Non-comparative Study of IFX-1 Alone or IFX-1+Pembrolizumab in Patients With Locally Advanced or Metastatic cSCC.

This is an open-label, "non comparative", non-randomized, Phase II study. Patients will be enrolled in 2 treatment arms

This is an open-label, non-randomized, Phase II study. Patients will be enrolled in 2 treatment arms (Arm A: Vilobelimab monotherapy; Arm B: Vilobelimab + pembrolizumab combination therapy), both consisting of 2 stages whereas Arm B starts with a safety run in portion. Enrollment follows an optimal Simon's 2-stage design with an interim analysis of treatment response after Stage 1 prior to patient enrollment into Stage 2.

Arm B will start after ≥3 patients have been treated in Arm A and no toxicity concerns have emerged. In a safety run-in part of Arm B, escalating doses of Vilobelimab will be investigated in combination with pembrolizumab in order to identify the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D). Patients will be treated until progression, occurrence of unacceptable toxicity, or treatment discontinuation for any other reason.

Eligibility Criteria:
Inclusion Criteria:

* At least 18 years of age on day of signing informed consent
* Patients with biopsy-proven, histologically or cytologically confirmed (a.) locally advanced cSCC not amenable for curative treatment or (b.) metastatic cSCC. Patients must have been treated with all approved therapies for (a.) inoperable locally advanced cSCC contraindicated for radiation therapy or (b.) metastatic cSCC. All patients to be included must have progressed on PD-1- or PD-L1-inhibitory antibody therapy.
* Patients must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:

  1. Has received ≥2 doses of an anti-PD-1/L1 mAb that has been approved for treatment of cSCC or any solid tumor
  2. Has demonstrated PD/iCPD after PD-1/L1 inhibitor treatment as defined by RECIST v1.1/iRECIST. The initial evidence of disease progression is to be confirmed by a second assessment ≥4 weeks from the date of the first documented disease progression, unless there is rapid clinical progression.
  3. Disease progression has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.
* The PD-1-/PD-L1 infusion must have been the most recent treatment for locally advanced or metastatic cSCC.
* In addition to providing the material for ensuring the diagnosis as stated in inclusion criterion 2a for patients with locally advanced cSCC, patients must consent to undergo the following biopsies (at each time point a punch biopsy of externally visible cSCC lesions or a biopsy of material from accessible metastases) for biomarker assessments:

  1. At baseline prior to the first administration of the investigational therapy and if possible, within 7 days prior to initiation of study treatment administration (mandatory for all patients)
  2. For Stage 2 patients only: on Cycle 2 Day 1 (±3 days) (mandatory)
  3. For Stage 2 patients only: at the time of CR/iCR/PR/iPR (optional, to be conducted only if the investigator considers this biopsy as clinically possible and potentially informative)
  4. For Stage 2 patients only: At the time of tumor progression (optional, to be conducted only if the investigator considers this biopsy as clinically possible and potentially informative).
* Patients must have the following minimum washout before first study treatment administration from previous treatments:

  1. ≥4 weeks for mAbs, systemic cytotoxic anticancer therapy, treatment with other anticancer investigational agents
  2. ≥3 weeks for local radiation therapy
* Eastern Cooperative Oncology Group performance status (ECOG PS) status of ≤1
* Adequate organ function
* Patient (or legally acceptable representative if applicable) provides written informed consent for the study.

Exclusion Criteria:

* Patients with limited cSCC, who do not require systemic therapy
* Has known active central nervous system metastases and/or carcinomatous meningitis.

Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for ≥4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for ≥14 days prior to first dose of study treatment.

* Has a diagnosis of immunodeficiency or autoimmune disease, or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 3 weeks prior the first dose of study treatment
* Patients who have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or co-inhibitory T cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen 4, OX 40, CD137) and was discontinued from that treatment due to a ≥Grade 3 irAE
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab or IFX-1 and/or any of their excipients or had a severe (≥Grade 3) infusion-related reaction to treatments with other mAbs
* Patients who fulfil inclusion criterion 6 (washout times) but who have not recovered from side effects of such therapies
* Has received a live vaccine within 30 days prior to the first dose of study treatment
* Patients who have undergone major surgery \<4 weeks prior to starting study treatment
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
* Patients with known ≥Grade 3 (per National Cancer Institute common terminology criteria for adverse events \[NCI CTCAE\] v5.0 criteria) active systemic or cutaneous viral, bacterial, or fungal infection
* Patients with known history of Hepatitis B or C infections or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
* Patients who have a history of human immunodeficiency virus infection
* Patients who have a history of interstitial lung disease
* Patients who have had an allogeneic tissue/solid organ transplant
* Patients with a history of other malignancies during the past 5 years.
* Patients who are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 3 months after the last dose of IFX-1 or 120 days after the last dose of pembrolizumab
* Women of childbearing potential (WOCBP) who have a positive serum pregnancy test result within 7 days before treatment
* Male patients and WOCBP who do not agree to practice an effective method of contraception during study and until 3 months after last dose of IFX-1 or 120 days after last dose of pembrolizumab
* Patients with congestive heart failure, Class III or IV, by New York Heart Association criteria
* Patients with any serious underlying medical condition that would impair their ability to receive or tolerate the planned treatment
* Patients with dementia or altered mental status that would preclude understanding and rendering of informed consent document