The purpose of this study is to describe the safety, tolerability and early signs of efficacy of the antibody-cytokine fusion protein IL12-L19L19 in patients with advanced or metastatic solid carcinomas, after previous immune checkpoint blockade therapy. The primary objective of the study is to evaluate the safety of IL12-L19L19 and to establish MTD in order to establish a recommended dose (RD). The secondary objectives of the study are to assess early signs of efficacy, the determination of pharmacokinetic (PK) properties and the immunogenicity of IL12-L19L19.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Part I - The dose escalation is designed with an initial accelerated phase followed by a standard 3+3 design. Cohorts contain one patient until first instance of moderate toxicity or a DLT in the DLT observation period (28 days). With the second occurrence of moderate toxicity or occurrence of a DLT the accelerated phase will be terminated and the dose escalation will continue with a 3+3 dose escalation. Initiation of the study treatment for an individual subject will occur not less than 7 days after initiation of the study treatment for the previous patient. Not more than 2 patients are to be treated simultaneously within their DLT observation period (i.e., Day 1 to Day 28). Part II - Dose expansion: Once the dose escalation is completed, additional 20 patients will be enrolled at the RD to better understand the safety profile and to explore early signs of efficacy in different disease indications.
Patients initially receive 8 consecutive administrations of IL12-L19L19 every week. At the end of this eight weeks treatment window, a tumor assessment is performed and those patients who achieve a clinical benefit (SD, PR, CR) may continue treatment with IL12-L19L19 as a biweekly maintenance therapy until disease progression, unacceptable toxicity, withdrawal of consent, at the discretion of the investigator or up to 1 year from study treatment start.
Universitaetsklinik Hamburg-Eppendorf
Hamburg, Free and Hanseatic City of Hamburg, Germany
RECRUITINGUniversitätsklinikum Heidelberg, Nationalen Centrum für Tumorerkrankungen (NCT), Dermatoonkologie
Heidelberg, Heidelberg, Germany
RECRUITINGUniversitätsklinikum Leipzig, Klinik für Dermatologie, Venerologie und Allergologie
Leipzig, Leipzig, Germany
RECRUITINGUniversitätsklinikum Tübingen, Klinik für Innere Medizin VIII Medizinische Onkologie und Pneumologie
Tübingen, Germany
RECRUITINGIEO - Istituto Europeo di Oncologia
Milan, Italy, Italy
RECRUITINGFondazione IRCCS Istituto Nazionale dei Tumori
Milan, Italy
ACTIVE_NOT_RECRUITINGAzienda Ospedaliero-Universitaria San Luigi Gonzaga
Orbassano, Italy
NOT_YET_RECRUITINGUniversitätsspital Basel
Basel, Basel, Switzerland
RECRUITINGInsel Gruppe AG
Bern, Canton of Bern, Switzerland
RECRUITINGGeneva University Hospital, Oncology Department
Geneva, Canton of Geneva, Switzerland
RECRUITING...and 1 more locations
For Part I: DLT
Occurrence of dose limiting toxicity (DLT) in dose escalation part of the study.
Time frame: From Day 1 to Day 28 of the treatment
For Part I: MAD
Definition of Maximum Administered Dose (MAD) (in dose escalation part). The MAD is defined when at least two patients within a cohort of 2-6 patients experience a DLT (i.e., ≥33% of patients with a DLT at that dose level)
Time frame: From Day 1 to Day 28 of the treatment
For Part I: MTD and RD
Defining the Maximum Tolerated Dose (MTD) and recommendation of the Recommended Dose (RD): when the DLT rate reaches 33% in a cohort, the next lower dose level will be called the MTD (so long as the DLT rate is less than 33%). Accordingly, the recommended dose (RD) for the Dose Expansion cohort will be the MTD.
Time frame: From Day 1 to Day 28 of the treatment
Safety (AE)
Safety of administration of IL12-L19L19, through an assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Time frame: Throughout study completion for each patient
Safety (SAE)
Safety of administration of IL12-L19L19, assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Time frame: Throughout study completion for each patient
Safety (DILI)
Evaluation of possible Drug Induce Liver Injury, caused by IL12-L19L19, assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Time frame: Throughout study completion for each patient, a maximum of 24 weeks for each patient
Plasma concentration of IL12-L19L19
Evaluation of individual plasma concentration of IL12-L19L19
Time frame: 30 min prior injection in week from 1 to 8, at End-of-Treatment Visit and Follow Up 1; in week 1 and 3: 15 min after start of infusion, 60 min after start of infusion, end of infusion, 2h, 4h and 24h after end of infusion
AUC of IL12-L19L19
Estimation of AUC of IL12-L19L19, as data permit
Time frame: In week 1 and 3: 15 min after start of infusion, 60 min after start of infusion, end of infusion, 2 h after end of infusion, 4 h after end of infusion, 24 h after end of infusion
Tmax of IL12-L19L19
Estimation of Tmax of IL12-L19L19, as data permit
Time frame: In week 1 and 3: 15 min after start of infusion, 60 min after start of infusion, end of infusion, 2 h after end of infusion, 4 h after end of infusion, 24 h after end of infusion
T1/2 of IL12-L19L19
Estimation of T1/2 of IL12-L19L19, as data permit
Time frame: in week 1 and 3: 15 min after start of infusion, 60 min after start of infusion, end of infusion, 2 h after end of infusion, 4 h after end of infusion, 24 h after end of infusion
Cmax of IL12-L19L19
Estimation of Cmax of IL12-L19L19, as data permit
Time frame: in week 1 and 3: 15 min after start of infusion, 60 min after start of infusion, end of infusion, 2 h after end of infusion, 4 h after end of infusion, 24 h after end of infusion
HAFA
Formation of human anti-fusion protein antibodies (HAFA) against IL12-L19L19
Time frame: At week 1, 2, 3 and 4
For Part II: ORR
Objective Response Rate (ORR, consisting of complete response (CR) + partial response (PR)), is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. Response duration usually is measured from the time of initial response until documented tumor progression. ORR is the sum of partial responses (PR) plus complete responses (CR), based on Response Evaluation Criteria in Solid Tumors (RECIST) (v. 1.1) criteria.
Time frame: At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.
For Part II: DoR
The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) untile the first date that recurrent or PD is objectively documented.
Time frame: At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.
For Part II: PFS
Progression Free Survival (PFS) the time from enrolment to progression or death from any cause.
Time frame: At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.
For Part II: OS
Overall Survival (OS) is defined beginning from enrolment to death from any cause
Time frame: At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.
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