Trial With BNT111 and Cemiplimab in Combination or as Single Agents in Patients With Anti-PD-1-refractory/Relapsed, Unresectable Stage III or IV Melanoma
Study Details
Study Description
Brief Summary
This is an open-label, randomized, multi-site, Phase II, interventional trial designed to evaluate the efficacy, tolerability, and safety of BNT111 + cemiplimab in anti-PD-1-refractory/relapsed patients with unresectable Stage III or IV melanoma. The contributions of BNT111 and cemiplimab will be delineated in single agent calibrator arms. Patients in single agent calibrator arms, who experience disease progression under single agent treatment, may be offered addition of the other compound to the ongoing treatment after re-consent.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: BNT111 + cemiplimab
|
Biological: BNT111
IV injection
Biological: Cemiplimab
IV infusion
|
Experimental: BNT111 monotherapy
|
Biological: BNT111
IV injection
|
Experimental: Cemiplimab monotherapy
|
Biological: Cemiplimab
IV infusion
|
Outcome Measures
Primary Outcome Measures
- Objective response rate (ORR) - Arm: BNT111 + cemiplimab [up to 24 months]
ORR defined as the proportion of patients in whom a complete response (CR) or partial response (PR) according to Response Criteria in Solid Tumors (RECIST 1.1) is observed as best overall response by blinded independent central review (BICR).
Secondary Outcome Measures
- Objective response rate - Arm: BNT111 monotherapy and Arm: Cemiplimab monotherapy [up to 24 months]
ORR defined as the proportion of patients in whom a CR or PR according to RECIST 1.1 is observed as best overall response by BICR.
- Duration of response (DOR) according to RECIST 1.1 [up to 24 months]
DOR defined as the time from first objective response (CR or PR) to first occurrence of objective tumor progression (progressive disease, PD) by BICR or death from any cause (whichever occurs first).
- Disease control rate (DCR) according to RECIST 1.1 [up to 24 months]
DCR defined as the proportion of patients in whom a CR, PR or stable disease (SD; assessed at least 6 weeks after first dose) is observed as best overall response by BICR.
- Time to response (TTR) according to RECIST 1.1 [up to 24 months]
TTR defined as the time from randomization to the first objective tumor response (CR or PR) by BICR.
- Progression-free survival (PFS) according to RECIST 1.1 [up to 24 months]
PFS defined as the time from randomization to first objective tumor progression (PD) by BICR or death from any cause (whichever occurs first).
- ORR according to RECIST 1.1 as assessed by the investigator [up to 24 months]
- DOR according to RECIST 1.1 as assessed by the investigator [up to 24 months]
- DCR according to RECIST 1.1 as assessed by the investigator [up to 24 months]
- TTR according to RECIST 1.1 as assessed by the investigator [up to 24 months]
- PFS according to RECIST 1.1 as assessed by the investigator [up to 24 months]
- Overall survival (OS) - Arm: BNT111 + cemiplimab [up to 48 months]
OS defined as the time from randomization to death from any cause.
- Occurrence of treatment-emergent adverse events (TEAE) within a patient including Grade ≥3, serious and/or fatal TEAE by relationship [up to 27 months]
- Occurrence of immune-related adverse events (irAE) [up to 27 months]
- Occurrence of dose reduction and discontinuation of trial treatment within a patient due to TEAE [up to 27 months]
- Occurrence of abnormal laboratory parameters (hematology) within a patient [up to 25 months]
Blood samples will be collected for the assessment of hematology parameters.
- Changes in laboratory parameters (hematology) compared to baseline [up to 25 months]
- Occurrence of abnormal laboratory parameters (clinical chemistry) within a patient [up to 25 months]
Blood samples will be collected for the assessment of clinical chemistry parameters.
- Changes in laboratory parameters (clinical chemistry) compared to baseline [up to 25 months]
- Occurrence of abnormal laboratory parameters (coagulation factors) within a patient [up to 25 months]
Blood samples will be collected for the assessment of coagulation factors.
