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

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.

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.

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.

Key Inclusion Criteria:

1. Age ≥18 years at ICF signature date.

2. 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

   1. Participants should have received at least 4 cycles of pembrolizumab.
   2. Planned treatment start should be within 12 weeks of documented radiographic disease progression.
   3. Participants should have received no more than 1 prior systemic anti-cancer treatment regimen for recurrent/metastatic cervical cancer (pembrolizumab + chemotherapy +/- bevacizumab).

3. 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

4. HPV16-positive tumor confirmed by nucleic acid amplification test in designated central laboratory

5. At least 1 measurable lesion per RECIST v1.1 as assessed by Blinded Independent Central Review.

   Overall function and organ function:

6. ECOG performance status (PS) ≤1

7. Gustave Roussy Immune (GRIm) score ≤1

Key Exclusion Criteria:

Disease specific:

1. Has disease that is suitable for local therapy with curative intent.

2. Rapidly progressing disease (e.g., tumor bleeding, uncontrolled tumor pain) in the opinion of the investigator.

3. Neuroendocrine carcinoma of the cervix.

   Prior, concurrent or future interventions:

4. 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.

5. Has received prior surgery or prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment.

6. Prior solid organ or tissue transplantation (except corneal transplant).

7. Prior autologous or allogeneic hematopoietic stem cell transplantation.

8. Prior chimeric antigen receptor T-cell (CAR-T) therapy.

9. 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.

10. Prior therapy with CPI in the locally advanced setting.

11. Prior administration with tisotumab vedotin.

12. 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.

13. Prior administration with a therapeutic HPV16 vaccine.

14. Prior severe hypersensitivity (≥ grade 3) to atezolizumab and/or any of its excipients.

15. Prior persistent toxicities (≥ grade 3) related to pembrolizumab administration.

16. Participants receiving systemic immunosuppression with immunosuppressive agents such as cyclosporine, azathioprine, methotrexate, or tumor necrosis factor alpha blockers for any concurrent condition.

17. 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.

18. Any planned major surgery.

    Prior or concurrent morbidity:

    Malignancy:

19. Past or current malignancy other than inclusion diagnosis, except for:

    1. Noninvasive basal cell or squamous cell skin carcinoma.
    2. Noninvasive, superficial bladder cancer.
    3. Ductal carcinoma in situ.
    4. Any curable cancer with a complete response of >2 years' duration.