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Nivolumab and BMS986205 in Treating Patients With Stage II-IV Squamous Cell Cancer of the Head and Neck

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ClinicalTrials.gov Identifier: NCT03854032
Recruitment Status : Recruiting
First Posted : February 26, 2019
Last Update Posted : April 12, 2019
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University

Tracking Information
First Submitted Date  ICMJE February 21, 2019
First Posted Date  ICMJE February 26, 2019
Last Update Posted Date April 12, 2019
Actual Study Start Date  ICMJE April 9, 2019
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2019)
Objective Response [ Time Frame: At 5 weeks ]
Will be assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The proportions of the primary endpoint in the two treatment groups will be compared at 25% significance level using a two-sided test in proportions. Will re-analyze the primary endpoints using a combined patients collection. Historical controls of patients who received nivolumab alone for 4 weeks in previous window of opportunity trial (CA209-9A7) will be included in the control group. Patients' demographic as well as pre-treatment clinical measurements will be compared between the combined control group versus the treatment group to ensure the homogeneity of the two groups. A multi-variable logistic regression model will be used in the statistical analysis, if any difference in the demographic and clinical predictors between treatment groups is detected. Otherwise, the proportions of the primary endpoint in the two treatment groups will be compared at 5% significance level using a two-sided test.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03854032 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2019)
  • Objective pathologic response at time of surgery [ Time Frame: At time of surgery ]
    If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the false discovery rate (FDR) among the secondary outcomes at 5%.
  • Change in immune cell polarization (Th1/Th2; M1/M2) in peripheral blood and tumor specimens [ Time Frame: Baseline up to 12 months ]
    Will be analyzed and compared using multiplex cytokine analysis collected before and after exposure to nivolumab +/- IDO1 inhibitor BMS-986205 (BMS986205). If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
  • Change in inflammatory markers [ Time Frame: Baseline up to 12 months ]
    These include soluble (s)CD40 ligand (L), EGF, eotaxin, FGF-2, Flt-3 ligand, fractalkine, granulocyte colony-stimulating factor (G-CSF), granulocyte colony-macrophage (GM)-CSF, GRO, IFN-alpha2, IL-1alpha, IL-1beta, IL-1ra, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-12 (p40), IL-13, IL-15, IL-17A, IP-10, MCP-1, MCP-3, MDC (CCL22), MIP-1alpha, MIP-1beta, PDGF-AA, PDGF-AB/BB, RANTES, TGF-alpha, TNF-alpha, VEGF. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%
  • Change in prevalence of intratumoral immune cell populations (effector T cells [Teff], regulatory T cells [Treg], and tumor-associated macrophages [TAM] in patients treated with Nivolumab and BMS986205 as compared to patients treated with Nivolumab alone [ Time Frame: Baseline up to 12 months ]
    Assessed by immunohistochemistry (IHC). If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
  • Localization of immune cells within the tumor [ Time Frame: Up to 12 months ]
    Will be analyzed using confocal microscopy.
  • Multiplex colocalization of resident immune cells [ Time Frame: Up to 12 months ]
    Will utilize 5-6 markers per section.
  • Kynurenine levels (blood and tumor) [ Time Frame: Up to 12 months ]
    Measured with commercial quantitative enzyme-linked immunosorbent assay (ELISA) kits. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
  • Intratumoral immune cell populations, immune polarization data, exosome composition, and exosome function in human papilloma virus (HPV) + and HPV- tumors [ Time Frame: Up to 12 months ]
    Baseline IHC staining for P16 will be performed as a surrogate for HPV status. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
  • Intratumoral immune cell populations, immune polarization data, exosome composition, and exosome function relative to PD-L1 expression levels [ Time Frame: Up to 12 months ]
    Assessed by IHC. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
  • Incidence of adverse events [ Time Frame: Up to 100 days ]
    Will be graded by Common Terminology Criteria for Adverse Events version 5.0. Safety outcomes will be summarized overall and by treatment arm.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 21, 2019)
  • Intratumoral T-cell receptor (TCR) repertoire and diversity [ Time Frame: Up to 12 months ]
    Assesses with next generation sequencing.
  • Change in exosome abundance and composition in the peripheral blood of patients both before and after exposure to both nivolumab and BMS986205 and nivolumab alone [ Time Frame: Baseline up to 12 months ]
    Will be compared between treatment arms using two-sample t-tests.
  • Rates of wound dehiscence, postop wound infection (requiring antibiotics), and fistula formation [ Time Frame: Up to 12 months ]
    Will be summarized by treatment arm and compared using Fisher's exact test.
  • Changes in tumor volume and rates of radiographic response [ Time Frame: Baseline up to 12 months ]
    Will be summarized by treatment arm and compared using two-sample t-tests or Fisher's exact test, as appropriate.
  • Patient-reported outcomes [ Time Frame: Up to 12 months ]
    Data will be collected and correlated to both immune cell composition and polarization and tumor radiographic response using scores from Patient Health Questionnaire (PHQ)2/9, Functional Assessment of Cancer Therapy- General (FACT-G), and FACT-head and neck (HN). Will conduct descriptive statistics and will summarize variable of interest using standard statistics such as frequency tables, means, and standard deviations. All measures will be evaluated for reliability and factor analyses will be conducted.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Nivolumab and BMS986205 in Treating Patients With Stage II-IV Squamous Cell Cancer of the Head and Neck
Official Title  ICMJE Window-of-Opportunity Trial of Nivolumab and BMS986205 in Patients With Squamous Cell Carcinoma of the Head and Neck (CA017-087)
Brief Summary This phase II trial studies how well nivolumab works, with or without BMS986205, in treating patients with stage II-IV squamous cell cancer of the head and neck. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. BMS986205 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab with BMS986205 may work better than nivolumab alone in treating patients with squamous cell cancer of the head and neck.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the impact of IDO1 inhibitor BMS-986205 (BMS986205) and nivolumab versus nivolumab alone on tumor radiographic response both at the primary tumor site and in regional lymph nodes by investigator assessment at 5 weeks.

