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A Clinical Trial Investigating the Safety, Tolerability, and Therapeutic Effects of BNT113 in Combination With Pembrolizumab Versus Pembrolizumab Alone for Patients With a Form of Head and Neck Cancer Positive for Human Papilloma Virus 16 and Expressing the Protein PD-L1 (AHEAD-MERIT)

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ClinicalTrials.gov Identifier: NCT04534205
Recruitment Status : Recruiting
First Posted : September 1, 2020
Last Update Posted : June 24, 2022
Sponsor:
Information provided by (Responsible Party):
BioNTech SE

Brief Summary:

An open-label, controlled, multi-site, interventional, 2-arm, Phase II trial of BNT113 in combination with pembrolizumab vs pembrolizumab monotherapy as first line treatment in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing programmed cell death ligand -1 (PD-L1) with combined positive score (CPS) ≥1.

This trial has two parts.

Part A, an initial non-randomized Safety Run-In Phase to confirm the safety and tolerability at the selected dose range level of BNT113 in combination with pembrolizumab.

Part B, the Randomized part of the trial to generate pivotal efficacy and safety data of BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy in the first line setting in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing PD-L1 with CPS ≥1.


Condition or disease Intervention/treatment Phase
Unresectable Head and Neck Squamous Cell Carcinoma Metastatic Head and Neck Cancer Recurrent Head and Neck Cancer Biological: BNT113 Biological: Pembrolizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 285 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Phase II Randomized Trial of BNT113 in Combination With Pembrolizumab Versus Pembrolizumab Monotherapy as a First Line Therapy in Patients With Unresectable Recurrent, or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) Which is Positive for Human Papilloma Virus 16 (HPV16+) and Expresses PD-L1 (AHEAD-MERIT)
Actual Study Start Date : January 7, 2021
Estimated Primary Completion Date : May 2025
Estimated Study Completion Date : May 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part A (Safety run-In) - BNT113 + Pembrolizumab
Safety Run-In Phase to confirm the safety and tolerability at the selected dose range level of BNT113 in combination with pembrolizumab.
Biological: BNT113
IV injection

Biological: Pembrolizumab
IV infusion

Experimental: Part B (Randomized phase) - BNT113 + Pembrolizumab
BNT113 in combination with pembrolizumab.
Biological: BNT113
IV injection

Biological: Pembrolizumab
IV infusion

Active Comparator: Part B (Randomized phase) - Pembrolizumab monotherapy
Pembrolizumab monotherapy.
Biological: Pembrolizumab
IV infusion




Primary Outcome Measures :
  1. Part A - Occurrence of treatment-emergent adverse event (TEAE) - BNT113 in combination with pembrolizumab [ Time Frame: up to 27 months ]
    TEAE assessed according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) including Grade ≥3, serious, fatal TEAE by relationship.

  2. Part B - Overall Survival (OS) [ Time Frame: up to 48 months ]
    OS defined as the time from randomization to death from any cause.

  3. Part B - Overall response rate (ORR) assessed by blinded independent central review (BICR) [ Time Frame: up to 48 months ]
    ORR defined as the proportion of patients in whom a complete response (CR) or partial response (PR) (per response evaluation criteria in solid tumors [RECIST 1.1]) is observed as best overall response.


Secondary Outcome Measures :
  1. Overall response rate (ORR) by investigator's assessment [ Time Frame: up to 48 months ]
    ORR defined as the proportion of patients in whom a CR or PR (per RECIST 1.1) is observed as best overall response.

  2. Progression free survival (PFS) [ Time Frame: up to 48 months ]
    PFS defined as the time from randomization to the first objective tumor progression (per RECIST 1.1) or death from any cause, whichever occurs first.

  3. Disease control rate (DCR) [ Time Frame: up to 48 months ]
    DCR defined as the proportion of patients in whom a CR or PR or stable disease (SD) (per RECIST 1.1, assessed at least 6 weeks after first dose) is observed as best overall response.

  4. Duration of Response (DOR) [ Time Frame: up to 48 months ]
    DOR defined as the time from first objective response CR or PR (per RECIST 1.1) to first occurrence of objective tumor progression (progressive disease (PD) per RECIST 1.1) or death from any cause, whichever occurs first.

  5. Occurrence of TEAE - BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy [ Time Frame: up to 27 months ]
    TEAE assessed according to CTCAE v5.0 including Grade ≥3, serious, fatal TEAE by relationship.

  6. Occurrence of dose reduction and discontinuation of trial treatments due to TEAEs [ Time Frame: up to 27 months ]
    BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy.

  7. Patient-reported outcome (PRO) EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) [ Time Frame: up to 48 months ]
    PRO scores derived from the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire as change from baseline.

  8. PRO European Quality of Life 5 Dimensions (EQ-5D) [ Time Frame: up to 48 months ]
    PRO scores derived from EuroQol EQ-5D questionnaire as change from baseline.

  9. PRO EORTC Quality of life - Head and Neck Cancer Module (QLQ-H&N35) [ Time Frame: up to 48 months ]
    PRO scores derived from EORTC QLQ-H&N35 questionnaire as change from baseline.

  10. Time to deterioration in PRO scores EORTC QLQ-C30 [ Time Frame: up to 48 months ]
    Time to deterioration in PRO scores derived from EORTC QLQ-C30 questionnaire.

  11. Time to deterioration in PRO scores EuroQol EQ-5D [ Time Frame: up to 48 months ]
    Time to deterioration in PRO scores derived from EQ-5D questionnaire.

  12. Time to deterioration in PRO scores EORTC QLQ-H&N35 [ Time Frame: up to 48 months ]
    Time to deterioration in PRO scores derived from EORTC QLQ-H&N35 questionnaire.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must sign the written informed consent form before any screening procedure. Informed consent must be documented before any trial-specific screening procedure is performed.
  • Patients must be aged ≥18 years on the date of signing the informed consent.
  • Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the trial.
  • Patients who present histologically confirmed recurrent or metastatic HPV16+ HNSCC that is considered incurable by local therapies.
  • Patients who have a tumor expressing PD-L1 [CPS ≥1] as determined by the Food and Drug Administration (FDA)-approved test PD-L1 22C3 pharmDx kit performed and evaluated according to the manufacturer's specifications.
  • The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Patients may not have a primary tumor site of nasopharynx (any histology).
  • Patients must not have had prior systemic anticancer therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization, if given as part of multimodal treatment for locally advanced disease is allowed.
  • Patients who have measurable disease based on RECIST 1.1 as determined by the site and confirmed by BICR. Tumor lesions situated in a previously irradiated area are considered measurable, if progression has been demonstrated in such lesions disease by RECIST 1.1.
  • Patients have Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
  • Patients have adequate bone marrow function.
  • Patients have adequate hepatic function.
  • Patients should have adequate kidney function, assessed by the estimated glomerular filtration rate ≥45 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CPK-EPI) equation.
  • Patients should be stable with adequate coagulation.
  • All patients must provide a tumor tissue sample (formalin fixed paraffin embedded (FFPE) blocks/slides) from archival tissue, or fresh biopsy if collected as part of patient's standard clinical practice before the first dose of trial treatment.
  • Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin) at screening. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential.

Exclusion Criteria:

Medical conditions:

  • Patients are pregnant or breastfeeding.
  • Patients present primary tumor site of nasopharynx (any histology).
  • Patients with uncontrolled intercurrent illness, including but not limited to:

    1. Ongoing or active infection which requires systemic treatment with antibiotics or corticoid therapy within 14 days before the first dose of trial treatment.
    2. Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), myocardial infarction within 3 months before screening, unstable angina pectoris, or cardiac arrhythmia.
    3. Arterial thrombosis or pulmonary embolism within ≤6 months before the start of trial treatment.
    4. Known recent history (in the past 5 years) or presence of significant pulmonary conditions such as uncontrolled chronic lung disease, or any evidence of interstitial lung disease, or active, non-infectious pneumonitis.
    5. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management.
    6. Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T negative severe combined immunodeficiency [SCID]) or combined T and B cell immunodeficiencies (e.g., T and B negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency).
    7. Ongoing or recent evidence (within the past year) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may suggest risk for immune-related adverse events (AEs).

      Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are in remission, or on a stable dose of thyroid-replacement hormone, vitiligo, or psoriasis may be included.

    8. Non-healing wound, skin ulcer (of any grade), or bone fracture.
    9. Patients with prior allogeneic stem cell or solid organ transplantation.
    10. Patients with the following risk factors for bowel perforation (e.g., history of acute diverticulitis or intra-abdominal abscess in the last 3 years; history of gastrointestinal obstruction or abdominal carcinomatosis).
    11. Patients with uncontrolled Type 1 diabetes mellitus. Note: Patients controlled on a stable insulin regimen are eligible.
    12. Patients with uncontrolled adrenal insufficiency.
    13. Any other disease, metabolic dysfunction, physical examination finding, and/or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or may render the patient at high risk for treatment of complications.
  • Patients with a known allergy, hypersensitivity, or intolerance to BNT113 or its excipients, or to pembrolizumab or its excipients.
  • Patients who have had a splenectomy.
  • Patients who have had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, or have not fully recovered from surgery, or have a surgery planned during the time of trial participation.
  • Patients who have a known history (testing not required) or has a positive test at screening of any of the following:

