A study to investigate the novel agent BNT111 and cemiplimab in combination or as single agents in patients with advanced melanoma that has not responded to other forms of treatment

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BioNTech SE

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Mar 2021 → 21 Nov 2025

Decision date (initial)

2024-04-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-509513-36-00

EudraCT number

2020-002195-12

ClinicalTrials.gov

NCT04526899

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacogenomic, Pharmacodynamic, Safety

Demonstrate the anti-tumor activity of BNT111 + cemiplimab (Arm 1) in terms of objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary objectives 5

1. Assess the anti-tumor activity of each single agent (i.e., monotherapy of BNT111 and cemiplimab) in terms of ORR according to RECIST 1.1
2. Assess additional measures of anti-tumor activity of BNT111 + cemiplimab (Arm 1), and each single agent (i.e., monotherapy of BNT111 and cemiplimab) according to RECIST 1.1.
3. Assess overall survival (OS) of BNT111 + cemiplimab (Arm 1).
4. Assess the safety and tolerability profile of BNT111 + cemiplimab (Arm 1), and each single agent (i.e., monotherapy of BNT111 and cemiplimab).
5. Assess health-related quality of life (HRQoL) of patients treated with BNT111 + cemiplimab (Arm 1) and of patients receiving BNT111 and cemiplimab as single agents as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30).

Conditions and MedDRA coding

Melanoma (Stage III and IV)

Regulatory references

Scientific advice from competent authorities

Swedish Medical Products Agency, Spanish Agency For Medicines And Medical Devices, Paul-Ehrlich-Institut, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-003274-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Patients must sign the written ICF before any screening procedure.
2. Patients must have an ECOG PS ≤1.
3. Patients must be aged ≥ 18 years on the date of signing the ICF.
4. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the trial.
5. Patients must have histologically confirmed, unresectable Stage III or IV (metastatic) cutaneous melanoma and measurable disease by RECIST 1.1
6. Patients must have confirmed disease progression on/after an approved anti-PD-1/PD-L1 regimen for melanoma as defined by RECIST 1.1. a) Previous exposure to approved anti-PD-1/PD-L1 containing regimen for at least 12 consecutive weeks and b) Current radiological progression to be confirmed by two scans 4 to 12 wks apart. If progression is accompanied by new symptoms, or deterioration of PS not attributed to toxicity, one scan is sufficient and c) Inclusion into this trial must be within 6 months of confirmation of disease progression on anti-PD-1/PD-L1 treatment, regardless of any intervening therapy.
7. Patients should have received at least one but no more than five lines of prior therapy for advanced disease.
8. Patients must be able to tolerate additional anti-PD-1/PD-L1 therapy (i.e., did not permanently discontinue anti-PD-1/PD-L1 therapy due to toxicity).
9. Patients must have known BRAF mutation status.
10. Patients with BRAF V600-positive tumor(s) should have received prior treatment with a BRAF inhibitor (alone or in combination with a MEK inhibitor).
11. Adequate bone marrow function as defined by hematological parameters: a) Absolute neutrophil count (ANC) ≥1.5× 10E9/L achieved without the use of granulocyte colony-stimulating factor (G-CSF). b) Hemoglobin ≥9.0 g/dL (5.59 mmol/L). No transfusion is allowed within 1 week prior to treatment initiation. c.) Platelet count ≥100× 10E9/L.
12. Patients must have serum LDH ≤ULN.
13. Patient should have adequate hepatic function, as determined by: a) aspartate aminotransferase (AST) ≤3× ULN; alanine aminotransferase (ALT) ≤3× ULN (regardless of liver involvement); b) serum bilirubin ≤1.5× ULN, except in patients with Gilbert's Syndrome who must have a total bilirubin <3 mg/dL.
14. 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.
15. Patient should be stable with adequate coagulation, as determined by: a) international normalized ratio (INR) or prothrombin time ≤1.5× ULN (unless on therapeutic anticoagulants with values within therapeutic window), and b) activated partial thromboplastin time (aPTT) ≤1.5× ULN (unless on therapeutic anticoagulants with values within therapeutic window).
16. Patients must provide the following biopsy samples: a) 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. b) Patients at selected trial sites: After additional consent, patients should be amenable to pre-treatment and on-treatment PBMC sampling and optional biopsy. If amenable, patients should provide a PBMC sample and optionally a biopsy which contains tumor tissue after failure/stop of last prior trial treatment.
17. Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) test at screening. Patients that are post-menopausal or permanently sterilized can be considered as not having reproductive potential. a) Female patients of reproductive potential must agree to use highly effective contraception during and for 6 months after the last trial drug administration.
18. 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.
19. 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 19