- Changes in laboratory parameters (coagulation factors) compared to baseline [up to 25 months]
- Occurrence of abnormal laboratory parameters (endocrine tests) within a patient [up to 25 months]
Blood samples will be collected for the assessment of endocrine tests.
- Changes in laboratory parameters (endocrine tests) compared to baseline [up to 25 months]
- Occurrence of abnormal laboratory parameters (serology) within a patient [up to 25 months]
Blood samples will be collected for the assessment of serology parameters.
- Changes in laboratory parameters (serology) compared to baseline [up to 25 months]
- Occurrence of abnormal laboratory parameters (urinalysis) within a patient [up to 25 months]
Urine samples will be collected for the assessment of urinalysis parameters.
- Changes in laboratory parameters (urinalysis) compared to baseline [up to 25 months]
- Occurrence of abnormal vital signs parameters (body temperature) within a patient [up to 25 months]
Body temperature (in °C) will be assessed.
- Changes in vital signs parameters (body temperature) compared to baseline [up to 25 months]
- Occurrence of abnormal vital signs parameters (pulse rate) within a patient [up to 25 months]
Pulse rate (in beats per minute [bpm]) will be assessed.
- Changes in vital signs parameters (pulse rate) compared to baseline [up to 25 months]
- Occurrence of abnormal vital signs parameters (blood pressure) within a patient [up to 25 months]
Blood pressure (systolic/diastolic, in mmHg) will be assessed.
- Changes in vital signs parameters (blood pressure) compared to baseline [up to 25 months]
- Occurrence of abnormal vital signs parameters (respiratory rate) within a patient [up to 25 months]
Respiratory rate will be assessed.
- Changes in vital signs parameters (respiratory rate) compared to baseline [up to 25 months]
- Mean changes from baseline in the global health status score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) [up to 25 months]
- Mean changes from baseline in scores of the EORTC QLQ C30 functional and symptoms scales [up to 25 months]
- Time to first clinically meaningful deterioration in global health status score as measured by EORTC QLQ-C30 [up to 25 months]
- Time to first clinically meaningful deterioration in symptoms and functioning as measured by EORTC QLQ-C30 [up to 25 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients must sign the written informed consent form (ICF) before any screening procedure.
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Patients must be aged ≥ 18 years on the date of signing the informed consent.
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Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the trial.
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Patients must have histologically confirmed unresectable Stage III or IV (metastatic) cutaneous melanoma and measurable disease by RECIST 1.1.
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Patients must have confirmed disease progression on/after an approved anti-PD-1 regimen for melanoma as defined by RECIST 1.1.
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Previous exposure to approved anti-PD-1 containing regimen for at least 12 consecutive weeks and
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Current radiological progression to be confirmed by two scans 4 to 12 weeks apart. If progression is accompanied by new symptoms, or deterioration of performance status not attributed to toxicity, one scan is sufficient and
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Inclusion into this trial must be within 6 months of confirmation of disease progression on anti-PD-1 treatment, regardless of any intervening therapy.
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Patients should have received pembrolizumab or nivolumab (with/without ipilimumab).
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Patients should have received at least one but no more than five lines of prior therapy for advanced disease.
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Patients must be able to tolerate additional anti-PD-1 therapy (i.e., did not permanently discontinue anti-PD-1 therapy due to toxicity).
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Patients must have known BRAF mutation status.
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Patients with BRAF V600-positive tumor(s) should have received prior treatment with a BRAF inhibitor (alone or in combination with a MEK inhibitor) in addition to treatment with pembrolizumab or nivolumab with or without ipilimumab Note: Considering the possible negative impact of a prior BRAF/MEK therapy on immune system targeting therapies, patients with BRAF V600-positive tumors with no clinically significant tumor-related symptoms or evidence of rapid PD may be eligible for participation. This should be based on investigator assessment AND provided they are ineligible for, intolerant to, or have refused BRAF V600 mutation targeted therapy after receiving the information on possible other therapies including BRAF/MEK inhibitor-based therapy during the informed consent process.
