Implementation and execution of a phase-II clinical trial investigating the efficacy of the immunocytokine F16-IL2 plus or minus paclitaxel for the therapy of patients with metastatic Merkel cell carcinoma (MCC).
Study design: Immune modulating therapies for cancer are anticipated to increase progression-free (PFS) and overall survival (OS), but not necessarily tumor response. Thus, the primary endpoint of the present study is progression-free survival; secondary endpoints are response to treatment, quality of life and induction of MCC-specific T cell responses. Response to treatment will be evaluated using both the recently established immune-related Response Criteria (irRC) as well as RECIST 1.1 and the respective local diagnosis will be confirmed by an external independent radiologic review. Notably, phase-II trials with time-to-event endpoints (PFS or OS) should be randomized, since randomized designs reduce the potential for bias existent incomparisons with historical controls. On the other hand, a randomized design substantially increases the sample size requirements. To overcome this limitation which is mandatory for a very rare cancer like MCC, we use the randomized phase-II screening design of Rubinstein (30). This design yields statistical properties and sample sizes appropriate to phase-II studies, and is particularly suitable for preliminary comparisons of an experimental study arm which is composed of a standard regimen (paclitaxel) plus an experimental agent (F16-IL2) with a study arm using the standard regimen alone (paclitaxel). With regard to sample size, 84 events would be required to observe when using the logrank test aiming at type I (significance level, α) and type II (power, β) error rates of 10% each, and a hazard ratio of D=1.75 (medium PFS = 5.25 months versus 3 months). This event number corresponds to 90 patients to be enrolled when accrual is 2 years with a follow-up time of 6 months. Patient inclusion / exclusion criteria: Inclusion criteria include histological confirmed MCC not amendable to surgery, no systemic therapy for MCC within the past 4 weeks, and informed consent; exclusion criteria include inadequate organ function, and a life expectancy of less than 3 months.
Treatment regimen and tumor assessment:
Arm A: Paclitaxel 90 mg/m2 i.v. on d1, d8 and d15, repeat every 4 weeks
F16-IL2 35 x 106 IL2-equivalents i.v. on d1, d8 and d15, repeat every 4 weeks
Arm B: Paclitaxel 90 mg/m2 i.v. on d1, d8 and d15, repeat every 4 weeks
Staging by CT scans of thorax and abdomen as well as the involved lymph node basins (if not included) will be performed prior to therapy, in week 12 and every 8 weeks thereafter until disease progression is detected.Physical examinations as well as routine lab work up will be done prior to administration of each therapy course. Sampling for translational research and life quality assessment: Sampling for biomarker studies (peripheral blood mononuclear cells, serum, whole blood, tumor biopsies) will be done prior to therapy, in week 12, and every 8 weeks there after until disease progression. In addition, at these time points the patient’s quality of life will be evaluated using a standard questionnaire (EORTC QLQ30).
PHG will manufacture in its GMP facility sufficient amount of clinical-grade F16-IL2 for the execution of the clinical trial, and ship the required doses to the participating clinical centers. PHG owns a 2’000 m² GMPProduction Facility, authorized to produce antibodies in mammalian cells.To ensure fast enrollment of patients with advanced MCC, clinical trial sites were distributed across Europe and were selected for their known expertise in MCC and immunotherapy. Most of the clinical partners have been already cooperating in trials testing immune modulating therapies (e.g. EORTC 18071). The present trial will be conducted according to ICH-GCP guidelines. Accordingly, the protocol will be reviewed by the respective ethics committees and institutional review boards, as well as registered at the European Clinical Trials Database(EudraCT). Additionally, both an external independent Ethics Advisor and an Ethics Board will be appointed to oversee and monitor the ethical concerns of the project in general and the clinical trial in particular.
Philogen will act as sponsor of the trial, and will offer practical and personal support for its execution (preparation of the application in close collaboration with the clinical centers, submission to regulatory authorities, case reportform (CRF) preparation, site-initiation visits, external monitoring services, etc.).
The individual clinical centers, i.e. MUG, CCIT, APHP, FCRB, CDO, and UoN, will recruit patients and care for them according to the study protocol and following ICH-GCP guidelines; they will monitor patient’s safety, perform radiological analyses, and assess patients’ survival. The radiological analyses will be also assessed by an independent radiological review. A special effort will be given to the collection of biological samples for immunomonitoring and translational research. Notably, the partners have been selected based on their experience to collect biological specimens in a standardized quality-controlled way.
The clinical data will be statistically evaluated both by Philogen and the Investigators.