Ensayos clínicos

Inclusion Criteria:

• Signed written informed consent in accordance to ICH-GCP and national/local regulation before any protocol-related procedures that are not part of normal patient care (for phase II part 2: part of normal patient care can be: e.g. CT or MRI, biopsy, determination of HPV-16 positivity by specified central laboratory).
• Female or male patients, aged at least 18 years (no upper limit of age for phase Ib and phase II part 1), 18 to 80 years of age (for phase II part 2).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
• Life expectancy of at least 3 months 5. Patients with histologically or cytologically documented metastatic or refractory/recurrent HPV16+ cancer (determined in an accredited central laboratory using a validated assay).
• Phase Ib and Phase II part 1: Patients with HPV-16+ cancers including oropharyngeal squamous cell carcinoma of the head and neck (SCCHN), cervical, vulvar, vaginal, penile, and anal cancer Phase II part 2: Patients with HPV-16+ cancers including cervical, vulvar, vaginal, penile, and anal cancer Disease MUST not be amenable to curative surgery resection or curative radiotherapy with documented disease progression after concertation with multidisciplinary board. 
• Phase Ib and Phase II part 1:
  • Patients MAY have received up to two prior lines of systemic chemotherapy for the management of metastatic or recurrent disease; for SCCHN, patients MUST have previously been exposed to platinum-based therapy, either as part of definitive chemo-radiation OR as first line systemic treatment for metastatic disease which may include cetuximab. Patients with recurrence/ progression within 6 months of prior multimodal therapy using platinum-based therapy are eligible.
  • Patients with cervical cancer may have undergone surgery and/or received definitive radiation or chemo-radiation therapy for localized disease.
  • Patients MUST have been exposed to platinum–based chemotherapy for metastatic disease which may include bevacizumab.
• Patients with platinum-refractory disease will be eligible Phase II part 2:
  • For recurrent/metastatic disease no more than one prior line of chemotherapy which can contain a platinum - Prior treatment for recurrent or metastatic disease is not required for:
  • Patients with recurrence/ progression within 6 months after completion of prior multimodal therapy for localized or locally advanced disease not amenable to curative treatment o Patients who are unsuitable for platinum-based therapy o Patients who refuse chemotherapy or other standard therapies for the treatment of metastatic or recurrent disease. The benefit of an immunotherapy over standard therapies must be validated by the medical board and duly documented. A minimum of 4 weeks interval should have elapsed between the completion of the last chemotherapy and study treatment start A minimum of 4 weeks interval between palliative bone directed radiotherapy and the start of the study treatment provided that radiation therapy does not affect the unique measurable lesion, if applicable.
• Phase II part 2: For patients with hepatic metastases - no more than 3 hepatic lesions in total (target and non-target lesions) - maximum size of hepatic target disease ≤ 30 mm according to RECIST 1.1.
• Phase Ib and Phase II part 1: Availability of tumor tissue from biopsy: at least 2 fresh tumor tissue samples are to be collected. Tumor tissue may come either from the local tumor or distant metastasis. Cytological material is not accepted Phase II part 2:
• Availability of archived or fresh tumor tissue for the determination of HPV-16 positivity. Patients must agree to undergo a core or excisional biopsy of a tumor lesion not previously irradiated (at least 2 fresh tissue samples to be collected). An archival sample obtained within one year prior to randomization is acceptable only if tumor is not accessible. Tumor tissue may come either from the local tumor or distant metastasis. Fine needle aspirates and bone biopsies are not adequate.
• At least one measurable lesion by CT scan according to RECIST 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy. 
• Adequate hematological, hepatic and renal function:
  • Hemoglobin ≥ 9.0 g/dL (for phase II part 2: without packed red blood cell transfusion within the prior 3 weeks);
  • Neutrophils ≥ 1.5x10^9 /L;
  • Total lymphocytes count ≥ 0.4x10^9 /L;
  • CD4 + ≥ 200 / µL;
  • Platelets count ≥ 100x10^9 /L.
  • Total bilirubin ≤ 1.5 x ULN;
  • Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) ≤ 3 x ULN;
  • Glomerular Filtration Rate ≥ 50 mL/min (according to Modification of the Diet in Renal Disease (MDRD) formula or Cockroft & Gault formula);
  • Serum albumin ≥ 30 g/L.
• Negative blood pregnancy test at screening for women of childbearing potential.
• Highly effective contraception (i.e., methods with a failure rate of less than 1% per year) during the study period and for 3 months after the last study treatment administration for female patients of childbearing potential (WOCBP) and for male patients who are sexually active with WOCBP. Highly effective contraception methods are defined as:
  • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, intrauterine devices (IUDs) such as Mirena and Nonhormonal IUDs such as ParaGard for WOCBP patient or male patient’s WOCBP partner;
  • Tubal ligation;
  • Vasectomy In addition to highly effective contraception, participating male patients;
  • must use a condom during the study period and for 3 months after the last study treatment administration when engaging in any activity that allows for exposure to ejaculate;
  • must refrain from donating sperm.

