Clinical Trials /

Therapy for High-Risk HPV 16-Positive Oropharynx Cancer Patients

NCT04001413

Description:

Combination immune checkpoint inhibitor and DNA vaccine will result in clearance of HPV DNA biomarkers (oral and/or plasma) for patients with persistent HPV-16 E6/E7 DNA (HPV biomarker) after treatment with curative intent.

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Therapy for High-Risk HPV 16-Positive Oropharynx Cancer Patients
  • Official Title: Phase II, Adjuvant Therapy for High-Risk HPV 16-Positive Oropharynx Cancer Patients With Durvalumab (MEDI4736) and MEDI0457 (INO-3112)

Clinical Trial IDs

  • ORG STUDY ID: J1918
  • SECONDARY ID: IRB00179194
  • NCT ID: NCT04001413

Conditions

  • HPV Positive Oropharyngeal Squamous Cell Carcinoma
  • Oropharynx Cancer
  • HPV-Related Carcinoma

Interventions

DrugSynonymsArms
MEDI0457INO-3112Arm C: MEDI0457 and Durvalumab
DurvalumabMEDI4736Arm B: Durvalumab Alone

Purpose

Combination immune checkpoint inhibitor and DNA vaccine will result in clearance of HPV DNA biomarkers (oral and/or plasma) for patients with persistent HPV-16 E6/E7 DNA (HPV biomarker) after treatment with curative intent.

Detailed Description

      Objectives:

      Primary Objectives:

      To determine whether combination immune checkpoint inhibitor, alone or together with a DNA
      vaccine will result in clearance of HPV biomarkers for patients at risk of disease
      progression.

      Secondary Objective(s):

        1. To evaluate the time to progression among patients with detectable HPV DNA when treated
           with the durvalumab/MEDI0457 versus durvalumab monotherapy versus observation.

        2. To assess the toxicity of durvalumab and MEDI0457 in the adjuvant setting.

      Exploratory Objective(s):

        1. To determine whether anti-PD-L1 alone or together with an HPV DNA vaccine will enhance
           HPV E6/E7-specific and/or mutation-associated neoantigen (MANA)-specific T cell
           responses and whether these responses correlate with enhanced clearance of HPV as
           measured by DNA in oral rinses and/or plasma.

        2. To determine whether anti-PD-L1 alone or together with an HPV DNA vaccine will enhance
           HPV 16 E6/E7-specific IgG and whether these responses correlate with enhanced clearance
           of HPV as measured by DNA in oral rinses and/or plasma
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: ObservationalNo InterventionNo intervention, observational arm.
    Arm B: Durvalumab AloneExperimentalDurvalumab will be administered as an IV Infusion.
    • Durvalumab
    Arm C: MEDI0457 and DurvalumabExperimentalMEDI0457 is an injection. Durvalumab will be administered as an IV Infusion.
    • MEDI0457
    • Durvalumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Capable of giving signed informed consent which includes compliance with the
                 requirements and restrictions listed in the informed consent form (ICF) and in the
                 protocol. Written informed consent and any locally required authorization (eg, Health
                 Insurance Portability and Accountability Act in the US, European Union [EU] obtained
                 from the patient/legal representative prior to performing any protocol-related
                 procedures, including screening evaluations.
    
              -  Men and women >or = 18 years at the time of study entry.
    
              -  Histologically proven HPV16-positive oropharyngeal squamous cell carcinoma.
    
              -  Formalin fixed paraffin block from time of primary diagnosis that has been confirmed
                 by a pathologist to contain tumor or a minimum of fifteen 5-micron tissue sections
                 (slides) of tumor biopsy sample for pathologic and possible biomarker evaluation,
                 including PDL1 immunohistochemistry (study pathologist must review for adequacy of
                 sampling).
    
              -  Eastern Cooperative Oncology Group (ECOG) 0-1 (Appendix A)
    
              -  Completion of primary therapy curative intent within past 5 months (date of last
                 treatment + 5 months)
    
              -  Body weight or = 30kg
    
              -  Adequate organ function as follows:
    
              -  Absolute neutrophil count (ANC) > or = 1000/mm3
    
              -  Platelet count > or = 75 x 109/L(> or = 75,000 per mm3)
    
              -  Hemoglobin > or =9 g/dL
    
              -  Creatinine < or = 1.5 x institutional ULN or creatinine clearance (CrCI) > or =
                 40mL/min (if using Cockcroft-Gault formula below):
    
            Female CrCI = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL
            Male CrCI= (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
    
              -  Total Bilirubin < or = 1.5 x institutional ULN (except subjects with Gilbert Syndrome,
                 who can have total bilirubin < 3.0 mg/dL)
    
              -  AST(SGOT)/ALT(SGPT) < or = 2.5 x institutional upper limit of normal unless liver
                 metastases are present, in which case it must be < or = 5x ULN
    
              -  Sexually active fertile men must use effective barrier birth control if their partners
                 are WOCBP for up to 217 days after the last dose of durvalumab.
    
