Open Label, Multicenter Phase II Study Of The C5a-Antibody IFX-1 Alone or IFX-1 + Pembrolizumab In Patients With PD-1- or PD-L1-Resistant/Refractory Locally Advanced Or Metastatic Cutaneous Squamous Cell Carcinoma (CSCC)
Clinical Trial Information
Trial Contact: Frankos, Marie; Donaldson, Karin M; Grofsik, Kiera; Caldwell, Chloe M
Primary objective: • To assess the antitumor activity of IFX-1
Secondary objectives: • To further assess efficacy of IFX-1 • To assess the safety profile of IFX-1 • To assess the PK of IFX-1 • To monitor the immunogenicity of IFX-1 • To assess the impact of IFX-1 on quality of life (QoL)
Other objectives: • To describe the TME in primary tumor samples and metastases • To assess pharmacodynamic effects of IFX-1 in skin tumors and peripheral blood • To describe oncogenic alterations of the tumor at baseline
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 treated with all approved therapies for metastatic disease and progressed on PD-1- or PD-L1-inhibitory antibody therapy
a. Locally advanced cSCC not amenable for curative treatment:
Patients must have disease that is considered inoperable or medical contraindication to surgery or radiation or have not achieved disease control with these treatments.
Patients must have ≥1 measurable baseline lesion in which the longest diameter and the perpendicular diameter are both ≥10 mm on digital medical photography.
Note: Non-measurable disease is defined as either uni-dimensionally measurable lesions, tumors with margins that are not clearly defined, or lesions with maximum perpendicular diameters <10 mm. Patients without measurable disease at baseline are not eligible for the study. • Surgery must be deemed contraindicated in the opinion of an expert in micrographics controlled surgery (Moh’s surgery, e.g., specifically trained dermatologic surgeon), a head and neck surgeon, or a plastic surgeon. A copy of the surgeon’s consultation note from a clinical visit within 60 days of enrollment must be submitted. Acceptable contraindications in the surgeon’s note include: o cSCC that has recurred in the same location after ≥2 surgical procedures and curative resection is deemed unlikely
o cSCCs with relevant local invasion that precludes complete resection
o cSCCs in anatomically challenging locations for which surgery may result in severe disfigurement or dysfunction (e.g., removal of all or part of a facial structure, such as nose, ear, or eye; or requirement for limb amputation)
Other conditions deemed to be contraindicating for surgery must be discussed with the medical monitor before enrolling the patient • Patients must be deemed as not appropriate for radiation therapy. Specifically, patients must meet ≥1 of the following criteria:
o A patient previously received radiation therapy for cSCC, such that further radiation therapy would exceed the threshold of acceptable cumulative dose, per the radiation oncologist. A copy of the radiation oncologist’s consultation note, from a clinical visit within 60 days of enrollment, must be submitted.
o Judgment of radiation oncologist that such tumor is unlikely to respond to therapy. A copy of the radiation oncologist’s consultation note, from a clinical visit within 60 days of enrollment, must be submitted.
o A clinic note from the investigator indicating that an individualized benefit-risk assessment was performed by a multidisciplinary team (consisting of, at minimum, a radiation oncologist AND EITHER a medical oncologist with expertise in cutaneous malignancies OR a dermato-oncologist, OR a head and neck surgeon) within 60 days prior to enrollment in the proposed study, and the radiation therapy was deemed to be contraindicated • Acceptable contraindications to radiation therapy in the investigator’s note for patients who have not received any prior radiation include:
o cSCCs in anatomically challenging locations for which radiation therapy would be associated with unacceptable toxicity risk in the context of the patient’s overall medical condition in the opinion of the multidisciplinary team (e.g., a neck tumor for which radiation therapy would result in potential need for a percutaneous gastrostomy tube). A copy of the investigator’s consultation note documenting the multidisciplinary assessment must be submitted.
o Other conditions deemed to be contraindicating for radiation therapy must be discussed with the medical monitor before enrolling the patient. • All patients in either group must consent to provide archived or newly obtained tumor material (either formalin-fixed, paraffin-embedded block or 10 unstained slides) for central pathology review for confirmation of diagnosis of cSCC. This material must be received by the sponsor prior to enrollment. • An investigator note which states that the natural history of the patient’s advanced cSCC would likely be life-threatening within 3 years with currently available management options outside of a clinical study
b. Metastatic cSCC treated with all approved therapies for metastatic disease:
Patients are required to have histologic confirmation of distant cSCC metastases (e.g., lung, liver, bone, or lymph node).
Patients must have ≥1 baseline measurable lesion ≥10 mm in maximal diameter (1.5 cm for lymph nodes) according to RECIST v1.1 criteria (Appendix 3; Eisenhauer et al., 2009).
Note: In the case of a patient with metastatic disease that does not meet target lesion criteria by RECIST v1.1 criteria (e.g., bone only lesions, perineural disease) and with externally visible cSCC target lesions, Appendix 3 may be used, in which bi-dimensional measurements are required (at baseline, perpendicular diameters must both be ≥10 mm), after communication with and approval from medical monitor. The patient would then be enrolled with the plan to follow externally visible disease as target lesion(s), and metastatic lesions that are not measurable by RECIST v1.1 criteria may be followed as non-target lesions.
Note: There is no limit to the number of prior treatment regimens.
3. Patients must have progressed on treatment with an anti-PD1/L1 mAb administered as monotherapy. 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 any solid tumor
b. Has demonstrated PD/iCPD after PD-1/L1 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, in the absence of rapid clinical progression.1,2
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 biopsies (punch biopsy) of externally visible cSCC lesions at baseline (within 7 days prior to initiation of study treatment administration), Cycle 2 Day 1 (±3 business days), at time of CR/iCR/PR/iPR, at time of tumor progression, and at other time points that may be clinically indicated in the opinion of 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: a. ≥4 weeks for mAbs, systemic cytotoxic anticancer therapy, treatment with other anticancer investigational agents
b. ≥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
Adequate organ function:
System Laboratory Value
Hematological Absolute neutrophil count ≥1500/µL Platelets ≥100 000/µL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
Creatinine OR Measured or calculatedb 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)
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
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCL=creatinine clearance; GFR=glomerular filtration rate; PT=prothrombin time; ULN=upper limit of normal. a Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks. b CrCl should be calculated per institutional standard.
9. Patient (or legally acceptable representative if applicable) provides written informed consent for the study.