A Phase Ib, single centre, open label study of a therapeutic Human Papillomavirus (HPV) DNA vaccine co-administered with an anti-PD-L1 immunotherapy, Durvalumab (MEDI4376), for recurrent and/or metastatic HPV-related Head and Neck Cancer

Inclusion Criteria43

• Histologically or cytologically-confirmed recurrent or metastatic or unknown primary of presumed, oropharyngeal squamous cell carcinoma (OPSCC).
• Previously received curative or palliative treatment which may include any of the following: surgery, chemotherapy and/or radiotherapy (RT) or presenting with known metastatic disease.
• Have results from local testing of HPV positivity for oropharyngeal cancer defined as a positive test for HPV16 DNA or HPV16 mRNA or p16 immunohistochemistry (IHC) testing using CINtec® p16 Histology assay and a 70% cut-off point. If HPV status has previously been tested using one or more of these procedures, no retesting is required, however HPV16 DNA or HPV16 mRNA testing may be performed on archived paraffin-embedded tumour tissue if not previously done.
• Confirmation of PD-L1 Status. (Patients with equal to or greater than 25% of tumour cells with membrane staining of any intensity will be considered PD-L1 positive while those with 0% to 24% of tumour cells with membrane staining will be considered PD-L1 negative).
• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 at enrollment.
• Able to communicate effectively with study personnel and is considered reliable, willing, and cooperative in terms of compliance with the protocol requirements.
• Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
• Aged 18 years or older at the time of informed consent.
• Males who are not surgically sterile must use a condom from screening through to 90 days after the last dose of Durvalumab, unless they have a female partner who is surgically sterile or post-menopausal. They must refrain from fathering a child during this time.
• Women of child-bearing potential (WOCBP) must use highly effective contraceptive measures (failure rate of < 1% per year when used consistently and correctly) and intend to continue use contraception for at least 90 days following completion of treatment. Highly effective contraceptive measures could include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone releasing system, bilateral tubal occlusion, vasectomized partner, and sexual abstinence.
• 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.
• Participant in otherwise general good health based on medical history and physical examination.
• Body weight > 30kg.
• Adequate normal organ and marrow function
• Received any prophylactic or therapeutic vaccine within 28 days, or investigational drug within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study.
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies, other investigational agent) 21 days prior to the first dose of study drug or 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug for patients who have received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C). If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the Investigator.
• Any previous treatment with a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD1) or programmed death ligand 1 (PD-L1) inhibitor, including Durvalumab.
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) equal to or greater than 470 ms calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 2-5 minutes apart).
• Current or prior use of immunosuppressive medication within 28 days before the first dose of study treatment, with the exceptions of intranasal, inhaled, injected or topical corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are also an exception to this criterion.
• Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
• 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 polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
• 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 another primary malignancy except for
• Malignancy treated with curative intent and with no known active disease for at least 5 years before the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• History of leptomeningeal carcinomatosis
• Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry
• History of autoimmunity or active primary immunodeficiency
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of Durvalumab.
• Pregnant as confirmed by a positive serum beta human chorionic gonadotropin (ß-HCG) pregnancy test at Screening or subsequent clinic visit.
• Inadequate venous access to allow collection of blood samples.
• Birthmarks, tattoos, wound or other skin conditions on the forearms that could reasonably obscure injection site reactions.
• Received medication known to have anti-HPV activity within 28-days of screening (prior vaccination with HPV prophylactic vaccines is not an exclusion criterion for this study).
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), known positive Hepatitis B virus surface antigen (HBsAg), Hepatitis C virus (HCV), or Human Immunodeficiency virus (HIV) positive for HIV 1/2 antibodies.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Prior randomisation or treatment in a previous Durvalumab clinical study regardless of treatment arm assignment.
• Unwilling to abstain from blood donation during the course of the study, and/or has donated blood or plasma within 60 days prior to the Screening visit.