| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041823 |
| E.1.2 | Term | Squamous cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Arm A:
• To assess the antitumor activity of IFX-1
Arm B:
• To determine the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D)
• To assess the antitumor activity of IFX-1 + pembrolizumab
• To assess the safety profile of IFX-1 + pembrolizumab |
|
| E.2.2 | Secondary objectives of the trial |
Arm A:
• To further assess efficacy of IFX-1
• To assess the safety profile of IFX-1
• To assess the pharmacokinetics (PK) of IFX-1
• To monitor the immunogenicity of IFX-1
• To assess the impact of IFX-1 on quality of life (QoL)
Arm B:
• To further assess efficacy of IFX-1
• To assess the PK of IFX-1
• To monitor the immunogenicity of IFX-1
• To assess the impact of IFX-1 + pembrolizumab on QoL |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years of age on day of signing informed consent
2. 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.
3. Patients must have progressed on treatment with an anti PD1/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:
a) Has received ≥2 doses of an anti-PD-1/L1 mAb that has been approved for treatment of cSCC or any solid tumor
b) Has demonstrated progressive disease (PD)/confirmed PD (iCPD) after PD-1/L1 inhibitor treatment as defined by modified response evaluation criteria in solid tumors (RECIST) version 1.1/RECIST for immune-base therapeutics (iRECIST). The initial evidence of PD is to be confirmed by a second assessment ≥4 weeks from the date of the first documented PD, unless there is rapid clinical progression.
c) Disease progression has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.
4. The PD-1-/PD-L1 infusion must have been the most recent treatment for locally advanced or metastatic cSCC.
5. 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:
a) 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)
b) For Stage 2 patients only: on Cycle 2 Day 1 (±3 days) (mandatory)
c) 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)
d) 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).
For all biopsies intended to analyze biomarkers, it is important to obtain sufficient material to conduct the biomarker program, which needs to be the equivalent to a 4 mm x 4 mm punch biopsy. If biopsies for biomarkers are not feasible due to the complete absence of any suitable cutaneous or metastatic lesions, then this is not an exclusion criterium. However, this needs to be documented and confirmed by the investigator. The biopsied lesion is not considered a target lesion.
6. Patients must have the following minimum washout before first study treatment administration from previous treatments:
• ≥4 weeks for mAbs, systemic cytotoxic anticancer therapy, treatment with other anticancer investigational agents
• ≥3 weeks for local radiation therapy
Note: Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease.
7. Eastern Cooperative Oncology Group performance status (ECOG PS) status of ≤1
8. Adequate organ function:
Hematological: Absolute neutrophil count ≥1500/μL; Platelets ≥100 000/μL; Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L
Renal: Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for patient with creatinine levels >1.5 × institutional ULN
Hepatic: Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels >1.5 × ULN; AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for patients with liver metastases)
Coagulation: International normalized ratio OR PT & aPTT ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
9. Patient (or legally acceptable representative if applicable) provides written informed consent for the study. |
|
| E.4 | Principal exclusion criteria |
1. Patients with limited cSCC, who do not require systemic therapy
2. 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.
3. 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
4. Patients who have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis
5. 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 immune-related adverse event (irAE)
6. 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
7. Patients who fulfil inclusion criterion 6 (washout times) but who have not recovered from side effects of such therapies
8. Has received a live vaccine within 30 days prior to the first dose of study treatment
9. Patients who have undergone major surgery <4 weeks prior to starting study treatment
10. 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
Note: Patients who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
11. 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
12. 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.
13. Patients who have a history of human immunodeficiency virus infection
14. Patients who have a history of interstitial lung disease
15. Patients who have had an allogeneic tissue/solid organ transplant
16. Patients with a history of other malignancies during the past 5 years. Note: The following are exempt from the 5-year limit: curatively resected basal cell carcinoma, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy.
17. 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
18. Women of childbearing potential (WOCBP) who have a positive serum pregnancy test result within 7 days before treatment. Note: Post-menopausal women must be amenorrheic for ≥12 months to be considered not WOCBP.
19. 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
20. Patients with congestive heart failure, Class III or IV, by New York Heart Association criteria
21. Patients with any serious underlying medical condition that would impair their ability to receive or tolerate the planned treatment
22. Patients with dementia or altered mental status that would preclude understanding and rendering of informed consent document |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Arm A:
• Investigator assessed best overall response rate (ORR) for IFX-1, with response being defined as best response of CR/confirmed CR (iCR) or PR/confirmed PR (iPR) per modified RECIST v1.1/iRECIST.
Arm B:
• Frequency of dose-limiting toxicities (DLTs) by dose cohort
• Investigator assessed best ORR per modified RECIST v1.1/iRECIST for IFX-1 + pembrolizumab
• Frequency, severity, and investigational new drug (IND) attribution of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) according to Medical Dictionary for Regulatory Activities (MedDRA) coding (version valid at time of reporting) and the NCI CTCAE grading system (version 5.0, 27 November 2017) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks for disease assessment. |
|
| E.5.2 | Secondary end point(s) |
Arm A:
• Response (CR/iCR/PR/iPR) and stable disease (SD) duration
• Disease control rate (CR/iCR+PR/iPR+SD)
• Progression-free survival (PFS)
• Overall survival (OS)
• Frequency, severity, and IND attribution of TEAEs and SAEs according to MedDRA coding (version valid at time of reporting) and the NCI CTCAE grading system v5.0
• Maximum (Cmax) and trough concentration (Ctrough) of IFX-1, and concentration at the infusion end (Clast)
• Area under the IFX-1 concentration time curve from Time 0 to Day 4 (AUC0-day4) and Time 0 to Day 8 (AUC0-day8)
• Development of human antidrug antibodies (ADAs) against IFX-1
• Changes in QoL as per the European Organisation for Research and Treatment of Cancer (EORTC)-QoL questionnaire (QLQ)-C30 total score
Arm B:
• Response (CR/iCR/PR/iPR) and SD duration
• Disease control rate (CR/iCR+PR/iPR+SD)
• PFS
• OS
• Cmax, Ctrough, and Clast of IFX-1
• AUC0-day4 and AUC0-day8 for IFX-1
• Development of human ADAs against IFX-1
• Changes in QoL as per the EORTC-QLQ-C30 total score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 6 weeks for disease assessment.
In between timepoints depending on central lab sampling/analysis, QoL questionnaires and SAE monitoring. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| optimal Simon’s 2-stage design (interim analysis after Stage 1 prior to enrollment into Stage 2) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| United States |
| Belgium |
| France |
| Germany |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS
The EOS for the individual patient is defined as the date of the last contact of the 12 months followup period, date of death, date of consent withdrawal from study participation, or the date of last contact when patients are lost to follow-up |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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