Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers (NCT03260023) — Spain Trial Details

Condition(s) studied

HPV-Related CarcinomaHPV-Related Cervical CarcinomaHPV-Related Anal Squamous Cell CarcinomaHPV-Related Penile Squamous Cell CarcinomaHPV-Related Vulvar Squamous Cell Carcinoma

Investigational drug(s) / intervention(s)

TG4001Avelumab →

TG4001: PhIb: Dose escalation PhII: Established RP2D for TG4001

Avelumab: Anti PD-L1

Study summary

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.

Eligibility

Sex

ALL

Min age

18 Years

Max age

—

Healthy volunteers

No

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

Primary outcome measure(s)

Phase Ib: To Evaluate the Safety and Tolerability of the Combination of TG4001 Plus Avelumab in Participants With Recurrent or Metastatic HPV-16 Positive Advanced Malignancies — From Day 1 to Day 28
Dose limiting toxicities (DLTs) includes the following: * Grade ≥ 3 drug related adverse event (AEs). However, fatigue, nausea/vomiting adequately treated with anti-emetics, endocrinopathies adequately controlled with one physiologic hormone replacement, skin toxicity and single laboratory values out of normal range without any clinical correlate, asymptomatic grade ≥3 lipase or amylase elevation, tumor flare defined as local pain, irritation, or rash localized at sites of known or suspected tumor or a transient Grade 3 infusion adverse event are excluded. * Liver function test abnormality: * AST or ALT \> 5 x ULN * Total bilirubin \> 3 x ULN * Concurrent AST or ALT \> 3 x ULN and total bilirubin \> 2 x ULN * Drug related AE requiring treatment interruption for more than 2 weeks
Phase II Part 1: Overall Response Rate (ORR) by RECIST 1.1 — From treatment start, every 6 weeks for the first 9 months, then every 12 weeks up to 2 years.
Percentage of participants whose best overall response is either a Complete Response or a Partial Response according to Response Evaluation Criteria In Solid Tumors (RECIST v1.0) criteria over the the total number of evaluable participants. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.", or similar definition that is accurate and appropriate.
Phase II Part 2 Cohort A: Progression Free Survival (PFS) by RECIST 1.1 — From randomization: Every 6 weeks for the first 9 months, then every 12 weeks through study completion, for an average of 1 year.
PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death due to any cause, whichever occurs first. If a participant has not had a PFS event at the cut-off date for analysis or at the date when a further antineoplastic therapy (other than those planned as study treatment in the protocol) is started, PFS will be censored at the date of last evaluable tumor assessment before the cut-off or start of further antineoplastic therapy.
Progression Free Survival (PFS) Phase II Part 2 Cohort A by Stratification — From randomization: Every 6 weeks for the first 9 months, then every 12 weeks through study completion, for an average of 1 year.
PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death due to any cause, whichever occurs first. If a participant has not had a PFS event at the cut-off date for analysis or at the date when a further antineoplastic therapy (other than those planned as study treatment in the protocol) is started, PFS will be censored at the date of last evaluable tumor assessment before the cut-off or start of further antineoplastic therapy.

Trial sites (20)

Facility	City	Region
Mayo Clinic	Jacksonville	Florida
Mayo Clinic	Rochester	Minnesota
I.C.O. Paul Papin	Angers	France
CHU Besançon	Besançon	France
Hôpital Saint André - CHU de Bordeaux	Bordeaux	France
Hôpitaux Civils de Colmar - Hôpital Pasteur	Colmar	France
CLCC Georges-François Leclerc	Dijon	France
Centre Léon Bérard	Lyon	France
Hopital de la Timone	Marseille	France
Institut Curie	Paris	France
I.C.O. Gauducheau	Saint-Herblain	France
Centre Paul Strauss - ICANS - Institut de cancérologie Strasbourg Europe	Strasbourg	France
Institut Claudius Regaud - IUCT - Oncopole	Toulouse	France
Institut Gustave Roussy	Villejuif	France
ICO Badalona - Hospital Germans Trias i Pujol	Badalona	Spain
Hospital Virgen de las Nieves	Granada	Spain
Fundación de Investigación biomédica H. 12 de Octubre	Madrid	Spain
Fundación de Investigación Biomédica Hospital Clínico San Carlos	Madrid	Spain
Hospital Virgen de La Victoria	Málaga	Spain
Hospital General de Valencia	Valencia	Spain

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