Trastuzumab and Pertuzumab in Combination With Tocilizumab in Subjects With Metastatic HER2 Positive Breast Cancer Resistant to Trastuzumab

A Phase 1 Multi-Center Trial of Trastuzumab and Pertuzumab in Combination With Tocilizumab in Subjects With Metastatic HER2 Positive Breast Cancer Resistant to Trastuzumab

The goal in this Phase 1 dose-escalation trial of the anti-IL-6R monoclonal antibody tocilizumab in combination with trastuzumab and pertuzumab in subjects with metastatic HER2 positive breast cancer is to determine the safety, tolerability and recommended Phase 2 dose of tocilizumab given with trastuzumab and pertuzumab every 3 weeks.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab; Drug: Pertuzumab; Drug: Tocilizumab

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • New York
    • New Haven, New York, United States, 06520
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Women or men with histologically confirmed breast cancer that overexpresses HER2 (defined by ASCO-CAP 2013 guidelines performed using FDA-approved tests by laboratories with demonstrated proficiency) that is metastatic or unresectable
• Subjects must have received trastuzumab in the metastatic setting and experienced disease progression on this drug.
• Any number of prior therapies is permitted. Prior therapy with other HER2 targeted agents (TDM-1, pertuzumab, lapatinib) is allowed.
• The last dose of chemotherapy must have occurred ≥3 weeks prior to study registration.
• The last radiation therapy must have occurred ≥3 weeks prior to study registration.
• Age≥ 18 years
• Eastern Cooperative Oncology Group Performance Status of 0 or 1 (An attempt to quantify cancer patients' general well-being and activities of daily life. The score ranges from 0 to 5 where 0 is asymptomatic and 5 is death.)
• Measurable and/or non-measureable disease by RECIST criteria must be present.
• Adequate organ and bone marrow function
• Subjects with treated brain metastases are eligible provided the metastases are clinically stable and greater than 8 weeks has elapsed from time of treatment and date of initiation of study drug.
• Males and females of reproductive potential must use two forms of effective contraception during the duration of the trial and for minimum of 7 months after last dose of tocilizumab, trastuzumab, or pertuzumab.

Exclusion Criteria:

• Intolerance to previous trastuzumab or pertuzumab therapy
• Previous treatment with tocilizumab or other cytokine-targeted biologic disease modifying antirheumatic drugs (including adalimumab, certolizumab, etanercept, golimumab, infliximab, anakinra) within 3 months of enrollment
• Participation in other investigational studies concurrently if these therapies include a therapeutic intervention
• Treatment with any investigational agent within 30 days (or 5 serum half-lives of the investigational drug, whichever is longer) of enrollment
• Concurrent second malignancy or history of HER2 negative breast cancer within five years
• Comorbidity or intercurrent illness
• Major surgery within 8 weeks or planned major surgery during study and up to 6 months after discontinuation of study drug
• Left ventricular systolic dysfunction, defined as ejection fraction below institutional normal by echocardiography or MUGA (multigated acquisition scan); current or past clinical diagnosis of congestive heart failure; history of ejection fraction decreased to below institutional normal or desease of greater than 15% attributable to past trastuzumab or pertuzumab therapy
• Evidence of current serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease.
• History of diverticulitis, diverticulosis requiring antibiotic treatment or chronic ulcerative lower GI (gastrointestinal) disease such as Crohn's disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations
• Infections as detailed in the protocol
• Immunization with a live/attenuated vaccine within 30 days of enrollment
• Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation
• Pre-existing CNS (Central Nervous System) demyelination or seizure disorders
• Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab, Pertuzumab and Tocilizumab	Drug: Trastuzumab; All dose levels will receive 8 mg/kg loading dose for cycle 1, followed by 6 mg/kg in subsequent cycles, every 3 weeks.; Drug: Pertuzumab; Dose Levels two and three will receive 840 mg loading dose for cycle 1, followed by 420 mg in subsequent cycles, every 3 weeks.; Drug: Tocilizumab; Tocilizumab 4-8 mg/kg, administered intravenously every three weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase II Dose of Tocilizumab	The primary objective is to determine the highest dose level of tocilizumab (up to 8 mg/kg every 3 weeks) that, when given in combination with trastuzumab and pertuzumab every three weeks in subjects with HER2 positive metastatic breast cancer, will result in less than 25% incidence of DLT. DLTs (Dose Limiting Toxicity) will be assessed within the first two cycles (up to 10 weeks) and defined as any toxicity of grade 3 or 4, unless specifically described in the protocol.	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Frequency of Adverse Events at Each Dose Level	The number of grade 3 and 4 adverse events at each dose level will be described.	30 days after last treatment dose

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Monika Burness, M.D., University of Michigan Rogel Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2017
• Primary Completion (Actual): March 16, 2020
• Study Completion (Actual): March 20, 2020

Study Registration Dates

• First Submitted: April 25, 2017
• First Submitted That Met QC Criteria: April 25, 2017
• First Posted (Actual): May 1, 2017

Study Record Updates

• Last Update Posted (Actual): September 10, 2021
• Last Update Submitted That Met QC Criteria: September 8, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab; Pertuzumab
• Other Study ID Numbers: UMCC 2017.002; HUM00125505 (Other Identifier: University of Michigan Comprehensive Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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