              -  The effects of Durvalumab and MEDI0475 on the developing human fetus are unknown.
                 Women of child-bearing potential (WOCBP) and mes must agree to use at least one highly
                 effective method of contraception (hormonal or barrier method form of birth control;
                 abstinence) prior to study entry and for the duration of study participation and for
                 up to 217 days after the last dose of Durvalumab or MEDI0457.
    
              -  Should a woman become pregnant or suspect she is pregnant while she or her partner is
                 participating in this study, she must inform her treating physician immediately.
    
              -  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
                 or equivalent units of HCG) within two weeks of screening.
    
              -  Women must not be breastfeeding
    
              -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
                 female pre-menopausal patients. Women will be considered post-menopausal if they have
                 been amenorrheic for 12 months without an alternative medical cause. The following
                 age-specific requirements apply:
    
                   -  Women <50 years of age would be considered post-menopausal if they have been
                      amenorrheic for 12 months or more following cessation of exogenous hormonal
                      treatments and if they have luteinizing hormone and follicle-stimulating hormone
                      levels in the post-menopausal range for the institution or underwent surgical
                      sterilization (bilateral oophorectomy or hysterectomy).
    
                   -  Women > or =50 years of age would be considered post-menopausal if they have been
                      amenorrheic for 12 months or more following cessation of all exogenous hormonal
                      treatments, had radiation-induced menopause with last menses >1 year ago, or
                      underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy
                      or hysterectomy).
    
              -  Patient is willing and able to comply with the protocol for the duration of the study
                 including undergoing treatment and scheduled visits and examinations including follow
                 up.
    
              -  Patient understands the study regimen, its requirements, risks and discomforts and is
                 able and willing to sign the informed consent form. Voluntary signed and dated IRB/IEC
                 guidelines must be obtained before the performance of any protocol related procedures
                 that are not part of normal care.
    
              -  Subjects must be competent to report AEs, understand the drug dosing schedule and use
                 of medications to control AEs.
    
              -  Individuals of all races and ethnic groups are eligible for this trial. There is no
                 bias towards age, gender or race in the clinical trial outlined. This trial is open to
                 accrual of men and women who meet the inclusion/exclusion criteria outlined.
    
            Exclusion Criteria:
    
              -  Participation in another clinical study with an investigational product during or
                 after primary therapy.
    
              -  Concurrent enrollment in another clinical study, unless it is an observational
                 (non-interventional) clinical study or during the follow-up period of an
                 interventional study.
    
              -  Subjects with active concurrent malignancies or recognized recurrent/metastatic cancer
                 are excluded.
    
              -  Any unresolved toxicity NCI CTCAE Grade > or = 2 from previous anticancer therapy with
                 the exception of alopecia, vitiligo, and the laboratory values defined in inclusion
                 criteria.
    
                   -  Patients with Grade > or = 2 neuropathy will be evaluated on a case-by-case basis
                      after consultation with Study Physician.
    
                   -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                      treatment with durvalumab may be included only after consultation with Study
                      Physician.
    
              -  Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
                 Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
                 replacement therapy) is acceptable.
    
              -  History of another primary malignancy except for
    
                   -  Malignancy treated with curative intent and with no known active disease > or = 3
                      years before the first dose of IP and of low potential risk of recurrence
    
                   -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                      of disease
    
                   -  Adequately treated carcinoma in situ without evidence of disease
    
              -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
                 first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
                 acceptable.
    
              -  History of allogenic organ transplantation
    
              -  Subjects are excluded if they have an active, known or suspected autoimmune disease.
                 Subjects are permitted to enroll if they have vitiligo, type 1 diabetes mellitus,
                 residual hypothyroidism due to autoimmune condition only requiring hormone
                 replacement, psoriasis not requiring systemic treatment, or conditions not expected to
                 recur in the absence of an external trigger.
    
