to a phase II clinical trial that will test the combination therapy of tucatinib with alpelisib in subjects with PIK3CA-mutant HER2+ locally advanced unresectable or metastatic breast cancer. Patients with PIK3CA-mutant HR-/HER2+ and HR+/HER2+ breast cancer may enroll, the latter cohort will receive concomitant treatment with standard doses of fulvestrant to block HR signaling. In phase Ib part, we will confirm the tolerability of tucatinib and alpelisib combination and determine the maximum tolerated dose (MTD). In phase II part, we will expand the testing of this drug combination at MTD to determine the PFS rate.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: This is a Multicenter, Single Arm, Open-label, run-in Phase Ib / Roll-over Phase II Study of Tucatinib in Combination With Alpelisib in Subjects With PIK3CA-mutant HER2-positive Locally Advanced Unresectable or Metastatic Breast Cancer.
Actual Study Start Date : August 25, 2022
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Ib Safety Cohort /II Expansion Cohort
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
Orally twice a day
Other Name: Piqray

Drug: Tucatinib
Orally once a day
Other Name: Tukysa

Drug: Fulvestrant

500 mg intramuscularly into the buttocks slowly

*Fulvestrant will be administered only in patients with HR+/HER2+ metastatic breast cancer

Other Name: Faslodex,

Primary Outcome Measures :
  1. 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 [ Time Frame: 10 Months ]
    MTD of tucatinib and alpelisib in combination, summary of all AEs and SAEs on study as evaluated by NCI-CTCAE v 5.0

  2. Phase II Efficacy of tucatinib combination evaluated by progression free survival (PFS) [ Time Frame: 20 Months ]
    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)

Secondary Outcome Measures :
  1. Phase Ib Pharmacokinetic (PK) properties of alpelisib and tucatinib [ Time Frame: 10 Months ]
    Plasma concentrations of alpelisib and tucatinib measured at cycle 1 day 15 of therapy

  2. Phase Ib Tumor response evaluation [ Time Frame: 10 Months ]
    CR, PR, or SD according to RECIST 1.1 (for subjects with CNS disease by RECIST 1.1 and RANO-BM); assessment of ORR (CR and PR), CBR (CR, PR and SD)

  3. Phase Ib Duration of Response (DOR) [ Time Frame: 10 months ]
    Duration of response defined as the time from enrollment into clinical trial until objective tumor progression or death whichever occurs first.

  4. Phase II Tumor response evaluation [ Time Frame: 20 months ]
    CR, PR, or SD according to RECIST 1.1 (for subjects with CNS disease by RECIST 1.1 and RANO-BM); assessment of ORR (CR and PR), CBR (CR, PR and SD)

  5. Phase II Incidence, nature and severity of all AEs that occur on or after C1D1 of therapy [ Time Frame: 20 months ]
    Safety and tolerability of the combination therapy

  6. Phase II Duration of Reponse (DOR) [ Time Frame: 20 months ]
    duration of response (DOR) defined as the time from enrollment into clinical trial until objective tumor progression or death whichever occurs first.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


Inclusion criteria:

• 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 in the course of their disease
  • Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria (appendix C). Bone only disease is allowed.
  • CNS inclusion criteria:

Based on screening contrast brain MRI, patients must have one of the following:

  1. 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. Adequate organ and marrow function as defined below:

    • Absolute neutrophil count ≥ 1,500/mm3

    • Platelets ≥ 75,000/mm3

    • Hemoglobin ≥ 9.0 mg/dL without red blood cell transfusion ≤ 7 days prior to Cycle 1 Day 1 of therapy

    • Total serum bilirubin ≤ 1.5 X upper limit of normal (ULN) except for subjects with known Gilbert's disease, who may enroll if the conjugated bilirubin is ≤ 1.5 ULN

    • AST (SGOT)/ALT (SGPT) ≤2.5 X ULN;

    • Serum creatinine Estimated creatinine clearance ≥50 mL/min as calculated by Cockroft-Gault formula; actual body weight must be used for creatinine clearance calculations unless BMI > 30 kg/m2 then lean body weight must be used;≤ 1.5 mg/dL

    • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT

    • Fasting blood glucose ≤140 mg/dL

    • HbA1C≤6.4%

    • Left ventricular ejection fraction (LVEF) ≥ 50% (as assessed by ECHO or MUGA) documented within 4 weeks prior to first dose of study treatment

    • Serum or urine pregnancy test (for women of childbearing potential, defined as premenopausal women who are not permanently sterile due to hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusion) negative ≤ 7 days of starting treatment 14. Patients with body mass index >25, or FBG 110-140mg/dL, or HbA1C 5.7 - 6.4% should be agreeable for low glycemic diet and lifestyle modifications, and consulted by nutritionist prior to initiation of the study drugs.

    Ability to understand and the willingness to sign a written informed consent and comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

    Exclusion criteria:

    Patients with with known brain metastases and 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:

    Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given 2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor 3. Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions). Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria 3b 4. Known or suspected leptomeningeal disease as documented by the investigator 5. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy 5. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the exception of peripheral neuropathy, which must have resolved to ≤ Grade 2, and alopecia 6. Previous treatment with tucatinib, lapatinib, neratinib, afatinib, or other EGFR-family receptor tyrosine kinase inhibitor, or HER2 tyrosine kinase inhibitor that lasted more than 30 days. Receiving the above medications for <30 days is not considered to be clinically significant, and should not be a reason for excluding a patient.

    • Previous treatment with alpelisib or other PI3K, mTOR or AKT inhibitor of more than 30 days duration. Receiving the above medications for <30 days is not considered to be clinically significant, and should not be a reason for excluding a patient.
    • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT05230810

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Contact: Ash Philpott, PharmD 5185830095
Contact: Femi Okubanjo, PharmD 5185830095

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United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
Contact: Lauren Dabdoub    303-724-8651    LAUREN.DABDOUB@CUANSCHUTZ.EDU   
Principal Investigator: Elena Shagisultanova         
United States, Florida
Mount Sinai Miami Cancer Research Program Not yet recruiting
Miami, Florida, United States, 33140
Contact: Carolina Bonometti    305-674-2625   
Principal Investigator: Ragisha Gopalakrishnan         
United States, Wisconsin
University of Wisconsin Carbone Cancer Center Not yet recruiting
Madison, Wisconsin, United States, 53792
Contact: Renae Quale    608-265-2789   
Principal Investigator: Kari Wisinski         
Sponsors and Collaborators
Criterium, Inc.
Seagen Inc.
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Principal Investigator: Elena Shagisultanova, MD University of Colorado, Denver
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Responsible Party: Criterium, Inc. Identifier: NCT05230810    
Other Study ID Numbers: 01AB21- PIK3CA
First Posted: February 9, 2022    Key Record Dates
Last Update Posted: January 3, 2023
Last Verified: December 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Criterium, Inc.:
HER2-positive Metastatic Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action