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

• Sponsor: Academic Thoracic Oncology Medical Investigators Consortium
• Collaborator: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver ( Academic Thoracic Oncology Medical Investigators Consortium )

Tracking Information

• First Submitted Date: February 7, 2017
• First Posted Date: February 15, 2017
• Last Update Posted Date: March 20, 2019
• Actual Study Start Date: November 13, 2017
• Estimated Primary Completion Date: October 2019 (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
• Change History: Complete list of historical versions of study NCT03054363 on ClinicalTrials.gov Archive Site

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 Outcome Measures: Not Provided
• Original Other 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: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

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
• IBRANCE
• Femara

Study Arms

Experimental: 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.

Intervention: Drug: Tucatinib in Combination with Palbociclib and Letrozole

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 18, 2019): 25
• Original Estimated Enrollment (submitted: February 10, 2017): 40
• Estimated Study Completion Date: October 2020
• Estimated Primary Completion Date: October 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subjects must have a histologically confirmed diagnosis of HR+/HER2+ positive locally advanced unresectable or metastatic breast cancer. Estrogen or progesterone receptor positivity is defined by IHC according to ASCO/CAP guidelines 2010. HER2 positivity is defined by standard of care fluorescence in situ hybridization (FISH) and/or 3+ staining by IHC according to ASCO/CAP guidelines 2014.
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 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 they are on or willing to be on mandatory ovarian function suppression)

8. Prior treatments:

   • Subjects with newly diagnosed untreated metastatic disease are eligible
   • Subjects who have had 1 line 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
   • Subjects may have had up to 1 line of prior chemotherapy, combination of chemotherapy with HER2-targeted antibodies (trastuzumab, pertuzumab, TDM-1), or HER2-targeted therapy alone in the metastatic setting. Prior adjuvant and/or neoadjuvant 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 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 ≤ 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 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 anti-viral.
11. Known active 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 (strong CYP3A4 or CYP2C8 inducers or inhibitors, or moderate CYP2C8 inhibitor trimethoprim) within 3 elimination half-lives of the inducer or inhibitor 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 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
• 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

• Responsible Party: University of Colorado, Denver ( Academic Thoracic Oncology Medical Investigators Consortium )
• Study Sponsor: Academic Thoracic Oncology Medical Investigators Consortium
• Collaborators: University of Colorado, Denver

Investigators

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

• PRS Account: University of Colorado, Denver
• Verification Date: March 2019