SECONDARY OBJECTIVES:

I. To investigate whether adding the IDO1 - inhibitor, BMS986205, to nivolumab therapy affects intratumoral and systemic anti-tumor immunity.

II. To assess the impact of BMS986205 and nivolumab verses nivolumab alone on pathologic treatment effect bother at the primary and regional lymph nodes.

III. To determine the effect of BMS986205 and nivolumab versus nivolumab alone on immune cell composition within the tumor microenvironment including the presence of effector T cells (Teff), regulatory T cells (Treg), and tumor-associated macrophages (TAM).

IV. To further characterize the effect of BMS986205 when combined with nivolumab on kynurenine production and correlate these levels with effects on immune cell composition and polarization.

V. To review the relationship of p16 status by immunohistochemistry with immune cell polarization, tumor radiographic response, and immune cell composition.

VI. To review the relationship of PD-L1 status by immunohistochemistry with immune cell polarization, tumor radiographic response, and immune cell composition.

VII. To assess the safety and tolerability of BMS986205 and nivolumab. VIII. Evaluate surgical wound healing post treatment.

EXPLORATORY OBJECTIVES:

I. To further characterize the effect of BMS986205 and nivolumab versus nivolumab alone through analysis of T cell repertoire.

II. To assess the interactions between the immune and metabolic microenvironment through analysis of alterations in exosome composition in peripheral blood as it related to immune, cytokine and metabolic alterations before, during and after treatment.

III. To identify risks for poor physical and mental health outcomes; examine bio-behavioral factors associated with cancer treatment outcomes; and evaluate the physical and psychosocial needs of cancer survivors through patient reported outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive IDO1 inhibitor BMS-986205 orally (PO) once daily (QD). Beginning week 2, patients also receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients showing a treatment response receive IDO1 inhibitor BMS-986205 PO QD for 4 additional weeks and receive nivolumab IV over 30 minutes on day 1, then undergo surgery at week 10. Those without a treatment response after 5 weeks undergo surgery within 7 days.

ARM II: Patients receive nivolumab IV over 30 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients showing treatment response after 4 weeks receive nivolumab IV over 30 minutes on day 1, then undergo surgery at week 9. Those without a treatment response after 4 weeks undergo surgery within 7 days.

After completion of study treatment, patients are followed up periodically for 12 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lip
  • Oral Cavity Squamous Cell Carcinoma
  • Pharynx
  • Larynx
  • Squamous Cell Carcinoma
Intervention  ICMJE
  • Biological: Nivolumab
    Given IV
    Other Names:
    • 946414-94-4
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Biological: IDO1 Inhibitor BMS-986205
    Given PO
    Other Names:
    • (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propenamide
    • BMS 986205
    • BMS-986205
    • BMS986205
    • IDO-1 Inhibitor BMS-986205
    • Indoleamine-pyrrole 2,3-Dioxygenase Inhibitor BMS-986205
    • ONO-7701
  • Procedure: Therapeutic Conventional Surgery
    Undergo Surgery
  • Other: Questionnaire Administration
    Ancillary studies
Study Arms  ICMJE
  • Experimental: Arm I (BMS986205, nivolumab)
    Patients receive IDO1 inhibitor BMS-986205 PO QD. Beginning week 2, patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients showing a treatment response receive IDO1 inhibitor BMS-986205 PO QD for 4 additional weeks and receive nivolumab IV over 30 minutes on day 1, then undergo surgery at week 10. Those without a treatment response after 5 weeks undergo surgery within 7 days.
    Interventions:
    • Biological: Nivolumab
    • Biological: IDO1 Inhibitor BMS-986205
    • Procedure: Therapeutic Conventional Surgery
    • Other: Questionnaire Administration
  • Active Comparator: Arm II (nivolumab)
    Patients receive nivolumab IV over 30 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients showing treatment response after 4 weeks receive nivolumab IV over 30 minutes on day 1, then undergo surgery at week 9. Those without a treatment response after 4 weeks undergo surgery within 7 days.
    Interventions:
    • Biological: Nivolumab
    • Procedure: Therapeutic Conventional Surgery
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 21, 2019)
48
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically confirmed head and neck squamous cell carcinoma (HNSC).
  • Any stage 2 or greater HNSCC (American Joint Committee on Cancer [AJCC] 8th edition) of the 1) oral cavity, 2) larynx, 3) hypopharynx, 4) nasal cavity/paranasal sinuses or 5) stage 1 oropharyngeal with lymphadenopathy. Patients with resectable disease that is amenable to surgery are eligible.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
  • White blood cells 2000/ul or more.
  • Absolute neutrophil count 1500/ul or more.
  • Platelets 100,000/ul or more.
  • Hemoglobin 9 g/dl or more.
  • Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with Gilbert syndrome, who can have total bilirubin < 3 mg/dl).
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x the upper limit of normal.
  • Glomerular filtration rate (GFR) greater than or equal to 40 ml/min using the Cockcroft-Gault formula or serum creatinine less than or equal to 1.5 x ULN.
  • Women of child bearing potential (WOCBP) should have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 21 days of study enrollment.
  • WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) plus 5 months post-treatment completion.
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) plus 7 months post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time.
  • Males who are sexually active with WOCBP must agree to use a condom during any sexual activity for the duration of treatment with study treatment plus 7 months after the last dose of the study treatment (i.e., 90 days [duration of sperm turnover] plus the time required for nivolumab to undergo approximately 5 half-lives). This criterion applies to azoospermic males as well. In addition, male participants must be willing to refrain from sperm donation during this time.

    • Male mandatory condom use is regardless of whether the participant has undergone a successful vasectomy or if the female partner is pregnant.
    • Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception, which have a failure rate of < 1% when used consistently and correctly. Hormonal contraceptives are prohibited methods of contraception for participants receiving BMS-986205 this study who are WOCBP.
  • All subjects must be able to comprehend and sign a written informed consent document.

Exclusion Criteria:

  • Patients with nasopharyngeal carcinoma, salivary gland or skin primaries.
  • Patients with recurrent head and neck cancer treated previously with chemotherapy, radiation or immunotherapy.
  • Any history of a severe hypersensitivity reaction to any monoclonal antibody.
  • Any history of allergy to the study drug components.
  • Participants with a personal or family (i.e., in a first-degree relative) history or presence of cytochrome b5 reductase deficiency (previously called methemoglobin reductase deficiency) or other diseases that puts them at risk of methemoglobinemia. All participants will be screened for methemoglobin levels prior to randomization.
  • Participants with a history of G6PD deficiency or other congenital or autoimmune hemolytic disorders. All participants will be screened for G6PD deficiency prior to randomization.
  • Participants with history of serotonin syndrome.
  • Participants with active interstitial lung disease (ILD)/pneumonitis or history of ILD/ pneumonitis requiring steroids.
  • Prior treatment with BMS-986205 or any other IDO1 inhibitors.
  • Quantitative or qualitative G6PD assay results suggesting underlying G6PD deficiency.
  • Blood methemoglobin > upper limit of normal (ULN), assessed in an arterial or venous blood sample or by co-oximetry.
  • History or presence of hypersensitivity or idiosyncratic reaction to methylene blue.
  • History of allergy or hypersensitivity to any study treatment components, specifically to that of BMS-986205.
  • Any concurrent malignancies; exceptions include- basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer that has undergone potentially curative therapy. Patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 2 years post-diagnosis.
  • Any diagnosis of immunodeficiency or receiving systemic steroid therapy (> 10 mg daily prednisone equivalents) or any other form of immunosuppressive therapy within 14 days of initiation of therapy.
  • Patients that have an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids (> 10 mg daily prednisone equivalents) or immunosuppressive agents. Subjects with vitiligo, type I diabetes mellitus, or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
  • Patients must not be receiving any other investigational agents.
  • Patients with uncontrolled intercurrent illnesses including, but not limited to an active infection requiring systemic therapy or a known psychiatric or substance abuse disorder(s) that would interfere with cooperation with the requirements of the trial.
  • Patients must not be pregnant or breastfeeding.
  • Patients with a known human immunodeficiency virus infection (HIV 1/2 antibodies) or acquired immunodeficiency syndrome (HIV/AIDS), active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).
  • Patients with any evidence of current interstitial lung disease (ILD) or pneumonitis.
  • Patients with prior history of ILD or non-infectious pneumonitis that required steroids.
  • Patients who have received a live vaccine within 30 days of the planned start of study therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Adam Luginbuhl, MD 215-955-6760 adam.luginbuhl@jefferson.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03854032
Other Study ID Numbers  ICMJE 18P.771
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Thomas Jefferson University
Study Sponsor  ICMJE Thomas Jefferson University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Adam Luginbuhl, MD Sidney Kimmel Cancer Center at Thomas Jefferson University
PRS Account Thomas Jefferson University
Verification Date April 2019

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