Safety and Efficacy Assessments of Osalmid in Multiple Myeloma

Study Overview
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Brief Summary
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This study aims to evaluate the safety and efficacy of a traditional cholagogue drug osalmid, 2-hydroxy-N-(4-hydroxyphenyl)-benzamide, in the treatment of multiple myeloma (MM).

Detailed Description
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Osalmid, 2-hydroxy-N-(4-hydroxyphenyl)-benzamide, is a traditional cholagogue and is clinically used in China to promote biliary drainage and protect liver function. Studies have shown that osalmid is an inhibitor of ribonucleotide reductase (RR). Recently, it was proven by our group that osalmid induced a dose-dependent lethality in multiple myeloma (MM) cell lines H929, OPM2, U266, OCI-MY5, and RPMI 8266, as well as in MM xenograft mouse models. This study aims to assess the safety and efficacy of osalmid in the treatment of MM.

Official Title
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Safety and Efficacy Assessments of Osalmid in the Treatment of Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Osalmid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with age≥ 18 years old who are willing to receive the treatment of osalmid; Patients must be diagnosed with active and measurable (symptomatic) multiple myeloma according to IMWG 2003/WHO 2008(V4) MM diagnosis criteria detailed as following:1). Positive M protein in serum and/or urine; 2). Pathologically diagnosed with multiple myeloma or found colonic plasma cells in bone marrow; 3). At least one symptom of related organ damage or tissue lesion: a. hypercalcemia: serum calcium increases 0.25mmol/L or more over upper limit of normal value(ULN) or > 2.75mmol/L; b. anemia: Hemoglobin decreases 20g/L or more over lower limit of normal value(LLN) or <100g/L；c. bone lesion: lytic bone lesion or osteoporosis accompanied with compressive fracture (confirmed with MRI、CT or PET-CT); d. others: symptomatic hyperviscosity, amyloidosis, recurrent infection (more than twice within 12 months); Eastern Cancer Organization Group (ECOG) score≤2 and expected survival>2 months; Belongs to measurable disease: serum M protein ≥10g/L and/or 24 hour urine M protein ≥200mg; No active infectious diseases; No severe organic dysfunction (except renal function insufficiency caused by multiple myeloma), lab results must meet the following criteria (within 7 days before initiation of therapy): a. Total bilirubin ≤ 1.5*ULN (same age group); b. AST and ALT ≤ 2.5*ULN (same age group); c. Cardiac enzyme < 2*ULN (same age group); d. Normal ejection fraction confirmed in echo; Able to swallow oral medicine; Volunteer to participate into this clinical trial and the informed consents must be written by patients themselves or their direct relatives. Authorized medical attorney or direct relatives can write the informed consents if it is not good for patients' treatment when consider the severity of their disease. Exclusion Criteria: Received anti-myeloma treatment before (not include radiotherapy, bisphosphonates or single short term steroids treatment [the dose and duration of prednisone should be no more than 40mg/d and 4 days and should discontinue this treatment within 14 days before the enrollment]); Primary or secondary plasma cell leukemia; Positive HIV tests or active infection phase of HAV, HBV and HCV; or HBV DNA copies >104/ml；AST and ALT > 2.5*ULN (same age group); Severe diseases that threaten patients with unacceptable risks; these diseases include but are not confined to unstable heart diseases, which can be defined as cardiac accidents such as MI within 6 months, NYHA stage Ⅲ-Ⅳ heart failure, uncontrolled atrial fibrillation or hypertension and myeloma requiring long term administration of steroids or immune-inhibitors; Renal failure requiring hemodialysis or peritoneal dialysis; Severe embolic or thrombotic events before therapy; Major surgery within 30 days before being enrolled; Total obstruction of biliary tract; Glaucoma; History of malignancies except multiple myeloma unless being cured for more than 3 years; Severe allergic to osalmide capsule; Gestation, lactation or disagreed pregnancy; Severe infectious diseases (uncured tuberculosis, pulmonary aspergillosis); Seizures requiring medicines, patients with dementias and other mental disorders who cannot understand or obey the protocol; Substance abuse, medical, psychological, or social conditions that may interfere with the subject's compliance in the study or assessment of the results of the study; Severe liver and kidney dysfunction; Patients who are considered unsuitable for enrollment by investigators.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: multi-center, single-arm, open-label, non-blind
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Osalmid<br>Participants are initially given oral capsules with 0.5g tid osalmid daily for two weeks. Thereafter, the dosage will be increased by 0.25g tid every two weeks as tolerated by participants to a maximum daily dosage of 1.0g tid for up to one year. One course of osalmid treatment lasts four weeks. Response will be assessed at the end of each treatment course, and patients who have achieved MR (minor remission) or more than MR at the end of the fourth course will continue to take 1.0g tid osalmid daily for consolidation / maintenance therapy. Otherwise, patients who have not achieved MR at the end of the fourth course and patients who are assessed for PD (progression of disease) at the end of each course will receive salvage treatment, such as a combined treatment of osalmid and dexamethasone or the VCD (bortezomib, cyclophosphamide and dexamethasone) regimen. | Drug: Osalmid<br>* Participants are initially given oral capsules with 0.5g tid osalmid daily for two weeks. Thereafter, the dosage will be increased by 0.25g tid every two weeks as tolerated by participants to a maximum daily dosage of 1.0g tid for up to one year.<br>* Other names: 2-hydroxy-N-(4-hydroxyphenyl)-benzamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | M protein qualification in serum and/or urine decline of at least 25%, 50%, 75%, or 90% | at week16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to progression | from the start of therapy to disease progression | at week 48 | 
| duration of response | from the time response was achieved to disease progression or death | at week 48 | 
| progression-free survival | from study entry to disease progression or death | at week 48 | 
| overall survival | from the date of study entry to the date of death or last follow-up | at week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, Osalmid