AHEAD-MERIT: 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

• Sponsor: BioNTech SE (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04534205
• Collaborator: (none)
• Enrollment: 285
• Locations: 60
• Arms: 3
• Anticipated Duration (Months): 51.7
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Study Design

• Study Type: Interventional
• Anticipated 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: Jan 7, 2021
• Anticipated Primary Completion Date: May 1, 2025
• Anticipated Study Completion Date: May 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Part A - Occurrence of treatment-emergent adverse event (TEAE) - BNT113 in combination with pembrolizumab [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) [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) [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 [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) [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) [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) [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 [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 [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) [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) [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) [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 [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 [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 [up to 48 months]

    Time to deterioration in PRO scores derived from EORTC QLQ-H&N35 questionnaire.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. Non-healing wound, skin ulcer (of any grade), or bone fracture.

2. Patients with prior allogeneic stem cell or solid organ transplantation.

3. 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).

4. Patients with uncontrolled Type 1 diabetes mellitus. Note: Patients controlled on a stable insulin regimen are eligible.

5. Patients with uncontrolled adrenal insufficiency.

6. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Research Institute	Los Angeles	California	United States	90027
2	Stanford Cancer Institute	Palo Alto	California	United States	94304
3	University Cancer and Blood Center	Athens	Georgia	United States	30607
4	Winship Cancer Institute	Atlanta	Georgia	United States	30322
5	Norton Cancer Institute	Louisville	Kentucky	United States	40241
6	Montefiore Medical Center	Bronx	New York	United States	10467
7	Providence Cancer Institute	Portland	Oregon	United States	97213
8	LKH - Univ. Klinikum Graz	Graz		Austria	8036
9	Landeskrankenhaus/ Univ.-Kliniken Innsbruck	Innsbruck		Austria	6020
10	HNO, Kopf-und Halschirurgie Ordensklinikum Linz Barmherzigen Schwestern	Linz		Austria	4010
11	Uniklinikum Salzburg, Univ. Klinik fur Innere Medizin III	Salzburg		Austria	5020
12	Universitair Ziekenhuis Brussel	Bruxelles		Belgium	1090
13	Universitair Ziekenhuis Gent UZ Gent	Gent		Belgium	9000
14	Cross Cancer Institute	Edmonton		Canada	T6G 1Z2
15	Princess Margaret Cancer Centre	Toronto		Canada	M5G 2C1
16	Fakultni Nemocnice Olomouc	Olomouc		Czechia	779 00
17	Hospital Na Bulovce (Nemocnice na Bulovce)	Prague 8 - Liben		Czechia	180 00
18	Charite - Campus Virchow Klinikum	Berlin		Germany	13353
19	SRH Wald-Klinikum Gera GmbH	Hamburg		Germany	07548
20	Kath. Marien Krankenhaus gGmbH	Hamburg		Germany	40878
21	Universitaetsklinik Heidelberg	Heidelberg		Germany	69124
22	Universitaetsklinikum Köln	Köln		Germany	50937
23	Universitatsklinikum Leipzig AoR	Leipzig		Germany	04103
24	Univeritätsklinikum Münster	Münster		Germany	48149
25	Universitaetsmedizin Rostock - Medizinische Klink III (Hamatologie, Onkologie, Palliativmedizin)	Rostock		Germany	18057
26	Caritas Klinikum Saarbrucken St. Theresia	Saarbruecken		Germany	66113
27	Medizinische Universitaetsklinik Tuebingen	Tübingen		Germany	72076
28	Universitaetsklinikum Wuerzburg	Würzburg		Germany	97080
29	MH Egeszsegugyi Kozpont	Budapest		Hungary	1062
30	Uzsoki Utcai Korhaz Onkologiai Osztaly	Budapest		Hungary	1145
31	DEKK Onkologiai Klinika	Debrecen		Hungary	4032
32	Zala Megyei S. Rafael Korhaz	Zalaegerszeg		Hungary	8900
33	ASST Spedali Civili Brescia	Brescia		Italy	1 25123
34	Mater Salutis Hospital AULSS 9 della Regione Veneto	Legnago		Italy	37045
35	Ospedale del Mare	Napoli		Italy	80147
36	Azienda Ospedaliera Universitaria Senese Policlinico Le Scotte	Siena		Italy	53100
37	Azienda Sanitaria Universitaria Integrata Friuli Centrale - Presidio ospedaliero di Udine	Udine		Italy	33100
38	Szpitale Pomorskie Sp.zo.o	Gdynia		Poland	81-519
39	Narodowy Instytut Onkologii-Oddział w Gliwicach	Gliwice		Poland	44-102
40	Przychodnia Lekarska KOMED Roman Karaszewski	Konin		Poland	62-500
41	Centrum Medyczne Pratia Kraków	Kraków		Poland	30-510
42	Centrum Medyczne Pratia Poznań	Poznań		Poland	60-185
43	Centro clinico academico	Braga		Portugal	4710-243
44	Instituto Português de Oncologia de Coimbra Francisco Gentil, E.P.E.	Coimbra		Portugal	3000-075
45	Centro Hospitalar de Vila Nova de GaiaEspinho	Gaia		Portugal	440-129
46	Instituto Portugues de Oncologia do Porto Francisco Gentil, E.P.E	Porto		Portugal	4200-072
47	Hospital Clinic Barcelona	Barcelona		Spain	08036
48	Hospital Univ. Dr. Josep Trueta	Girona		Spain	17007
49	Complejo Hospitalario de Jaen	Jaén		Spain	23007
50	Clinica Universidad de Navarra (CUN)	Madrid		Spain	28027
51	Hospital Fundacion Jimenez Diaz	Madrid		Spain	28040
52	Hospital Universitario La Paz	Madrid		Spain	28046
53	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda		Spain	28222
54	Hospital Regional de Malaga	Malaga		Spain	29010
55	Hospital Universitario Son Espases	Palma de Mallorca		Spain	07120
56	Clinica Universidad de Navarra - Pamplona (CUN-P)	Pamplona		Spain	31008
57	Hospital La Fe	Valencia		Spain	46026
58	Hospital Miguel Servet	Zaragoza		Spain	50009
59	Sahlgrenska University Hospital	Goteborg		Sweden	413 45
60	The Clatterbridge Cancer Centre	Liverpool		United Kingdom	L7 8YA

Sponsors and Collaborators

• BioNTech SE

Investigators

• Study Director: BioNTech Responsible Person, BioNTech SE

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: BioNTech SE
• ClinicalTrials.gov Identifier: NCT04534205
• Other Study ID Numbers: BNT113-01; 2020-001400-41
• First Posted: Sep 1, 2020
• Last Update Posted: Aug 25, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Carcinoma; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Squamous Cell Carcinoma of Head and Neck; Papilloma; Recurrence; Pembrolizumab

Study Results

No Results Posted as of Aug 25, 2022