Squamous Cell Carcinoma of the Head and Neck, Anal Canal Cancer, Cervical Cancer
Conditions
Keywords
Human PapillomaVirus (HPV), Atezolizumab, Cancer vaccine, Cancer immunotherapy, Telomerase
Brief summary
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.
Interventions
BIOLOGICALBlood sample collection
Four blood samples will be collected at: * baseline * 2 months from inclusion (+/- 1 week) * 4 months from inclusion (+/- 1 week) * the end of vaccination visit (+/- 1 week). A total of 8 EDTA (ethylenediaminetetraacetic acid) tubes of 6 ml will be collected at each time point to perform: PBMC collection: 6 EDTA tubes of 6 ml of peripheral blood mononuclear cell \[PBMC\] will be sent to the central laboratory (Biomonitoring Platform of Besançon, CHRU de Besançon located at Etablissement Français du Sang) at room temperature within 24 hours via an approved carrier for their processing, storage and immunomonitoring analysis. A sending sheet of the samples will be attached to each single sample. Plasma collection: One 6 ml EDTA tube should be frozen in each investigation center for plasma collection. Plasma for circulating tumoral DNA (ctDNA) collection: One 6 ml EDTA tube should be frozen in each investigation center for ctDNA collection.
PROCEDURETumor biopsies
A tumor biopsy will be realized and centralized at baseline and at 2 months. Collection of tumor biopsies will be guided by ultrasound or CT scan
OTHERCT scan
A CT scan will be planned * at baseline * at tumor evaluation visit (8 weeks) * every 8 weeks (+/- 1 week) * at end of treatment visit.
DRUGAtezolizumab
Induction phase: Atezolizumab 1200 mg intravenous every 3 weeks since day 1 Boost phase: Atezolizumab 1200 mg intravenous every 3 weeks until disease progression or unacceptable toxicity until disease progression or unacceptable toxicity.
DRUGUCPVax
Induction phase: 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).
Sponsors
Roche Pharma AG
National Cancer Institute, France
Centre Hospitalier Universitaire de Besancon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate at 4 months | 4 months | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | through study completion, an average of 2 years | Delay from the date of inclusion to death from any cause |
| Progression free-survival | through study completion, an average of 2 years | Delay from the date of inclusion to the disease progression or death from any cause whichever occurs first |
| Health related quality of life (HrQoL) | From to inclusion patient for maximum of 2 years | Health related quality of life will be assessed using EORTC (European Organisation for Research and Treatment of Cancer) questionnaire |
| Safety of UCPVax in association with anti-PD-L1 | From to inclusion patient for maximum of 2 years | Toxicities graded according to NCI-CTCAE criteria version 5 |
Countries
France
Outcome results
None listed