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SST0001 (Roneparstat) in Advanced Multiple Myeloma

Primary Purpose

Multiple Myeloma

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

SST0001 (Roneparstat)

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Heparanase inhibitor, Multiple myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Advanced, heavily pretreated refractory multiple myeloma (MM).
Patient should have exhausted all available anti MM therapies.
Age ≥18 years.
ECOG (Eastern Cooperative Oncology Group)performance status ≤ 2.
Life expectancy of more than 3 months.
No concomitant use of anticoagulants or antiplatelets drugs such as aspirin, NSAIDs (Nonsteroidal Antiinflammatory Drug), Clopidogrel, Unfractionated Heparin, Low Molecular Weight Heparin (e.g. Enoxaparin), Fondaparinux, Dabigatran, Rivaroxaban, Apixaban and Warfarin.
No platelets diseases or allergy to anticoagulants.
WBC (White Blood Cell) ≥2000/µL; Platelets ≥50,000/µL; Hb ≥ 8 g/dL.
Total bilirubin ≤ 1.5 x upper limit of normal (ULN); AST (aspartate aminotransferase)and ALT (alanine aminotransferase)≤ 3 x the ULN; serum creatinine ≤ 1.5 x the ULN (Upper Limit of Normal).
aPTT, TT, INR, fibrinogen, D-dimer within ULN.
Disease free of prior malignancies for ≥ 3 years.
No acute gastrointestinal bleeding or any major bleeding (e.g CNS) in the past 2 years or any significant bleeding history.
No known central nervous system involvement by myeloma.
Capacity of understanding the nature of the trial and giving written informed consent.
Unless a female patient is post-menopausal or surgically sterilized, must be willing to use an acceptable method of birth control (hormonal contraceptive, intrauterine device, barrier contraceptive with spermicide, or abstinence) for the duration of the study.
Male patient must agree to use an acceptable method for contraception (barrier contraceptive or abstinence) for the duration of the study.

Exclusion Criteria:

Pregnancy or lactation or unwillingness to use adequate method of birth control
Ascertained or presumptive hypersensitivity to the active principle and/or formulations ingredients.
Active uncontrolled viral, bacterial, or fungal infection or history of HIV, hepatitis B or C, or any infection requiring systemic antivirals or antimicrobials.
Grade ≥ 2 toxicity due to previous anti-neoplastic therapy (except alopecia), and Grade ≥ 3 peripheral motor or sensory neuropathy, in the 2 weeks before treatment (CTCAE V4.0).
Less than 2 weeks since most recent chemotherapy, or concurrent chemotherapy.
Presence of cirrhosis or chronic hepatitis.
Diagnosis of amyloidosis or diagnosis of plasma cell leukaemia.
Presence of serious cardiac (congestive heart failure, angina pectoris, myocardial infarction within one year prior to study entry, uncontrolled hypertension or arrhythmia), neurological or psychiatric disorder.
Presence of uncontrolled intercurrent illness or any condition which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study.

Sites / Locations

Manik Chatterjee
Division of Hematology, Chaim Sheba Medical Center
U.O. Ematologia con Trapianto, Dipartimento dell'Emergenza e dei Trapianti di Organi
USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII
S.C. Ematologia, ASO S. Croce e Carle - Cuneo

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

SST0001 (Roneparstat)

Arm Description

SST0001 once daily for 5 or 10 days in a cycle of 28 days. Starting dose 25 mg, to be escalated in subsequent cohorts. Duration of treatment depending on toxicities observed or until documentation of disease progression or other discontinuation criteria are met.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

Maximum plasma concentration (Cmax)

Blood pharmacokinetics of SST0001 using Activated Partial Thromboplastin Time (aPTT)as indirect measurement of SST0001 equivalent plasma concentrations.

Time to achieve Cmax (Tmax)

Area under the concentration curve from administration to the last observed concentration time (AUClast)

Half-life (T1/2)

aPTT (Activated Partial Thromboplastin Time)

Pharmacodynamics of SST0001 in terms of effects on coagulation profile (aPTT, seconds).

TT (Thrombin Time)

Pharmacodynamics of SST0001 in terms of effects on coagulation profile (TT, seconds).

INR (International Normalized Ratio)

Pharmacodynamics of SST0001 in terms of effects on coagulation profile (INR).

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.

Full Information

NCT ID

NCT01764880

First Posted

January 7, 2013

Last Updated

October 20, 2017

Sponsor

Sigma Tau Research Switzerland SA

1. Study Identification

Unique Protocol Identification Number

NCT01764880

Brief Title

SST0001 (Roneparstat) in Advanced Multiple Myeloma

Official Title

Phase I Dose Finding Study Assessing Safety and Tolerability of SST0001 in Advanced Multiple Myeloma.

Study Type

Interventional

2. Study Status

Record Verification Date

October 2017

Overall Recruitment Status

Completed

Study Start Date

November 2012 (undefined)

Primary Completion Date

November 2016 (Actual)

Study Completion Date

November 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sigma Tau Research Switzerland SA

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

Detailed Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma

Keywords

Heparanase inhibitor, Multiple myeloma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

19 (Actual)

8. Arms, Groups, and Interventions

Arm Title

SST0001 (Roneparstat)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

SST0001 (Roneparstat)

Intervention Description

SST0001 once daily for 5 or 10 days in a cycle of 28 days.

