Efficacy and Safety of VB10.16 Alone or in Combination With Atezolizumab in Patients With Advanced Cervical Cancer.

Study Overview
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Brief Summary
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This is a multi-center study in patients with recurrent or metastatic HPV16-positive, PD-L1 positive cervical cancer who has progressed during or after treatment with the first-line standard of care (pembrolizumab with chemotherapy with/without bevacizumab). The trial is designed to investigate VB10.16 alone or in combination with the immune checkpoint inhibitor, atezolizumab. The trial consist of 2 parts: the first part which investigates VB10.16 + placebo versus VB10.16 + atezolizumab. Approximately 30 patients will be included in each group. The goal of this part is to evaluate which of the two treatments is the best. The second part of the study will select the best treatment from part 1 and investigate the safety and efficacy of additional 70 patients.

Detailed Description
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This is a two-arm randomized, double-blind, placebo-controlled phase 2 selection trial to evaluate the efficacy and safety of VB10.16 alone or in combination with atezolizumab in patients with HPV16-positive, PD-L1-positive, recurrent or metastatic cervical cancer who are refractory to pembrolizumab with chemotherapy with/without bevacizumab. A selection design with a margin of practical equivalence will be implemented to monitor efficacy of the two experimental arms (VB10.16 + atezolizumab vs. VB10.16 + placebo). The trial consist of 2 parts: the first part which investigates VB10.16 + placebo versus VB10.16 + atezolizumab. Approximately 30 patients will be included in each group. The goal of this part is to evaluate which of the two treatments is the superior. The second part of the study will select the superior treatment from part 1 and investigate the safety and efficacy of additional 70 patients.

Official Title
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A Two-Arm Randomized, Double-Blind, Placebo-Controlled Phase 2 Selection Trial to Evaluate the Efficacy and Safety of VB10.16 Alone or in Combination With Atezolizumab in Patients With HPV16-Positive, PD-L1-positive, Recurrent or Metastatic Cervical Cancer Who Are Refractory to Pembrolizumab With Chemotherapy With/Without Bevacizumab.

Conditions
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HPV-Related Cervical Carcinoma, HPV-Related Malignancy, Cervical Cancer

