Rebastinib Tosylate and Paclitaxel or Eribuilin Mesylate in Treating Patients with HER2 Negative Metastatic Breast Cancer

Status: Active

Description

This phase Ib trial studies the best dose and side effects of rebastinib tosylate when given together with paclitaxel or eribulin mesylate in treating patients with HER2 negative breast cancer that has spread to other parts of the body. Rebastinib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and eribulin mesylate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving rebastinib tosylate with paclitaxel or eribulin may work better in treating patients with breast cancer.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed adenocarcinoma of the breast that is Her2 negative (by DAKO Herceptest, fluorescence in situ hybridization [FISH], or other approved assay)
  • Metastatic breast cancer not amenable to potentially curative surgery; patients must have disease that is measurable and/or non-measurable as defined by RECIST 1.1 criteria (assessed by computed tomography [CT] scan chest/abdomen/pelvis with contrast or fludeoxyglucose [FDG] positron emission tomography [PET]-CT scan obtained within 4 weeks of registration)
  • Prior therapy * Arm A: Rebastinib plus paclitaxel: up to two prior non-taxane chemotherapy regimens for metastatic or incurable locally advanced disease permitted (no prior paclitaxel or eribulin); patients with estrogen receptor (ER)-positive disease are required to have relapse or progression on at least one line of endocrine therapy * Arm B: Rebastinib plus eribulin: up to three prior chemotherapy regimens for metastatic or incurable locally advanced disease permitted (no prior eribulin, but prior paclitaxel allowed): patients with ER-positive disease are required to have relapse or progression on at least one line of endocrine therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Leukocytes >= 3,000/uL
  • Absolute neutrophil count >= 1,500/uL
  • Platelets >= 100,00/uL
  • Hemoglobin > 9 g/dL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits
  • Left ventricular ejection fraction at or above institutional lower limits of normal (by echocardiogram within 12 weeks of registration)
  • Electrocardiogram (EKG) corrected QT interval (QTc) < 450 msec (females)
  • Serum calcium & phosphorus within normal institutional limits
  • Glucose within normal institutional limits
  • Negative urine or serum beta-human chorionic gonadotropin (BHCG) for women of childbearing potential only (within 7 days of registration)
  • No prior known history of retinal neovascularization, macular edema or macular degeneration; patients without such a history are required to have a baseline ophthalmologic exam as part of screening, and must not have evidence of retinal neovascularization, macular edema or macular degeneration on the screening exam in order to be eligible
  • Patients must be disease-free of prior invasive malignancies for >= 2 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix; patient with the following prior concurrent diagnoses are eligible: lobular carcinoma in situ, contralateral ductal carcinoma in situ, or contralateral invasive ductal and/or lobular carcinoma
  • Women of child-bearing potential must not be pregnant or breast feeding; they must also agree to use adequate contraception (hormonal or barrier method of birth control) and not be breast feeding prior to study entry, for the duration of study participation, and for up to 30 days after completion of all protocol therapy; should a woman become pregnant or suspect she is pregnant while participating in this study or up to 30 days after completion of protocol therapy, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • At least 30 days from major surgery before study enrollment, with full recovery
  • Concomitant therapy with bisphosphonates, RANKL inhibitors or growth-colony-stimulating factors (G-CSF) is allowed as per physician decision
  • Patients for the expansion cohort must have a CTC (TelomeScan) drawn in the screening phase if other eligibility criteria are met, and must be CTC-positive in order to be eligible for enrollment in the expansion cohort

