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

• ClinicalTrials.gov Identifier: NCT04001413
• Recruitment Status: Withdrawn
• First Posted: June 28, 2019
• Last Update Posted: July 29, 2022
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HPV Positive Oropharyngeal Squamous Cell Carcinoma; Oropharynx Cancer; HPV-Related Carcinoma	Drug: MEDI0457; Drug: Durvalumab	Phase 2

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II, Adjuvant Therapy for High-Risk HPV 16-Positive Oropharynx Cancer Patients With Durvalumab (MEDI4736) and MEDI0457 (INO-3112)
• Actual Study Start Date: September 17, 2019
• Actual Primary Completion Date: March 25, 2021
• Actual Study Completion Date: March 25, 2021

Arms and Interventions

Arm	Intervention/treatment
No Intervention: Arm A: Observational; No intervention, observational arm.
Experimental: Arm B: Durvalumab Alone; Durvalumab will be administered as an IV Infusion.	Drug: Durvalumab; Durvalumab is an investigational drug in this study.; Other Name: MEDI4736
Experimental: Arm C: MEDI0457 and Durvalumab; MEDI0457 is an injection. Durvalumab will be administered as an IV Infusion.	Drug: MEDI0457; MEDI0457 is an investigational drug that will be administered with the Cellectra Device in this study; Other Name: INO-3112; Drug: Durvalumab; Durvalumab is an investigational drug in this study.; Other Name: MEDI4736

Outcome Measures

Primary Outcome Measures :

1. Number of participants in whom there is clearance of Human Papiloma Virus (HPV) biomarkers post-intervention [ Time Frame: Up to 5 years ]

Secondary Outcome Measures :

1. Time to Progression [ Time Frame: Up to 5 years ]
   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.
2. Safety of Study Drugs [ Time Frame: Up to 30 days after the last dose of study drug ]
   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).

Other Outcome Measures:

1. Clearance of HPV Measured by DNA in participants with HPV E6/E7-specific and MANA-specific T-cell response [ Time Frame: Up to 5 years ]
   Clearance of HPV as measured by DNA in oral rinses and/or plasma (milliliters) in participants with HPV E6/E7-specific and mutation-associated neoantigen (MANA)-specific T-cell responses.
2. Clearance of HPV Measured by DNA in participants with HPV E6/E7-specific IgG [ Time Frame: Up to 5 years ]
   Clearance of HPV as measured by DNA in oral rinses and/or plasma (milliliters) in participants with HPV E6/E7-specific IgG

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 or cytologically proven HPV16-positive or p16-positive oropharyngeal squamous cell carcinoma.
• Eastern Cooperative Oncology Group (ECOG) 0-1 (Appendix A)
• Completion of primary therapy curative intent )surgery based or radiation based) within the past year (date of last treatment + 1 year) OR newly diagnosed with a plan for treatment with curative intent OR currently in primary treatment with curative intent.
• 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.

• 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.

• Subjects with a previous diagnosis of another primary malignancy are excluded with the exception of

  • Malignancy treated with curative intent and with no known active disease > or = 3 years 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
  • Thyroid or salivary cancer
• 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

• 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
  • Patients with stable, inactive rheumatoid arthritis
• 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.

Contacts and Locations

Locations

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, New York

Mount Sinai School of Medicine, The Tisch Cancer Institute

New York, New York, United States, 10029

Mount Sinai School of Medicine

New York, New York, United States, 10029

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

AstraZeneca

Investigators

• Principal Investigator: Carole Fakhry, MD, MPH; Johns Hopkins University/Sidney Kimmel Cancer Center

More Information

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT04001413
• Other Study ID Numbers: J1918; IRB00179194 ( Other Identifier: JHM IRB )
• First Posted: June 28, 2019
• Last Update Posted: July 29, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Carcinoma; Squamous Cell Carcinoma of Head and Neck; Oropharyngeal Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Neoplasms by Site; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Durvalumab; Antineoplastic Agents, Immunological; Antineoplastic Agents