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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase IB/II Open-label Single Arm Study to Evaluate Safety and Efficacy of Tucatinib in Combination With Palbociclib and Letrozole in Subjects With Hormone Receptor Positive and HER2-positive Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Tucatinib in Combination with Palbociclib and Letrozole
* Drug: Tucatinib in Combination with Palbociclib and Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. CNS inclusion criteria: 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 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 1Day 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 ≤ 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 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) negative ≤ 7 days of starting treatment 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. 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: 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) 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b<br>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<br>* 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<br>* Other names: Femara;|
| Experimental: Phase II<br>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<br>* Subjects Tucatinib 300 mg PO BID Palbociclib 75mg PO daily 21 days on followed by 7 days off Letrozole 2.5 mg PO daily.<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib Secondary Outcome: Tucatinib and Palbociclib AUC[0-6] Post Tucatinib and Palbociclib Dose | Pharmacokinetic (PK) assessments of blood levels of tucatinib and palbociclib will be performed on Cycle 1 Day 15 and Cycle 2 Day 1 of therapy in 20 participants enrolled in the phase Ib part of the study. Plasma samples will be collected to measure levels of tucatinib and its hydroxyl metabolite ONT-993, as well as levels of palbociclib and, if needed, its metabolites at steady state on Cycle 1 Day 15. The area under the curve (AUC) of the concentration vs. time plot is computed from 0 to 6 hours after the 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 | Additional pharmacokinetic (PK) assessment will be done in 5 to 10 patients enrolled in phase II part of the study to evaluate the levels of tucatinib and palbociclib. These PKs will be done on Cycle 1 Day 9 and Cycle 2 Day 9. Prior to the first set of PKs, on Cycle 1 Days 1-8, patient will take palbociclib and letrozole; tucatinib will be on hold. Tucatinib will be started per usual study schedule after the first set of PKs is obtained on Day 9. Prior to the second set of PKs, on Cycle 2 Days 1-8, patient will take palbociclib, letrozole and tucatinib (all study drugs) per usual study schedule. On the day prior to PK evaluation (Day 8 of Cycle 1 and Day 8 of Cycle 2), patient should consume high calorie / high fat meal and take study drugs. On the next day, plasma samples will be collected to measure PKs at 10, 13, 16 and 19 hrs +/- 10 minutes post dose. | 10, 13, 16, and 19 hours post-dose | 
| Phase II Secondary Outcome: Clinical Benefit Rate (CBR) | Clinical benefit rate (CBR) was assessed in patients with measurable lesions and defined as the proportion of patients with complete response, partial response, or stable disease for 6 months or more. It is one of the parameters used to assess tumor response in this study and was evaluated using RECIST 1.1 (and/or RANO-BM for patients with CNS disease). | 4 years | 
| Phase II Secondary Outcome: Overall Response Rate (ORR) | Overall response rate (ORR) is defined as the proportion of subjects who had complete or partial response by RECIST 1.1 (and/or RANO-BM for patients with CNS disease). | 4 years | 
| Phase II Secondary Outcome: Median Duration of Response (mDOR) | Median duration of response (mDOR) is defined as the time from enrollment in the clinical trial until objective tumor progression or death, whichever occurs first. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Breast Cancer, Tucatinib, Palbociclib, Letrozole, HR-positive, HER2-positive, ER-positive, PR-positive, HER2-targeted therapy, CDK4/6 inhibitor, ONT-380, Ibrance