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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

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: NCT04526899
Recruitment Status : Recruiting
First Posted : August 26, 2020
Last Update Posted : September 9, 2022
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
BioNTech SE

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
Melanoma Stage III Melanoma Stage IV Unresectable Melanoma Biological: BNT111 Biological: Cemiplimab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label, Randomized Phase II 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
Actual Study Start Date : May 19, 2021
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Objective response rate (ORR) - Arm: BNT111 + cemiplimab [ Time Frame: 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 :
  1. Objective response rate - Arm: BNT111 monotherapy and Arm: Cemiplimab monotherapy [ Time Frame: 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.

  2. Duration of response (DOR) according to RECIST 1.1 [ Time Frame: 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).

  3. Disease control rate (DCR) according to RECIST 1.1 [ Time Frame: 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.

  4. Time to response (TTR) according to RECIST 1.1 [ Time Frame: up to 24 months ]
    TTR defined as the time from randomization to the first objective tumor response (CR or PR) by BICR.

  5. Progression-free survival (PFS) according to RECIST 1.1 [ Time Frame: 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).

  6. ORR according to RECIST 1.1 as assessed by the investigator [ Time Frame: up to 24 months ]
  7. DOR according to RECIST 1.1 as assessed by the investigator [ Time Frame: up to 24 months ]
  8. DCR according to RECIST 1.1 as assessed by the investigator [ Time Frame: up to 24 months ]
  9. TTR according to RECIST 1.1 as assessed by the investigator [ Time Frame: up to 24 months ]
  10. PFS according to RECIST 1.1 as assessed by the investigator [ Time Frame: up to 24 months ]
  11. Overall survival (OS) - Arm: BNT111 + cemiplimab [ Time Frame: up to 48 months ]
    OS defined as the time from randomization to death from any cause.

  12. Occurrence of treatment-emergent adverse events (TEAE) within a patient including Grade ≥3, serious and/or fatal TEAE by relationship [ Time Frame: up to 27 months ]
  13. Occurrence of immune-related adverse events (irAE) [ Time Frame: up to 27 months ]
  14. Occurrence of dose reduction and discontinuation of trial treatment within a patient due to TEAE [ Time Frame: up to 27 months ]
  15. Occurrence of abnormal laboratory parameters (hematology) within a patient [ Time Frame: up to 25 months ]
    Blood samples will be collected for the assessment of hematology parameters.

  16. Changes in laboratory parameters (hematology) compared to baseline [ Time Frame: up to 25 months ]
  17. Occurrence of abnormal laboratory parameters (clinical chemistry) within a patient [ Time Frame: up to 25 months ]
    Blood samples will be collected for the assessment of clinical chemistry parameters.

  18. Changes in laboratory parameters (clinical chemistry) compared to baseline [ Time Frame: up to 25 months ]
  19. Occurrence of abnormal laboratory parameters (coagulation factors) within a patient [ Time Frame: up to 25 months ]
    Blood samples will be collected for the assessment of coagulation factors.

  20. Changes in laboratory parameters (coagulation factors) compared to baseline [ Time Frame: up to 25 months ]
  21. Occurrence of abnormal laboratory parameters (endocrine tests) within a patient [ Time Frame: up to 25 months ]
    Blood samples will be collected for the assessment of endocrine tests.

  22. Changes in laboratory parameters (endocrine tests) compared to baseline [ Time Frame: up to 25 months ]
  23. Occurrence of abnormal laboratory parameters (serology) within a patient [ Time Frame: up to 25 months ]
    Blood samples will be collected for the assessment of serology parameters.

  24. Changes in laboratory parameters (serology) compared to baseline [ Time Frame: up to 25 months ]
  25. Occurrence of abnormal laboratory parameters (urinalysis) within a patient [ Time Frame: up to 25 months ]
    Urine samples will be collected for the assessment of urinalysis parameters.

  26. Changes in laboratory parameters (urinalysis) compared to baseline [ Time Frame: up to 25 months ]
  27. Occurrence of abnormal vital signs parameters (body temperature) within a patient [ Time Frame: up to 25 months ]
    Body temperature (in °C) will be assessed.

  28. Changes in vital signs parameters (body temperature) compared to baseline [ Time Frame: up to 25 months ]
  29. Occurrence of abnormal vital signs parameters (pulse rate) within a patient [ Time Frame: up to 25 months ]
    Pulse rate (in beats per minute [bpm]) will be assessed.

