A Vaccine (PDS0101) and Chemoradiation for the Treatment of Stage IB3-IVA Cervical Cancer, the IMMUNOCERV Trial

PRIMARY OBJECTIVE:

I. Evaluate the safety and toxicity profile of delivering the immune nanoparticle liposomal HPV-16 E6/E7 multipeptide vaccine PDS0101 (PDS0101) with standard-of-care chemoradiation (chemoRT) in patients with locally advanced cervical cancer.

SECONDARY OBJECTIVES:

I. Rate of complete metabolic response on day 170 (+/- 14 days) positron emission tomography computed tomography (PET CT).

II. Rate of >= 90% gross tumor volume reduction day 35 magnetic resonance imaging (MRI) (+/- 5 days).

III. Report rates of local control (LC), progression-free survival (PFS), and overall survival (OS) at 12 and 18 months following chemoRT completion.

IV. Long-term safety: rate of grade >= 3 chronic toxicity (from day 81 to completion of trial).

EXPLORATORY HPV-SPECIFIC IMMUNE RESPONSE OBJECTIVES:

I. Enzyme-linked immunosorbent spot (ELISpot) assays on interferon-gamma and granzyme B levels in E6/7-specific T cells isolated from peripheral blood mononuclear cells (PBMCs).

II. Compare intratumoral T-cell receptor (TCR) clonality at baseline and end of treatment by TCR sequencing.

III. Measure CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from cervical brush samples by using markers of T-cell exhaustion (PD1, CTLA4) and T cell-activation (granzyme B, CD69+).

IV. Assess the intestinal and cervical microbiome by analyzing rectal and cervical swab samples with 16s ribosomal ribonucleic acid (rRNA) sequencing.

V. Additional assays such as circulating tumor cells, circulating cell-free tumor deoxyribonucleic acid (DNA) (ccfDNA), and other assays will be performed at the discretion of the principal investigator.

OUTLINE:

Patients undergo radiation therapy over 1 hour 5 days per week (Monday-Friday) for 5-7 weeks and receive cisplatin intravenously (IV) over 4 hours once per week (QW) during the 5 weeks of radiation therapy in the absence of disease progression and unacceptable toxicity. Patients also receive PDS0101 subcutaneously (SC) on days -10, 7, 28, 49, and 170 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 1, 4, 6, 12, and 18 weeks, and 18 months.

Inclusion criteria

• Age 18 years or older
• Newly diagnosed locally advanced squamous cell carcinoma of cervix (FIGO 2018 stage IB3-IVA with primary tumor ≥ 5 cm and/or positive pelvic or periaortic nodal disease assessed by imaging).
• Histologic diagnosis of squamous cell carcinoma of the cervix.
• Written informed consent before initiation of any study-related procedures;
• WHO/ECOG performance status 0-2.
• Adequate liver (ALT, AST, Alk Phos and total Bili ≤ 2-fold the upper limit of normal), and renal functions (Creatinine ≤ 1.5).
• Absence of current malignancies at other sites, except for adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors who have undergone potentially curative therapy for a prior malignancy who have no evidence of that disease for 5 years and who are deemed at low risk for recurrence are eligible for the study

Exclusion criteria

• HIV infection, cellular immune deficiencies, hypogammaglobulinemia or dysgammaglobulinemia, or hereditary or congenital immunodeficiencies
• Prior diagnosis of hepatitis B or C (unless anti-hepatitis C therapy has produced a sustained virologic response);
• History of clinically significant autoimmune disease, Crohn's disease, or ulcerative colitis
• Serious concomitant disorder, including active systemic infection requiring treatment, as judged by the Investigator.
• Receipt of immunotherapy (e.g., IFNs, check-point inhibitors, tumor necrosis factor, interleukins, etc.) or biological response modifiers (GM-CSF, granulocyte colony-stimulating factor, macrophage colony-stimulating factor) within 4 weeks before the first study vaccination.
• Receipt of chronic systemic steroid therapy (in dosing exceeding 10mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

• Current or recent use of physiologic doses of intra-articular, topical, or inhaled corticosteroids is acceptable.
• History of previous therapeutic HPV vaccination (individuals who have been immunized with licensed prophylactic HPV vaccines [e.g., Silgard®, Cervarix®, Gardasil®] are not excluded)
• Known or suspected hypersensitivity to any component of the investigational product or contraindications to cisplatin (e.g., peripheral neuropathy grade ≤ 2 or ototoxicity ≤grade 2 per CTCAE v5.0)
• Previous pelvic RT.
• Previous chemotherapy for the cervix tumor
• Previous hysterectomy or will have a hysterectomy as part of their initial cervical cancer therapy
• Prior major surgery within 4 weeks of enrollment from which the patient has not recovered
• Other condition or prior therapy that, in the opinion of the Investigator, compromises the subject's welfare or may confound study results
• Concurrent participation in another therapeutic investigational study or use of another investigational drug within 6 months before the first study vaccination
• Previous enrollment in this study
• HPV genotyping is to be done from cervical swab samples. Enrollment will not require HPV testing.
• Pregnancy: a female subject defined as a WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.