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Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
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Adequate bone marrow function, as defined in the protocol.
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Patients must have serum lactate dehydrogenase (LDH) ≤ upper limit of normal (ULN).
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Patient should have adequate hepatic function, as defined in the protocol.
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Patient should have adequate kidney function, assessed by the estimated glomerular filtration rate (eGFR) ≥ 30 mL/min using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation.
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Patient should be stable with adequate coagulation, as defined in the protocol.
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Patients must provide the following biopsy samples:
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All patients: must provide a tumor tissue sample (formalin fixed paraffin-embedded [FFPE] blocks/slides) from a fresh biopsy collected before Visit C1D1, or archival tissue. The archival tissue can be an FFPE block (not older than 3 years) or freshly cut slides (special storage conditions and immediate shipment to specialty lab are required), preferably derived from advanced disease stage.
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Patients at selected trial sites: After additional consent, patients must be amenable to a pre-treatment and on-treatment biopsy and must provide a mandatory biopsy which contains tumor tissue and is taken after failure/stop of last prior treatment and an on-treatment biopsy.
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Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) at screening. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential. Female patients of reproductive potential must agree to use highly effective contraception during and for 6 months after the last trial drug administration.
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WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial starting at screening, during the trial and for 6 months after receiving the last trial treatment.
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A man who is sexually active with a WOCBP and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 6 months after receiving the last trial treatment.
Exclusion Criteria:
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Patients must not be pregnant or breastfeeding.
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Patients must not have history of uveal, acral, or mucosal melanoma.
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Patients must have no ongoing or recent evidence (within the last 5 years) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may pose a risk for immune-related adverse events (irAEs). 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.
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Patients must have no known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T cell-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).
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Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are not eligible.
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Patients must have no uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Mild cancer-related immunodeficiency (such as immunodeficiency treated with gamma globulin and without chronic or recurrent infection) is allowed.
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Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable anti-viral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards.
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Patients with known hepatitis B virus (HBV) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of trial treatment.
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Patients who are known hepatitis C virus (HCV) antibody positive who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
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Patients with HIV or hepatitis must have their disease reviewed by the specialist (e.g., infectious disease specialist or hepatologist) managing this disease prior to commencing and throughout the duration of their participation in the trial.
- 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, progression or death (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, non-invasive, superficial bladder cancer or breast ductal carcinoma in situ).
Prior/concomitant therapy:
- Current use or use within 3 months prior to trial enrollment of systemic immune suppression including:
-
use of chronic systemic steroid medication (up to 5 mg/day prednisolone equivalent is allowed); patients using physiological replacement doses of prednisone for adrenal or pituitary insufficiency are eligible,
-
other clinically relevant systemic immune suppression.
- Treatment with other anti-cancer therapy including chemotherapy, radiotherapy, investigational, or biological cancer therapy within 3 weeks prior to the first dose of trial treatment (6 weeks for nitrosureas). Adjuvant hormonotherapy used for breast cancer in long term remission is allowed.
Other comorbidities:
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Current evidence of ongoing National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade > 1 toxicity of prior therapies before the start of treatment, with the exception of hair loss, hearing loss, Grade 2 peripheral neuropathy, or laboratory abnormalities not considered clinical significant per investigator's discretion, and those Grade 2 toxicities listed as permitted in other eligibility criteria.
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Patients who have a local infection (e.g., cellulitis, abscess) or systemic infection (e. g., pneumonia, septicemia) which requires systemic antibiotic treatment within 2 weeks prior to the first dose of trial treatment.
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Patients who have had a splenectomy.
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Patients who have had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, have not fully recovered from surgery, or have a surgery planned during the time of trial participation.