Exclusion Criteria

  • History of allergic reactions attributed to compounds of similar chemical or biological composition to rebastinib or other agents used in the study (e.g., Cremophor)
  • History of cardiac disease, including: (a) myocardial infarction within 6 months of the start of study, (b) history of QTc prolongation or QTc >= 450 msec on screening EKG, history of additional risk factors for torsade de pointes (e.g., heart failure, hyperkalemia), and family history of long QT syndrome; (c) use of concomitant drugs that prolong QT/QTc interval; (d) New York Heart Association class III or IV heart disease, (e), active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically signification cardiac arrhythmia requiring therapy
  • Intercurrent illness that would substantially increase the risk of treatment associated complications (e.g., active infection, uncontrolled diabetes mellitus or hypertension) and/or psychiatric illness/social situations that would interfere with the patient's ability to comply with the treatment regimen
  • Patients with human immunodeficiency virus (HIV) infection are excluded from the study
  • Patients with untreated brain metastasis are excluded; patients with a prior history of brain metastasis are eligible if they have received prior brain radiation, have improved or stable intracranial disease for at least 3 months after completion of last course of radiation, and are not taking corticosteroids for treatment of brain metastasis; patients with a prior history of brain metastases who meet other eligibility criteria
  • Treatment with other chemotherapy regimen within the past 2 weeks
  • Treatment with trastuzumab, bevacizumab or other targeted therapies within the past 4 weeks

Locations & Contacts

New York

Bronx
Montefiore Medical Center-Weiler Hospital
Status: Active
Contact: Jesus Del Santo Anampa Mesias
Phone: 718-405-8404
Email: janampa@montefiore.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (Arm A1-dose escalation cohort) and overall safety profile (Arm A2-expansion cohort) of rebastinib tosylate (rebastinib) (50 mg orally [PO] twice daily [BID] or 100 mg PO BID) given concurrently with weekly paclitaxel (80 mg/m^2 weekly x 12) over 3 consecutive weeks (1 cycle) in patients with breast cancer. (Arm A)

II. To determine the recommended phase II dose (Arm B1-dose escalation cohort) and overall safety profile (Arm B2-expansion cohort) of rebastinib (50 mg PO BID or 100 mg PO BID) given concurrently with weekly eribulin mesylate (eribulin) (1.4 mg/m^2 days 1 and 8 every 21 days) over 3 consecutive weeks (1 cycle) in patients with breast cancer. (Arm B)

SECONDARY OBJECTIVES:

I. To determine the objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), progression-free survival, and overall survival of patients treated with rebastinib plus paclitaxel, and rebastinib plus eribulin (at all rebastinib dose levels). (Arm A1-2 and Arm B1-2)

II. To determine correlation between rebastinib plasma concentration and angiopoietin (ANG1 and/or ANG2) levels. (Arm A1-2 plus Arm B1-2)

III. To perform an exploratory analysis of the effects of rebastinib plus antitubulin therapy on circulating tumor cell (CTCs) during cycle 1. (Arm A2 plus Arm B2)

IV. To perform an exploratory analysis of the effects of rebastinib plus antitubulin therapy on TIE-2 expressing monocytes (TEM) during cycle 1. (Arm A2 plus Arm B2)

V. To perform an exploratory analysis of the effects of rebastinib plus antitubulin therapy on tumor microenvironment of metastasis (TMEM) score and TMEM function in a cohort of up to 6 patients with metastatic cancer who have their primary tumor in place and are agreeable to up to 2 research biopsies of the primary tumor before and during (i.e., after 3 weeks of) rebastinib therapy. (Arm A2 or Arm B2)

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

ARM A2: Patients receive rebastinib tosylate PO BID beginning on days 1-21 of courses 1 or 2. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive paclitaxel intravenously (IV) over 1 hour on day 1. Treatment repeats weekly for up to 12 weeks in the absence of disease progression or unacceptable toxicity.

ARM B2: Patients receive rebastinib tosylate PO BID beginning on days 1-21 of courses 1 or 2. Patients also receive eribulin mesylate IV over 3-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and for up to 3 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Montefiore Medical Center-Weiler Hospital

Principal Investigator
Jesus Del Santo Anampa Mesias

Trial IDs

Primary ID 2016-6488
Secondary IDs NCI-2016-01662
Clinicaltrials.gov ID NCT02824575