Overview

This study is a multicentric double-blind placebo-controlled dose escalation trial of a CD40HVac vaccine (humanized anti-CD40 mAb fused to HPV16 E6/E7 oncoproteins) adjuvanted with poly-ICLC (Hiltonol) in patients with HPV16 oropharyngeal carcinoma with no evidence of residual or recurrent disease after surgery and/or radiochemotherapy.

The primary objective is to determine the recommended phase 2 dose (RP2D) of a poly-ICLC(Hiltonol)-adjuvanted CD40HVac vaccine according to the safety and the capacity to elicit immune responses of different doses Two dose levels of poly-ICLC-adjuvanted CD40.HVac will be explored

• 1st dose level: CD40.HVac 1.0 mg, with 1.0 mg poly-ICLC
• 2nd dose level: CD40.HVac 3.0 mg, with 1.0 mg poly-ICLC The safety data will be reviewed by an IDSMB that will give recommendations.

Eligibility

Inclusion Criteria:

1. Males and females ≥ 18 years of age.
2. Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
3. Subjects with histologically confirmed oropharyngeal squamous cell carcinoma.
4. HPV16 genotyping determined by a specified central reference laboratory with an established polymerase chain reaction (PCR)- based assay on FFPE archived tumor biopsies (or 10 slices of 5µm).If local HPV16 genotype assessment has been performed, the subject can be enrolled if the result shows HPV16 positivity. Confirmation of HPV16 positive status will be performed retrospectively by the central laboratory on archived tissue. Formalin- fixed tumour biopsies or surgical piece before local radical treatment can be optionally available for translational research.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
6. Comprehensive curative treatment according to the disease stage and national guidelines, completed at least 18 weeks (±2 weeks) prior to study drug administration.
7. No evidence of residual or recurrent disease on the last assessment, comprising a physical examination, a head and neck CT-scan or a head and neck MRI, and a thoracic CT Scan and TEP-scan.
8. Vaccination for Covid and Flu vaccines are authorised 4 weeks before or after the administration of poly-ICLC-adjuvanted CD40HVac (2 weeks during flu period for the Flu vaccine)
9. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
10. White blood cell count (WBC) ≥ 2 x 109/L ii) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L iii) Platelets ≥ 100 x 109/L iv) Hemoglobin ≥ 9.0 g/dL v) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) > 40 mL/min (using the Cockcroft-Gault formula): Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL vi) Hepatic function: Total bilirubin ≤ 1.5 x ULN. Subjects with Gilbert's Disease and total bilirubin up to 3 x ULN may be eligible if total bilirubin< 3.0 mg/dL.Transaminases (ALT and AST) ≤ 3 x ULN, Alkaline phosphatase ≤ 2.5 x ULN
11. Participants who were born female: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed before randomisation and on the day of initial IMP administration (W0)

    • Reproductive status: if heterosexually active female, consistently using an effective method of contraception with partner for sexual activity that could lead to pregnancy from at least 21 days prior to enrolment through 4 months after the last administration.

    Effective contraception is defined as using any of the following methods:

    • Condoms (male or female) with or without a spermicide;
    • Intrauterine device (IUD);
    • Intrauterine hormone releasing system (IUS);
    • Hormonal contraception (progesterone only);
    • Successful vasectomy in the male partner (considered successful if a participant reports that a male partner has (i) documentation of azoospermia by microscopy, or (ii) a vasectomy more than 2 years ago with no resultant pregnancy despite unprotected sexual activity postvasectomy);
    • Or not be of reproductive potential, such as having reached menopause (no menses for 1 year without an alternative medical cause) or having undergone hysterectomy, bilateral oophorectomy, or tubal ligation.
    • Agree not to seek pregnancy including through alternative methods, such as artificial insemination or in vitro fertilization until 4 months after the last administration.

