Clinical trial NCT00834678: Bendamustine and Erlotinib in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Breast Cancer
Official title: Phase I/II Study of Bendamustine and Erlotinib for Metastatic or Locally Advanced Triple Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Keywords: male breast cancer
recurrent breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
estrogen receptor-negative breast cancer
HER2-negative breast cancer
progesterone receptor-negative breast cancer
triple-negative breast cancer
Lead sponsor: Ohio State University Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Comprehensive Cancer Network
name: Genentech, Inc.
First posted: 2009-02-03
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum-tolerated Dose of Bendamustine Hydrochloride (Phase I)
timeFrame: Up to two years
measure: Maximum-tolerated Dose of Erlotinib Hydrochloride (Phase I)
timeFrame: Up to two years
measure: Dose-limiting Toxicity (Phase I)
timeFrame: Up to two years
measure: Progression-free Survival at 6 Months and 12 Months (Phase II)
timeFrame: Up to two years
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to two years
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to two years
measure: Duration of Response (DR)
timeFrame: Up to two years
measure: Overall Survival (OS)
timeFrame: from time of study enrollment until death, for up to 2 years
measure: Relationship of EGFR Expression or Amplification, Basal-like Tumors, and DNA Damage-repair Checkpoint Activation With ORR, CBR, DR, and OS
timeFrame: up to two years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center
name: Rachel Layman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.