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

This study is currently recruiting participants.
Verified April 2014 by NewLink Genetics Corporation
Sponsor:
Information provided by (Responsible Party):
NewLink Genetics Corporation
ClinicalTrials.gov Identifier:
NCT01792050
First received: February 11, 2013
Last updated: April 4, 2014
Last verified: April 2014

February 11, 2013
April 4, 2014
February 2013
January 2015   (final data collection date for primary outcome measure)
Progression Free Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
The primary objective of this phase 2 study is the progression free survival of docetaxel in combination with indoximod compared to docetaxel plus placebo in metastatic breast cancer.
Progression Free Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
The primary objective of this phase 2 study is the progression free survival of docetaxel in combination with indoximod compared to docetaxel alone in metastatic breast cancer.
Complete list of historical versions of study NCT01792050 on ClinicalTrials.gov Archive Site
  • Frequency and grade of adverse events of docetaxel in combination with indoximod versus docetaxel alone [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    A secondary objective of this phase 2 study is to determine the safety/toxicity (frequency and grade of adverse events) of docetaxel in combination with indoximod versus docetaxel plus placebo.
  • Correlation of clinical and pathologic variables and clinical benefit (progression free survival rate) from treatment [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    A secondary objective of this phase 2 study is determining the correlation between clinical and pathologic variables and clinical benefit from docetaxel and indoximod.
  • Median Overall Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    A secondary objective of this phase 2 study is to observe median overall survival of all patients.
  • Objective Response Rate (Complete Response + Partial Response) [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    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 + indoximod compared to docetaxel plus placebo.
  • Frequency and grade of adverse events of docetaxel in combination with indoximod versus docetaxel alone [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    A secondary objective of this phase 2 study is to determine the safety/toxicity (frequency and grade of adverse events) of docetaxel in combination with indoximod versus docetaxel alone.
  • Correlation of clinical and pathologic variables and clinical benefit (progression free survival rate) from treatment [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    A secondary objective of this phase 2 study is determining the correlation between clinical and pathologic variables and clinical benefit from docetaxel and indoximod.
  • Median Overall Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    A secondary objective of this phase 2 study is to observe median overall survival of all patients.
  • Objective Response Rate (Complete Response + Partial Response) [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    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 + indoximod compared to docetaxel alone.
Not Provided
Not Provided
 
Study of Chemotherapy in Combination With IDO Inhibitor in Metastatic Breast Cancer
A Phase II Double-Blinded, Randomized, Placebo-Controlled Study of Docetaxel in Combination With 1-methyl-D-tryptophan (Indoximod) in Metastatic Breast Cancer

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

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 with indoximod in metastatic breast cancer.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Metastatic Breast Cancer
  • Drug: Docetaxel
    Docetaxel chemotherapy regimen given by vein over 1 hour on day 8 of each cycle.
    Other Name: Taxotere®
  • Other: Placebo
    Placebo taken orally every morning 1 hour prior to breakfast and 1 hour prior to dinner on days 1-14. Six pills to be taken each time for a total of 12 pills per day.
  • Drug: Indoximod
    Indoximod (1200 mg) taken orally every morning 1 hour prior to breakfast and 1 hour prior to dinner on days 1-14. Six 200 mg pills to be taken twice a day for a total of 12 pills per day.
    Other Name: 1-methyl-D-tryptophan, Indoximod, D-1MT, 1-MT
  • Placebo Comparator: Arm A: Docetaxel + Placebo
    Arm A: 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).
    Interventions:
    • Drug: Docetaxel
    • Other: Placebo
  • Experimental: Arm B: Docetaxel + Indoximod
    Arm B: 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).
    Interventions:
    • Drug: Docetaxel
    • Drug: Indoximod
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
154
January 2015
January 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically or cytologically confirmed estrogen/progesterone receptors (ER/PR) +/-; human epidermal growth factor receptor 2 (HER2)-, metastatic breast cancer.
  • 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.
  • 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 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 or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier.
  • 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 1-Methyl-D-tryptophan 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 1-Methyl-D-tryptophan, breastfeeding should be discontinued if the mother is treated with 1-Methyl-D-tryptophan. Also, docetaxel is a category D cytotoxic agent and is 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.
Both
18 Years and older
No
Not Provided
United States
 
NCT01792050
NLG2101
Yes
NewLink Genetics Corporation
NewLink Genetics Corporation
Not Provided
Study Director: Nicholas Vahanian, MD NewLink Genetics Corporation
NewLink Genetics Corporation
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP