This is a multicenter run-in phase Ib / roll-over phase II study of triple targeted drug combination (HER2-targeted small molecule inhibitor tucatinib, CDK4/6 inhibitor palbociclib and aromatase inhibitor letrozole) as a first or second line of therapy in patients with metastatic hormone receptor positive and HER2-positive breast cancer.



Eligible Ages
Between 18 Years and 100 Years
Eligible Genders
Accepts Healthy Volunteers

Inclusion Criteria

  1. Subjects must have a histologically confirmed diagnosis of HR+/HER2+ locally advanced unresectable or metastatic breast cancer. Estrogen or progesterone receptor positivity is defined by IHC according to the most recent ASCO/CAP guidelines [29]. HER2 positivity is defined by standard of care fluorescence in situ hybridization (FISH) and/or 3+ staining by IHC according to the most recent ASCO/CAP guidelines [30].
  2. Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria (Appendix C). Bone only disease is allowed.
  3. CNS inclusion criteria:
  4. Subjects without CNS metastases are eligible. Note: brain imaging is not required for asymptomatic subjects without known brain metastatic disease prior to enrollment into the study
  5. Subjects with untreated asymptomatic CNS metastases not needing immediate local therapy in the opinion of investigator are eligible. For subjects with untreated asymptomatic CNS lesions > 2.0 cm by contrast-enhanced MRI, discussion with and approval from the Lead PI is required prior to enrollment
  6. Subjects with stable brain metastases previously treated with radiation therapy or surgery are allowed to enroll, provided that they are off corticosteroids or on stable/tapering dose of corticosteroids and stability of CNS metastatic disease for at least 4 weeks has been demonstrated, with the last MRI taken within 2 weeks prior to cycle 1 day 1 of the study. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
  7. Age ≥ 18 years
  8. ECOG performance status 0-1
  9. Life expectancy of more than 6 months, in the opinion of the investigator
  10. Study subjects should be post-menopausal women; premenopausal women are eligible if on ovarian suppression, or agreeable to mandatory ovarian suppression. Women of childbearing potential, defined as premenopausal women who are not permanently sterile (i.e., due to hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusion) are required to have negative pregnancy tests prior to initiation of treatment.
  11. Prior treatments:
  12. Subjects should have received at least two approved HER2-targeted agents (trastuzumab, pertuzumab, or TDM-1) in the course of their disease
  13. Subjects should have had at least 1 line of prior HER2-targeted therapy in the metastatic setting, with the exception of asymptomatic subjects with oligometastatic or bone / soft tissue only disease who, on investigator opinion, are appropriate for a single agent anti-endocrine therapy per NCCN guidelines
  14. Subjects who have had up to 2 lines of prior endocrine therapy in the metastatic setting are allowed. Prior adjuvant and/or neoadjuvant endocrine regimens are allowed and not counted towards this limit
  15. Adequate organ and marrow function as defined below:
  16. Absolute neutrophil count ≥ 1,500/mm3
  17. Platelets ≥ 75,000/mm3
  18. Hemoglobin ≥ 9.0 mg/dL without red blood cell transfusion ≤ 7 days prior to Cycle 1 Day 1 of therapy
  19. 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
  20. AST (SGOT)/ALT (SGPT) ≤2.5 X ULN;
  21. Serum creatinine ≤ 1.5 mg/dL
  22. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT
  23. Left ventricular ejection fraction (LVEF) ≥ 50% (as assessed by ECHO or MUGA) documented within 4 weeks prior to first dose of study treatment
  24. Serum or urine pregnancy test (for women of childbearing potential) negative ≤ 7 days of starting treatment
  25. 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.
  26. Subject or legally authorized representative of a subject must provide signed informed consent per a consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the subject's disease.