1. Patients must not be pregnant or breastfeeding.
2. Patients must not have history of uveal, acral, or mucosal melanoma.
3. 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 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.
4. 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).
5. Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are not eligible.
6. 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. a) 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. b) 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 antiviral 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. c) 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. d) 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.
7. 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).
8. Current use or use within 3 months prior to trial enrollment of systemic immune suppression including: a) 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, b) other clinically relevant systemic immune suppression.
9. Treatment with other anti-cancer therapy including chemotherapy, radiotherapy, or 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 (refer to exclusion criterion 7).
10. Current evidence of ongoing 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.
11. Patients who have a local infection (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia) which requires systemic antibiotic treatment within 2 wks prior to the first dose of trial treatment.
12. Patients who have had a splenectomy.
13. Patients who have had major surgery (e.g., requiring general anesthesia) within 4 wks before screening, have not fully recovered from surgery, or have a surgery planned during the time of trial participation.
14. 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: a) had radiotherapy or another appropriate therapy for the brain or spinal bone metastases, b) have no neurological symptoms that can be attributed to the current brain lesions, c) have stable brain or spinal disease on the CT or MRI scan within 4 wks before randomization (confirmed by stable lesions on two scans at least 4 weeks apart, the second scan can be carried out during screening), d) do not require steroid therapy within 14 days before the first dose of trial treatment, e) spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.
15. History or current evidence of significant cardiovascular disease including, but not limited to: a) angina pectoris requiring anti-anginal medication, uncontrolled cardiac arrhythmia(s), severe conduction abnormality, or clinically significant valvular disease; b) QTc (F) prolongation >480 ms; c) arterial thrombosis or pulmonary embolism within ≤6 months before the start of treatment; d) myocardial infarction within ≤6 months before the start of treatment; e) 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; f) Grade ≥3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥II within ≤6 months before the start of treatment.
16. Patients who have received a live vaccine within 28 days of planned start of trial therapy.
17. Known hypersensitivity to the active substances or to any of the excipients.
18. 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.
19. Prior treatment with BNT111 and/or with cemiplimab.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response rate (ORR) defined as the proportion of patients in whom a complete response (CR) or partial response (PR) is observed as best overall response by blinded independent central review (BICR)

Secondary endpoints 18

1. Objective response rate (ORR) defined as the proportion of patients in whom a CR or PR is observed as best overall response by BICR.
2. Duration of response (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) defined as the proportion of patients in whom a CR, PR or stable disease (SD; assessed at least 6 weeks +/- 1 week after first dose) is observed as best overall response by BICR.
4. Time to response (TTR) defined as the time from randomization to the first objective tumor response (CR or PR) by BICR.
5. Progression-free survival (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, DOR, DCR, TTR, PFS, as assessed by the investigator.
7. Overall survival (OS) defined as the time from randomization to death from any cause.
8. Occurrence of treatment-emergent adverse events (TEAE) within a patient including Grade ≥3 serious and/or fatal TEAE by relationship.
9. Occurrence of immune-related adverse events (irAE).
10. Occurrence of dose reduction and discontinuation of trial treatment within a patient due to TEAE.
11. Changes in laboratory parameters compared to baseline.
12. Occurrence of abnormal laboratory parameters within a patient.
13. Changes in vital signs parameters compared to baseline.
14. Occurrence of abnormal vital signs parameters within a patient.
15. Mean changes from baseline in the global health status score of the EORTC- QLQ-C30.
16. Mean changes from baseline in scores of the EORTC QLQC30 functional and symptoms scales.
17. Time to first clinically meaningful deterioration in global health status score as measured by EORTC QLQ-C30.
18. Time to first clinically meaningful deterioration in symptoms and functioning as measured by EORTC QLQ-C30.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BioNTech SE

Sponsor organisation

BioNTech SE

Address

An Der Goldgrube 12, Oberstadt Oberstadt

City

Mainz

Postcode

55131

Country

Germany

Scientific contact point

Organisation

BioNTech SE

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

BioNTech SE

Contact name

Clinical Trial Information Desk

Third parties 8

Locations

4 EU/EEA countries · 39 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 38 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications