Clinical Trials /

Nivolumab & IRX-2 With Surgery for Resectable Stage III-IVA Oral Cavity Cancer or HPV-Positive Oropharyngeal Cancer

NCT03575234

Description:

This phase I trial studies the side effects of nivolumab and IRX-2 and how well they work in treating participants with stage III-IVA oral cavity cancer or human papillomavirus (HPV)-positive oropharyngeal cancer that can be removed by surgery. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. IRX-2 may turn on the immune system and stimulate an immune response against tumor cells. Giving nivolumab and IRX-2 followed by surgery may work better at treating oral cavity and oropharyngeal cancer.

Related Conditions:
  • Oral Cavity Squamous Cell Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab & IRX-2 With Surgery for Resectable Stage III-IVA Oral Cavity Cancer or HPV-Positive Oropharyngeal Cancer
  • Official Title: Phase I Neo-Adjuvant Nivolumab + IRX-2 Followed by Surgery for Resectable Oral Cavity Cancer or HPV-Associated Oropharynx Cancer

Clinical Trial IDs

  • ORG STUDY ID: IRB00102105
  • SECONDARY ID: NCI-2018-00411
  • SECONDARY ID: Winship4300-18
  • NCT ID: NCT03575234

Conditions

  • Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma
  • Stage II Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7
  • Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7
  • Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7

Interventions

DrugSynonymsArms
CyclophosphamideCytophosphane, Cytoxan, Neosar, RevimmuneCohort 1: HPV-Related Oropharynx SCC
IRX-2Cohort 1: HPV-Related Oropharynx SCC
NivolumabBMS-936558, MDX-1106, ONO-4538, OpdivoCohort 1: HPV-Related Oropharynx SCC

Purpose

This phase I trial studies the side effects of nivolumab and IRX-2 and how well they work in treating participants with stage III-IVA oral cavity cancer or human papillomavirus (HPV)-positive oropharyngeal cancer that can be removed by surgery. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. IRX-2 may turn on the immune system and stimulate an immune response against tumor cells. Giving nivolumab and IRX-2 followed by surgery may work better at treating oral cavity and oropharyngeal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety profile of combination immunotherapy, nivolumab + IRX-2, for HPV+
      oropharyngeal squamous cell carcinoma (OPSCC) and HPV- oral cavity squamous cell carcinoma
      (OCSCC).

      II. To assess the oncologic efficacy of neo-adjuvant immunotherapy using pathologic
      confirmation of response after surgical resection.

      SECONDARY OBJECTIVES:

      I. To correlate tumor microenvironment histopathology with pathologic findings, with
      progression free survival (PFS) and other outcome parameters in patients with resectable
      OPSCC and OCSCC after the above treatments.

      II. To evaluate swallowing function before and after surgery and risk-adjusted adjuvant
      therapy.

      III. To evaluate quality of life (QOL), swallowing perception and performance, voice
      outcomes, and head and neck symptoms.

      OUTLINE: Fifteen subjects with HPV-related oropharynx HNSCC (cohort 1) and 15 subjects with
      HPV-negative oral cavity HNSCC (cohort 2) patients will be included. Patients will take
      nivolumab on days 1 and 15 and IRX-2 for 10 days between days 4-21. Patients will have
      surgery to remove their cancer between days 25-30 (for oropharynx cancer this will be via
      transoral robotic surgery, TORS). Treatment after surgery will depend on institutional
      guidelines.

      After completion of study treatment, patients are followed up at 3 months, every 3 months for
      2 years, then every 6 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: HPV-Related Oropharynx SCCExperimentalHPV-positive oropharynx cancer patients receive nivolumab IV over 60 minutes on days 1 and 15, cyclophosphamide IV on day 1, and IRX-2 SC over 10 consecutive days between days 4-21 in the absence of disease progression or unacceptable toxicity. Beginning days 25-30, patients undergo surgery.
  • Cyclophosphamide
Cohort 2: HPV-Negative Oral Cavity SCCExperimentalHPV-negative oral cavity cancer patients receive nivolumab IV over 60 minutes on days 1 and 15, cyclophosphamide IV on day 1, and IRX-2 SC over 10 consecutive days between days 4-21 in the absence of disease progression or unacceptable toxicity. Beginning days 25-30, patients undergo surgery.
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Pathologically confirmed (histology or
             cytology) stage III or IVA squamous cell cancer of the oral cavity (excluding lip)

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Disease is surgically resectable with
             curative intent

