Pembrolizumab and Epacadostat in Treating Participants with Squamous Cell Carcinoma of the Head and Neck before Surgery

Status: Approved

Description

This phase II trial studies how well pembrolizumab and epacadostat work in treating participants with squamous cell carcinoma of the head and neck before surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and epacadostat may work better in shrinking tumors to the degree that surgery may be easier or more successful and potentially avoid additional or lesson side effects of standard of care treatments.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed squamous cell carcinoma of the head and neck including the oral cavity, oropharynx, hypopharynx or larynx, excluding nasopharynx
  • Be willing and able to provide written informed consent/assent for the trial
  • Patients with non-bulky/non-bulky squamous cell carcinomas of the head and neck, with an indication for surgical therapy * T1N1-N2B, T2-4N0-N2b stage are generally eligible * If determined per tumor board that a low-volume/non-bulky tumor of another stage is appropriate for resection (e.g. small volume T4 with a small amount of bone invasion) such tumors may also be considered for this study if recommendation in tumor board is such
  • Be appropriate candidates for resection and curative intent therapy in general
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Consent to undergo biopsy from a newly obtained core or excisional biopsy of a tumor lesion before study drug administration, and during treatment; biopsy in case of progressive disease is optional
  • Ability to swallow epacadostat tablets. In case Incyte at a later time point provides support to administer epacadostat tablets parenterally (via gastrostomy [G]-tube), such administration would also be acceptable as an alternative (once official documentation has been obtained from Incyte)
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Known human papillomavirus (HPV) status for oropharyngeal primary tumors
  • Pre-operative scans including MRI/computed tomography (CT) neck and, CT chest with contrast; if contrast is contraindicated, staging positron emission tomography (PET) or PET-CT is acceptable although high quality/diagnostic cross-sectional imaging of the head and neck area is recommended
  • Within 10 days of treatment initiation: Absolute neutrophil count (ANC) >= 1,500/mcL
  • Within 10 days of treatment initiation: Platelets >= 100,000/mcL
  • Within 10 days of treatment initiation: Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Within 10 days of treatment initiation: Serum creatinine within upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > institutional ULN
  • Within 10 days of treatment initiation: Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Within 10 days of treatment initiation: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
  • Within 10 days of treatment initiation: Albumin >= 2.5 mg/dL
  • Within 10 days of treatment initiation: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Within 10 days of treatment initiation: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy; abstinence is considered an adequate contraception method

Exclusion Criteria

  • Has a diagnosis now or in the past of immunodeficiency requiring systemic steroid therapy in excess of physiologic dose (or any other form of immunosuppressive therapy within 10 days prior to the first dose of trial treatment)
  • Has bulky tumor (define as N3 lymph node or equivalent lymph conglomerate (>= 6 cm in one dimension), or primary tumor > 4 cm); cystic HPV+ lymph nodes should be assessed in tumor board and may not be considered bulky
  • Has a known history of active TB (Bacillus tuberculosis)
  • Other life-threatening illness that is expected to impact life expectancy within 3 years
  • Hypersensitivity to pembrolizumab, epacadostat or any of its excipients
  • Has a known additional malignancy that was diagnosed within the last five years that is either progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, or in a broader sense is not felt to impact life-expectancy
  • Has active autoimmune disease that has required systemic (large physiologic dose) treatment in the past year (i.e. with use of disease modifying agents, corticosteroids or any other immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic immunosuppressive treatment
  • History of non-infectious pneumonitis requiring steroids or current pneumonitis
  • Has an active viral infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known 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)
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • Allogeneic organ or stem cell transplant
  • History of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids and patients with active ILD/pneumonitis

Locations & Contacts

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Approved
Contact: Tanguy Y. Seiwert
Phone: 773-702-2452
Email: tseiwert@medicine.bsd.uchicago.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine rate of major treatment effect (MTE) to neoadjuvant pembrolizumab + epacadostat immunotherapy in squamous cell carcinoma of the head and neck (SCCHN) compared to historic data with neoadjuvant pembrolizumab alone.

II. To determine the rate of pathologic complete response rate at surgery compared to historic data with chemotherapy (assessed at 8 weeks).

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS) in patients treated with neoadjuvant immunotherapy (pembrolizumab + epacadostat) followed by surgical resection.

II. To determine the median overall survival for head and neck squamous cell carcinoma (HNSCC) patients treated with neoadjuvant immunotherapy (pembrolizumab + epacadostat) followed by surgical resection.

III. To determine the ability to eliminate adjuvant treatment in patients with a pathologic complete response (CR).

IV. To determine the safety of neo-adjuvant and adjuvant pembrolizumab + epacadostat treatment prior to and after surgery/definitive therapy.

EXPLORATORY AND BIOMARKER OBJECTIVES:

I. To determine if the use of neoadjuvant anti-PD-1+anti-IDO1 therapy can successfully down-stage original tumor.

II. To determine whether magnetic resonance imaging (MRI) (namely diffusion weighted imaging, and radiomics) can predict response to immunotherapy.

III. To determine whether circulating cell free deoxyribonucleic acid (DNA) (ctDNA) can predict response to immunotherapy.

IV. To determine whether circulating cell free DNA (ctDNA) can predict early recurrence.

V. To determine whether a histoculture assay exposed to various immunotherapy treatments, namely anti-PD-1 and anti-PD-1 + anti-IDO, is able to predict from baseline tissue response to immunotherapy.

VI. To determine micro-environmental changes induced by pembrolizumab or pembrolizumab + epacadostat by comparing pre- and post-treatment biopsies.

VII. To perform multicolor immunohistochemistry staining for PD-L1, PD-1, CD8, FOXP3, IDO1, CD163 (as well as related markers) on baseline and surgical/on-treatment specimens.

VIII. To characterize the T-cell receptor repertoire of tumor infiltrating lymphocytes (TILs) compared to circulating T cells (spectrotyping, T-cell repertoire sequencing (e.g. using the Nakamura lab established T-cell receptor [TCR] pipeline, or adaptive).

IX. To determine changes in density of tumor infiltrating lymphocytes (TILs).

X. To characterize immunogenic tumor-private mutations based on tumor and normal tissue exome sequencing, and tumor ribonucleic acid sequencing (RNAseq) analysis using an established computational pipeline for prediction and validation (collaboration with Dr. Yusuke Nakamura).

XI. To determine changes in PD-L1 expression (using the Merck developed 22C3 antibody) between baseline and after pembrolizumab (pre-/on treatment with pembrolizumab) and using established interpretation guidelines.

XII. To determine the rate of induction of an inflammatory gene signature (e.g. 18-gene GEP) in patients treated with neoadjuvant immunotherapy.

XIII. To determine whether week 3-4 on-treatment identified microenvironment changes (presence of an immune response) correlates with pathologic CR or major histologic response on surgery.

OUTLINE:

Participants receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and epacadostat orally (PO) twice daily (BID). Treatment repeats every 3 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after last dose, participants undergo surgery. Participants then receive pembrolizumab IV over 30 minutes on day 1 and epacadostat PO BID. Courses repeat every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, every 2-4 months for 1 year, every 6 months for 1 year, and then yearly for 3 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Tanguy Y. Seiwert

Trial IDs

Primary ID IRB17-0993
Secondary IDs NCI-2018-00340
Clinicaltrials.gov ID NCT03325465