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Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection

NCT04247282

Description:

Background: Some people who get head and neck cancer will need surgery to treat their cancer. Research suggests that immunotherapy drugs may help fight head and neck cancer if given before surgery. In most cases, there is enough time between cancer diagnosis and surgery to test immunotherapy drugs. In this study, researchers are testing the safety and anti-cancer abilities of 3 drugs given before surgery for head and neck cancer. Objective: To learn if giving M7824 alone, or with the TriAd vaccine, or with TriAd vaccine plus N-803 can shrink previously untreated head and neck tumors before surgery or stop the tumors from coming back after all treatment. Eligibility: People age 18 and older who have a head and neck cancer that has not been treated before, and the tumor must be removed with surgery. Design: Participants will be screened in a separate protocol. Participants will have the following tests: - medical history and physical exams - computed tomography or magnetic resonance imaging scans - tumor, mucosa, and skin biopsies - electrocardiograms to monitor heart activity - endoscopies (a tube is inserted through the nose to see the upper airway) - blood and urine tests. All participants will get M7824 through an intravenous infusion. For this, a small plastic tube is put into an arm vein. Some may also get the TriAd vaccine. It is injected under the skin on the arms or legs. Some may also get N-803. It is injected under the skin on the stomach. Participants will have clinic visits while they are getting treatment and after treatment ends. After treatment ends, participants will have their scheduled surgery. There will be two follow up visits at the NIH after your surgery. They will be contacted by phone or email every 2 weeks for 3 months. Then they will be contacted every 3 months for 2 years. ...

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection
  • Official Title: A Sequential Window of Opportunity Trial of Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine, and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection

Clinical Trial IDs

  • ORG STUDY ID: 200024
  • SECONDARY ID: 20-C-0024
  • NCT ID: NCT04247282

Conditions

  • Head and Neck Cancer
  • Head and Neck Neoplasms

Interventions

DrugSynonymsArms
M7824A/arm A
N803C/arm C
TriAd vaccineB/ arm B

Purpose

Background: Some people who get head and neck cancer will need surgery to treat their cancer. Research suggests that immunotherapy drugs may help fight head and neck cancer if given before surgery. In most cases, there is enough time between cancer diagnosis and surgery to test immunotherapy drugs. In this study, researchers are testing the safety and anti-cancer abilities of 3 drugs given before surgery for head and neck cancer. Objective: To learn if giving M7824 alone, or with the TriAd vaccine, or with TriAd vaccine plus N-803 can shrink previously untreated head and neck tumors before surgery or stop the tumors from coming back after all treatment. Eligibility: People age 18 and older who have a head and neck cancer that has not been treated before, and the tumor must be removed with surgery. Design: Participants will be screened in a separate protocol. Participants will have the following tests: - medical history and physical exams - computed tomography or magnetic resonance imaging scans - tumor, mucosa, and skin biopsies - electrocardiograms to monitor heart activity - endoscopies (a tube is inserted through the nose to see the upper airway) - blood and urine tests. All participants will get M7824 through an intravenous infusion. For this, a small plastic tube is put into an arm vein. Some may also get the TriAd vaccine. It is injected under the skin on the arms or legs. Some may also get N-803. It is injected under the skin on the stomach. Participants will have clinic visits while they are getting treatment and after treatment ends. After treatment ends, participants will have their scheduled surgery. There will be two follow up visits at the NIH after your surgery. They will be contacted by phone or email every 2 weeks for 3 months. Then they will be contacted every 3 months for 2 years.

Detailed Description

      Background:

        -  Approximately 50% of patients with advanced p16-negative head and neck squamous cell
           carcinoma (HNSCC) will develop locoregional or distant relapse within two years of
           completing definitive standard-of-care treatment.

        -  Two ongoing clinical trials investigating neoadjuvant PD-1 blockade before surgical
           resection of HNSCC suggest that immunotherapy can both cytoreduce existing disease
           before surgery and reduce the risk of locoregional or distant disease relapse after
           surgery.

        -  Preliminary data from these studies suggest neoadjuvant treatments can be administered
           without delaying planned surgical intervention.

        -  Experiments conducted by the Laboratory of Tumor Immunology and Biology (LTIB)
           demonstrated synergistic activity with tumor-targeted adenoviral vaccine plus M7824 plus
           N-803 in humanized mice bearing human carcinomas and in vitro studies.

        -  M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand
           1(PD-L1) antibody and the extracellular domain of transforming growth factor beta
           (TGF-beta) receptor type 2, a TGF-beta trap.

        -  Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific
           T cells.

