Clinical Trials /

Combination of UCPVax Vaccine and Atezolizumab for the Treatment of Human Papillomavirus Positive Cancers (VolATIL)

NCT03946358

Description:

70% all cases of cervical cancer, 95% of anal cancers and about 70% of oropharyngeal cancers are linked to Human Papillomavirus (HPV) infection. HPV oncogenic proteins are trans-activators of telomerase. Indeed, E6 oncoprotein transactivates the human telomerase (hTert). Our group has conducted a clinical trial (NCT02402842) in advanced squamous cell anal cancer (SCCA) and investigators have shown a correlation between the presence of anti-HPV immunity and anti-telomerase T helpher 1 (TH1) CD4 T cell responses, establishing telomerase as an appropriate antigen in HPV-related cancers. Tumor-reactive CD4+ T cells have been found to ensure efficient effector Cytotoxic T Lymphocytes (CTL) recruitment at the tumor site. Promoting tumor specific TH1 CD4 activation might be an attractive therapeutic option to enhance anti-PD-1/PD-L1 (Programmed cell Death-1/Programmed cell Death-Ligand1) efficacy. However, no option is currently available to expand tumor specific TH1 lymphocytes in most patients. Then, investigators have identified four novel MHC (Major Histocompatibility Complex) class II-restricted peptides derived from human telomerase reverse transcriptase (TERT) referred as "Universal Cancer Peptides" (UCP). UCPVax is a therapeutic cancer vaccine developed by our team and composed of two separate peptides called UCP2 and UCP4 derived from telomerase. This UCPVax vaccine is currently evaluated in a multicenter phase I/II study in Non Small Lung Cancer (NSCLC) (NCT2818426) and seems to show to be safe and immunogenic. PD-1/PD-L1 immune checkpoint is a relevant candidate target for immunotherapy in HPV+ cancers, based on the prominent role of PD-1 and its ligand PD-L1 in HPV-driven immune-evasion. There is a strong rational of using PD-1 therapy in HPV+ cancers, however anti-PD-1/PD-L1 treatment induces a limited number of long term responses in HPV disease. Combining anti-PD-1/PD-L1 therapy with an antitumor vaccine gains serious consideration in HPV+ cancers. Indeed, anti-cancer vaccines can induce tumor-specific T cells expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. So investigators propose to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer vaccine (UCPVax) with atezolizumab in patients with HPV+ cancers by evaluation of the objective response rate at 4 months according to iRecist criteria.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of UCPVax Vaccine and Atezolizumab for the Treatment of Human Papillomavirus Positive Cancers (VolATIL)
  • Official Title: A Phase II Study Evaluating the Interest to Combine UCPVax a CD4 TH1-inducer Cancer Vaccine and Atezolizumab for the Treatment of Human PapillomaVirus Positive Cancers

Clinical Trial IDs

  • ORG STUDY ID: P/2019/418
  • NCT ID: NCT03946358

Conditions

  • Squamous Cell Carcinoma of the Head and Neck
  • Anal Canal Cancer
  • Cervical Cancer

Interventions

DrugSynonymsArms
Blood sample collectionAtezolizumab and UCPVax
Atezolizumabanti-PD-L1Atezolizumab and UCPVax
UCPVaxVaccineAtezolizumab and UCPVax

Purpose

70% all cases of cervical cancer, 95% of anal cancers and about 70% of oropharyngeal cancers are linked to Human Papillomavirus (HPV) infection. HPV oncogenic proteins are trans-activators of telomerase. Indeed, E6 oncoprotein transactivates the human telomerase (hTert). Our group has conducted a clinical trial (NCT02402842) in advanced squamous cell anal cancer (SCCA) and investigators have shown a correlation between the presence of anti-HPV immunity and anti-telomerase T helpher 1 (TH1) CD4 T cell responses, establishing telomerase as an appropriate antigen in HPV-related cancers. Tumor-reactive CD4+ T cells have been found to ensure efficient effector Cytotoxic T Lymphocytes (CTL) recruitment at the tumor site. Promoting tumor specific TH1 CD4 activation might be an attractive therapeutic option to enhance anti-PD-1/PD-L1 (Programmed cell Death-1/Programmed cell Death-Ligand1) efficacy. However, no option is currently available to expand tumor specific TH1 lymphocytes in most patients. Then, investigators have identified four novel MHC (Major Histocompatibility Complex) class II-restricted peptides derived from human telomerase reverse transcriptase (TERT) referred as "Universal Cancer Peptides" (UCP). UCPVax is a therapeutic cancer vaccine developed by our team and composed of two separate peptides called UCP2 and UCP4 derived from telomerase. This UCPVax vaccine is currently evaluated in a multicenter phase I/II study in Non Small Lung Cancer (NSCLC) (NCT2818426) and seems to show to be safe and immunogenic. PD-1/PD-L1 immune checkpoint is a relevant candidate target for immunotherapy in HPV+ cancers, based on the prominent role of PD-1 and its ligand PD-L1 in HPV-driven immune-evasion. There is a strong rational of using PD-1 therapy in HPV+ cancers, however anti-PD-1/PD-L1 treatment induces a limited number of long term responses in HPV disease. Combining anti-PD-1/PD-L1 therapy with an antitumor vaccine gains serious consideration in HPV+ cancers. Indeed, anti-cancer vaccines can induce tumor-specific T cells expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. So investigators propose to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer vaccine (UCPVax) with atezolizumab in patients with HPV+ cancers by evaluation of the objective response rate at 4 months according to iRecist criteria.

