Combination Therapy of F8IL10 and Methotrexate in Rheumatoid Arthritis Patients

NCT02076659 | Completed Phase 1 DMC

• 2 other identifiers: PH-F8IL10-02/082008-008729-31
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 5

Brief Summary

Phase I, multicenter, open-label, dose escalation study to test the efficacy and safety of F8IL10 and methotrexate when given as a combination in rheumatoid arthritis patients.

Conditions

Rheumatoid Arthritis

Keywords

F8; IL10; Interleukin; monoclonal; antibody; Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (1)

• Number of patients with adverse events that are related to treatment and classified as DLTs for each administered dosage

  To establish the MTD and the RD of F8IL10 when administered in combination with methotrexate

  Up to day 28

Secondary Outcomes (16)

• Maximum drug concentration [Cmax]

  At day 1, 4, 5, 6 of week 1; at day 1, 2, 3, 4, 5, 6 of week 4

• Time to reach maximum drug concentration [Tmax]

  At day 1, 4, 5, 6 of week 1; at day 1, 2, 3, 4, 5, 6 of week 4

• Terminal half-life [t1/2]

  At day 1, 4, 5, 6 of week 1; at day 1, 2, 3, 4, 5, 6 of week 4

• Area under the drug concentration-time curve [AUC(0 - t last)]

  At day 1, 4, 5, 6 of week 1; at day 1, 2, 3, 4, 5, 6 of week 4

• Area under the drug concentration-time curve, extrapolated to infinity [AUC]

  At day 1, 4, 5, 6 of week 1; at day 1, 2, 3, 4, 5, 6 of week 4

Study Arms (1)

F8IL10 + MTX

EXPERIMENTAL

Ten cohorts of 3-6 RA patients will be treated at increasing doses per cohort of F8IL10 plus fixed doses of MTX and folic acid. An additional 12 patients will be randomized (6+6) in a double blind, placebo controlled cohort with F8IL10 given at RD and placebo. In both arms, MTX will be administered as concomitant medication. In all coohorts a stable dose of folic acid (5 mg) will be administered on Day 2.

Drug: F8IL10; Drug: Methotrexate

Interventions

F8IL10 DRUG

Weekly administration of F8IL10 (from 6 to 600 μg/kg), starting from 6 μg/kg cohort 1. The cohort 10 represents the last dose-level of the study. F8IL10 will be administered as subcutaneous (s.c.) injections. Patients will receive 4 cycles of treatment unless there is unacceptable toxicity or withdrawal of consent.

F8IL10 + MTX

Methotrexate DRUG

Methotrexate will be administered at a fixed dose of 10-15 mg on Day 1, orally (p.o.), subcutaneously (s.c.) or intramuscularly (i.m.). Patients will receive 4 cycles of treatment unless there is unacceptable toxicity or withdrawal of consent.

F8IL10 + MTX

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged ≥ 18 and \< 75 years.
• Diagnosis of RA according to ACR criteria (1987) with a disease duration exceeding 12 months.
• Active RA (DAS28 ≥ 3.2) for ≥ 4 months at time of signing informed consent.
• Receiving treatment on an outpatient basis.
• MTX at 10-15 mg/w for a period ≥ 8 weeks prior to treatment.
• Inadequate clinical response to at least one anti-TNF therapy applied for at least 4 months.
• If patients are receiving an oral corticosteroid, the dose must have been stable for at least 25 out of 28 days prior to study treatment and the dose must be less than 10 mg/day (prednisolone equivalent).
• All acute toxic effects of any prior therapy must have returned to classification "mild" according to RCTC V.2.0 \[1\] .
• Sufficient hematologic, liver and renal function:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin (Hb) ≥ 9.5 g/dL
• Alkaline phosphatase (AP), alanine aminotransferase (ALT) and or aspartate aminotransferase (AST) ≤ 3 x upper limit of normal range (ULN), and total bilirubin ≤ 2.0 mg/dL (34.2 µmol/L)
• Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 50 mL/min
• Documented negative test for human immunodeficiency virus, HBV, and HCV. For patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV DNA is required.
• Male and female patients, who are potentially fertile, must agree to use adequate contraceptive methods at the beginning of the screening visit that must be continued until 3 months following the last treatment with study drug.
• Negative serum pregnancy test (for women of child-bearing potential only) at screening.

You may not qualify if:

• Presence of active infections (e.g. requiring antibiotic therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or would interfere with the study objectives or conduct.
• Pregnancy, lactation or unwillingness to use adequate contraceptive methods.
• Active or latent tuberculosis (TB).
• Chronic active hepatitis or active autoimmune diseases other than RA.
• History of currently active primary or secondary immounodeficiency.
• HIV Infection.
• Acute or chronic-active infection with HBV or HCV, as assessed by serology or HBV DNA.
• Evidence of active malignant disease at screening or advanced malignancies diagnosed within the previous 5 years.
• Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil or with total lymphoid irradiation.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Treatment with warfarin or other coumarin derivatives.
• Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria).
• Irreversible cardiac arrhythmias requiring permanent medication.
• Clinically significant (to clinical investigator's discretion) abnormalities in baseline MUGA, ECHO or ECG analyses.
• Uncontrolled hypertension.

Sponsors & Collaborators

• Philogen S.p.A.: lead

Study Sites (5)

Policlinico San Matteo, Pavia

Pavia, Italy

Location

Pisa University Hospital

Pisa, Italy

Location

Azienda Ospedaliera San Camillo-Forlanini Roma

Roma, Italy

Location

Policlinico A. Gemelli, Università Cattolica del Sacro Cuore

Roma, Italy

Location

Siena University Hospital

Siena, Italy

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Mauro Galeazzi, Prof

  Siena University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2014
• First Posted: March 3, 2014
• Study Start: September 1, 2011
• Primary Completion: April 1, 2017
• Study Completion: April 13, 2017
• Last Updated: May 18, 2018

Record last verified: 2018-05

Locations

IT (5)