Primary Outcome Measure Information:

Title

Maximum tolerated dose (MTD).

Description

Time Frame

28 days of first cycle of therapy.

Secondary Outcome Measure Information:

Title

Adverse events, physical examination and laboratory tests.

Description

Time Frame

28 days of each cycle of therapy.

Title

Maximum plasma concentration (Cmax)

Description

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.

Title

Time to achieve Cmax (Tmax)

Time Frame

28 days of first cycle of therapy.

Title

Area under the concentration curve from administration to the last observed concentration time (AUClast)

Time Frame

28 days of first cycle of therapy.

Title

Half-life (T1/2)

Time Frame

28 days of first cycle of therapy.

Title

aPTT (Activated Partial Thromboplastin Time)

Description

Pharmacodynamics of SST0001 in terms of effects on coagulation profile (aPTT, seconds).

Time Frame

28 days of first cycle of therapy.

Title

TT (Thrombin Time)

Description

Pharmacodynamics of SST0001 in terms of effects on coagulation profile (TT, seconds).

Time Frame

28 days of first cycle of therapy.

Title

INR (International Normalized Ratio)

Description

Pharmacodynamics of SST0001 in terms of effects on coagulation profile (INR).

Time Frame

28 days of first cycle of therapy.

Title

Tumor response.

Description

Time Frame

28 days of each cycle of therapy.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Advanced, heavily pretreated refractory multiple myeloma (MM). Patient should have exhausted all available anti MM therapies. Age ≥18 years. ECOG (Eastern Cooperative Oncology Group)performance status ≤ 2. Life expectancy of more than 3 months. No concomitant use of anticoagulants or antiplatelets drugs such as aspirin, NSAIDs (Nonsteroidal Antiinflammatory Drug), Clopidogrel, Unfractionated Heparin, Low Molecular Weight Heparin (e.g. Enoxaparin), Fondaparinux, Dabigatran, Rivaroxaban, Apixaban and Warfarin. No platelets diseases or allergy to anticoagulants. WBC (White Blood Cell) ≥2000/µL; Platelets ≥50,000/µL; Hb ≥ 8 g/dL. Total bilirubin ≤ 1.5 x upper limit of normal (ULN); AST (aspartate aminotransferase)and ALT (alanine aminotransferase)≤ 3 x the ULN; serum creatinine ≤ 1.5 x the ULN (Upper Limit of Normal). aPTT, TT, INR, fibrinogen, D-dimer within ULN. Disease free of prior malignancies for ≥ 3 years. No acute gastrointestinal bleeding or any major bleeding (e.g CNS) in the past 2 years or any significant bleeding history. No known central nervous system involvement by myeloma. Capacity of understanding the nature of the trial and giving written informed consent. Unless a female patient is post-menopausal or surgically sterilized, must be willing to use an acceptable method of birth control (hormonal contraceptive, intrauterine device, barrier contraceptive with spermicide, or abstinence) for the duration of the study. Male patient must agree to use an acceptable method for contraception (barrier contraceptive or abstinence) for the duration of the study. Exclusion Criteria: Pregnancy or lactation or unwillingness to use adequate method of birth control Ascertained or presumptive hypersensitivity to the active principle and/or formulations ingredients. Active uncontrolled viral, bacterial, or fungal infection or history of HIV, hepatitis B or C, or any infection requiring systemic antivirals or antimicrobials. Grade ≥ 2 toxicity due to previous anti-neoplastic therapy (except alopecia), and Grade ≥ 3 peripheral motor or sensory neuropathy, in the 2 weeks before treatment (CTCAE V4.0). Less than 2 weeks since most recent chemotherapy, or concurrent chemotherapy. Presence of cirrhosis or chronic hepatitis. Diagnosis of amyloidosis or diagnosis of plasma cell leukaemia. Presence of serious cardiac (congestive heart failure, angina pectoris, myocardial infarction within one year prior to study entry, uncontrolled hypertension or arrhythmia), neurological or psychiatric disorder. Presence of uncontrolled intercurrent illness or any condition which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alessandro Rambaldi, MD

Organizational Affiliation

USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Arnon Nagler, MD

Organizational Affiliation

Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Manik Chatterjee, MD

Organizational Affiliation

Universitätsklinik Würzburg, Medizinische Klinik und Poliklinik II (ZIM), Würzburg, Germany

Official's Role

Principal Investigator

Facility Information:

Facility Name

Manik Chatterjee

City

Würzburg

ZIP/Postal Code

97080

Country

Germany

Facility Name

Division of Hematology, Chaim Sheba Medical Center

City

Tel Hashomer

Country

Israel

Facility Name

U.O. Ematologia con Trapianto, Dipartimento dell'Emergenza e dei Trapianti di Organi

City

Bari

ZIP/Postal Code

70124

Country

Italy

Facility Name

USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII

City

Bergamo

ZIP/Postal Code

24127

Country

Italy

Facility Name

S.C. Ematologia, ASO S. Croce e Carle - Cuneo

City

Cuneo

ZIP/Postal Code

12100

Country

Italy

12. IPD Sharing Statement

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SST0001 (Roneparstat) in Advanced Multiple Myeloma

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