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab and UCPVaxExperimentalInduction phase: Atezolizumab 1200 mg intravenous (IV) every 3 weeks since day 1 UCPVax (combined with Montanide ISA51 as adjuvant) at 1 mg subcutaneously in two separate sites (one site per peptide) at day 1, 8, 15, 29, 36 and 43 (induction phase). Boost phase: UCPVax boosts vaccine every 6 weeks for the 2 first boosts (boost 1 and boost 2) and then every 9 weeks (boost 3 to boost 5) Atezolizumab 1200 mg IV every 3 weeks until disease progression or unacceptable toxicity until disease progression or unacceptable toxicity.
  • Blood sample collection
  • Atezolizumab
  • UCPVax

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent

          2. Histologically confirmed HPV+ cancers, defined by p16+ (IHC) or HPV genotyping,
             corresponding to one of the following selected squamous cell carcinoma types:

               -  Anal cancer

               -  Head and Neck carcinoma,

               -  cervical and vulvar carcinoma

          3. Locally advanced or metastatic disease

          4. Pre-treated with at least 1 line of anticancer standard treatment (chemotherapy,
             radiochemotherapy or targeted therapy…)

          5. Age ≥ 18 and ≤ 75 years old

          6. Measurable disease defined according to iRECIST v1.1 guidelines (Note: Previously
             irradiated lesions can be considered as measurable disease only if disease progression
             has been unequivocally documented at that site since radiation.)

          7. Patients must have a mandatory treatment-free interval of at least 21 days following
             previous systemic anti-cancer treatments

          8. Patients who have received previous systemic anticancer treatment and/or radiotherapy
             should have recovered from any treatment related toxicity, to a level of ≤ grade 1
             (according to National Cancer Institute [NCI] common terminology criteria for adverse
             events, version 5 (CTCAE v5) with the exception of Grade 2 alopecia

          9. Performance status < 2 (Annex 3)

         10. Availability of a pre-treatment tumor sample (archival FFPE [formalin-fixed
             paraffin-embedded] block) and presence of a tumor lesion suitable for a biopsy

         11. Patient affiliated to or beneficiary of French social security system

         12. Ability to comply with the study protocol, in the Investigator's judgment.

        Exclusion Criteria:

        Non-eligible to a clinical trial:

          1. Patients previously exposed to anti-tumor immunotherapy as anti-PD-1, anti-PD-L1, or
             anti-CTLA4 agent or any immune therapy. (HPV vaccination is allowed)

          2. Diagnosis of additional malignancy within 3 years prior to the inclusion with the
             exception of curatively treated basal cell carcinoma of the skin and/or curatively
             resected in situ cervical or breast cancer

          3. Patient with any medical or psychiatric condition or disease, which would make the
             patient inappropriate for entry into this study

          4. Current participation in a study of an investigational agent or in the period of
             exclusion

          5. Pregnancy, breast-feeding or absence/refusal of adequate contraception for fertile
             patients during the period of treatment and for 6 months from the last treatment
             administration

          6. Patient under guardianship, curatorship or under the protection of justice

             Cancer-specific exclusion criteria:

          7. Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula

          8. Uncontrolled tumor-related pain: exposing patients to risk of exposure to corticoids
             or iterative hospitalizations. Symptomatic lesions amenable to palliative radiotherapy
             should be treated prior to randomization. Patients should be recovered from the
             effects of radiation. There is no required minimum recovery period

          9. Known active central nervous system metastases and/or carcinomatous meningitis.
             Subject with previously treated brain metastases and with radiological and clinical
             stability are allowed

             Non-eligible to treatment:

         10. Inadequate organ functions: known cardiac failure of unstable coronaropathy,
             respiratory failure, or uncontrolled infection or another life-risk condition

         11. Active or chronic hepatitis B or C and/or HIV positive (HIV 1/2 antibodies patients),
             or a known history of active Tuberculosis bacillus

         12. Any immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or
             equivalent dose) within 14 days before the planned start of study therapy

         13. Active autoimmune disease that has required a systemic treatment in past 2 years (i.e.
             corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine,
             insulin) is allowed

             Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
             or multiple sclerosis, (see Annex 5 for a more comprehensive list of autoimmune
             diseases and immune deficiencies) with the following exceptions:

               -  Patients with a history of autoimmune-related hypothyroidism who are on thyroid
                  replacement hormone are eligible for the study,

               -  Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study,

               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are
                  excluded) are eligible for the study provided all of following conditions are
                  met:

                    1. Rash must cover < 10% of body surface area,

                    2. Disease is well controlled at baseline and requires only low-potency topical
                       corticosteroids,

                    3. No occurrence of acute exacerbations of the underlying condition requiring
                       psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
                       agents, oral calcineurin inhibitors, or high potency or oral corticosteroids
                       within the previous 12 months,

         14. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

         15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         16. Known hypersensitivity or allergy to Chinese hamster ovary cell products or any
             component of atezolizumab formulation

         17. History of idiopathic or secondary pulmonary fibrosis (History of radiation
             pneumonitis in the radiation field fibrosis is permitted), or evidence of active
             pneumonitis requiring a systemic treatment with 28 days before the planned start of
             study therapy

         18. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             course of the study

         19. Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia

         20. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
             urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
             eligible for the study

         21. Patients under chronic treatment with systemic corticoids or other immunosuppressive
             drugs (prednisone or prednisolone ≤ 10 mg/day is allowed) for a period of at least 4
             weeks and whose treatment was not stopped 1 week prior to the start of the study
             treatment

         22. Patient with intra-alveolar hemorrhage, pulmonary fibrosis, or uncontrolled asthma, or
             chronic obstructive disease (COPD), defined as at least 1 hospitalization within 4
             months prior to enrollment or as at least 3 exacerbations during the last year prior
             to enrollment

         23. Patients requiring oxygen therapy

         24. Patients with LEVF (Left Ejection Ventricular Fraction) <40%

         25. Hospitalization for cardiovascular or pulmonary disease within 4 weeks prior to
             enrollment.

         26. Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or
             anticipation that such a live, attenuated vaccine will be required during the study
             Note: Patients must agree not to receive live, attenuated influenza vaccine
             (e.g.,FluMist®) within 28 days prior to randomisation, during treatment or within 5
             months following the last dose of atezolizumab

         27. Inadequate hematology function: Lymphocyte count at baseline < 800/mm3 ; neutrophil
             count <1500/mm3, platelets <100000/mm3, Hemoglobin<9g/dL

         28. Inadequate hepatic function: bilirubin 2.5 fold ULN (upper limit of normal), AST/ALT
             (ASpartate Transaminase /ALanine Transaminase) 2.5 fold ULN or 5 fold ULN with liver
             metastasis, International normalized thromboplastin time ratio >1.5

         29. Inadequate renal function: MDRD (Modification of Diet in Renal Disease ) CrCl
             (Creatinine Clearance) <40ml/min

         30. Others inadequate laboratory values: serum albumin<30 g/L; troponin > ULN ; BNP
             (Brain-Type Natriuretic Peptide) > ULN.

         31. Active alcohol or drug abuse.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate at 4 months
Time Frame:4 months
Safety Issue:
Description:The main objective of this clinical trial is to assess the efficacy of a strategy combining UCPVax and atezolizumab treatment in patients with HPV+ cancer by evaluation of the objective response rate at 4 months according to iRecist.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:through study completion, an average of 2 years
Safety Issue:
Description:Delay from the date of inclusion to death from any cause
Measure:Progression free-survival
Time Frame:through study completion, an average of 2 years
Safety Issue:
Description:Delay from the date of inclusion to the disease progression or death from any cause whichever occurs first
Measure:Health related quality of life (HrQoL)
Time Frame:From to inclusion patient for maximum of 2 years
Safety Issue:
Description:HrQoL will be assessed using EORTC QLQ-C30

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Hospitalier Universitaire de Besancon

Trial Keywords

  • Human PapillomaVirus (HPV)
  • Atezolizumab
  • Cancer vaccine
  • Cancer immunotherapy
  • Telomerase

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