  30. Changes in vital signs parameters (pulse rate) compared to baseline [ Time Frame: up to 25 months ]
  31. Occurrence of abnormal vital signs parameters (blood pressure) within a patient [ Time Frame: up to 25 months ]
    Blood pressure (systolic/diastolic, in mmHg) will be assessed.

  32. Changes in vital signs parameters (blood pressure) compared to baseline [ Time Frame: up to 25 months ]
  33. Occurrence of abnormal vital signs parameters (respiratory rate) within a patient [ Time Frame: up to 25 months ]
    Respiratory rate will be assessed.

  34. Changes in vital signs parameters (respiratory rate) compared to baseline [ Time Frame: up to 25 months ]
  35. 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) [ Time Frame: up to 25 months ]
  36. Mean changes from baseline in scores of the EORTC QLQ C30 functional and symptoms scales [ Time Frame: up to 25 months ]
  37. Time to first clinically meaningful deterioration in global health status score as measured by EORTC QLQ-C30 [ Time Frame: up to 25 months ]
  38. Time to first clinically meaningful deterioration in symptoms and functioning as measured by EORTC QLQ-C30 [ Time Frame: up to 25 months ]


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 (ICF) before any screening procedure.
  • 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 must have histologically confirmed unresectable Stage III or IV (metastatic) cutaneous melanoma and measurable disease by RECIST 1.1.
  • Patients must have confirmed disease progression on/after an approved anti-PD-1 regimen for melanoma as defined by RECIST 1.1.

    1. Previous exposure to approved anti-PD-1 containing regimen for at least 12 consecutive weeks and
    2. 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
    3. Inclusion into this trial must be within 6 months of confirmation of disease progression on anti-PD-1 treatment, regardless of any intervening therapy.
  • Patients should have received pembrolizumab or nivolumab (with/without ipilimumab).
  • Patients should have received at least one but no more than five lines of prior therapy for advanced disease.
  • Patients must be able to tolerate additional anti-PD-1 therapy (i.e., did not permanently discontinue anti-PD-1 therapy due to toxicity).
  • Patients must have known BRAF mutation status.
  • 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.
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
  • Adequate bone marrow function, as defined in the protocol.
  • Patients must have serum lactate dehydrogenase (LDH) ≤ upper limit of normal (ULN).
  • Patient should have adequate hepatic function, as defined in the protocol.
  • 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.
  • Patient should be stable with adequate coagulation, as defined in the protocol.
  • Patients must provide the following biopsy samples:

    1. 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.
    2. 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.
  • 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.
  • 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.
  • 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:

  • Patients must not be pregnant or breastfeeding.
  • Patients must not have history of uveal, acral, or mucosal melanoma.
  • 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.
  • 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).
  • Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are not eligible.
  • 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.

    1. 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.
    2. 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.
    3. 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.
    4. 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:

    1. 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,
    2. 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:

  • 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.
  • 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.
  • Patients who have had a splenectomy.
  • 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.
  • 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:

    1. had radiotherapy or another appropriate therapy for the brain or spinal bone metastases,
    2. have no neurological symptoms that can be attributed to the current brain lesions,
    3. 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),
    4. do not require steroid therapy within 14 days before the first dose of trial treatment,
    5. 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:

    1. angina pectoris requiring anti-anginal medication, uncontrolled cardiac arrhythmia(s), severe conduction abnormality, or clinically significant valvular disease,
    2. QTc (F) prolongation > 480 ms,
    3. arterial thrombosis or pulmonary embolism within ≤ 6 months before the start of treatment,
    4. myocardial infarction within ≤ 6 months before the start of treatment,
    5. 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,
    6. 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:

  • Known hypersensitivity to the active substances or to any of the excipients.
  • 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.

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): NCT04526899


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

Locations
Show Show 55 study locations
Sponsors and Collaborators
BioNTech SE
Regeneron Pharmaceuticals
Investigators
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Study Director: BioNTech Responsible Person BioNTech SE
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Responsible Party: BioNTech SE
ClinicalTrials.gov Identifier: NCT04526899    
Other Study ID Numbers: BNT111-01
2020-002195-12 ( EudraCT Number )
First Posted: August 26, 2020    Key Record Dates
Last Update Posted: September 9, 2022
Last Verified: September 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
Melanoma
Checkpoint inhibitor
Libtayo®
BNT111
Cemiplimab
RNA vaccine
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cemiplimab
Antineoplastic Agents, Immunological
Antineoplastic Agents