Clinical Trials /

Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer

NCT02824575

Description:

The purpose of this study is to determine the safety and tolerability of rebastinib when combined with antitubulin therapy with paclitaxel or eribulin in patients with advanced breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer
  • Official Title: Phase Ib Study of Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Patients With Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2016-6488
  • NCT ID: NCT02824575

Conditions

  • Breast Cancer
  • Breast Adenocarcinoma
  • Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer

Interventions

DrugSynonymsArms
RebastinibDCC-2036Arm A1-2: Paclitaxel plus Rebastinib.
PaclitaxelTaxolArm A1-2: Paclitaxel plus Rebastinib.
Eribulin MesylateHalavenArm B1-2: Eribulin plus Rebastinib.

Purpose

The purpose of this study is to determine the safety and tolerability of rebastinib when combined with antitubulin therapy with paclitaxel or eribulin in patients with advanced breast cancer.

Detailed Description

      Metastasis is the primary cause of death from breast cancer, invasive carcinoma cells in
      mouse and rat mammary tumors co-migrate accompanied by macrophages towards intravasation
      sites . The intravasation occurs at sites where a TIE2-expressing macrophage, a
      mena-expressing tumor cell, and an endothelial cell are in direct contact, forming a
      micro-anatomic structure called tumor micro-environment of metastasis (TMEM). Ablation of the
      presence or activity of the TMEM associated macrophages blocks intravasation at TMEM
      demonstrating an essential role of perivascular macrophages in TMEM function. Rebastinib, a
      TIE2 inhibitor , blocks TMEM assembly and function in-vivo and in-vitro assays. We
      hypothesize that rebastinib combined with antitubulin therapy (eribulin or paclitaxel) could
      improve clinical outcomes in breast cancer by preventing intravasation at TMEM sites and
      preventing further metastasis.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A1-2: Paclitaxel plus Rebastinib.ExperimentalArm A1 (Dose Escalation Cohort): Paclitaxel 80 mg/m2 weekly x 12 weeks plus Rebastinib (50 mg PO BID or 100 mg PO BID) beginning on cycle 1, day 1 and given continuously. Arm A2 (Expansion Cohort): Paclitaxel 80 mg/m2 weekly x 12 weeks. Patients will be randomized to receive Rebastinib (at RP2D) beginning on cycle 1, day 1 OR cycle 2, day 1.
  • Rebastinib
  • Paclitaxel
Arm B1-2: Eribulin plus Rebastinib.ExperimentalArm B1 (Dose Escalation Cohort): Eribulin Mesylate 1.4 mg/m2 day 1 & 8 q21 days plus Rebastinib (50 mg PO BID or 100 mg PO BID) beginning on cycle 1, day 1 and given continuously. Arm B2 (Expansion Cohort): Eribulin Mesylate 1.4 mg/m2 day 1 & 8 q21 days. Patients will be randomized to receive Rebastinib (at RP2D) beginning on cycle 1, day 1 OR cycle 2, day 1.
  • Rebastinib
  • Eribulin Mesylate

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed adenocarcinoma of the breast that is HER2 (human epidermal
             growth factor receptor 2) negative; based on ASCO(american society of clinical
             oncology)/ CAP (college of American Pathologists) guidelines as: (a) IHC
             (immuno-histochemistry) 1+ negative or IHC 0 negative; or (b) ISH (in situ
             hybridization ) negative using single probe ISH( average HER2 copy number < 4.0
             signals/cell), or dual probe ISH ( HER2/CEP17 ratio <2.0, average HER2 copy number
             <4.0 signals/cell)

          2. 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

          3. Prior chemotherapy and/or endocrine therapy. Patients will be assigned to arm A or arm
             B depending on their prior exposure to paclitaxel and eribulin.

               -  Arm A: Rebastinib plus paclitaxel: Up to two prior non-taxane chemotherapy
                  regimens for metastatic or incurable locally advanced disease permitted (no prior
                  paclitaxel, docetaxel, or eribulin for metastatic disease)..Prior therapy with
                  paclitaxel or docetaxel in the neo/adjuvant setting is allowable if there is at
                  least a 6 month interval between the last adjuvant/neoadjuvant paclitaxel or
                  docetaxel dose and recurrence.

               -  Arm B: Rebastinib plus Eribulin: Patients must have previously received at least
                  two chemotherapeutic regimens for the treatment of metastatic disease (no prior
                  eribulin, but prior paclitaxel, nab-paclitaxel, or docetaxel allowed). Prior
                  therapy should have included a taxane in either the adjuvant or metastatic
                  setting.

               -  Arms A and B: Patients with hormone receptor positive disease must have had
                  progressive disease and at least 2 lines of endocrine therapy, including one
                  endocrine regimen used in combination with an approved CDK 4/6 (cyclin-dependent
                  kinase ) inhibitor (eg, palbociclib). Relapse while receiving or within 6 months
                  of completing adjuvant endocrine therapy may be considered failure of one prior
                  endocrine regimen

          4. Female and age >18 years. Because breast carcinoma is a disease of adults that rarely
             occurs in children, children are excluded from this study. In addition, the safety of
             rebastinib in pediatric patients has not been evaluated.

          5. ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1.