             Participants who were born male, if heterosexually active male, using an effective
             method of contraception with their partner from the first day of IMP administration
             until 4 months after the last administration. This also applies to sperm donation.
         11. Patient should understand, sign, and date the written informed consent form prior to
             any protocol-specific procedures performed.
         12. Patients must be affiliated to a social security system or beneficiary of the same
        Exclusion Criteria:
          1. Clinical evidence on physical or radiological examination of residual or recurrent
             HPV-driven carcinoma on the primary site, in neck lymph nodes, or in any distant site
             metastasis.
          2. Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the subject to receive protocol therapy, or
             interfere with the interpretation of study results.
          3. Subjects with active, known, diagnosed or suspected auto-immune disease. Subjects
             suffering from vitiligo, type I diabetes mellitus, residual hypothyroidism due to
             autoimmune thyroiditis only requiring thyroid hormone replacement therapy, or
             psoriasis not requiring systemic treatment can be enrolled.
          4. Patients diagnosed with active interstitial lung disease (ILD)/pneumonitis or a
             history of ILD/pneumonitis within the last 5 years, or another condition requiring
             immunosuppressive doses of medication such as systemic corticosteroids or absorbed
             topical corticosteroids (doses ≥ 10 mg/day prednisone or equivalent) or other
             immunosuppressive medications within 14 days of study drug administration. Inhaled or
             topical corticosteroids and adrenal replacement doses < 10 mg daily prednisone or
             equivalent are permitted.
          5. Subjects requiring maintenance treatment with immunosuppressive doses of systemic
             corticosteroids. Subjects being treated with a short course of corticosteroids (> 10
             mg/day prednisone equivalents) should discontinue this therapy at least 2 weeks prior
             to start of study treatment.
          6. Prior treatment with therapeutic anti-HPV vaccines.
          7. Invasive surgery (defined as surgical intervention requiring general or spinal
             anesthesia, and hospital admission) within 28 days prior to start of study treatment.
          8. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus or
             hepatitis C virus.
          9. Patient with active infection must be postponed until infection resolution
         10. Subjects with an uncontrolled or significant heart disease such as long QT syndrome
             with QTcF > 480 ms on baseline ECG, NYHA III/IV or uncontrolled arrhythmia.
         11. History of organ transplantation, including allogenic peripheral stem cell or bone
             marrow transplantation.
         12. Participation in another clinical study with an investigational product during the
             last 6 months and while on study treatment
         13. Vaccination for Covid and Flu vaccines is not permitted within 4 weeks prior the first
             vaccination with polyICLC adjuvanted CD40HPVac (2 weeks during flu period for the Flu
             vaccine.
         14. Treatment is not permitted within 4 weeks prior the first vaccination and 4 months
             after the last injection. Furthermore, the use of this medication will be considered
             as a deviation to the protocol.
               -  curative treatment within 12 weeks before the first injection,
               -  Corticosteroids,
               -  Live attenuated vaccines (such as measles, mumps, and rubella [MMR]; oral polio
                  vaccine [OPV]; varicella; yellow fever) or any vaccines that are not live
                  attenuated (eg, tetanus, pneumococcal, Hepatitis A or B) except IMP vaccine.
               -  Immunosuppressive medications (Not excluded: [1] corticosteroid nasal spray; [2]
                  inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated
                  dermatitis; or [4] a single course of oral/parenteral corticosteroids at doses <
                  2 mg/kg/day and length of therapy < 11 days with completion at least 30 days
                  prior to enrollment)
               -  Blood products
               -  Immunoglobin
               -  Anti-tuberculosis drugs
               -  Immunomodulators (such as cytokines or interferons) or immunosuppressive drugs
                  during 8 weeks preceding the screening visit and as of 4 months after the last
                  injection will not be allowed. If any patient needs chronic use of one of these
                  medicine during this period, the subject will be withdrawn from the
                  investigational product but should be followed at all visits as planned by the
                  protocol
               -  Antipyretic will not be allowed twelve (12) hours before immunization as
                  preventive treatment of pain or fever.
         15. Pregnant or breastfeeding women or intending to become pregnant during study
         16. Patient under guardianship or deprived of his liberty by a judicial or administrative
             decision or incapable of giving its consent