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

• ClinicalTrials.gov Identifier: NCT01792050
• Recruitment Status: Completed
• First Posted: February 15, 2013
• Last Update Posted: May 28, 2020
• Sponsor: NewLink Genetics Corporation
• Information provided by (Responsible Party): Lumos Pharma ( NewLink Genetics Corporation )

Tracking Information

• First Submitted Date: February 11, 2013
• First Posted Date: February 15, 2013
• Last Update Posted Date: May 28, 2020
• Study Start Date: February 2013
• Actual Primary Completion Date: July 1, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 4, 2014)

Progression Free Survival [ Time Frame: 12 months ]

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.

Original Primary Outcome Measures (submitted: February 12, 2013)

Progression Free Survival [ Time Frame: 12 months ]

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.

Current Secondary Outcome Measures (submitted: November 4, 2014)

• Frequency and grade of adverse events of docetaxel and paclitaxel in combination with indoximod versus docetaxel alone [ Time Frame: 12 months ]
  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.
• Correlation of clinical and pathologic variables and clinical benefit (progression free survival rate) from treatment [ Time Frame: 12 months ]
  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.
• Median Overall Survival [ Time Frame: 12 months ]
  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 ]
  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.

Original Secondary Outcome Measures (submitted: February 12, 2013)

• Frequency and grade of adverse events of docetaxel in combination with indoximod versus docetaxel alone [ Time Frame: 12 months ]
  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 ]
  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 ]
  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 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer

Intervention

• 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
• Drug: Paclitaxel
  Paclitaxel chemotherapy regimen given by vein over 1 hour weekly x 3 followed by a week of rest each cycle.
  Other Name: Taxol

Study Arms

• Placebo Comparator: Arm 1A: Docetaxel + Placebo
  Arm 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).
  Interventions:

  • Drug: Docetaxel
  • Other: Placebo
• Experimental: Arm 1B: Docetaxel + Indoximod
  Arm 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).
  Interventions:

  • Drug: Docetaxel
  • Drug: Indoximod
• Placebo Comparator: Arm 2A: Paclitaxel + Placebo
  Arm 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).
  Interventions:

  • Other: Placebo
  • Drug: Paclitaxel
• Experimental: Arm 2B: Paclitaxel + Indoximod
  Arm 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).
  Interventions:

  • Drug: Indoximod
  • Drug: Paclitaxel

• Publications *: Mariotti V, Han H, Ismail-Khan R, Tang SC, Dillon P, Montero AJ, Poklepovic A, Melin S, Ibrahim NK, Kennedy E, Vahanian N, Link C, Tennant L, Schuster S, Smith C, Danciu O, Gilman P, Soliman H. Effect of Taxane Chemotherapy With or Without Indoximod in Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Jan 1;7(1):61-69. doi: 10.1001/jamaoncol.2020.5572. Erratum In: JAMA Oncol. 2021 Jan 1;7(1):140.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 14, 2016): 169
• Original Estimated Enrollment (submitted: February 12, 2013): 96
• Actual Study Completion Date: July 7, 2017
• Actual Primary Completion Date: July 1, 2016 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Poland, United States

Administrative Information

• NCT Number: NCT01792050
• Other Study ID Numbers: NLG2101
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Lumos Pharma ( NewLink Genetics Corporation )
• Original Responsible Party: Same as current
• Current Study Sponsor: NewLink Genetics Corporation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Lumos Pharma
• Verification Date: May 2020