Exclusion Criteria:

• Prior exposure to cancer immunotherapy including cancer vaccines, any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD-L1, anti-PD-1, or anticytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody 2.
  • Concurrent anticancer treatment within 28 days before the start of study treatment (e.g., chemotherapy, radiotherapy or cytokine therapy except erythropoietin);
  • Recurrent drainage procedures (once monthly or more frequently) for pleural effusion, pericardial effusion, or ascites 3. Major surgery within 28 days before the start of study treatment.
• Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to the first study treatment, with the exception of patients with adrenal insufficiency who may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
• Patients with central nervous system (CNS) metastases except those meeting the following criteria:
  • Brain metastases that have been treated locally and are clinically stable during 4 weeks prior to start of study treatment;
  • No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable).
• Other active malignancy requiring concurrent systemic intervention.
• Patients with previous malignancies other than the target malignancy to be investigated in this trial (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period  
• Patient with any organ transplantation, including allogeneic stem cell transplantation.
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTC V4.03 or V5.0 for phase II part 2), any history of anaphylaxis, or uncontrolled asthma.
• Any known allergy or reaction to eggs, gentamycin or attributed to compounds of similar chemical or biological composition to therapeutic vaccines/immunotherapeutic products . Any known allergy or reaction to any component of anti-PD-L1/PD-1 or its excipients.
• Patients with history of interstitial lung disease (phase Ib and phase II part 1).
• Patients with known history or any evidence of active interstitial lung disease / pneumonitis (phase II part 2).
•  Administration of a live vaccine within 28 days prior to the start of the study treatment.
• Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment.
• Patients with active, known, or suspected auto-immune disease or immunodeficiency, except type I diabetes mellitus, hypothyroidism only requiring hormone replacement or skin disorders (such as vitiligo, psoriasis) not requiring systemic treatment.
• Significant chronic or acute infectionsincluding infection with mpox and SARS-CoV-2 (COVID19) PCR positive testing.
• Positive serology for Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) or presence in the serum of the Hepatitis B surface antigens (HBsAg), at Baseline.
• Persisting toxicity related to prior therapy of Grade ≥ 2 NCI-CTCAE v4.03 or v5.0 for phase II part 2 (except neuropathy [see exclusion criterion below] and alopecia).
• Neuropathy ≥ Grade 3.
• Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction (< 6 months prior to enrollment), unstable angina pectoris, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication/active intervention, history of myocarditis (history of myocarditis for phase II part 2).
• Patient with any underlying medical condition that the treating physician considers might be aggravated by treatment or might impair the patient’s tolerance to study treatment.
• History of uncontrolled intercurrent illness including but not limited to:
  • Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or lower);
  • Uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%);
  • Uncontrolled infection (phase II part 2).
• Patients with pulse oximetry of less than 92% on room air (phase II part 2).
• Any psychological, familiar, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL).

Eligibility last updated 7/13/23. Questions regarding updates should be directed to the study team contact.