        -  N-803 is an IL-15/IL-15R alpha super agonist complex that can enhance both NK cell and T
           cell anti-tumor activity via expansion and activation.

        -  Activity observed with neoadjuvant anti-PD-1 agents alone provides rationale for testing
           of M7824 alone and in combination with other immune oncologic agents that have been
           shown to work in concert with M7824 in preclinical studies.

        -  Analysis of pre- and post-treatment tissues from HNSCC patients presents a unique
           opportunity to interrogate the effects the above treatment(s) on tumor.

        -  A dose escalation of N-803 in combination with a flat dose of M7824 was conducted at the
           National Cancer Institute. Thirteen patients have been treated with the combination. No
           DLTs were observed.

      Objectives:

      -Determine the rate of pathologic complete response (pCR) or clinical-to-pathological
      downstaging in patients with previously untreated intermediate/high risk, non-HPV associated,
      squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) who
      receive any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824
      plus TriAd vaccine plus N803 prior to definite surgery.

      Eligibility:

        -  Patients must have histologically or cytologically confirmed, previously untreated
           intermediate/high risk, p16-negative (if oropharyngeal), squamous cell carcinoma of the
           head and neck (T1-T4, N0-N3, M0 stage II, III or IV)

        -  Men or Women; Age greater than or equal to 18 years

        -  ECOG performance status less than or equal to 1

      Design:

        -  This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-beta trap
           (M7824) alone and in combination with TriAd Vaccine and N-803 for non-HPV associated
           resectable Head and Neck Squamous Cell Carcinoma (HNSCC).

        -  Patients will be referred to the NIH for this immunotherapy treatment from surrounding
           academic medical centers and private physicians.

        -  Upon referral to the NIH, patients will be rapidly screened, and enrolled on the
           protocol, if appropriate.

        -  This trial will enroll patients in three arms sequentially to permit safety evaluation
           before adding the next agent.

        -  In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on
           day 1 and 15.

        -  If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll
           with M7824 (1200mg; intravenous) and TriAd vaccine (5 x 10 (11) VP; subcutaneous)
           treatment on day 1 and 15.

        -  If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll
           with M7824 ((1200mg; intravenous) plus TriAd vaccine (5 x 10(11) VP; subcutaneous
           injection) on day 1 and 15 plus N-803 (15mcg/kg, subcutaneously) treatment on day 1.

        -  After obtaining pre-treatment biopsies, imaging and blood collection, patients will
           receive the neoadjuvant immunotherapy at the NIH Clinical Center.

        -  Patients will then be sent back to their referring providers for their definitive
           standard of care surgery and adjuvant therapy as indicated based upon pathologic
           analysis of the surgical specimen. NCI investigators will have no role in directing the
           ensuing standard of care surgeries performed at outside institutions.

        -  For consistency in pathologic analysis of resection specimens, tissue blocks and/or
           slides will be obtained from outside institutions and be reviewed by the NCI Laboratory
           of Pathology.

        -  It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12
           patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be
           completed within 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
A/arm AExperimentalM7824 (Days 1, 15)
  • M7824
B/ arm BExperimentalM7824 + TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) (Days 1, 15)
  • M7824
  • TriAd vaccine
C/arm CExperimentalM7824 + TriAd vaccine (Days 1, 15) + N-803 (Day 1)
  • M7824
  • N803
  • TriAd vaccine

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed, previously untreated
             intermediate/high risk, p16-negative (if oropharyngeal primary tumor), squamous cell
             carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV).

          -  Male or female; Age greater than or equal to 18 years.

          -  ECOG performance status less than or equal to 1.

          -  Prothombin time (PT) and partial thromboplastin time (PTT) within normal institutional
             limits. Patients with prolonged PTT determined to be due to lupus anticoagulant will
             not be excluded.

          -  Patients must have adequate organ and marrow function as defined below:

               -  Absolute neutrophil count greater than or equal to 1000/mcL

               -  Platelets greater than or equal to 100,000/mcL

               -  Hemoglobin greater than or equal to 10.0 g/dL

               -  Total bilirubin within normal institutiona l limits; in patients with Gilbert s,
                  less than or equal to 3.0 mg/dL

               -  AST (AGOT)/ALT (AGPT) less than or equal to 3X upper limit of normal.

               -  Creatinine within 1.5X upper limit of normal institutional limits

          -  The effects of M7824, TriAd vaccines, and N-803 on the developing human fetus are
             unknown. For this reason, men and women of child bearing capacity must agree to use
             highly-effective contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry, during the study and maintain such contraception
             until 2 months following the last dose of any study agent. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document

          -  Patients with successfully treated hepatitis C virus (HCV) are eligible if HCV viral
             load is undetectable.