    1. Human immunodeficiency virus (HIV) 1 or 2.
    2. Hepatitis B (carrier or active infection).
    3. Hepatitis C (unless considered cured 5 years post curative anti-viral therapy).
  • Patients with another primary malignancy that has not been in complete remission for at least 2 years, with the exception of those with a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, non-invasive basal or non-invasive squamous cell skin cancer, localized prostate cancer, non-invasive superficial bladder cancer or breast ductal carcinoma in situ).
  • Patients with any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

Prior/concomitant therapy:

  • Patients who have received or currently receive the following therapy/medication:

    1. Chronic systemic immunosuppressive corticosteroid treatment (prednisone >5 mg daily orally [PO] or IV, or equivalent) during the trial. Note: Replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.
    2. Prior treatment with other immune modulating agents that was (a) within fewer than 4 weeks (28 days) or 5 half-lives of the agent (whichever is longer) prior to the first dose of BNT113, or (b) associated with immune-mediated AEs that were Grade ≥1 within 90 days prior to the first dose of BNT113, or (c) associated with toxicity that resulted in discontinuation of the immune-modulating agent.
    3. Prior treatment with other immune modulating agents for any non-cancer disease within 4 weeks or 5 half-lives of the agent (whichever is longer) before the first dose of BNT113.
    4. Prior treatment with live attenuated vaccines within 4 weeks before the first dose of BNT113.
    5. Prior treatment with an investigational drug (including investigational vaccines) within 4 weeks or 5 half-lives of the agent (whichever is longer) before the planned first dose of BNT113.
    6. Therapeutic PO or IV antibiotics within 14 days prior to enrollment. • Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) may be enrolled.
  • Prior anti-cancer therapy in the metastatic or in the unresectable recurrent HNSCC setting.
  • Prior treatment with anti-cancer immunomodulating agents, such as blockers of programmed death receptor-1 (PD 1), PD-L1, tumor necrosis factor receptor superfamily member 9 (TNRSF9, 4 1BB, CD137), OX 40, therapeutic vaccines, cytokine treatments, or any investigational agent within 4 weeks before the first dose of BNT113.
  • Treatment with other anti-cancer therapy including chemotherapy, radiotherapy with curative intent, major surgery with curative intent or biological cancer therapy within 6 months prior to randomization. Adjuvant hormone therapy used for breast cancer in long term remission is allowed.

    • Note 1: Palliative radiotherapy and palliative surgery are allowed.
    • Note 2: Prior treatment with bone resorptive therapy, such as bisphosphonates (e.g., pamidronate, zoledronic acid) and denosumab, is allowed assuming that the patients have been on stable doses for ≥4 weeks prior to first dose of trial treatment.

Other comorbidities:

  • Current evidence of Common Terminology Criteria for Adverse Events (CTCAE, v5.0) Grade >1 toxicity before the start of treatment, except for hair loss and those Grade 2 toxicities listed as permitted in other eligibility criteria. Patients with Grade 2 neuropathy may be eligible at investigator's discretion.
  • Current evidence of new or growing brain or spinal metastases during screening. Patients with known brain or spinal metastases may be eligible if they:

    1. had radiotherapy or another appropriate therapy for the brain or spinal metastases,
    2. have no neurological symptoms (excluding Grade ≤2 neuropathy),
    3. have stable brain or spinal disease on the computer tomography (CT) or magnetic resonance imaging (MRI) scan within 4 wks before signing the informed consent,
    4. do not require steroid therapy within 7 d before randomization,
    5. spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.

Other exclusions:

  • Patients who have previously been enrolled in this trial.
  • Patients with substance abuse or known medical, psychological, or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results.
  • Patients affiliated with the investigational site (e.g., a close relative of the investigator or dependent person, such as an employee or student of the trial site).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04534205


Contacts
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Contact: BioNTech clinical trials patient information +49 6131 9084 ext 0 patients@biontech.de

Locations
Show Show 58 study locations
Sponsors and Collaborators
BioNTech SE
Investigators
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Study Director: BioNTech Responsible Person BioNTech SE
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Responsible Party: BioNTech SE
ClinicalTrials.gov Identifier: NCT04534205    
Other Study ID Numbers: BNT113-01
2020-001400-41 ( EudraCT Number )
First Posted: September 1, 2020    Key Record Dates
Last Update Posted: June 24, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by BioNTech SE:
Cancer vaccine
RNA vaccine
HNSCC
BNT113
Pembrolizumab
HPV16
Metastatic
Unresectable
Recurrent
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Squamous Cell Carcinoma of Head and Neck
Papilloma
Recurrence
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
Pathologic Processes
Neoplasms, Squamous Cell
Neoplasms by Site
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents