Clinical Trials /

Study of Chemotherapy in Combination With IDO Inhibitor in Metastatic Breast Cancer

NCT01792050

Description:

The purpose of this study is to compare the effects, good and/or bad, of standard of care therapy (docetaxel or paclitaxel) with or without the addition of 1-Methyl-D-tryptophan (referred to as indoximod) an experimental drug to find out which treatment is better.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Chemotherapy in Combination With IDO Inhibitor in Metastatic Breast Cancer
  • Official Title: A Phase II Double-Blinded, Randomized, Placebo-Controlled Study of Indoximod in Combination With a Taxane Chemotherapy in Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NLG2101
  • NCT ID: NCT01792050

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
DocetaxelTaxotere®Arm 1A: Docetaxel + Placebo
Indoximod1-methyl-D-tryptophan, Indoximod, D-1MT, 1-MTArm 1B: Docetaxel + Indoximod
PaclitaxelTaxolArm 2A: Paclitaxel + Placebo

Purpose

The purpose of this study is to compare the effects, good and/or bad, of standard of care therapy (docetaxel or paclitaxel) with or without the addition of 1-Methyl-D-tryptophan (referred to as indoximod) an experimental drug to find out which treatment is better.

Detailed Description

      It is estimated that 232,340 US women will be diagnosed with and 40,030 women will die of
      breast cancer in 2013. Metastatic breast cancer is a terminal condition and treatments are
      palliative in nature. The median survival for patients with metastatic breast cancer is
      approximately 2.5 years. The standard therapies currently in use include anti-estrogen
      therapies (anastrazole, letrozole, fulvestrant, tamoxifen), chemotherapy agents (taxanes,
      capecitabine, navelbine, gemcitabine, eribulin, ixabepilone), targeted therapies
      (trastuzumab, lapatinib), and supportive care agents (zolendronic acid, denosumab). While
      breast cancer typically responds well to treatment, the response is transient and their
      disease becomes more refractory with continued therapy. Also, quality of life is a
      significant issue for these patients as many of these therapies are associated with
      significant side effects. Well tolerated, novel agents which improve the efficacy of existing
      chemotherapy agents would prove quite useful in managing metastatic breast cancer.

      Preclinical data derived from MMTV-Neu mice with autochthonous tumors studied the interaction
      between indoximod and various chemotherapeutic agents. Mice with 5-10mm tumors were enrolled
      into control and treatment groups. Mice were treated with indoximod alone, chemotherapy alone
      (paclitaxel, doxorubicin, cyclophosphamide, and others), and the combination of indoximod and
      chemotherapy. treatment with indoximod or paclitaxel alone caused retardation of tumor growth
      in this model but no regressions were seen. the combination of indoximod plus paclitaxel
      caused 30% tumor regression and histologically there was significantly enhanced tumor cell
      death with the combination versus either agent alone. This synergism was abrogated when the
      mice underwent CD4+ T cell depletion prior to treatment with the combination, suggesting the
      immune response played a role in the observed effect. Based on this data and other reports
      suggesting systemic immunomodulating drugs like indoximod can synergize with chemotherapy
      agents such as taxanes, the decision was made to devise this combination of therapy of
      docetaxel or paclitaxel with indoximod in metastatic breast cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1A: Docetaxel + PlaceboPlacebo ComparatorArm 1A: Docetaxel 75 mg/m^2 IV given every 3 weeks (on day 8 of 21 day cycle), plus placebo PO BID (days 1-14 of 21 day cycle).
  • Docetaxel
Arm 1B: Docetaxel + IndoximodExperimentalArm 1B: Docetaxel 75 mg/m^2 IV given every 3 weeks (on day 8 of 21 day cycle), plus Indoximod 1200 mg PO BID (days 1-14 of 21 day cycle).
  • Docetaxel
  • Indoximod
Arm 2A: Paclitaxel + PlaceboPlacebo ComparatorArm 2A: Paclitaxel 80 mg/m^2 IV given weekly x3 followed by a week of rest (28 day cycle), plus placebo PO BID (days 1-21 of 28 day cycle).
  • Paclitaxel
Arm 2B: Paclitaxel + IndoximodExperimentalArm 2B: Paclitaxel 80 mg/m^2 IV given weekly x3 followed by a week of rest (28 day cycle), plus Indoximod 1200 mg PO BID (days 1-21 of 28 day cycle).
  • Indoximod
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed estrogen/progesterone receptors (ER/PR) +/-;
             human epidermal growth factor receptor 2 (HER2)-, metastatic breast cancer.

          -  Metastatic disease that is evaluable on imaging. May have measureable disease, defined
             as at least one lesion that can be accurately measured in at least one dimension
             (longest diameter to be recorded for non-nodal lesions and short axis for nodal
             lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI,
             or calipers by clinical exam. Patients can also have non-measurable disease including
             bone only metastatic disease, evaluated by bone scan, PET or MRI.

