Clinical Trials /

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

NCT03054363

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 16-1661.cc
  • NCT ID: NCT03054363

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Tucatinib in Combination with Palbociclib and LetrozoleONT-380, IBRANCE, FemaraTucatinib in Combination with Palbociclib and Letrozole

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Tucatinib in Combination with Palbociclib and LetrozoleExperimentalDuring 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.
  • Tucatinib in Combination with Palbociclib and Letrozole

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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:The number of patients in the Pase 1b part of the study with any adverse events (AE).
Time Frame:2.5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Identify the pharmacokinetic (PK) properties of tucatinib and palbociclib current RP2D.
Time Frame:6 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Colorado, Denver

Trial Keywords

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

Last Updated

December 8, 2017