Intervention / Treatment
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* Biological: VB10.16
* Drug: Atezolizumab Injection [Tecentriq]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥18 years at ICF signature date. Persistent recurrent or metastatic (R/M) (stage IVB) PD-L1 positive cervical cancer with squamous cell, adenocarcinoma or adenosquamous histology with confirmed disease progression during or after treatment with 1st line systemic standard of care pembrolizumab + platinum-containing chemotherapy +/- bevacizumab Participants should have received at least 4 cycles of pembrolizumab. Planned treatment start should be within 12 weeks of documented radiographic disease progression. Participants should have received no more than 1 prior systemic anti-cancer treatment regimen for recurrent/metastatic cervical cancer (pembrolizumab + chemotherapy +/- bevacizumab). PD-L1-positive tumor confirmed by Ventana SP263 clone (the Food and Drug Administration approved companion diagnostic test for atezolizumab in other indications), with tumor area positivity ≥5% in designated central laboratory HPV16-positive tumor confirmed by nucleic acid amplification test in designated central laboratory At least 1 measurable lesion per RECIST v1.1 as assessed by Blinded Independent Central Review. Overall function and organ function: ECOG performance status (PS) ≤1 Gustave Roussy Immune (GRIm) score ≤1 Key Exclusion Criteria: Disease specific: Has disease that is suitable for local therapy with curative intent. Rapidly progressing disease (e.g., tumor bleeding, uncontrolled tumor pain) in the opinion of the investigator. Neuroendocrine carcinoma of the cervix. Prior, concurrent or future interventions: Radiotherapy (or other non-systemic therapy) ≤14 days prior to VB10.16 treatment start, or the patient has not fully recovered (i.e., Grade ≤1 at baseline) from AEs due to a previously administered treatment. Has received prior surgery or prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment. Prior solid organ or tissue transplantation (except corneal transplant). Prior autologous or allogeneic hematopoietic stem cell transplantation. Prior chimeric antigen receptor T-cell (CAR-T) therapy. Prior therapy with a monoclonal antibody, bispecific antibody, or antibody fragment (or other molecule with similar mechanism of action) that engages with stimulatory or co-inhibitory molecules on T cells (e.g., CD3, CTLA-4, PD-1, 4-1BB/CD137), except pembrolizumab in the metastatic setting. Prior therapy with CPI in the locally advanced setting. Prior administration with tisotumab vedotin. Administration of a live (attenuated replicating organism) or non-live (pathogen component or killed whole organism) vaccine, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine within 30 days prior to VB10.16 treatment start. Prior administration with a therapeutic HPV16 vaccine. Prior severe hypersensitivity (≥ grade 3) to atezolizumab and/or any of its excipients. Prior persistent toxicities (≥ grade 3) related to pembrolizumab administration. Participants receiving systemic immunosuppression with immunosuppressive agents such as cyclosporine, azathioprine, methotrexate, or tumor necrosis factor alpha blockers for any concurrent condition. Chronic administration of systemic corticosteroids: prednisone >10 mg daily (or dose equivalent) or an average cumulative dose of >140 mg prednisone (or dose equivalent) within the last 14 consecutive days prior to VB10.16 treatment start. Any planned major surgery. Prior or concurrent morbidity: Malignancy: Past or current malignancy other than inclusion diagnosis, except for: Noninvasive basal cell or squamous cell skin carcinoma. Noninvasive, superficial bladder cancer. Ductal carcinoma in situ. Any curable cancer with a complete response of >2 years' duration.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A modified randomized phase 2 selection ('pick-the-winner') design with a margin of practical equivalence will be implemented to monitor efficacy of the two individual arms, and to decide which of the two arms that may be continued further based on the primary endpoint of confirmed ORR.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VB10.16 + placebo<br>9 mg VB10.16 via i.m. needle free injections in the deltoid muscles and quadricep or gluteus muscle. Placebo will be given via IV infusions. | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 49. A total of up to 11 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Placebo<br>* Intravenous (IV) infusions of placebo (saline solution) every 3 weeks.<br>|
| Experimental: VB10.16 + atezolizumab<br>9 mg VB10.16 via i.m. needle free injections in the deltoid muscles and quadricep or gluteus muscle. Atezolizumab will be given via IV infusions. | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 49. A total of up to 11 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Atezolizumab Injection [Tecentriq]<br>* Intravenous (IV) infusions of atezolizumab (saline solution) every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1 as assessed by blinded independent central review (BICR). | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1 as assessed by the investigator. | Up to approximately 2 year | 
| Duration of Response (DOR) | Duration of response (DOR) based upon RECIST v1.1 assessed by BICR. DOR is defined as time from the date of first documented response of confirmed CR or PR to the date of the first documented progression or death due to any cause, whichever occur first. | Up to approximately 2 years | 
| Duration of Response (DOR) | Duration of response (DOR) based upon RECIST v1.1 assessed by the investigator. DOR is defined as time from the date of first documented response of confirmed CR or PR to the date of the first documented progression or death due to any cause, whichever occur first. | Up to approximately 2 years | 
| Time to Response (TTR) | Time to response (TTR) based upon RECIST v1.1 assessed by BICR. TTR is defined as the time from VB10.16 treatment start date to the date of first documented response of either confirmed CR or confirmed PR. | Up to approximately 2 years | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR) based upon RECIST v1.1 assessed by BICR. DCR is defined as the proportion of patients who have either confirmed CR, confirmed PR, or SD as best overall response. | Up to approximately 2 years | 
| Duration of Disease Control (DODC) | Duration of disease control (DODC) based upon RECIST v1.1 assessed by BICR. DODC is defined as time from the date of first documented response of confirmed CR, confirmed PR or SD to the date of the first documented progression or death due to any cause. | Up to approximately 2 years | 
| Progression Free Survival (PFS) | Progression-free survival (PFS) as assessed by BICR. PFS is defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first. | Up to approximately 2 years | 
| Progression Free Survival (PFS) | Progression-free survival (PFS) as assessed by the investigator. PFS is defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first. | Up to approximately 2 years | 
| Overall survival (OS) | Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause. | Up to approximately 2 years | 
| Minimal Response | Proportion of participants with tumor shrinkage ≥10.0% to <30% assessed by BICR. | Up to approximately 2 years | 
| Proportion of participants who are Progression-free | Proportion of participants who are progression-free and alive based upon RECIST v1.1 assessed by BICR. | 26 weeks | 
| Proportion of participants who are Progression-free | Proportion of participants who are progression-free and alive based upon RECIST v1.1 assessed by BICR. | 52 weeks | 
| Proportion of participants who are Progression-free | Proportion of participants who are progression-free and alive based upon RECIST v1.1 assessed by BICR. | 104 weeks | 
| Proportion of participants who are alive. | Proportion of participants who are alive. | 26 weeks | 
| Proportion of participants who are alive. | Proportion of participants who are alive. | 52 weeks | 
| Proportion of participants who are alive. | Proportion of participants who are alive. | 104 weeks | 
| Molecular Response | Proportion of participants with molecular response defined as ≥30% decrease from baseline in HPV16 ctDNA. | Up to week 52 | 
| Molecular Response | Proportion of participants with molecular response defined as ≥50% decrease from baseline in HPV16 ctDNA. | Up to week 52 | 
| Proportion of participants with treatment emergent adverse events | Proportion of participants with treatment-emergent adverse events (TEAEs) by severity grade. | Up to week 104 | 
| Proportion of participants with treatment-emergent serious adverse events | Proportion of participants with treatment-emergent serious adverse events | Up to week 104 | 
| Proportion of participants with drug related toxicity | Proportion of participants with drug-related toxicity of CTCAE grade ≥3 | Up to week 104 | 
| Proportion of participants with discontinuation | Proportion of participants discontinuing treatment due to an adverse reaction. | Up to week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent, metastatic, HPV16-positive, PD-L1 positive