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Current evidence of new or growing brain or spinal metastases during screening. Patients with leptomeningeal disease are excluded. Patients with known brain or spinal metastases may be eligible if they:
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had radiotherapy or another appropriate therapy for the brain or spinal bone metastases,
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have no neurological symptoms that can be attributed to the current brain lesions,
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have stable brain or spinal disease on the CT or MRI scan within 4 weeks before signing the informed consent (confirmed by stable lesions on two scans at least 4 weeks apart),
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do not require steroid therapy within 14 days before the first dose of trial treatment,
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spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.
- History or current evidence of significant cardiovascular disease including, but not limited to:
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angina pectoris requiring anti-anginal medication, uncontrolled cardiac arrhythmia(s), severe conduction abnormality, or clinically significant valvular disease,
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QTc (F) prolongation > 480 ms,
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arterial thrombosis or pulmonary embolism within ≤ 6 months before the start of treatment,
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myocardial infarction within ≤ 6 months before the start of treatment,
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pericarditis (any NCI-CTCAE grade), pericardial effusion (NCI-CTCAE Grade ≥ 2), non-malignant pleural effusion (NCI-CTCAE Grade ≥ 2) or malignant pleural effusion (NCI-CTCAE Grade ≥ 3) within ≤ 6 months before the start of treatment,
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Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥ II within ≤ 6 months before the start of treatment.
- Patients who have received a live vaccine within 28 days of planned start of trial therapy.
Other exclusions:
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Known hypersensitivity to the active substances or to any of the excipients.
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Presence of a severe concurrent illness or other condition (e.g., psychological, family, sociological, or geographical circumstances) that does not permit adequate follow-up and compliance with the protocol.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University Of Arizona College Of Medicine | Tucson | Arizona | United States | 85724 |
2 | University of California, San Francisco: Helen Diller Family Comprehensive Cancer Center | San Francisco | California | United States | 94158-3214 |
3 | Saint John's Health Center - John Wayne Cancer Institute (JWCI) | Santa Monica | California | United States | 90404 |
4 | Sylvester Comprehensive Cancer Center/ UMHC | Miami | Florida | United States | 33136 |
5 | Lewis Hall Singletary Oncology Center at John D. Archbold Memorial Hospital | Thomasville | Georgia | United States | 31792 |
6 | Rush University Medical Center | Chicago | Illinois | United States | 60612 |
7 | Norton Cancer Institute | Louisville | Kentucky | United States | 40241 |
8 | Oncology Hematology West P.C. dba Nebraska Cancer Specialists | Grand Island | Nebraska | United States | 68893 |
9 | Oncology Hematology West P.C. dba Nebraska Cancer Specialists | Omaha | Nebraska | United States | 68310 |
10 | Atlantic Health System / Morristown Medical Center | Morristown | New Jersey | United States | 07962 |
11 | Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center | New York | New York | United States | 10029 |
12 | Guthrie Medical Group, PC | Sayre | Pennsylvania | United States | 18840 |
13 | Tennessee Oncology Nashville / Sarah Cannon | Nashville | Tennessee | United States | 37203 |
14 | Inova Dwight and Martha Schar Cancer Institute | Fairfax | Virginia | United States | 22031 |
15 | Border Medical Oncology | East Albury | Australia | 2640 | |
16 | Gold Coast Hospital | Southport | Australia | 4215 | |
17 | Melanoma Institute Australia | Sydney | Australia | 2060 | |
18 | Helios Klinikum Erfurt | Erfurt | Germany | 99089 | |
19 | Universitaetsklinikum Essen (AoR) | Essen | Germany | 45147 | |
20 | Universitaetsklinikum Freiburg, Klinik fuer Dermatologie und Venerologie | Freiburg | Germany | 79104 | |
21 | Medizinische Hochschule Hannover (MHH) | Hannover | Germany | 30625 | |
22 | Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel Hautkrebszentrum Kiel | Kiel | Germany | 24105 | |
23 | Universitaetsklinikum Leipzig | Leipzig | Germany | 04103 | |
24 | Universitaetsmedizin der Johannes Gutenberg Universitat Mainz KoeR | Mainz | Germany | 55131 | |
25 | Universitaetsklinikum Mannheim GmbH | Mannheim | Germany | 68167 | |
26 | Klinikum Nürnberg Nord | Nürnberg | Germany | 90419 | |
27 | University Hospital Tuebingen | Tübingen | Germany | 72076 | |
28 | Istituto Di Ricovero E Cura A Carattere Scientifico - Istituto Tumori Giovanni Paolo Ii | Bari | Italy | 70124 | |
29 | Azienda ospedaliera universitaria Bologna | Bologna | Italy | 40138 | |
30 | Fondazione del Piemonte per l'Oncologia, Istituto di Candiolo (IRCCs) | Candiolo | Italy | 10060 | |
31 | Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumpori (IRST) | Meldola | Italy | 47014 | |
32 | Istituto Nazionale Tumori Fondazione Pascale - IRCCS · S.C. Oncologia Medica Melanoma, Immunoterapia Oncologica e Terapie Innovative | Napoli | Italy | 80131 | |
33 | Universita di Siena -Azienda Ospedaliera Universitaria Senese-Policlincio Santa Maria Alle Scotte | Siena | Italy | 53100 | |
34 | AOU Citta della Salute e della Scienza di Torino | Turin | Italy | 10126 | |
35 | Uniwersyteckie Centrum Kliniczne | Gdańsk | Poland | 80214 | |
36 | Szpital Specjalistyczny im. Luwika Rydygiera w Krakowie Sp. z o.o. | Kraków | Poland | 31-826 | |
37 | Centrum Onkologii Ziemii Lubelskiej im. sw. Jana z Dukli | Lublin | Poland | 20-090 | |
38 | Zachodniopomorskie Centrum Onkologii | Szczecin | Poland | 71-730 | |
39 | Specjalistyczny Szpital Onkologiczny NU-MED | Tomaszów Mazowiecki | Poland | 97-200 | |
40 | Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi | Łódź | Poland | 93-513 | |
41 | Hospital Teresa Herrera (CHUAC) | A Coruña | Spain | 15009 | |
42 | Hospital Universitari Germans Trias i Pujol (HUGTP) | Badalona | Spain | 8916 | |
43 | Hospital Clinic de Barcelona | Barcelona | Spain | 08036 | |
44 | Hospital De La Santa Creu I Sant Pau | Barcelona | Spain | 08041 | |
45 | Institut Català d'Oncologia l'Hospitalet | Barcelona | Spain | 08907 | |
46 | Hospital General Universitario Gregorio Maranon | Madrid | Spain | 28007 | |
47 | MD Anderson Cancer Center | Madrid | Spain | 28033 | |
48 | Hospital Universitario Puerta de Hierro - Majadahonda | Madrid | Spain | 28222 | |
49 | Hospital Universitario Marques De Valdecilla | Santander | Spain | 39008 | |
50 | Complejo Hospitalario Universitario De Santiago De Compostela | Santiago De Compostela | Spain | 15706 | |
51 | Hospital Universitario Virgen del Rocio | Sevilla | Spain | 41013 | |
52 | Universitat de Valencia - Hospital Universitari i Politecnic La Fe de Valencia (Hospital La Fe Bulevar Sur) | Valencia | Spain | 46026 | |
53 | The Christie - The Christie NHS Foundation Trust | Manchester | United Kingdom | M20 4BX | |
54 | Royal Cornwall Hospital | Truro | United Kingdom | TR1 3LJ |
Sponsors and Collaborators
- BioNTech SE
- Regeneron Pharmaceuticals
Investigators
- Study Director: BioNTech Responsible Person, BioNTech SE
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- BNT111-01
- 2020-002195-12