              -  Active or prior documented autoimmune or inflammatory disorders (including
                 inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
                 the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
                 or Wegener syndrome [granulomatosis with polyangitis, Graves' disease, rheumatoid
                 arthritis, hypophysitis, uveitis, etc.]. The following are exceptions to this
                 criterion:
    
                   -  Patients with vitiligo or alopecia
    
                   -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                      hormone replacement
    
                   -  Any chronic skin condition that does not require systemic therapy
    
                   -  Patients without active disease in the last 5 years may be included but only
                      after consultation with study physician
    
                   -  Patients with celiac disease controlled by diet alone
    
              -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
                 infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
                 angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
                 gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
                 situations that would limit compliance with study requirement, substantially increase
                 risk of incurring AEs or compromise the ability of the patient to give written
                 informed consent
    
              -  History of active primary immune deficiency
    
              -  Active infection including:
    
                   -  tuberculosis (clinical evaluation that includes history, physical examination and
                      radiographic findings, and TB testing in line with local practice).
    
                   -  Hepatitis B and or hepatitis C, (positive tests for hepatitis B surface antigen
                      or hepatitis C ribonucleic acid (RNA) or
    
                   -  Patients with a past or resolved HBV infection (defined as the absence of
                      hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
                      positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
                      reaction is negative for HCV RNA.
    
                   -  human immunodeficiency virus (positive HIV 1/2 antibodies).
    
              -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
                 excipients.
    
              -  Active systemic infection requiring therapy.
    
              -  Current or prior use of immunosuppressive medication within 14 days before the first
                 dose of durvalumab. The following are exceptions to this criterion:
    
                   -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                      articular injection)
    
                   -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                      prednisone or its equivalent C. Corticosteroids as premedication for
                      hypersensitivity reactions (e.g., CT scan premedication)
    
              -  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
                 Patients, if enrolled, should not received live vaccine whilst receiving IP and up to
                 30 days after the last dose of IP.
    
              -  Prior randomization or treatment in a previous durvalumab clinical study regardless of
                 treatment arm assignment.
    
              -  Use of anticoagulants and irreversible platelet inhibitors (e.g. clopidogrel,
                 prasugrel, ticagrelor, etc.) are not allowed. Low dose aspirin for cardiac prophylaxis
                 is allowed.
    
              -  Subjects are excluded if they have a condition requiring systemic treatment with
                 either corticosteroids (>10 mg daily prednisone equivalents) or other
                 immunosuppressive medications within 14 days of study drug administration. Inhaled or
                 topical steroids and adrenal replacement doses > 10mg daily prednisone equivalents are
                 permitted in the absence of active autoimmune disease.
    
              -  Female patients who are pregnant or intend to become pregnant, breastfeeding or male
                 or female patients of reproductive potential who are not willing to employ effective
                 birth control from screening to 217 days after the last dose of durvalumab
                 monotherapy.
    
              -  Men with female partners (WOCBP) that are not willing to use contraception from
                 screening to 217 days after the last dose of durvalumab monotherapy.
    
              -  Unable to follow up per study schedule.
    
              -  Patient is 1 year or greater from completion of primary treatment.
    
              -  Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for
                 treatment of either psychiatric or physical (e.g. infectious disease) illness.
    
              -  Patients weighing <30kg at time of screening are to be excluded from enrollment.
    
              -  Prior therapy with an anti-PD-1, anti-PD-L1, including durvalumab anti-PDL-2, or
                 anti-CTLA-4 antibody (or any other antibody targeting T cell co-regulatory pathways).
    
              -  Judgement by the investigator that the patient is unsuitable to participate in the
                 study and the patient is unlikely to comply with study procedures, restrictions and
                 requirements.
    
              -  Underlying medical conditions that, in the Investigator's opinion, will make the
                 administration of study drug hazardous or obscure the interpretation of toxicity or
                 adverse events. For example, prior symptomatic pneumonitis.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of participants in whom there is clearance of Human Papiloma Virus (HPV) biomarkers post-intervention
    Time Frame:Up to 5 years
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure:Time to Progression
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Time until progression, followed for up to five years, among patients with detectable HPV DNA when treated with the durvalumab/MEDI0457 versus durvalumab monotherapy versus observation.
    Measure:Safety of Study Drugs
    Time Frame:Up to 30 days after the last dose of study drug
    Safety Issue:
    Description:Adverse events will be reviewed to determine the safety of durvalumab and MEDI0457 in the adjuvant setting. Observed Adverse events and toxicities will be tabulated by treatment group, type and grade. AEs and other toxicities will be graded using NCI Common Terminology Criteria for Adverse Events 5.0 (CTCAE).

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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