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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03260023
Recruitment Status : Recruiting
First Posted : August 24, 2017
Last Update Posted : February 15, 2022
Sponsor:
Collaborators:
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Pfizer
Information provided by (Responsible Party):
Transgene

Tracking Information
First Submitted Date  ICMJE August 17, 2017
First Posted Date  ICMJE August 24, 2017
Last Update Posted Date February 15, 2022
Actual Study Start Date  ICMJE September 11, 2017
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 2021)
  • Phase Ib: To evaluate the safety and tolerability of the combination of TG4001 plus avelumab in patients with recurrent or metastatic HPV-16 positive advanced malignancies [ Time Frame: 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 [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Percentage of patients whose best overall response is either a Complete Response or a Partial Response according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria over the the total number of evaluable patients.
  • Phase II part 2: Progression Free Survival (PFS) by RECISIT 1.1 [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Time from the date of randomization to death due to any cause, whichever occurs first.
Original Primary Outcome Measures  ICMJE
 (submitted: August 23, 2017)
  • Phase Ib: To evaluate the safety and tolerability of the combination of TG4001 plus avelumab in patients with recurrent or metastatic HPV-16 positive advanced malignancies [ Time Frame: 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: To evaluate the efficacy of TG4001 combined to avelumab in terms of Overall Response Rate (ORR) by using RECIST 1.1 in the expansion cohort of oropharyngeal recurrent or metastatic (R/M) SCCHN [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2021)
  • Overall Response Rate (ORR) by using RECIST 1.1 (phase Ib, phase II part 2) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Percentage of patients whose best overall response is either a Complete Response or a Partial Response according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria over the the total number of evaluable patients
  • Progression Free Survival (PFS) (phase Ib, Phase II part 1) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Time from the date of first study treatment administration (Phase IB, Phase II Part1) to the date of first documented tumor progression or death due to any cause, whichever occurs first.
  • Overall Survival (OS) [ Time Frame: Every 3 months and up to 3 years ]
    Time from the date of first study treatment administration (Phase Ib, Phase II part 1) or time from the date of randomization (Phase II part 2) to the date of death due to any cause.
  • Duration of overall Response (DoR) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Time from first documented response (CR or PR) until documented disease progression or death, whichever occurs first.
  • Disease control rate (DCR) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Proportion of patients whose best overall response is either CR, PR, or SD.
  • Incidence of Adverse Event reported per CTCAE v4.03 [ Time Frame: up to 90 days after last study treatment administration ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2017)
  • Overall response rate (ORR) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Using RECIST 1.1 (phase Ib part)
  • Progression Free Survival (PFS) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Time from the date of first study treatment administration to the date of first documented tumor progression or death due to any cause, whichever occurs first.
  • Overall Survival (OS) [ Time Frame: Every 3 months and up to 3 years ]
    Time from the date of first study treatment administration to the date of death due to any cause.
  • Duration of overall Response (DoR) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Time from first documented response (CR or PR) until documented disease progression or death, whichever occurs first.
  • Disease control rate (DCR) [ Time Frame: Every 6 weeks for the first 9 months, then every 12 weeks up to 3 years ]
    Proportion of patients whose best overall response is either CR, PR, or SD.
  • Incidence of Adverse Event reported per CTCAE v4.03 [ Time Frame: up to 90 days after last study treatment administration ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers
Official Title  ICMJE A Phase Ib/II Trial Evaluating the Combination of TG4001 and Avelumab in Patients With HPV-16 Positive Recurrent or Metastatic Malignancies.
Brief Summary

The study will consist of two parts :

In the phase Ib: safety will be assessed in consecutive cohorts of 3 to 6 patients at increasing doses of TG4001 in combination with avelumab according to a 3+3 design. There will be no intra-patient 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 patients 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 patients with HPV-16 positive advanced malignancies.

In both phases, tumor response will be evaluated on local assessment using RECIST 1.1.

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

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • HPV-Related Carcinoma
  • HPV-Related Cervical Carcinoma
  • HPV-Related Anal Squamous Cell Carcinoma
  • HPV-Related Penile Squamous Cell Carcinoma
  • HPV-Related Vulvar Squamous Cell Carcinoma
Intervention  ICMJE
  • Biological: TG4001
    PhIb: Dose escalation PhII: Established RP2D for TG4001
  • Drug: Avelumab
    Anti PD-L1
Study Arms  ICMJE
  • Experimental: TG4001/Avelumab
    Interventions:
    • Biological: TG4001
    • Drug: Avelumab
  • Experimental: Avelumab
    Applicable for Phase II part 2.
    Intervention: Drug: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 11, 2021)
150
Original Estimated Enrollment  ICMJE
 (submitted: August 23, 2017)
52
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • Patients 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:

      • Patients with recurrence/progression within 6 months after completion of prior multimodal therapy for localized or locally advanced disease
      • Patients who are unsuitable for platinum-based therapy
      • Patients who refuse chemotherapy or other standard therapies for the treatment of metastatic or recurrent disease
  • Limited hepatic disease for patients 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 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), 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 known history or any evidence of active interstitial lung disease / pneumonitis
  • 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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Transgene EU, Clinical Operations Department + 33 (0) 3 88 27 91 00 clinical.trials@transgene.fr
Listed Location Countries  ICMJE France,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03260023
Other Study ID Numbers  ICMJE TG4001.12
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Transgene
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Transgene
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Merck KGaA, Darmstadt, Germany
  • EMD Serono Research & Development Institute, Inc.
  • Pfizer
Investigators  ICMJE Not Provided
PRS Account Transgene
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP