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

NCT03946358 | Completed Phase 2 DMC

• 1 other identifier: P/2019/418
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 4

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Objective response rate at 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.

  4 months

Secondary Outcomes (4)

• Overall survival

  through study completion, an average of 2 years

• Progression free-survival

  through study completion, an average of 2 years

• Health related quality of life (HrQoL)

  From to inclusion patient for maximum of 2 years

• Safety of UCPVax in association with anti-PD-L1

  From to inclusion patient for maximum of 2 years

Study Arms (1)

Atezolizumab and UCPVax

EXPERIMENTAL

Induction 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.

Biological: Blood sample collection; Procedure: Tumor biopsies; Other: CT scan; Drug: Atezolizumab; Drug: UCPVax

Interventions

Blood sample collection BIOLOGICAL

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.

Atezolizumab and UCPVax

Tumor biopsies PROCEDURE

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

Atezolizumab and UCPVax

CT scan OTHER

A CT scan will be planned * at baseline * at tumor evaluation visit (8 weeks) * every 8 weeks (+/- 1 week) * at end of treatment visit.

Atezolizumab and UCPVax

Atezolizumab DRUG

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.

Also known as: anti-PD-L1

Atezolizumab and UCPVax

UCPVax DRUG

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).

Also known as: Vaccine

Atezolizumab and UCPVax

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• 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
• Locally advanced or metastatic disease
• Pre-treated with at least 1 line of anticancer standard treatment (chemotherapy, radiochemotherapy or targeted therapy…)
• Age ≥ 18 and ≤ 75 years old
• 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.)
• Patients must have a mandatory treatment-free interval of at least 21 days following previous systemic anti-cancer treatments
• 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
• Performance status \< 2 (Annex 3)
• Availability of a pre-treatment tumor sample (archival FFPE \[formalin-fixed paraffin-embedded\] block) and presence of a tumor lesion suitable for a biopsy
• Patient affiliated to or beneficiary of French social security system
• Ability to comply with the study protocol, in the Investigator's judgment.

You may not qualify if:

• Non-eligible to a clinical trial:
• 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)
• Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study
• 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
• Patient under guardianship, curatorship or under the protection of justice
• Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula
• 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
• 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:
• Inadequate organ functions: known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition
• Active or chronic hepatitis B or C and/or HIV positive (HIV 1/2 antibodies patients), or a known history of active Tuberculosis bacillus
• Any immunosuppressive therapy (i.e. corticosteroids \>10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy
• 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,

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Besancon: lead
• Roche Pharma AG: collaborator
• National Cancer Institute, France: collaborator

Study Sites (4)

CHU de Besançon

Besançon, France

Location

Centre Georges François Leclerc

Dijon, France

Location

Centre Léon Bérard

Lyon, 69000, France

Location

Hospices Civils de Lyon

Lyon, 69000, France

Location

Related Publications (5)

• Kim S, Francois E, Andre T, Samalin E, Jary M, El Hajbi F, Baba-Hamed N, Pernot S, Kaminsky MC, Bouche O, Desrame J, Zoubir M, Ghiringhelli F, Parzy A, De La Fouchardiere C, Smith D, Deberne M, Spehner L, Badet N, Adotevi O, Anota A, Meurisse A, Vernerey D, Taieb J, Vendrely V, Buecher B, Borg C. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2018 Aug;19(8):1094-1106. doi: 10.1016/S1470-2045(18)30321-8. Epub 2018 Jul 2.

  PMID: 30042063 BACKGROUND

• Godet Y, Fabre E, Dosset M, Lamuraglia M, Levionnois E, Ravel P, Benhamouda N, Cazes A, Le Pimpec-Barthes F, Gaugler B, Langlade-Demoyen P, Pivot X, Saas P, Maillere B, Tartour E, Borg C, Adotevi O. Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase-derived epitopes: potential synergistic effect with chemotherapy response. Clin Cancer Res. 2012 May 15;18(10):2943-53. doi: 10.1158/1078-0432.CCR-11-3185. Epub 2012 Mar 8.

  PMID: 22407833 BACKGROUND

• Dosset M, Godet Y, Vauchy C, Beziaud L, Lone YC, Sedlik C, Liard C, Levionnois E, Clerc B, Sandoval F, Daguindau E, Wain-Hobson S, Tartour E, Langlade-Demoyen P, Borg C, Adotevi O. Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. Clin Cancer Res. 2012 Nov 15;18(22):6284-95. doi: 10.1158/1078-0432.CCR-12-0896. Epub 2012 Oct 2.

  PMID: 23032748 BACKGROUND

• Dosset M, Vauchy C, Beziaud L, Adotevi O, Godet Y. Universal tumor-reactive helper peptides from telomerase as new tools for anticancer vaccination. Oncoimmunology. 2013 Mar 1;2(3):e23430. doi: 10.4161/onci.23430.

  PMID: 23802085 BACKGROUND

• Rebucci-Peixoto M, Vienot A, Adotevi O, Jacquin M, Ghiringhelli F, de la Fouchardiere C, You B, Maurina T, Kalbacher E, Bazan F, Meynard G, Clairet AL, Fagnoni-Legat C, Spehner L, Bouard A, Vernerey D, Meurisse A, Kim S, Borg C, Mansi L. A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study. Front Oncol. 2022 Jul 19;12:957580. doi: 10.3389/fonc.2022.957580. eCollection 2022.

  PMID: 35928870 DERIVED

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Anal Canal Carcinoma; Uterine Cervical Neoplasms

Interventions

atezolizumab; Vaccines

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Biological Products; Complex Mixtures

Study Officials

• Christophe BORG, Pr

  CHU Besançon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 10, 2019
• Study Start: February 18, 2020
• Primary Completion: March 1, 2024
• Study Completion: November 1, 2024
• Last Updated: December 20, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4)