          6. Normal organ and marrow function as defined below within 2 weeks of registration
             (except where specified otherwise):

             Leukocytes >3,000/µL ; Absolute neutrophil count >1,500/µL ; Platelets >100,000/ µL
             Hemoglobin > 9 g/dL ; Total bilirubin (within normal institutional limits) AST
             (aspartate aminotransferase)/ALT (alanine aminotransferase) <2.5 X institutional upper
             limit of normal ; Creatinine (within normal institutional limits) ; EKG QTc < 450 msec
             (females)

             Left ventricular ejection fraction at or above institutional lower limits of normal
             (by echocardiogram within 12 weeks of registration) ; Glucose (within normal limits)
             Serum calcium & phosphorus (within normal institutional limits); Negative urine or
             serum B-HCG(Beta-Human Chorionic Gonadotropin)

          7. No significant ocular disease: 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.

          8. No other active cancer: 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 or concurrent diagnoses are eligible: lobular carcinoma in situ, contralateral
             ductal carcinoma in situ, or contralateral invasive ductal and/or lobular carcinoma.

          9. 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.

         10. Ability to understand and the willingness to sign a written informed consent document.

         11. At least 30 days from major surgery before study enrollment, with full recovery.

         12. Concomitant therapy with bisphosphonates, RANKL inhibitors or
             growth-colony-stimulating factor (G-CSF) is allowed as per physician decision.

         13. Expansion cohort: 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:

          1. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Rebastinib or other agents used in the study (e.g., Cremophor)

          2. History of cardiac disease, including: (a) myocardial infarction within 6 months of
             the start of study, (b) history of QTc(corrected QT interval ) 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.(see "Study reference manual" for
             further details) (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 significant cardiac arrhythmia requiring therapy.

          3. bIntercurrent 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.

          4. Patients with HIV infection are excluded from the study because of possible
             pharmacokinetic interactions with Rebastinib and antiretroviral therapy.

          5. 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

          6. Treatment with other chemotherapy regimen within the past 2 weeks.

          7. Treatment with trastuzumab, bevacizumab or other targeted therapies within the past 4
             weeks.

          8. Patients who have not recovered (i.e., CTCAE Grade ≤1 or baseline) from an adverse
             event due to a previously administered agent, excluding alopecia.

          9. Patients with Grade >1 neuropathy

         10. Patients with uncontrolled hypertension (defined as systolic blood pressure > 150
             and/or diastolic blood pressure > 90 mm/mg).

         11. Patients that have a malabsorption syndrome or other illness which could affect oral
             absorption
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 dose(RP2D).
Time Frame:After 1 treatment cycle (3 weeks) during dose escalation cohort (N=24)
Safety Issue:
Description:Arm A: To determine the recommended phase II dose (Arm A1 - dose escalation cohort) and overall safety profile (Arm A2 - expansion cohort) of Rebastinib (50 mg PO BID or 100 mg PO BID) given concurrently with weekly paclitaxel (80 mg/m2 weekly x 12 ) over 3 consecutive weeks (1 cycle) in patients with metastatic breast cancer. Arm B: 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 (1.4 mg/m2 days 1 and 8 every 21 days) over 3 consecutive weeks (1 cycle) in patients with metastatic breast cancer.

Secondary Outcome Measures

Measure:Median Progression Free Survival (PFS)
Time Frame:From treatment start until progression or death, whichever occurs first, assessed up to 36 months
Safety Issue:
Description:Arm A1-2 and Arm B1-2 (evaluate separately for each arm): To determine the progression-free survival of patients treated with Rebastinib plus paclitaxel, and Rebastinib plus eribulin (at all Rebastinib dose levels).
Measure:Median Overall Survival (OS).
Time Frame:From treatment start until death by any cause, assessed up to 36 months.
Safety Issue:
Description:Arm A1-2 and Arm B1-2 (evaluate separately for each arm): To determine overall survival of patients treated with Rebastinib plus paclitaxel, and Rebastinib plus eribulin (at all Rebastinib dose levels).
Measure:Clinical benefit rate
Time Frame:Proportion of patients who achieved complete response or partial response for at least 24 weeks after study start.
Safety Issue:
Description:Arm A1-2 and Arm B1-2 (evaluate separately for each arm): To determine clinical benefit rate of patients treated with Rebastinib plus paclitaxel, and Rebastinib plus eribulin (at all Rebastinib dose levels).
Measure:Change of ANG1 and ANG2 levels
Time Frame:Before and after cycle 1( week 3) for each patient.
Safety Issue:
Description:Arm A1-2 plus Arm B1-2 (evaluate combined dataset including both arms): To determine correlation between Rebastinib and angiopoietin (ANG1 and/or ANG2) levels (a surrogate marker for TIE2 inhibition)
Measure:Change in Circulating Tumor Cells (CTC) levels.
Time Frame:Before and after cycle 1( week 3) for each patient.
Safety Issue:
Description:Arm A2 plus Arm B2: To perform an exploratory analysis of the effects of Rebastinib plus antitubulin therapy on circulating tumor cell (CTCs) during cycle 1, by comparing CTCs during cycle 1 in patients randomized to receive or not rebastinib during cycle 1.
Measure:Change in TIE-2 expressing monocyte levels.
Time Frame:Before and after cycle 1( week 3) for each patient.
Safety Issue:
Description:Arm A2 plus Arm B2: To perform an exploratory analysis of the effects of Rebastinib plus antitubulin therapy on TIE-2 expressing monocytes (TEM) during cycle 1.
Measure:Change in TMEM score.
Time Frame:Before and after cycle 1( week 3) for each patient.
Safety Issue:
Description:Arm A2 or Arm B2: To perform an exploratory analysis of the effects of Rebastinib plus antitubulin therapy on 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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Montefiore Medical Center

Trial Keywords

  • breast cancer
  • chemotherapy
  • metastasis
  • tumor micro-environment

Last Updated

December 11, 2020