Evaluation of TG4001 and Avelumab in HPV-16 Positive Recurrent or Metastatic Malignancies: A Phase Ib/II Clinical Trial
- Trial ID
- 2024-515119-23-00
- Protocol
- TG4001.12
- Sponsor
- Transgene
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of the combination of TG4001 and avelumab in patients with recurrent or metastatic HPV-16 positive advanced malignancies. This is crucial for determining the feasibility of this combination therapy in a clinical setting, ensuring that it does not pose undue risk to patients. Additionally, the study aims to assess the efficacy of this combination in terms of Overall Response Rate (ORR) using RECIST 1.1 criteria, and to compare the Progression-Free Survival (PFS) of TG4001 combined with avelumab versus avelumab alone in patients without liver metastases at baseline. These efficacy measures are vital for understanding the potential clinical benefits of the treatment.
Secondary objectives include evaluating the combination of TG4001 and avelumab with respect to: - Overall Response Rate (ORR) using RECIST 1.1 in both phase Ib and phase II part 2. - Progression-Free Survival (PFS) in phase Ib and phase II part 1. - Overall Survival (OS). - Duration of Response (DoR). - Disease Control Rate (DCR). - Safety profile in phase II. - Percentage of patients with liver metastases at baseline who experience disease progression at day 43 in phase II part 2.
Participants
The clinical trial involves **participants** with **HPV-16 positive recurrent or metastatic malignancies**, including cervical, vulvar, vaginal, penile, anal cancers, and oropharyngeal squamous cell carcinoma of the head and neck. The study population comprises both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals with a life expectancy of at least three months and requires adequate hematological, hepatic, and renal function. The sponsor has not provided the total number of participants. The selection criteria include patients whose disease is not amenable to curative surgery or radiotherapy and who have documented disease progression. Participants may have received prior systemic chemotherapy, with specific conditions based on the phase of the trial. The trial population includes a vulnerable population, and lifestyle considerations such as effective contraception are mandated for participants at risk of conception during the study period and for three months after the last treatment administration.
Plans and Procedures
The clinical trial is designed to evaluate the combination of **TG4001** and **avelumab** in patients with **HPV-16 positive recurrent or metastatic malignancies**. This study is structured as a Phase Ib/II trial, incorporating a randomized, double-blind, controlled methodology. The trial is expected to span from September 2017 to December 2026, with participant involvement anticipated to last for the duration of their treatment cycles, which may vary based on individual response and disease progression.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, **ECOG performance status**, and prior treatment history. The screening will include a negative blood pregnancy test for women of childbearing potential and confirmation of adequate hematological, hepatic, and renal function. Following successful screening, participants will be enrolled in the trial and randomized to receive either the combination therapy or avelumab alone, depending on the phase of the study.
Subsequent follow-up visits will be scheduled to monitor safety, tolerability, and efficacy, with assessments conducted using **RECIST 1.1** criteria. These visits will include evaluations of overall response rate, progression-free survival, and overall survival. The end-of-study visit will occur upon completion of the treatment regimen or in the event of disease progression, unacceptable toxicity, or withdrawal of consent. Conditions that may lead to early termination from the study include significant adverse events or non-compliance with study protocols.
The primary endpoints of the trial focus on safety and tolerability in Phase Ib, overall response rate in Phase II part 1, and progression-free survival in Phase II part 2. Secondary endpoints include overall survival, duration of response, and the overall safety profile. The trial aims to provide comprehensive data on the efficacy and safety of the combination therapy in the specified patient population.
Treatment
The clinical trial involves the administration of **Bavencio**, a pharmaceutical product containing the active substance **avelumab**. Bavencio is provided as a 20 mg/mL concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The administration schedule involves a specific dosage and frequency, which are determined based on the trial protocol. Avelumab is a recombinant human monoclonal IgG1 antibody targeting the programmed death ligand-1 (PD-L1), and it is produced by Merck Europe B.V. The trial aims to evaluate the safety, tolerability, and efficacy of Bavencio in combination with other treatments in patients with HPV-16 positive recurrent or metastatic malignancies.
Another experimental treatment used in the trial is **TG4001**, which contains the active substance **tipapkinogene sovacivec**. TG4001 is formulated as a solution for injection and is administered via the **subcutaneous route**. The active substance is a recombinant attenuated Vaccinia virus (MVA) containing sequences coding for modified forms of the HPV16 proteins E6 and E7, as well as the cytokine human interleukin-2 (hIL2). This product is developed by Transgene SA and is classified under other antineoplastic agents. The trial evaluates the combination of TG4001 with avelumab to assess its efficacy in terms of overall response rate and progression-free survival in the specified patient population.
In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial protocol includes detailed dosing schedules and participant compliance monitoring to ensure adherence to the treatment regimen. The study is designed to provide insights into the potential benefits of combining these two experimental treatments in the targeted patient group.
Efficacy
The efficacy of the clinical trial evaluating the combination of TG4001 and **avelumab** in patients with HPV-16 positive recurrent or metastatic malignancies will be assessed using specific endpoints. In Phase II part 1, the primary efficacy endpoint is the Overall Response Rate (ORR) as determined by RECIST 1.1 criteria. In Phase II part 2, the primary endpoint is Progression-Free Survival (PFS), also evaluated according to RECIST 1.1. Secondary endpoints include ORR, PFS, Overall Survival (OS), Duration of Response (DoR), and the overall safety profile. Additionally, the percentage of patients with liver metastases at baseline who experience disease progression at Day 43 will be assessed in Phase II part 2.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Female or male patients, aged at least 18 years (no upper limit of age)
- ECOG PS 0 or 1
- Life expectancy of at least 3 months
- Phase Ib and Phase II part 1: Patients with histologically or cytologically documented metastatic or refractory/recurrent HPV-16 + cancer (cervical, vulvar, vaginal, penile, anal cancers and oropharyngeal squamous cell carcinoma of head and neck); 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
- Prior therapy: Phase Ib and Phase II part 1: Patients MAY have received up to 2 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 chemoradiation 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. Phase II part 2: - No more than one prior systemic treatment for recurrent /metastatic disease - Prior treatment for recurrent or metastatic disease is not required for: o Patients with recurrence/progression within 6 months after completion of prior multimodal therapy for localized or locally advanced disease 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
- 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
- At least one measurable lesion by CT scan according to RECIST 1.1.
- Adequate hematological, hepatic and renal function
- Negative blood pregnancy test at screening for women of childbearing potential
- Highly effective contraception for both male and female patients if the risk of conception exists during the study period and for 3 months after the last study treatment administration
Exclusion Criteria
- Prior exposure to cancer immunotherapy including cancer vaccines, any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints)
- 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 CNS metastases except those with brain metastases treated locally and clinically stable during 4 weeks prior to start of study treatment, and those without ongoing neurological symptoms that are related to the brain localization of the disease
- 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), 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
- 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 infections including SARS-CoV-2 (COVID19) PCR positive testing
- 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 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%)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Sept 2017 | 128 |
 Spain | Not Recruiting | 01 Sept 2017 | 14 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TG4001 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | — | — | PRD4569127 |
Bavencio 20 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD5432333 |