Trastuzumab, Pertuzumab, Tocilizumab in Treating Participants with Metastatic or Unresectable HER2 Positive Breast Cancer

Status: Active

Description

This phase I trial studies the best dose and side effects of trastuzumab, pertuzumab and tocilizumab in treating participants with HER2 positive breast cancer that has spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies such as trastuzumab, pertuzumab and tocilizumab, may interfere with the ability of tumor cells to grow and spread

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed breast cancer that overexpresses HER2 (defined by American Society of Clinical Oncology [ASCO]- College of American Pathologists [CAP] 2013 guidelines performed using Food and Drug Administration [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 (trastuzumab emtansine [TDM-1], pertuzumab, lapatinib) is allowed; the last dose of cytotoxic chemotherapy must have occurred >= 3 weeks prior to study registration; the last radiation therapy must have occurred >= 3 weeks prior to study registration
  • Eastern Cooperative Oncology Group Performance Status of 0 or 1
  • Measurable and/or non-measureable disease by RECIST criteria must be present
  • White blood cell count >= 3,000 /ul
  • Neutrophil count >= 1,500/ul
  • Hemoglobin >= 8.5 g/dL
  • Platelet count >= 150,000/ul
  • Total bilirubin up to 1.5 X institutional normal reference range
  • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) but =< 5.0 x ULN in case of liver metastases; in the presence of liver metastases the liver isoenzyme fraction must be measured and liver isoenzyme fraction (absolute value) must be =< 2 x ULN
  • Alkaline phosphatase (ALP) =< 1.5 x ULN but =< 2.5 x ULN in case of liver metastases or =< 5 x ULN in the case of bone metastasis; in the presence of liver metastases the liver isoenzyme fraction must be measured and liver isoenzyme fraction (absolute value) must be =< 2 x UNL
  • Albumin within normal limits
  • Creatinine clearance >= 50 ml/min measured by Cockcroft-Gault
  • 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; a woman of reproductive potential is defined as a premenopausal female with intact uterus and ovaries
  • Ability to understand and the willingness to sign a written informed consent

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 incurrent illness
  • Major surgery within 8 weeks of study enrollment 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 multi-gated acquisition scan (MUGA); or current or past clinical diagnosis of congestive heart failure; history of ejection fraction decreased to below institutional normal or decrease 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 gastrointestinal (GI) disease such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations
  • Infections: * Known active current or history of recurrent bacterial, viral, fungal, parasitic, mycobacterial or other opportunistic infections (including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds) * Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to enrollment * History of tuberculosis or positive PPD without anti-mycobacterial therapy and/or active tuberculosis (TB) requiring treatment within the previous 3 years; subjects treated for tuberculosis with no recurrence in 3 years are permitted * Human immunodeficiency virus (HIV) positive, hepatitis B surface antigen or core antibody positive, hepatitis C infections (current or past), active Epstein-Barr virus infection * History of 2 or more episodes of cellulitis within the past 12 months * History of recurrent herpes simplex infections requiring suppressive antiviral therapy * History of invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii * History of recurring or chronic infection
  • 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 central nervous system (CNS) 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

Locations & Contacts

Connecticut

New Haven
Yale University
Status: Approved
Contact: Lajos Pusztai
Phone: 203-737-8309

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Rita Nanda
Phone: 855-702-8222

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Active
Contact: Monika Leigh Burness
Phone: 734-763-0807
Email: mburness@umich.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. 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 dose-limiting toxicity (DLT).

SECONDARY OBJECTIVES:

I. To assess the frequency of adverse events (AEs) via National Cancer Institute (NCI)’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

TERTIARY OBJECTIVES:

I. To describe the pharmacokinetics of tocilizumab when administered in combination with trastuzumab and pertuzumab every three weeks.

II. To describe any preliminary evidence of anti-tumor activity by assessment of objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria in subjects with measurable disease.

III. To describe changes in the relative proportion of cancer stem cells (CSCs), and specific proteins of interest in tumor biopsies performed before, during, and after study treatment.

IV. To describe effect of tocilizumab treatment in three different dose combinations on circulating tumor cells (CTCs) and serum proteins.

V. To describe changes in subject-reported outcomes of depression and fatigue after treatment with tocilizumab.

OUTLINE: This is a dose-escalation study of tocilizumab. Patients are assigned to 1 of 2 arms.

ARM I: Participants receive trastuzumab intravenously (IV) over 90 minutes on day 1, and tocilizumab IV over 60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants receive pertuzumab intravenously IV over 60 minutes on day 1, trastuzumab IV over 90 minutes on day 1, and tocilizumab IV over 60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Monika Leigh Burness

Trial IDs

Primary ID UMCC 2017.002
Secondary IDs NCI-2017-02497
Clinicaltrials.gov ID NCT03135171