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-programmed death protein 1 (PD-1)/anti-programmed death ligand 1 (PD-L1)-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 will be randomized in a 2:1:1 ratio to Arm 1 (BNT111 + cemiplimab) and calibrator Arm 2 (BNT111 monotherapy), and Arm 3 (cemiplimab monotherapy). Patients in single agent calibrator arms (Arms 2 and 3), who experience centrally verified disease progression under single agent treatment, may be offered addition of the other compound to the ongoing treatment after re-consent.

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 v1.1.

• Patients must have confirmed disease progression on/after an approved anti-PD-1/PD-L1 regimen for melanoma as defined by RECIST v1.1.

  1. Previous exposure to approved anti-PD-1/PD-L1 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/PD-L1 treatment, regardless of any intervening therapy.

• 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/PD-L1 therapy (i.e., did not permanently discontinue anti-PD-1/PD-L1 therapy due to toxicity).

• Patients must have known B-Raf proto-oncogene (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 mitogen-activated protein kinase kinase [MEK] inhibitor).

  • 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 performance status (PS) <=1.

• Adequate bone marrow function, as defined by hematological parameters (as defined in the protocol).

• Patients must have serum lactate dehydrogenase <= upper limit of normal.

• Patient should have adequate hepatic function, as defined in the protocol.

• Patient should have adequate kidney function, assessed by the estimated glomerular filtration rate >= 30 mL/min using the chronic kidney disease epidemiology collaboration 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 Cycle1 Day1, 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 pre-treatment and on-treatment peripheral blood mononuclear cell (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.

• 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 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 (HIV), 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 polymerase chain reaction (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).

• 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.

• Current evidence of ongoing National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (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 clinically 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 computed tomography or magnetic resonance imaging scan within 4 weeks before randomization (confirmed by stable lesions on two scans at least 4 weeks apart, the second scan can be carried out during screening),
  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.

• 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.

• Prior treatment with BNT111 and/or with cemiplimab.

Inclusion criteria for entering add-on therapy

• Patients must have confirmed disease progression on monotherapy in Arm 2 or 3 of the trial.

  1. An initial radiological progression needs to be verified by BICR.
  2. Radiological progression to be confirmed by two scans 4 to 12 weeks apart unless initial progression is accompanied by new symptoms, or deterioration of PS not attributed to toxicity, in which case one scan is sufficient.

• Patients must sign a new ICF to continue with add-on therapy. Informed consent must be documented before any add-on-specific procedure is performed.

• WOCBP must have a negative serum (beta-hCG) at baseline. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential.

• Female patients of reproductive potential must agree to use adequate 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 for entering add-on therapy

• Prior toxicity related to trial medication should have resolved to NCI-CTCAE v5.0 Grade ≤ 1 before the start of add-on treatment and may not have led to permanent discontinuation.

• The time between confirmed PD on monotherapy and start of add-on therapy shall not exceed 6 weeks.

• Current evidence of new or growing brain or spinal metastases at baseline (lesions that remained stable during initial treatment are allowed).

• Systemic immune suppression:

  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.

• Presence of cardiovascular, renal, hepatic or any other disease that in the investigator's opinion, may increase the risks associated with trial participation or require treatments that may interfere with the conduct of the trial or the interpretation of trial results.