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

Phase 2

Terminated

Conditions: SCC - Squamous Cell Carcinoma of Skin

Interventions: Drug: Vilobelimab
Drug: Vilobelimab + pembrolizumab combination therapy

Registration Number: NCT04812535

Lead Sponsor: InflaRx GmbH

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

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 30

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A:	Vilobelimab	Vilobelimab monotherapy; Vilobelimab monotherapy was administered as a 30-minute (-5 / +10 minutes) intravenous infusion as follows: 800 mg on Days 1, 4, 8, and 15, followed by 1600 mg Q2W starting on Day 22 of Cycle 1 until end of treatment (EOT)
Arm B: Regimen 1:	Vilobelimab + pembrolizumab combination therapy	Vilobelimab + pembrolizumab combination therapy; Vilobelimab was administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 400 mg on Days 1, 4, 8, and 15, followed by 800 mg Q2W starting on Day 22 of Cycle 1 until EOT. Vilobelimab treatment was combined with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle
Arm B: Regimen 2:	Vilobelimab + pembrolizumab combination therapy	Vilobelimab + pembrolizumab combination therapy; Vilobelimab was administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 600 mg on Days 1, 4, 8, and 15, followed by 1200 mg Q2W starting on Day 22 of Cycle 1 until EOT. Vilobelimab treatment was combined with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle
Arm B: Regimen 3:	Vilobelimab + pembrolizumab combination therapy	Vilobelimab + pembrolizumab combination therapy; Vilobelimab was administered as a 30-minute (-5/+10 minutes) intravenous infusion as follows: 800 mg on Days 1, 4, 8, and 15, followed by 1600 mg Q2W starting on Day 22 of Cycle 1 until EOT. Vilobelimab treatment was combined with pembrolizumab, administered as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 400 mg starting at Day 8 of Cycle 1 and then Q6W on Day 1 of each treatment cycle

Primary Outcome Measures

Name	Time	Method
Dose-limiting Toxicity (DLT) - Arm B	Cycle 1 Day 1 - Cycle 1 Day 36	Frequency of dose-limiting toxicities (DLTs) by dose cohort.
Best Overall Response Rate (Best ORR) - Arm A and Arm B	Up to 36 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and immunologic RECIST (iRECIST) for target lesions and assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): ≥30% decrease in the sum of the diameters of target lesions; Best Overall Response (OR) = CR + PR, from the start of the treatment until PD/recurrence.

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate - Arm A and Arm B	Up to 36 months	Disease control rate is defined as the relative number of patients achieving stable disease (SD/iSD), CR/iCR or PR/iPR according to modified RECIST v1.1 (including clinical response)/iRECIST response.
Progression-free Survival (PFS)- Arm A and Arm B	Up to 36 months	PFS is defined as the time from first study treatment administration to progression (i.e. PD, iUPD, iCPD) or death. Patients without progression are censored at their last visit/study treatment administration.
Overall Survival (OS)- Arm A and Arm B	Up to 36 months	Overall survival is defined as the time from first study treatment administration to death. Patients alive when they discontinue the study are censored at their last recorded date of being alive.
Antidrug Antibodies (ADAs) - Arm A and Arm B	Up to 27 months	Development of human antidrug antibodies (ADAs) against Vilobelimab. In contrast to the time frame of the secondary efficacy outcome measures (3.-5., 7.-8), which were reported until EOS (up to 36 months), the time frames of ADAs (6.) and PK (9.) are measured (only) until first FU. Therefore, the time frame is different, i.e. 24 months of treatment until EOT + (approx.) 12 weeks/3 months until first FU up to 27 months.
Plasma Concentration of Vilobelimab - Arm A and Arm B	Up to 27 months	The plasma concentration of vilobelimab was assessed at different time points pre- and post-dose. The post-dose Cycle 1 Day 22 values correspond to Cmax and the pre-dose Cycle 1 Day 8, pre-dose Cycle 1 Day 22, pre-dose Cycle 2 Day 1 and per-dose Cycle 5 Day 1 values to Ctrough. In contrast to the time frame of the secondary efficacy outcome measures (3.-5., 7.-8), which were reported until EOS (up to 36 months), the time frames of ADAs (6.) and PK (9.) are measured (only) until first FU. Therefore, the time frame is different, i.e. 24 months of treatment until EOT + (approx.) 12 weeks/3 months until first FU up to 27 months.
Quality of Life (QoL) - Arm A and Arm B	Up to 36 months	The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 version 3.0 measures the different aspects that define the quality of life of cancer patients or survivors. The reported total score ranges from 0 to 100 whereas a higher score represents a higher response level. The total score was calculated as mean of all 15 single scores. It was only calculated if all 15 single scores were non-missing (for more information see Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001.). The absolute changes from baseline are presented.
Response (Complete Response (CR) / CR According to iRECIST (iCR) / Partial Response (PR) / PR According to iRECIST (iPR)) and Stable Disease (SD) Duration - Arm A and Arm B	Up to 36 months	Duration of stable disease is defined as the time from first diagnosis of response or stable disease (i.e., CR/iCR/PR/iPR/SD/iSD) to progression (i.e. progressive disease (PD), unconfirmed progressive disease according to iRECIST (iUPD), confirmed progressive disease (iCPD)) or death. Responding and stable patients without progression are censored at their last visit/study treatment administration. Patients who never respond or have a stable disease are excluded from this analysis.

Trial Locations

Locations (25): Sylvester Comprehensive Cancer Center
🇺🇸
Miami, Florida, United States
UC San Diego Moores Cancer Center
🇺🇸
La Jolla, California, United States
Inova Schar Cancer Institute
🇺🇸
Fairfax, Virginia, United States
St. Augustinus Hospital
🇧🇪
Wilrijk, Belgium
CHU APHM la Timone / Aix Marseille University, Dermatology and Skin Cancer Department
🇫🇷
Marseille, France
St. Louis Hospital
🇫🇷
Paris, France
University Hospital Erlangen, Department of Dermatology
🇩🇪
Erlangen, Germany
University Hospital Center of Poitiers, Department of Oncology
🇫🇷
Poitiers, France
University Hospital Hamburg-Eppendorf
🇩🇪
Hamburg, Germany
University Hospital Leipzig, Department of Dermatology, Venereology and Allergology
🇩🇪
Leipzig, Germany
MD Anderson International Cancer Center Spain
🇪🇸
Madrid, Spain
ICO Hospitalet
🇪🇸
Barcelona, Spain
University Clinical Hospital of Salamanca
🇪🇸
Salamanca, Spain
University Hospital Antwerp (UZA)
🇧🇪
Edegem, Belgium
University Hospital Vall d'Hebron
🇪🇸
Barcelona, Spain
Frankfurt University Clinic, Department of Dermatology, Venereology and Allergology
🇩🇪
Frankfurt, Germany
University Hospital Tuebingen, Department of Dermatology
🇩🇪
Tuebingen, Germany
Regional University Hospital of Malaga
🇪🇸
Málaga, Spain
Anschutz Cancer Pavilion
🇺🇸
Aurora, Colorado, United States
Orlando Health, Inc.
🇺🇸
Orlando, Florida, United States
H. Lee Moffitt Cancer Center & Research Institute
🇺🇸
Tampa, Florida, United States
University Hospital Center of Grenoble Alpes, Department of Dermatology
🇫🇷
Grenoble, France
University Hospital Regensburg, Clinic and Policlinic for Dermatology
🇩🇪
Regensburg, Germany
South Lyon Hospital Center
🇫🇷
Lyon, France
University Duisburg-Essen, University Hospital Essen, Department of Dermatology
🇩🇪
Essen, Germany