Clinical Trials /

Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

NCT03379428

Description:

This is a Phase I/II, open-label dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting side effects of ibrutinib (560 or 840 or 420 mg daily oral dose), given in combination with trastuzumab administered through the vein, in patients with HER2-amplified Metastatic Breast Cancer that has gotten worse after prior therapy with ado-trastuzumab emtansine (T-DM1).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer
  • Official Title: Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 14059
  • SECONDARY ID: 14-05914-059
  • NCT ID: NCT03379428

Conditions

  • Breast Neoplasms
  • Malignant Neoplasm of Breast

Interventions

DrugSynonymsArms
TrastuzumabHerceptinTrastuzumab plus Ibrutinib 560 mg
Ibrutinib 560 mgImbruvica, PCI-32765Trastuzumab plus Ibrutinib 560 mg
Ibrutinib 840 mgImbruvica, PCI-32765Trastuzumab plus Ibrutinib 840 mg
Ibrutinib 420 mgImbruvica, PCI-32765Trastuzumab plus Ibrutinib 420 mg

Purpose

This is a Phase I/II, open-label dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting side effects of ibrutinib (560 or 840 or 420 mg daily oral dose), given in combination with trastuzumab administered through the vein, in patients with HER2-amplified Metastatic Breast Cancer that has gotten worse after prior therapy with ado-trastuzumab emtansine (T-DM1).

Detailed Description

      Ado-trastuzumab emtansine (T-DM1) is approved by the FDA for patients with HER2-positive
      metastatic breast cancer (MBC) previously treated with a taxane and trastuzumab, and is
      currently listed as the preferred second-line therapy in the NCCN guidelines (NCCN 2014).
      While the benefit of continued HER2 inhibition has been conclusively established for disease
      that has progressed on a trastuzumab-containing regimen, there are currently no data
      regarding the efficacy of HER2- targeted therapies following progression on T-DM1.

      With the population of T-DM1-treated patients steadily growing, clinical trials are needed to
      investigate novel therapies in this setting,to meet the medical need for effective,
      evidence-based therapies for these patients.

      The oral small-molecule Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib has also
      demonstrated the ability to inhibit erythroblastosis virus oncogene B (ErbB)/HER receptor
      family kinases in preclinical studies at clinically relevant concentrations, with an
      equivalent or greater potency than other HER2-directed tyrosine kinase inhibitors (TKIs) with
      demonstrated activity in HER2-positive MBC, including lapatinib, neratinib, and afatinib. Of
      note, in preclinical HER2-positive cell model systems the growth inhibitory ability of
      ibrutinib was substantially greater in HER2-amplified breast cancer cells versus those that
      simply overexpressed the HER2 protein.

      Ibrutinib is currently approved for use in patients with Chronic lymphocytic leukemia (CLL)
      or Mantle cell lymphoma (MCL), and has an established safety record from clinical trials in
      these patient populations. Thus there is a reasonable rationale to investigate ibrutinib in
      patients with HER2- amplified MBC, in the setting of T-DM1-pretreated disease. Previous
      studies have demonstrated that combined targeting of HER2 with multiple HER2-directed agents
      is more effective that single agent therapy and therefore this study will explore the safety
      and efficacy of ibrutinib in combination with trastuzumab.

      This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation
      study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities
      (DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8
      mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with
      HER2-amplified MBC that has progressed on prior therapy with ado-trastuzumab emtansine.

      Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more
      than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3
      possible dose levels, additional patients will be enrolled on the phase II part of the study
      at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients
      total.
    

Trial Arms

NameTypeDescriptionInterventions
Trastuzumab plus Ibrutinib 560 mgExperimentalIn Phase I, starting dose of Ibrutinib will be 560 mg orally per day. 3 patients will be enrolled first. If none of these have DLTs, 3 new patients will be enrolled at the next higher Ibrutinib dose level (840 mg orally per day). If 1 of these 3 patients have a DLT, expand this arm to 6 patients. If 2 or more of these 6 patients have a DLT, enroll 3 patients in lower dose lever (420 mg).
  • Trastuzumab
  • Ibrutinib 560 mg
Trastuzumab plus Ibrutinib 840 mgExperimentalIf no patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this higher dose is tolerated.
  • Trastuzumab
  • Ibrutinib 840 mg
Trastuzumab plus Ibrutinib 420 mgExperimentalIf 2 or more patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this lower dose is tolerated.
  • Trastuzumab
  • Ibrutinib 420 mg
Phase II- Trastuzumab plus Maximum Tolerated DoseExperimentalMaximum tolerated dose from Phase I will be used here in Phase II.
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  1. Female, Age ≥ 18 years

          -  2. Histologic or cytologic confirmation of HER2-amplified breast cancer according to
             most recent biopsy (local testing permitted)

               -  a. HER2-amplified status is defined as a HER2/CEP17 ratio ≥2 or an average of ≥6
                  HER2 gene copies per cell by in situ hybridization (ISH) according to the 2013
                  American Society of Clinical Oncology (ASCO)/CAP guidelines

          -  3. Measurable or evaluable metastatic disease by RECIST (v1.1).

          -  4. Progression of disease on or ≤6 months of completing prior TDM1 therapy

          -  5. ≤ 4 prior chemotherapy regimens for MBC (Phase I portion) or ≤ 3 prior chemotherapy
             regimens for MBC (Phase II portion)

          -  6. Adequate hematologic function independent of transfusion and growth factor support
             for ≤7 days prior to screening, with the exception of pegylated G-CSF (pegfilgrastim)
             and darbepoetin which require discontinuation at least 14 days prior to screening,
             defined as:

               -  Absolute neutrophil count >1500 cells/mm3 (0.75 x 10^9/L).

               -  Platelet count >100,000 cells/mm3 (50 x 10^9/L).

               -  Hemoglobin >9.0 g/dL.

          -  7. Adequate hepatic and renal function defined as:

               -  Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper
                  limit of normal (ULN) if liver metastases, or ≤3 x ULN in the absence of liver
                  metastases.

               -  Alkaline phosphatase <2.5 x ULN, unless bone metastases are present and in the
                  absence of liver metastases

               -  Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault)

               -  Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
                  non-hepatic origin, such as hemolysis)

          -  8. Prothrombin time (PT)/international normalized ratio (INR) < 1.5xULN and PTT (aPTT)
             < 1.5x ULN

          -  9. Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline as determined by either
             ECHO or multiple gated acquisition scan (MUGA) and within normal limits per
             institutional guidelines

          -  10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

          -  11. Negative urine/serum pregnancy test within 72 hours before starting study
             medications for women of childbearing potential

          -  12. Women of childbearing potential who agree to use two highly effective methods of
             birth control (e.g., some intrauterine devices [IUD], diaphragm with spermicide,
             condom with spermicide, sterilized partner, or complete abstinence) for the duration
             of the study and for 30 days after the last dose of study drug

             o Note: Women are considered postmenopausal and not of childbearing potential if they
             have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
             profile (e.g. age appropriate, history of vasomotor symptoms), or if they have
             undergone surgical sterilization

          -  13. Signed informed consent obtained prior to any screening procedures.

          -  14. Signed Patient Authorization Form (HIPAA) obtained prior to any screening
             procedures.

        Exclusion Criteria:

          -  1. Uncontrolled or untreated central nervous system metastases, defined as clinical or
             radiologic evidence of progression of brain metastases or clinical signs of
             leptomeningeal disease

               1. Patients with treated brain metastases are eligible provided they do not have
                  clinical or radiologic evidence of disease progression and have been off of
                  dexamethasone for ≥2 weeks prior to first dose of study drugs

               2. Brain MRI at baseline required for patients with known brain metastases at study
                  entry

          -  2. Chemotherapy ≤ 21 days prior to first administration of study treatment

          -  3. History of other malignancies, except:

               -  Malignancy treated with curative intent and with no known active disease present
                  for ≥3 years before the first dose of study drug and felt to be at low risk for
                  recurrence by treating physician.

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               -  Adequately treated carcinoma in situ without evidence of disease.

          -  4. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus,
             etc., or chronic administration days] [ > 14 days] of >5 mg/day of prednisone) ≤28
             days of the first dose of study drug.

          -  5. Vaccinated with live, attenuated vaccines ≤4 weeks of first dose of study drug.

          -  6. Recent infection requiring systemic treatment that was completed ≤14 days before
             the first dose of study drug.

          -  7. Unresolved toxicities from prior anti-cancer therapy, defined as having not
             resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade 0
             or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception
             of alopecia.

          -  8. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.

          -  9. History of stroke or intracranial hemorrhage ≤6 months prior to first dose of study
             drug.

          -  10. Known history of human immunodeficiency virus (HIV) or active with hepatitis C
             virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core
             antibody or hepatitis B surface antigen must have a negative polymerase chain reaction
             (PCR) result before enrollment. Those who are PCR positive will be excluded.

          -  11. Any uncontrolled active systemic infection.

          -  12. Major surgery ≤ 4 weeks of first dose of study drug.

          -  13. Any life-threatening illness, medical condition, or organ system dysfunction that,
             in the investigator's opinion, could compromise the subject's safety or put the study
             outcomes at undue risk.

          -  14. Currently active, clinically significant cardiovascular disease, such as
             uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New
             York Heart Association Functional Classification; or a history of myocardial
             infarction, unstable angina, or acute coronary syndrome within 6 months prior to
             randomization.

          -  15. Unable to swallow capsules or malabsorption syndrome, disease significantly
             affecting gastrointestinal function, or resection of the stomach or small bowel,
             symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete
             bowel obstruction.

          -  16. Concomitant use of warfarin or other Vitamin K antagonists.

          -  17. Receipt of a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the
             first dose of ibrutinib or requirement for continuous treatment with a strong CYP3A
             inhibitor.

          -  18. Chronic liver disease with hepatic impairment Child-Pugh class B or C.

          -  19. Lactating or pregnant.

          -  20. Unwilling or unable to participate in all required study evaluations and
             procedures.

          -  21. Unable to understand the purpose and risks of the study and to provide a signed
             and dated informed consent form (ICF) and authorization to use protected health
             information (in accordance with national and local subject privacy regulations).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum Tolerated Dose
Time Frame:24 months
Safety Issue:
Description:Highest dose of ibrutinib from Phase 1 (420, 560, or 840 mg by mouth daily) that had fewer than two dose-limiting toxicities in its respective cohort

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:24 months
Safety Issue:
Description:To determine the objective response rate (ORR = CR + PR) associated with ibrutinib plus trastuzumab.
Measure:Median Overall Survival
Time Frame:24 months
Safety Issue:
Description:To assess median overall survival (OS) associated with ibrutinib plus trastuzumab.
Measure:Median Progression-free Survival
Time Frame:24 months
Safety Issue:
Description:To assess median progression-free survival (PFS) associated with ibrutinib plus trastuzumab
Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of ibrutinib plus trastuzumab.
Time Frame:24 months
Safety Issue:
Description:Number of Adverse Events and Serious Adverse Events from informed consent signature to 30 days after last dose of study drug, using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.03: June 14, 2010)
Measure:Pharmacokinetic Analysis for Ibrutinib (Phase I only)- Cmax
Time Frame:24 months
Safety Issue:
Description:maximum (or peak) serum concentration that Ibrutinib achieves in Cycle 1 at indicated time points, and on Day 1 of cycle 3 for pharmacokinetic analysis
Measure:Pharmacokinetic Analysis for Ibrutinib (Phase I only)- Area under Curve
Time Frame:24 months
Safety Issue:
Description:Area Under the Curve of Ibrutinib in 24 hours

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:US Oncology Research

Trial Keywords

  • Breast Cancer
  • Metastatic Breast Cancer
  • HER2-amplified Metastatic Breast Cancer
  • HER2-positive Metastatic Breast Cancer

Last Updated

December 19, 2017