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

• ClinicalTrials.gov Identifier: NCT03054363
• Recruitment Status: Active, not recruiting
• First Posted: February 15, 2017
• Last Update Posted: March 9, 2023
• Sponsor: University of Colorado, Denver
• Collaborators: Pfizer; Cascadian Therapeutics Inc.; Criterium, Inc.
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: February 7, 2017
• First Posted Date: February 15, 2017
• Last Update Posted Date: March 9, 2023
• Actual Study Start Date: November 27, 2017
• Actual Primary Completion Date: January 17, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2017)

• The number of patients in the Pase 1b part of the study with any adverse events (AE). [ Time Frame: 2.5 years ]
  To measure safety and tolerability of tucatinib used in combination with palbociclib and letrozole (phase Ib part) we will assess the incidence, nature and severity of all adverse events (AE) that occur on or after C1D1 of therapy, AE severities will be classified using the CTCAE criteria.
• The number of patients with progression-free survival (PFS) [ Time Frame: 2.5 years ]
  To measure efficacy of tucatinib used in combination with palbociclib and letrozole PFS (phase II part) will be assessed. PFS 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 PFS 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2017)

Identify the pharmacokinetic (PK) properties of tucatinib and palbociclib current RP2D. [ Time Frame: 6 months ]

PK assessments of blood levels of tucatinib and palbociclib will be performed on Cycle 1 Day 15 and Cycle 2 Day 1 of therapy. Plasma samples will be collected to measure levels of tucatinib and its hydroxyl metabolite, as well as levels of palbociclib and its metabolites at steady state on Cycle 1 Day 15. Plasma samples will also be collected prior to administration of tucatinib and palbociclib on the first day of Cycles 2 to assess trough levels.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tucatinib, Palbociclib and Letrozole in Metastatic Hormone Receptor Positive and HER2-positive Breast Cancer
• Official Title: 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
• 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.
• 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 Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Tucatinib in Combination with Palbociclib and Letrozole (Safety Cohort)

  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

  Other Names:

  • ONT-380
  • IBRANCE
  • Femara
• Drug: Tucatinib in Combination with Palbociclib and Letrozole
  Subjects 11-20 Tucatinib 300 mg PO BID Palbociclib 75mg PO daily 21 days on followed by 7 days off Letrozole 2.5 mg PO daily.
  Other Names:

  • ONT-380
  • IBRANCE
  • Femara

Study Arms

• Experimental: Baseline Starting Dose Patients (1-10): Tucatinib in Combination with Palbociclib and Letrozole

  Enroll 10 subjects at the baseline starting doses (DL1) of 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. After 10 subjects are accrued to the study and complete at least 1 cycle of treatment, an interim analysis of the safety phase Ib cohort will be done.

  Plan - 10 subjects enrolled, completed at least one cycle of treatment (28 days) and evaluable for safety analysis: If there are 7 or fewer subjects experience DLTs due to palbociclib, 3 or fewer subjects experience DLTs due to tucatinib, and 7 or fewer subjects experience DLTs potentially attributable to both drugs, then the interim safety of the Phase Ib cohort will be considered acceptable and accrual will continue to enroll to 20 subjects without change of the starting doses.

  Intervention: Drug: Tucatinib in Combination with Palbociclib and Letrozole (Safety Cohort)
• Experimental: Subject 11-20: Tucatinib in Combination with Palbociclib and Letrozole

  The study completed the final phase Ib safety analysis on January 31, 2019. It was determined the study did not cross safety thresholds and full doses of tucatinib, palbociclib, and letrozole are reasonably well tolerated.

  Therefore, the recommended phase II doses (RP2D) were declared as tucatinib 300 mg PO BID; palbociclib 125 mg PO daily 21 days on followed by 7 days off; and letrozole 2.5 mg PO daily (DL1). However, new information on tucatinib became available via Safety Letter from Seattle Genetics sent to investigators on February 13, 2019 ("Re: Safety Communication: Potential Risk of Drug-Drug Interaction"). According to the FDA prescribing information, the dose of palbociclib needs to be decreased to 75mg PO daily 21 days on, 7 days off when palbociclib is used with strong CYP3A4 inhibitors.

  The decision was made to change the dose of palbociclib to 75mg daily for all patients who were on study, and for all newly enrolled patients.

  Intervention: Drug: Tucatinib in Combination with Palbociclib and Letrozole

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 13, 2020): 42
• Original Estimated Enrollment (submitted: February 10, 2017): 40
• Estimated Study Completion Date: March 31, 2024
• Actual Primary Completion Date: January 17, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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. 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.

2. Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria

   . Bone only disease is allowed.

3. 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

4. Age ≥ 18 years
5. ECOG performance status 0-1
6. Life expectancy of more than 6 months, in the opinion of the investigator
7. 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.

8. 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

9. 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
10. 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.
11. 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 antifungal, 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 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03054363
• Other Study ID Numbers: 16-1661.cc; NCI-2017-01776 ( Other Identifier: CTRP )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current

Collaborators

• Pfizer
• Cascadian Therapeutics Inc.
• Criterium, Inc.

Investigators

• Principal Investigator: Elena Shagisultanova, MD, PhD; University of Colorado, Denver

• PRS Account: University of Colorado, Denver
• Verification Date: February 2023