Heparanase cleaves heparan sulfate (HS) chains, a natural substrate for heparanase, and participates in degradation and remodelling of the extra-cellular matrix (ECM) facilitating, among other activities, cell invasion associated with cancer metastasis, angiogenesis, and inflammation. The heparanase enzyme is a promising target for development of new anticancer drugs. HS and the structurally related heparin are present in most animal species. As an analogue of the natural substrate of heparanase HS, heparin is considered to be a potent inhibitor of heparanase. SST0001 is a polymer with a heparin-like structure. It is a reduced oxidized N-acetyl heparin, these modifications cause the reduction of anticoagulant activity and are strictly related to the anti-heparanase activity. In preclinical murine models SST0001 showed a significant anti myeloma effect in multiple myeloma mice xenograft models, with a significant reduction of subcutaneous growth of different multiple myeloma cell lines, when SST0001 was administered either alone or in combination with dexamethasone. The purpose of this study is to determine the safety and tolerability of escalating doses of SST0001 in the treatment of advanced refractory multiple myeloma.
Multicenter, open label, uncontrolled Phase I First In Man trial in advanced refractory multiple myeloma, to determine the Maximum Tolerated Dose (MTD) of SST0001 given subcutaneously (sc) once daily for 5 or 10 days, in a cycle of 28 days. A starting dose of 25 mg (flat dose) is given once daily for 5 days (from Day 1 to Day 5). In the subsequent cohort 25 mg are administered once daily for 10 days (from Day 1 to 5 and from Day 8 to 12). Dose escalation with SST0001 administered for 10 days is performed in subsequent cohorts, depending on toxicities observed. Indirect pharmacokinetics based on Activated Partial Thromboplastin Time (aPTT) modifications in all patients (minimum of 3 patients in each cohort) during the first cycle of treatment and direct SST0001 concentrations measurements. Pharmacodynamics in all patients during the first cycle of treatment, based on modifications of coagulation parameters. During the study any hints of anti-tumor activity will also be evaluated based on use of surrogate parameters (monoclonal serum and urine protein modifications).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
19
SST0001 once daily for 5 or 10 days in a cycle of 28 days.
Manik Chatterjee
Würzburg, Germany
Division of Hematology, Chaim Sheba Medical Center
Tel Litwinsky, Israel
U.O. Ematologia con Trapianto, Dipartimento dell'Emergenza e dei Trapianti di Organi
Bari, Italy
USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII
Bergamo, Italy
S.C. Ematologia, ASO S. Croce e Carle - Cuneo
Cuneo, Italy
Maximum tolerated dose (MTD).
Maximum tolerated dose (MTD) (based upon first cycle study drug related dose limiting toxicities \[DLTs\]) of SST0001 given subcutaneously over repeated administration during each treatment cycle. MTD definition: ≥ 2/6 patients with a DLT at the first cycle (28 days).
Time frame: 28 days of first cycle of therapy.
Adverse events, physical examination and laboratory tests.
Number of patients with adverse events, number of patients with abnormalities at physical examination and laboratory tests (hematology and biochemistry) as a measure of safety and local tolerability of SST0001. Safety assessments and severity of adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) V4.0.
Time frame: 28 days of each cycle of therapy.
Maximum plasma concentration (Cmax)
Blood pharmacokinetics of SST0001 using Activated Partial Thromboplastin Time (aPTT)as indirect measurement of SST0001 equivalent plasma concentrations.
Time frame: 28 days of first cycle of therapy.
Time to achieve Cmax (Tmax)
Time frame: 28 days of first cycle of therapy.
Area under the concentration curve from administration to the last observed concentration time (AUClast)
Time frame: 28 days of first cycle of therapy.
Half-life (T1/2)
Time frame: 28 days of first cycle of therapy.
aPTT (Activated Partial Thromboplastin Time)
Pharmacodynamics of SST0001 in terms of effects on coagulation profile (aPTT, seconds).
Time frame: 28 days of first cycle of therapy.
TT (Thrombin Time)
Pharmacodynamics of SST0001 in terms of effects on coagulation profile (TT, seconds).
Time frame: 28 days of first cycle of therapy.
INR (International Normalized Ratio)
Pharmacodynamics of SST0001 in terms of effects on coagulation profile (INR).
Time frame: 28 days of first cycle of therapy.
Tumor response.
Antitumor activity through the use of surrogate parameters (monoclonal serum and urine protein modifications), by means of serum and urine protein electrophoresis, immunoelectrophoresis and immunofixation, Serum Free Light Chain (FLC) Ratio and/or 24-h Bence-Jones urine protein. M-protein (g/dL), Bence-Jones protein (g/24h), kappa FLC (mg/dL) and lambda FLC (mg/dL) will be assessed at each cycle of therapy. Responses will be evaluated according to International Myeloma Working Group (IMWG) Guidelines.
Time frame: 28 days of each cycle of therapy.
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