        EXCLUSION CRITERIA:

          -  Patients who are immunocompromised as follows:

               -  Human immunodeficiency virus (HIV) positive patients not on or not compliant with
                  appropriate anti-retroviral therapy, patients with newly diagnosed (i.e. < 6
                  months) HIV, patients with an HIV viral load exceeding 400 copies/mL, HIV+
                  patients with a CD4 count < 150 cells/ L, and HIV+ patients on antiretroviral
                  therapy < 1 month are excluded. HIV-positive patients will also be excluded if
                  the PI determines that there is a clinically significant drug-drug interaction.

               -  Chronic administration (defined as daily or every other day for continued use >14
                  days) of systemic corticosteroids or other immune suppressive drugs, within 14
                  days before treatment on study. Physiologic daily dosing of steroids is allowed.
                  Nasal, or inhaled steroid, topical steroid creams and eye drops for small body
                  areas are allowed.

               -  Patients who have undergone allogeneic peripheral stem cell transplantation, or
                  solid organ transplantation requiring immunosuppression

          -  Pregnant women are excluded from this study because M7824 is an agent with the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with M7824 breastfeeding should be discontinued if the mother is treated with
             M7824. These potential risks may also apply to other agents used in this study.

          -  Patients with active systemic autoimmune disease, except patients with type 1 diabetes
             mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current
             immunosuppression, or with other endocrine disorders on replacement hormones, are not
             excluded if the condition is well controlled.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to study agents to be used in the cohort the subject will be enrolled
             into.

          -  Known allergy to eggs, egg products, aminoglycoside antibiotics (for example,
             gentamicin or tobramycin). Patients enrolling on the M7824 only arm will be exempt
             from this exclusion.

          -  Patients with a history of bleeding diathesis or recent clinically significant
             bleeding events considered by the Investigator as high risk for investigational drug
             treatment are excluded.

          -  Any condition which, in the opinion of the investigator, would prevent full
             participation in this trial (including the long-term follow-up), or would interfere
             with the evaluation of the trial endpoints.

          -  Patients with prior live vaccine, investigational drug, chemotherapy, immunotherapy or
             any prior radiotherapy (except for palliative bone directed therapy) within the past
             28 days prior to enrollment.

          -  Uncontrolled intercurrent acute or chronic illness including, but not limited to,
             ongoing or active infection, symptomatic congestive heart failure (>New York Heart
             Association Class I), hepatic disease, unstable angina pectoris, serious cardiac
             arrhythmia, requiring medication, uncontrolled hypertension (SBP>170/ DBP>105) or
             psychiatric illness/social situations within 12 months that would limit compliance
             with study requirements.

          -  Patients who have undergone major surgery within 4 weeks prior to enrollment. A biopsy
             will not preclude a patient from starting study.

          -  Patients with a history of hepatitis B (HBV) are excluded due to potential risk for
             viral reactivation and resulting liver injury in persons with latent HBV.

          -  Patients with treated or active brain metastases are not eligible because we are
             enrolling non-metastatic head and neck cancer patients in this trial. Standard of care
             treatment is different for head and neck cancer patients with and without metastatic
             disease.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response (pCR) or clinical to pathologic downstaging
Time Frame:1 and 2 year
Safety Issue:
Description:The number of patients who experience a pCR or clinical to pathologic downstaging will be determined

Secondary Outcome Measures

Measure:To estimate the rate of grade 3 or 4 immune-related adverse events
Time Frame:2 weeks
Safety Issue:
Description:The actual number of patients experiencing grade 3 or 4 adverse events
Measure:To determine the rate of patients whose surgery is delayed 4 weeks or greater beyond planned surgery
Time Frame:4 weeks
Safety Issue:
Description:The number of the patients whose surgery is delayed
Measure:To estimate the response rate (CR+PR) of the primary disease by RECIST
Time Frame:At tumor progression
Safety Issue:
Description:Proportion of patients whose tumors shrunk after therapy
Measure:To estimate the 1 year and 2 year RFS rates
Time Frame:1 and 2 years
Safety Issue:
Description:Median amount of time subject survives without disease recurrence after treatment
Measure:To estimate the 1 year and 2- year overall survival.
Time Frame:1 and 2 years
Safety Issue:
Description:Median amount of time subject survives after therapy

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immuno-oncology
  • Neoadjuvant Treatments
  • Vaccine
  • Immunotherapy
  • Head and Neck Cancer

Last Updated

June 18, 2020