          -  Any number of prior endocrine therapies in the metastatic setting are allowed. The
             patient must not have received any prior chemotherapy agents in the metastatic
             setting. Prior treatment with adjuvant docetaxel or paclitaxel is allowed if disease
             relapse occurred greater than 12 months from the completion of adjuvant therapy.

          -  Age ≥18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥60%).

          -  Life expectancy of greater than 4 months.

          -  Patients must have normal organ and marrow function as defined below: leukocytes
             ≥3,000/mcL, absolute neutrophil count ≥1,500/mcL, platelets ≥100,000/mcL, total
             bilirubin within normal institutional limits, aspartate aminotransferase AST(SGOT)/
             alanine aminotransferase ALT(SGPT) ≤2.5 X institutional upper limit of normal,
             creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73
             m^2 for patients with creatinine levels above institutional normal.

          -  Patients with known brain metastases will only be eligible after their tumors have
             been treated with definitive resection and/or radiotherapy and they are neurologically
             stable for at least 1 month off steroids.

          -  Male and female subjects of child producing potential must agree to use adequate forms
             of contraception or avoidance of pregnancy measures prior to study entry, while
             enrolled on study and for a minimum of one month after completion of the study.

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

        Exclusion Criteria:

          -  Patients who have had chemotherapy for the treatment of metastatic breast cancer are
             not eligible. Patients who have had radiotherapy within 3 weeks prior to entering the
             study or those who have not recovered from adverse events due to agents administered
             more than 3 weeks earlier are not eligible.

          -  Patients who are currently receiving any other investigational agents.

          -  Patients with known active, untreated brain metastases should be excluded from this
             clinical trial. Those with previously treated inactive brain metastases with no
             evidence of active disease documented on brain MRI at least 4 weeks after radiation
             and off all steroids may be eligible.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to docetaxel or tryptophan containing substances. This would include
             L-tryptophan or 5-hydroxy-tryptophan supplements. Also patients with a history of
             severe hypersensitivity reactions to docetaxel or to other drugs formulated with
             polysorbate 80 are excluded.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Pregnant women are excluded from this study because indoximod is an immunoregulatory
             agent with the potential for abortifacient effects due to fetal rejection by the
             maternal immune system. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with indoximod,
             breastfeeding should be discontinued if the mother is treated with indoximod. Also,
             docetaxel and paclitaxel are category D cytotoxic agents and are not administered to
             pregnant females.

          -  Known HIV-positive patients and those with other acquired/inherited immunodeficiencies
             are ineligible due to the possibility of affecting the response to indoximod and the
             higher risk of active opportunistic infections.

          -  Patients with more than one active malignancy at the time of enrollment.

          -  Patients who have received any prior experimental active immunotherapy consisting of
             targeted monoclonal antibodies (ipilimumab) or pharmaceutical compounds are excluded.

          -  Patients with any active autoimmune disease (i.e. psoriasis, extensive atopic
             dermatitis, asthma, inflammatory bowel disease (IBD), multiple sclerosis (M.S.),
             uveitis, vasculitis), chronic inflammatory condition, or any condition requiring
             concurrent use of any systemic immunosuppressants or steroids for any reason would be
             excluded from the study. Any patient with an allo-transplant of any kind would be
             excluded as well. This would include those with a xenograft heart valve to avoid the
             potential risk of any immune reaction causing valvular degeneration. Mild-intermittent
             asthma requiring only occasional beta-agonist inhaler use or mild localized eczema
             will not be excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:12 months
Safety Issue:
Description:The primary objective of this phase 2 study is the progression free survival of docetaxel or paclitaxel in combination with indoximod compared to docetaxel or paclitaxel plus placebo in metastatic breast cancer.

Secondary Outcome Measures

Measure:Frequency and grade of adverse events of docetaxel and paclitaxel in combination with indoximod versus docetaxel alone
Time Frame:12 months
Safety Issue:
Description:A secondary objective of this phase 2 study is to determine the safety/toxicity (frequency and grade of adverse events) of docetaxel or paclitaxel in combination with indoximod versus docetaxel or paclitaxel plus placebo.
Measure:Correlation of clinical and pathologic variables and clinical benefit (progression free survival rate) from treatment
Time Frame:12 months
Safety Issue:
Description:A secondary objective of this phase 2 study is determining the correlation between clinical and pathologic variables and clinical benefit from docetaxel or paclitaxel and indoximod.
Measure:Median Overall Survival
Time Frame:12 months
Safety Issue:
Description:A secondary objective of this phase 2 study is to observe median overall survival of all patients.
Measure:Objective Response Rate (Complete Response + Partial Response)
Time Frame:12 Months
Safety Issue:
Description:A secondary objective is to determine the objective response rate (CR+PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of docetaxel or paclitaxel + indoximod compared to docetaxel or paclitaxel plus placebo.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:NewLink Genetics Corporation

Trial Keywords

  • IDO
  • IDO Inhibitor
  • Metastatic Breast Cancer

Last Updated

March 14, 2016