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Hemoglobin > 9 g/dL

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Lymphocyte count > 500/µL

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Neutrophil count > 1500/µL

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Platelet count > 100,000/µL

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Serum albumin > 3.0 g/dL

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Aspartate aminotransferase (AST/serum
             glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/ serum
             glutamate pyruvate transaminase [SGPT]) < 3 x the upper limits of normal (ULN)

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Alkaline phosphatase < 2 x ULN

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prothrombin time (PT) and partial
             thromboplastin time (PTT) < 1.4 x ULN

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Calculated creatinine clearance > 50
             mL/min

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Willing and able to give informed consent
             and adhere to protocol therapy

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Eastern Cooperative Oncology Group (ECOG)
             performance status < 2

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Female of childbearing potential (less
             than 12 months post-menopausal) or male with a partner of childbearing potential
             either agrees to be abstinent or uses a medically acceptable form of birth control
             during the study and for a period of 1 year

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Negative urine/serum pregnancy test
             (females only) at the time of screening and within 24 hours of study treatment, if
             applicable

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Stage 1 (T1/2 N1) squamous
             cell carcinoma of the oropharynx associated with HPV as determined by p16 protein
             expression using immunohistochemistry (IHC) performed by a Clinical Laboratory
             Improvement Act [CLIA] approved laboratory; using p16 antibody obtained from Roche mtm
             laboratories AG (CINtec, clone E6H4) is recommended

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: No prior radiation above the
             clavicles

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Patients with a history of a
             curatively treated malignancy must be disease-free for at least two years except for
             carcinoma in situ of cervix, melanoma in-situ (if fully resected), and/or
             non-melanomatous skin cancer

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Patients must not have
             evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Hemoglobin > 9 g/dL

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Lymphocyte count > 500/µL

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Neutrophil count > 1500/µL

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Platelet count > 100,000/µL

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Serum albumin > 3.0 g/dL

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Aspartate aminotransferase
             (AST/ SGOT) and alanine aminotransferase (ALT/ SGPT) < 3 x the upper limits of normal
             (ULN)

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Alkaline phosphatase < 2 x
             ULN

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prothrombin time (PT) and
             partial thromboplastin time (PTT) < 1.4 x ULN

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Calculated creatinine
             clearance > 50 mL/min

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Willing and able to give
             informed consent and adhere to protocol therapy

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: ECOG performance status < 2

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Female of childbearing
             potential (less than 12 months post-menopausal) or male with a partner of childbearing
             potential either agrees to be abstinent or uses a medically acceptable form of birth
             control during the study and for a period of 1 year

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Negative urine/serum
             pregnancy test (females only) at the time of screening and within 24 hours of study
             treatment, if applicable

        Exclusion Criteria:

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior surgery, radiation therapy, or
             chemotherapy other than biopsy or emergency procedure required for supportive care

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior treatment with an anti-PD-1,
             anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4)
             antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior treatment with cetuximab or
             epidermal growth factor receptor (EGFR) inhibitors in any treatment setting

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Any medical contraindications or previous
             therapy that would preclude treatment with either nivolumab, IRX-2, the surgery,
             reconstruction or adjuvant therapy required to treat the oral tumor appropriately

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Clinical status of either subject or tumor
             such that administration of 10 day neoadjuvant IRX-2 1 or 2 before surgery would be
             medically inappropriate

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Primary tumor of the oropharynx

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Tumor involvement of the following sites
             or any of these signs or symptoms likely to be associated with T4b cancer:

               -  Involvement of pterygopalatine fossa, maxillary sinus, or facial skin

               -  Gross extension of tumor to the skull base

               -  Pterygoid plate erosion

               -  Sphenoid bone or foramen ovale involvement

               -  Direct extension to involve prevertebral fascia

               -  Extension to superior nasopharynx or Eustachian tube

               -  Direct extension into the neck with involvement of the deep neck musculature
                  (neck node fixation)

               -  Suspected invasion (encasement) of the common or internal carotid arteries;
                  encasement will be assessed radiographically and will be defined as tumor
                  surrounding the carotid artery 270 degrees or greater

               -  Direct extension of neck disease to involve the external skin

               -  Direct extension to mediastinal structures

               -  Regional metastases to the supraclavicular neck (low level VB and IVB)

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Any investigational agent within the
             previous 30 days

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Daily administration of systemic
             immunosuppressive therapy or corticosteroids (except in physiological doses for
             hormone deficiency) during the previous 30 days

