A Phase I Study to Evaluate Safety and Early Signs of Efficacy of the Human Monoclonal Antibody-cytokine Fusion Protein IL12-L19L19.
Overview
- Phase
- Phase 1
- Intervention
- IL12-L19L19
- Conditions
- Advanced Solid Tumor
- Sponsor
- Philogen S.p.A.
- Enrollment
- 80
- Locations
- 11
- Primary Endpoint
- For Part I: DLT
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or Female aged 18 to 80 years at the time of consent.
- •Patients must have a histological or cytological diagnosis of advanced/metastatic immunotherapy responsive solid carcinoma for which immune checkpoint blockade is approved, that has progressed on immune checkpoint-blockade therapy.
- •Patients must have received an immune checkpoint blockade therapy-based regimen as prior treatment.
- •Only patients without other therapeutic alternatives with curative or survival prolonging potential per investigator judgement are able to participate.
- •Subjects must have had clinical benefit in terms of disease control (CR/PR/SD) while on checkpoint inhibitor treatment defined as ≥ 3 month free from progression from initial imaging documenting advanced/metastatic disease followed by radiographic disease progression after checkpoint inhibitor per investigator's opinion.
- •Patients must have progressive disease or relapse at the time of screening.
- •Patients may have previously received chemotherapy, immunotherapy or radiation therapy. Such therapies must be completed at least 4 weeks prior to study drug administration. Radiotherapy within 4 weeks of the first dose of study drug, is allowed for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. During the expansion part, to allow evaluation of response to treatment, patients must have remaining measurable disease that has not been irradiated.
- •Eastern cooperative oncology group (ECOG) performance status ≤
- •Patient has an estimated life expectancy of at least 12 weeks.
- •At least one unidimensionally measurable lesion either by computed tomography (CT), MRI or PET/CT as defined by RECIST (v. 1.1) for solid tumors.
Exclusion Criteria
- •Subjects who participated in an investigational drug or device study within 4 weeks prior to study treatment start.
- •Radiotherapy within 4 weeks prior to study treatment start.
- •Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent.
- •Patients with primary brain tumors or CNS disease (including brain metastases).
- •Patient taking herbal medications within 7 days prior to study treatment start.
- •Known history of allergy to an excipient in study medication or any other intravenously administered human proteins/peptides/antibodies.
- •Absolute neutrophil count (ANC) \< 1.5 x 10\^9/L, platelets \< 100 x 10\^9/L or haemoglobin (Hb) \< 9.0 g/dl.
- •Chronically impaired renal function as indicated by creatinine clearance \< 60 mL/min or serum creatinine \> 1.5 ULN.
- •Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN). At the discretion of the investigator, an increased exclusion threshold for patients with liver metastasis can be accepted as follows: ALT, AST, ALP and bilirubin ≥ 5 x ULN.
- •Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator.
Arms & Interventions
Treatment
The study will take place in two stages: 1. In the dose escalation part, participants will be enrolled in cohorts and will be treated with different doses of IL12-L19L19 in order to identify a RD to be further explored in the subsequent dose expansion part. In the dose escalation part, patients will be treated in cohorts of 1 to 6 patients with escalating doses of IL12-L19L19 until the MAD is reached. 2. Following successful identification of the RD, the study will proceed with a dose expansion part and 20 patients will be treated at the RD dose level.
Intervention: IL12-L19L19
Outcomes
Primary Outcomes
For Part I: DLT
Time Frame: From Day 1 to Day 28 of the treatment
Occurrence of dose limiting toxicity (DLT) in dose escalation part of the study.
Safety (DILI)
Time Frame: Throughout study completion for each patient, a maximum of 24 weeks for each patient
Evaluation of possible Drug Induce Liver Injury, caused by IL12-L19L19, assessed by Common Toxicity Criteria (version 5.0, CTCAE)
For Part I: MAD
Time Frame: From Day 1 to Day 28 of the treatment
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)
For Part I: MTD and RD
Time Frame: From Day 1 to Day 28 of the treatment
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.
Safety (AE)
Time Frame: Throughout study completion for each patient
Safety of administration of IL12-L19L19, through an assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Safety (SAE)
Time Frame: Throughout study completion for each patient
Safety of administration of IL12-L19L19, assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Secondary Outcomes
- AUC of IL12-L19L19(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(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)
- Plasma concentration of IL12-L19L19(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)
- Cmax of IL12-L19L19(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(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(At week 1, 2, 3 and 4)
- For Part II: ORR(At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.)
- For Part II: DoR(At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.)
- For Part II: PFS(At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.)
- For Part II: OS(At 8 weeks, 16 weeks, 24 weeks, 36 weeks and 48 weeks.)