Exclusion Criteria

  1. Subjects with previously treated progressing brain metastases are excluded from the study
  2. Subjects with known brain metastases and contraindications to undergo contrast MRI imaging of the brain are excluded from the study
  3. Pregnancy or breast feeding
  4. Current active treatment with an investigational agent
  5. Known history of hypersensitivity to aromatase-inhibitor drugs
  6. 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
  7. Previous treatment with lapatinib, neratinib, afatinib, or other investigational EGFR-family receptor tyrosine kinase inhibitor or HER2 tyrosine kinase inhibitor
  8. Previous treatment with palbociclib, abemaciclib, ribociclib or other investigational CDK4/6 inhibitors
  9. Any systemic anti-cancer therapy (including hormonal therapy), radiation, or experimental agent ≤ 2 weeks of first dose of study treatment
  10. Active bacterial, fungal or viral infections requiring treatment with IV antibiotic, IV anti-fungal, or IV anti-viral drugs
  11. Known hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV) infections. Note: pretesting is not required.
  12. Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications
  13. Use of prohibited medications listed in Appendix D within 3 elimination half-lives prior to first dose of the study treatment
  14. Known 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
  15. 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)
  16. 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.

Study Design

Phase 1/Phase 2
Study Type
Intervention Model
Single Group Assignment
Primary Purpose
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Tucatinib in Combination with Palbociclib and Letrozole
During phase 1b part of this trial (N=20 patients), treatment will be administered in cycles of 28 days and consist of tucatinib 300 mg PO BID, palbociclib 125 mg PO daily for 21 days followed by 7 days off, and letrozole 2.5 mg PO daily. Dose modifications of tucatinib, palbociclib and letrozole will be allowed per protocol. There will be an interim safety analysis performed after enrollment of 10 patients. Safety analysis will take into account proportion of patients requiring dose modifications or interruption for therapy because of toxicity. If excessive toxicity or significant changes in PKs are found, further patients will be enrolled at a lower starting dose level. There will be a second interim safety analysis after enrollment of 20 patients in the study. Once the recommended phase II dose (RP2D) has been determined, testing of this drug combination will be expanded in the phase II part of this trial (N=20 patients) to determine the progression-free survival (PFS) rate.
  • Drug: Tucatinib in Combination with Palbociclib and Letrozole
    Starting dose of combination therapy : Tucatinib 300 mg PO BID Palbociclib 125 mg PO daily 21 day on, 7 days off Letrozole 2.5 mg PO daily Dose modifications, if necessary: If Palbociclib toxicity increased: Tucatinib 300 mg PO BID Palbociclib 100 mg PO daily 21 day on, 7 days off Letrozole 2.5 mg PO daily If Tucatinib toxicity increased: Tucatinib 250 mg PO BID Palbociclib 125 mg PO daily 21 day on, 7 days off Letrozole 2.5 mg PO daily If Palbociclib and Tucatinib toxicity increased: Tucatinib 250 mg PO BID Palbociclib 100 mg PO daily 21 day on, 7 days off Letrozole 2.5 mg PO daily Additional dose levels per protocol if PKs indicate a significant change to the metabolism of Tucatinib regardless of clinical toxicity.
    Other names:
    • ONT-380
    • Femara

Recruiting Locations

University of Texas Health Science Center San Antonio
San Antonio, Texas 78229

More Details

University of Colorado, Denver

Study Contact

Tiffany Colvin

Detailed Description

This is a multicenter, single arm, open-label, run-in phase Ib / roll-over phase II study of novel HER2-targeted tyrosine kinase inhibitor tucatinib in combination with CDK4/6 inhibitor palbociclib and aromatase inhibitor letrozole in subjects with HR+/HER2+ locally advanced unresectable or metastatic breast cancer. The study will enroll post-menopausal women and premenopausal women if on treatment with or willing to be treated with standard ovarian suppression. The phase Ib part of the study will determine safety and tolerability of the combination of tucatinib, palbociclib and letrozole to confirm that current RP2D of tucatinib and FDA approved dosing of palbociclib remains the same in the triplet combination. The dose of letrozole will be constant through the study period. Once the safety of the combination is established, we will move to the phase II part of the study in the expansion cohort of subjects at RP2D for the purpose of assessing efficacy while further refining assessment of safety of the combination treatment.


Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.