Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers

A Phase Ib/II Trial Evaluating the Combination of TG4001 and Avelumab in Patients With HPV-16 Positive Recurrent or Metastatic Malignancies.

The study will consist of two parts :

In the phase Ib: safety will be assessed in consecutive cohorts of 3 to 6 participants at increasing doses of TG4001 in combination with avelumab according to a 3+3 design. There will be no intra-participant dose escalation.

In the phase II part 1, evaluation of efficacy and further evaluation of safety of the combination of TG4001 and avelumab will be performed in a single arm of participants with recurrent or metastatic HPV-16 positive advanced malignancies.

In the phase II part 2, evaluation of efficacy of the combination of TG4001 and avelumab will be performed in a randomized, open-label controlled study comparing TG4001 in combination with avelumab to avelumab alone in participants with HPV-16 positive advanced malignancies.

In both phases, evaluation of tumor response will be done locally according to RECIST 1.1.

All participants will be followed up until disease progression, death, or unacceptable toxicity, or study withdrawal for any reason, whichever occurs first.

Inclusion Criteria:

• Female or male participants, aged at least 18 years (no upper limit of age)

• ECOG PS 0 or 1

• Life expectancy of at least 3 months

• Participants with histologically or cytologically documented metastatic or refractory/recurrent HPV-16 + cancer: cervical, vulvar, vaginal, penile and anal.

• Disease MUST not be amenable to curative surgery resection or curative radiotherapy with documented disease progression

• Prior therapy:

  • No more than one prior systemic treatment for recurrent /metastatic disease

  • Prior treatment for recurrent or metastatic disease is not required for:

    • Participants with recurrence/progression within 6 months after completion of prior multimodal therapy for localized or locally advanced disease
    • Participants who are unsuitable for platinum-based therapy
    • Participants who refuse chemotherapy or other standard therapies for the treatment of metastatic or recurrent disease

• Limited hepatic disease for participants with liver metastases at baseline

• Availability of tumor tissue from biopsy

• 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 participants 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)

• Participants 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 participants 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

• Participants 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

• Participants 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

• Participant with any organ transplantation, including allogeneic stem cell transplantation

• Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTC), 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

• Participants with known history or any evidence of active interstitial lung disease / pneumonitis

• Participants 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

• 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 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