Bendamustine and Erlotinib in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Breast Cancer

Phase I/II Study of Bendamustine and Erlotinib for Metastatic or Locally Advanced Triple Negative Breast Cancer

RATIONALE: Drugs used in chemotherapy, such as bendamustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving bendamustine together with erlotinib may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving bendamustine together with erlotinib in treating patients with stage IIIB, stage IIIC, or stage IV breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: bendamustine; Drug: erlotinib; Drug: Maintenance erlotinib

Detailed Description

OBJECTIVES:

Primary

• To determine the phase II dose and assess the toxicity of bendamustine hydrochloride and erlotinib hydrochloride in patients with triple-receptor (estrogen receptor, progesterone receptor, and HER-2)-negative, stage IIIB, IIIC, or IV breast cancer. (Phase I)
• To determine the efficacy of this regimen in these patients. (Phase II)

Secondary (Correlative)

• To assess the correlation between tumor EGFR expression and EGFR gene amplification and treatment efficacy and toxicity.
• To assess for differences in treatment efficacy between basal-like and non-basal-like cancers.
• To assess for differences in treatment efficacy between tumors with and without expression of DNA damage-response (DDR) checkpoint proteins.
• To assess for differences in the activation state of DDR checkpoint proteins based on breast cancer subtype.

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study.

Patients receive bendamustine hydrochloride IV over 30 minutes on days 1-2 and oral erlotinib hydrochloride once daily on days 5-21. Treatment repeats every 28 days for at least 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with no evidence of disease progression may continue with daily single-agent oral erlotinib hydrochloride on days 1-28. Treatment continues every 28 days in the absence of disease progression or unacceptable toxicity.

Breast cancer tissue blocks from prior procedures are obtained for correlative studies. After a tissue microarray (TMA) and a TMA map are prepared, TMA slides are used for hematoxylin and eosin (H&E) staining, FISH, and IHC.

After completion of study treatment, patients are followed every 3 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center

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

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer meeting 1 of the following criteria:

  • Unresectable stage IIIB or IIIC disease
  • Stage IV disease

• Must be negative for all of the following:

  • Estrogen receptor (< 10%)
  • Progesterone receptor (<10%)
  • HER-2 (negative FISH, IHC 0 - 1+, or IHC +2 with negative FISH)
• Measurable or evaluable disease

• No symptomatic or progressive CNS (central nervous system) metastases

  • Previously treated CNS metastases allowed provided all of the following criteria are met:

    • At least 8 weeks since prior radiation to brain or CNS metastases
    • No concurrent steroids
    • No leptomeningeal disease

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG (Eastern Cooperative Oncology Group) performance status 0-2
• Life expectancy ≥ 6 months
• WBC > 1,500/mm³
• Platelet count > 100,000/mm³
• Creatinine clearance > 40 mL/min
• Normal electrolytes (i.e., Na, K, and Ca normal; minor deviations are allowed if they do not impact on patient safety in the clinical judgment of the treating physician)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN in the presence of documented liver metastases)
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver or bone metastases)
• Not pregnant or nursing
• Fertile patients must use effective barrier contraception
• No uncontrolled intercurrent illness
• No active infection requiring systemic therapy

• Able to swallow oral medications and with no medical problems or prior surgeries that may interfere with the absorption of oral medications including the following:

  • Uncontrolled nausea, vomiting, or diarrhea
  • Lack of the physical integrity of the upper gastrointestinal tract
  • Malabsorption syndrome
• No known hypersensitivity to bendamustine hydrochloride, mannitol, or erlotinib hydrochloride
• No prior malignancy in the past 5 years except for adequately treated basal cell or squamous cell skin carcinoma, or adequately treated stage I-II cancer for which the patient is in complete remission

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior adjuvant or neoadjuvant chemotherapy and 1 prior chemotherapy regimen in the metastatic setting allowed provided recovered from all acute toxicities
• No prior bendamustine hydrochloride or EGFR-directed therapy

• No other concurrent antineoplastic treatments, including radiotherapy, chemotherapy, biological therapy, hormonal therapy, immunotherapy, gene therapy, and surgery

  • Intravenous bisphosphonates allowed
• No concurrent antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Bendamustine and Erlotinib; Bendamustine 100 or 120 mg/m2 IV on days 1 and 2 and erlotinib 100 or 150 mg po on days 5 - 21 of each 28 day cycle.	Drug: bendamustine; 100 or 120 mg/m2 IV on days 1 and 2; Other Names: Treanda; Ribomustin; SDX- 105; Drug: erlotinib; 100 or 150 mg po on days 5 - 21 of each 28 day cycle; Other Names: Tarceva; Drug: Maintenance erlotinib; 150 mg po daily (days 1 - 28 of 28 day cycle); Other Names: Tarceva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum-tolerated Dose of Bendamustine Hydrochloride (Phase I)	28 day cycle included intravenous bendamustine on days 1 and 2.	Up to two years
Maximum-tolerated Dose of Erlotinib Hydrochloride (Phase I)	28 day cycle included intravenous erlotinib on days 15-21.	Up to two years
Dose-limiting Toxicity (Phase I)		Up to two years
Progression-free Survival at 6 Months and 12 Months (Phase II)	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions	Up to two years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to two years
Clinical Benefit Rate (CBR)		Up to two years
Duration of Response (DR)		Up to two years
Overall Survival (OS)		from time of study enrollment until death, for up to 2 years
Relationship of EGFR Expression or Amplification, Basal-like Tumors, and DNA Damage-repair Checkpoint Activation With ORR, CBR, DR, and OS		up to two years

Collaborators and Investigators

• Sponsor: Ohio State University Comprehensive Cancer Center
• Collaborators: Genentech, Inc.; National Comprehensive Cancer Network
• Investigators: Principal Investigator: Rachel Layman, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

General Publications

• Layman RM, Ruppert AS, Lynn M, Mrozek E, Ramaswamy B, Lustberg MB, Wesolowski R, Ottman S, Carothers S, Bingman A, Reinbolt R, Kraut EH, Shapiro CL. Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer. Cancer Chemother Pharmacol. 2013 May;71(5):1183-90. doi: 10.1007/s00280-013-2112-2. Epub 2013 Feb 21.

Helpful Links

• Jamesline

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2009
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: January 31, 2009
• First Submitted That Met QC Criteria: January 31, 2009
• First Posted (ESTIMATE): February 3, 2009

Study Record Updates

• Last Update Posted (ACTUAL): April 17, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer; stage IIIB breast cancer; male breast cancer; stage IIIC breast cancer; estrogen receptor-negative breast cancer; progesterone receptor-negative breast cancer; triple-negative breast cancer; HER2-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Bendamustine Hydrochloride
• Other Study ID Numbers: OSU-08164; NCI-2011-03164 (REGISTRY: Clinical Trial Reporting Program (CTRP))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No