Tucatinib, Palbociclib and Letrozole in Metastatic Hormone Receptor Positive and HER2-positive Breast Cancer

NCT03054363 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 16-1661.ccNCI-2017-01776
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Breast Cancer

Keywords

Metastatic Breast Cancer; Tucatinib; Palbociclib; Letrozole; HR-positive; HER2-positive; ER-positive; PR-positive; HER2-targeted therapy; CDK4/6 inhibitor; ONT-380; Ibrance

Outcome Measures

Primary Outcomes (2)

• Phase Ib Primary Outcome: Proportion of Patients Who Experienced DLTs Attributable to Palbociclib, Tucatinib, or Both

  To measure safety and tolerability of tucatinib used in combination with palbociclib and letrozole, we will assess the proportion of subjects experiencing dose-limiting toxicities (DLTs) potentially attributable to tucatinib, palbociclib, or both drugs, and compare them to predefined safety thresholds. DLT was defined as any grade ≥ 3 nonhematologic adverse event, grade 3 neutropenia with fever, grade 3 thrombocytopenia with bleeding, or any hematologic toxicity grade ≥ 4 using NCI CTCAE version 4.03. Safety was considered clinically meaningfully altered if ≥60% of subjects experienced DLTs secondary palbociclib, ≥20% of subjects had toxicity secondary to tucatinib, or ≥50% of subjects had DLTs attributable to both drugs. If the proportion of patients with DLTs cross safety boundaries, doses of tucatinib, palbociclib or both medications would be decreased. Letrozole dose was kept constant for all study subjects.

  15 months (From date of first consent until final safety analysis of Phase Ib)

• Phase II Primary Outcome: Median Progression-free Survival (mPFS)

  To measure efficacy of tucatinib used in combination with palbociclib and letrozole, the median PFS (primary objective of Phase II) will be assessed. mPFS is defined as the time from allocation to the first documented disease progression according to RECIST 1.1, or death due to any cause, whichever occurs first. For subjects with brain metastatic disease enrolled in the study, assessment of bi-compartmental mPFS in the non-CNS and CNS compartments, defined as the time from allocation to the first documented disease progression according to RECIST 1.1 and/or RANO-BM criteria, or death due to any cause, whichever occurs first. For patient with CNS metastases who had an event of isolated CNS progression, underwent local therapy, and remained on study per protocol, mPFS was calculated as the time from the start of treatment until the first CNS progression.

  4 years (data cutoff of PFS calculation was when PFS became mature according to study statistician)

Secondary Outcomes (5)

• Phase Ib Secondary Outcome: Tucatinib and Palbociclib AUC[0-6] Post Tucatinib and Palbociclib Dose

  0, 0.5, 1, 2, 3, 4, and 6 hours post-dose

• Phase II Secondary Outcome: Palbociclib AUC[10-19] Post Tucatinib and Palbociclib Dose

  10, 13, 16, and 19 hours post-dose

• Phase II Secondary Outcome: Clinical Benefit Rate (CBR)

  4 years

• Phase II Secondary Outcome: Overall Response Rate (ORR)

  4 years

• Phase II Secondary Outcome: Median Duration of Response (mDOR)

  4 years

Study Arms (2)

Phase 1b

EXPERIMENTAL

Tucatinib 300 mg PO BID, palbociclib 125 mg PO daily 21 days on and 7 days off, and letrozole 2.5 mg PO daily on a 28 day cycle length.

Drug: Tucatinib in Combination with Palbociclib and Letrozole

Phase II

EXPERIMENTAL

Tucatinib 300 mg BID; palbociclib 75 mg PO daily 21 days on, 7 days off; letrozole 2.5 mg PO daily.

Drug: Tucatinib in Combination with Palbociclib and Letrozole

Interventions

Tucatinib in Combination with Palbociclib and Letrozole DRUG

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

Also known as: ONT-380, IBRANCE, Femara

Phase 1b

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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. 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.
• Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria
• Bone only disease is allowed.
• 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
• 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
• 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
• Age ≥ 18 years
• ECOG performance status 0-1
• Life expectancy of more than 6 months, in the opinion of the investigator
• 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.
• Prior treatments:
• Subjects should have received at least two approved HER2-targeted agents (trastuzumab, pertuzumab, or TDM-1) in the course of their disease
• 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 antiendocrine therapy per NCCN guidelines
• 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

You may not qualify if:

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

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Pfizer: collaborator
• Cascadian Therapeutics Inc.: collaborator
• Criterium, Inc.: collaborator

Study Sites (6)

University of Arizona

Tucson, Arizona, 85724, United States

Location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

New Mexico Cancer Care Alliance

Albuquerque, New Mexico, 87131, United States

Location

Stony Brook University

Stony Brook, New York, 11794, United States

Location

University of Texas Health Science Center San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (2)

• Shagisultanova E, Crump LS, Borakove M, Hall JK, Rasti AR, Harrison BA, Kabos P, Lyons TR, Borges VF. Triple Targeting of Breast Tumors Driven by Hormonal Receptors and HER2. Mol Cancer Ther. 2022 Jan;21(1):48-57. doi: 10.1158/1535-7163.MCT-21-0098. Epub 2021 Nov 2.

  PMID: 34728571 RESULT

• Shagisultanova E, Gradishar W, Brown-Glaberman U, Chalasani P, Brenner AJ, Stopeck A, Parris H, Gao D, McSpadden T, Mayordomo J, Diamond JR, Kabos P, Borges VF. Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer. Clin Cancer Res. 2023 Dec 15;29(24):5021-5030. doi: 10.1158/1078-0432.CCR-23-0117.

  PMID: 37363965 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

tucatinib; palbociclib; Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Elena Shagisultanova, MD, PhD
• Organization: University of Colorado Hospital

elena.shagisultanova@cuanschutz.edu

7208480300

Study Officials

• Elena Shagisultanova, MD, PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: February 7, 2017
• First Posted: February 15, 2017
• Study Start: November 27, 2017
• Primary Completion: January 17, 2023
• Study Completion: February 7, 2023
• Last Updated: November 13, 2023
• Results First Posted: October 27, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)