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-PD1-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
- Patients must sign the written informed consent form (ICF) before any screening
- 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 approved anti-PD1 regimen
for melanoma as defined by RECIST 1.1 and further defined according to the Society for
ImmunoTherapy of Cancer (SITC) Immunotherapy Resistance Taskforce:
1. Previous exposure to approved anti-PD1 containing regimen for at least 12
consecutive weeks and
2. Radiological progression to be confirmed by 2 scans 4-12 weeks apart. If
progression is accompanied by new symptoms, or deterioration of performance
status not attributed to toxicity, one scan is sufficient.
3. Progression must be while on treatment with approved anti-PD1 regimen for
melanoma or within 6 months of discontinuing anti-PD1 treatment, and regardless
of any intervening therapy.
- Patients should have received pembrolizumab or nivolumab (with/without ipilimumab).
- Patients should have received at least 1 but no more than 5 lines of prior therapy for
- Patients must be able to tolerate additional anti-PD1 therapy (i.e., did not
permanently discontinue anti-PD1 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: Patients with BRAF
V600-positive tumors with no clinically significant tumor-related symptoms or evidence
of rapidly progressive disease are not required to be treated with a BRAF inhibitor
(alone or in combination with a MEK inhibitor) based on investigator's decision.
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
- Adequate bone marrow function as defined in the protocol.
- Patients must have serum lactate dehydrogenase (LDH) ≤ 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 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 fresh biopsy collected before Cycle
1 Day 1, preferably derived from advanced disease stage, or archival tissue (not
older than 3 years).
2. Patients at selected trial sites: 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
- 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. For a definition of adequate contraception.
- 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 suggest risk for immune-related adverse events (irAEs).
- 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 antiviral regimen)
are permitted. For patients with controlled HIV infection, monitoring will be
performed per local standards.
2. Patients with known hepatitis B (HepBsAg+) 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 antibody positive (HCV Ab+) 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.
- 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.
- 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 Common Terminology Criteria for Adverse Events (CTCAE version 5.0)
Grade >1 toxicity before the start of treatment, except for hair loss, hearing loss,
or laboratory abnormalities not considered clinical significant per investigator's
discretion, and those Grade 2 toxicities listed as permitted in other eligibility
criteria. Patients with Grade 2 neuropathy may be eligible at investigator's
- 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, or 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
2. have no neurological symptoms that can be attributed to the current brain
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
4. do not require steroid therapy within 14 days before the first dose of trial
5. spinal bone metastases are allowed, unless imminent fracture or cord compression
- History or current evidence of significant cardiovascular disease including, but not
1. angina pectoris requiring anti-anginal medication, uncontrolled cardiac
arrhythmia(s), severe conduction abnormality, or clinically significant valvular
2. QTc (F) prolongation >480 ms,
3. arterial thrombosis or pulmonary embolism within ≤6 months before the start of
4. myocardial infarction within ≤6 months before the start of treatment,
5. pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥2),
non-malignant pleural effusion (CTCAE Grade ≥2) or malignant pleural effusion
(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
- 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.