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

NCT03379428 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 1405914-059
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Breast Neoplasms; Malignant Neoplasm of Breast

Keywords

Breast Cancer; Metastatic Breast Cancer; HER2-amplified Metastatic Breast Cancer; HER2-positive Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose

  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

  24 months

• Phase II: Clinical Benefit Rate

  To define the clinical benefit rate (CBR = CR \[complete response\] + PR \[partial response\] + SD \[stable disease\] \> 6 months) of ibrutinib plus trastuzumab in patients with HER2-amplified, T-DM1-pretreated MBC

  24 months

Secondary Outcomes (6)

• Objective Response Rate

  24 months

• Median Overall Survival

  24 months

• Median Progression-free Survival

  24 months

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of ibrutinib plus trastuzumab.

  24 months

• Pharmacokinetic Analysis for Ibrutinib (Phase I only)- Cmax

  24 months

Other Outcomes (1)

• Cytokine Gene Expression Analysis

  24 months

Study Arms (4)

Trastuzumab plus Ibrutinib 560 mg

EXPERIMENTAL

In 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).

Drug: Trastuzumab; Drug: Ibrutinib 560 mg

Trastuzumab plus Ibrutinib 840 mg

EXPERIMENTAL

If no patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this higher dose is tolerated.

Drug: Trastuzumab; Drug: Ibrutinib 840 mg

Trastuzumab plus Ibrutinib 420 mg

EXPERIMENTAL

If 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.

Drug: Trastuzumab; Drug: Ibrutinib 420 mg

Phase II- Trastuzumab plus Maximum Tolerated Dose

EXPERIMENTAL

Maximum tolerated dose from Phase I will be used here in Phase II.

Drug: Trastuzumab

Interventions

Trastuzumab DRUG

8 mg/kg loading dose (first dose), followed by 6 mg/kg every 3 weeks, administered intravenously (IV)

Also known as: Herceptin

Phase II- Trastuzumab plus Maximum Tolerated Dose; Trastuzumab plus Ibrutinib 420 mg; Trastuzumab plus Ibrutinib 560 mg; Trastuzumab plus Ibrutinib 840 mg

Ibrutinib 560 mg DRUG

560 mg by mouth daily

Also known as: Imbruvica, PCI-32765

Trastuzumab plus Ibrutinib 560 mg

Ibrutinib 840 mg DRUG

840 mg by mouth daily

Also known as: Imbruvica, PCI-32765

Trastuzumab plus Ibrutinib 840 mg

Ibrutinib 420 mg DRUG

420 mg by mouth daily

Also known as: Imbruvica, PCI-32765

Trastuzumab plus Ibrutinib 420 mg

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Based on biological gender
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Female, Age ≥ 18 years
• \. 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
• \. Measurable or evaluable metastatic disease by RECIST (v1.1).
• \. Progression of disease on or ≤6 months of completing prior TDM1 therapy
• \. ≤ 4 prior chemotherapy regimens for MBC (Phase I portion) or ≤ 3 prior chemotherapy regimens for MBC (Phase II portion)
• \. 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.
• \. 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)

You may not qualify if:

• \. Uncontrolled or untreated central nervous system metastases, defined as clinical or radiologic evidence of progression of brain metastases or clinical signs of leptomeningeal disease
• 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
• Brain MRI at baseline required for patients with known brain metastases at study entry
• \. Chemotherapy ≤ 21 days prior to first administration of study treatment
• \. 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.
• \. 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.
• \. Vaccinated with live, attenuated vaccines ≤4 weeks of first dose of study drug.
• \. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
• \. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.
• \. History of stroke or intracranial hemorrhage ≤6 months prior to first dose of study drug.
• \. 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.
• \. Any uncontrolled active systemic infection.

Sponsors & Collaborators

• US Oncology Research: lead
• AbbVie: collaborator
• Pharmacyclics LLC.: collaborator

Study Sites (1)

10 sites incl TX, WA, VA, and NV

Dallas, Texas, 75246, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Trastuzumab; ibrutinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Joyce O'Shaughnessy, MD

  US Oncology Research/McKesson Specialty Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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. 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.

Study Record Dates

• First Submitted: December 12, 2017
• First Posted: December 20, 2017
• Study Start: November 29, 2017
• Primary Completion: January 1, 2025
• Study Completion: January 1, 2025
• Last Updated: December 6, 2024

Record last verified: 2024-12

Locations

US (1)