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Chronic anticoagulation, not including
             aspirin, but including heparins, warfarin, oral anticoagulation or other platelet
             function inhibitors

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Symptomatic cardiopulmonary disease
             (including congestive heart failure and hypertension), coronary artery disease,
             serious arrhythmia or chronic lung disease; patients with these conditions who are
             stable with relatively minor symptoms and who are appropriate candidates for surgical
             treatment of their tumor need not be excluded

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Myocardial infarction within the last 3
             months

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Evidence of distant metastases (M1
             disease) or other concurrent primary malignancy

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Known infection with hepatitis B,
             hepatitis C, or human immunodeficiency virus (HIV)

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Signs or symptoms of systemic systemic
             infection (use of antibiotics to treat superficial infection or contamination of tumor
             shall not, by itself, be considered evidence of infection

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Stroke or other symptoms of cerebral
             vascular insufficiency within the last 3 months

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Allergy to ciprofloxacin (or other
             quinolones), acetylsalicylic acid

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Previous diagnosis of invasive cancer from
             which the individual is NOT disease-free AND that has required treatment within the
             past 5 years, except for superficial skin, cervical cancer in-situ,
             well-differentiated thyroid or early stage prostate or bladder cancer (i.e., treatment
             with curative intent and long term disease-free expectations)

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior axillary dissection

          -  ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: History of pneumonitis or interstitial
             lung disease

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prior surgery, radiation
             therapy, or chemotherapy other than biopsy or emergency procedure required for
             supportive care

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prior treatment with an
             anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
             specifically targeting T-cell co-stimulation or checkpoint pathways

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Any medical
             contraindications or previous therapy that would preclude treatment with either
             nivolumab or IRX-2 or the surgery, reconstruction or adjuvant therapy required to
             treat the oropharynx tumor appropriately

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Tumor of the oral cavity

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Tumor involvement of the
             following sites or any of these signs or symptoms likely to be associated with T4b
             cancer:

               -  Involvement of pterygopalatine fossa, maxillary sinus

               -  Gross extension of tumor to the skull base

               -  Pterygoid plate erosion

               -  Sphenoid bone or foramen ovale involvement

               -  Direct extension to involve prevertebral fascia

               -  Extension to superior nasopharynx or Eustachian tube

               -  Direct extension into the neck with involvement of the deep neck musculature
                  (neck node fixation)

               -  Suspected invasion (encasement) of the common or internal carotid arteries;
                  encasement will be assessed radiographically and will be defined as tumor
                  surrounding the carotid artery 270 degrees or greater

               -  Direct extension of neck disease to involve the external skin

               -  Direct extension to mediastinal structures

               -  Regional metastases to the supraclavicular neck (low level VB and IVB)

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Any investigational agent
             within the previous 30 days

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Daily administration of
             systemic immunosuppressive therapy or corticosteroids (except in physiological doses
             for hormone deficiency) during the previous 30 days

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Chronic anticoagulation, not
             including aspirin, but including heparins, warfarin, oral anticoagulation or other
             platelet function inhibitors

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Symptomatic cardiopulmonary
             disease (including congestive heart failure and hypertension), coronary artery
             disease, serious arrhythmia or chronic lung disease; patients with these conditions
             who are stable with relatively minor symptoms and who are appropriate candidates for
             surgical treatment of their tumor need not be excluded

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Myocardial infarction within
             the last 3 months

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Evidence of distant
             metastases (M1 disease) or other concurrent primary malignancy

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Known infection with
             hepatitis B, hepatitis C, or HIV

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Signs or symptoms of
             systemic bacterial infection (use of antibiotics to treat superficial infection or
             contamination of tumor shall not, by itself, be considered evidence of infection)

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Stroke or other symptoms of
             cerebral vascular insufficiency within the last 3 months

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Allergy to ciprofloxacin (or
             other quinolones), acetylsalicylic acid

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Previous diagnosis of
             invasive cancer from which the individual is NOT disease-free AND that has required
             treatment within the past 5 years, except for superficial skin, cervical cancer
             in-situ, well-differentiated thyroid or early stage prostate or bladder cancer (i.e.,
             treatment with curative intent and long term disease-free expectations)

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prior axillary dissection

          -  HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: History of pneumonitis or
             interstitial lung disease
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (AEs) described using Common Terminology Criteria for Adverse Events 4.03
Time Frame:Up to 4 years
Safety Issue:
Description:Non-hematologic toxicities will be evaluated via the ordinal Common Toxicity Criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Last Updated