Clarithromycin in Multiple Myeloma Induction Therapy

Study Overview
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Brief Summary
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This study evaluates the potential synergic anti-myeloma activity of clarithromycin when combined with VCD induction therapy in patients with newly diagnosed multiple myeloma.

Detailed Description
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The survival in younger myeloma patients improved in the nineties with the introduction of high-dose melphalan with autologous stem cell support (HDT). However, all patients will eventually experience relapse after HDT and there is a need for improvement of the response after HDT. The choice of induction treatment before HDT affects the outcome after induction therapy as well as the outcome after HDT. Clarithromycin is a macrolide antibiotic frequently utilized in the treatment of respiratory tract infections and is often used in patients with known hypersensitivity to beta-lactam antibiotic. Besides antibiotic activity, clarithromycin may exert immunomodulatory and anti-inflammatory effects. The toxicity profile of clarithromycin is favourable and the cost is very low. Studies on cell lines have shown that clarithromycin attenuates autophagy in myeloma cells and a recent study has demonstrated that treatment with clarithromycin enhanced bortezomib-induced cytotoxicity in myeloma cells. Phase II studies without control groups have indicated that clarithromycin might enhance the effect of the thalidomide and lenalidomide. A case-matched analysis compared patients at one centre receiving clarithromycin, lenalidomide and dexamethasone with an equal number of patients at another centre receiving lenalidomide and dexamethasone. This study indicated a favourable effect of clarithromycin with a higher frequency of complete response, very-good-partial-response or better response and progression-free survival. However, there is a need for controlled studies to determine whether clarithromycin might enhance the effect of other myeloma agents. This randomized placebo-controlled study will include 160 patients with newly diagnosed multiple myeloma eligible for HDT. The study evaluates the potential synergic anti-myeloma activity of clarithromycin when combined with VCD induction therapy in patients with newly diagnosed multiple myeloma, and is conducted by the Danish Myeloma Study Group (DMSG) at seven clinics in Denmark. The first patient was included in May 2015 and enrolment is expected to continue until October 2016. The study ends when the last included patient has been followed for two months after HDT.

Official Title
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A Randomized Placebo-controlled Phase II Study of Clarithromycin or Placebo Combined With VCD Induction Therapy Prior to High-dose Melphalan With Stem Cell Support in Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Clarithromycin
* Drug: Placebo
* Drug: VCD induction therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myeloma diagnosis according to IMWG criteria Treatment demanding disease High-dose melphalan with stem cell support scheduled as a part of the treatment Signed informed consent given prior to any study related activities Age > 18 years Exclusion Criteria: Allogeneic transplantation scheduled as a part of the treatment Myeloma treatment prior to entry in the study, except radiotherapy, bisphosphonates/denosumab or corticosteroids for symptom control Concurrent disease making clarithromycin treatment unsuitable Positive pregnancy test (only applicable for women with childbearing potential) Known or suspected hypersensitivity or intolerance to clarithromycin Prolonged QT corrected (QTc) interval ( > 500 msec on screening ECG) Concurrent treatment with cabergoline, fluconazole, ketoconazole, pimozide, quetiapine, sirolimus, verapamil, tacrolimus, ergot alkaloid, simvastatin or other statins Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrolment, uncontrolled angina or known cardiac amyloidosis Severe renal dysfunction (estimated creatinine clearance <10 mL/min) Serious medical or psychiatric illness which, in the judgment of the investigator, would make the patient inappropriate for entry into the study

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clarithromycin<br>Clarithromycin combined with VCD induction therapy | Drug: Clarithromycin<br>* p.o. clarithromycin 500 mg twice daily for 63 days<br>Drug: VCD induction therapy<br>* Three courses of VCD (sc bortezomib 1.3 mg/sqm days 1, 4, 8, 11, iv cyclophosphamide 500 mg/sqm on days 1 and 8, and p.o. dexamethasone 40 mg days 1, 2, 4, 5, 8, 9, 11, 12 in each 21-days course)<br>|
| Placebo Comparator: Placebo<br>Placebo combined with VCD induction therapy | Drug: Placebo<br>* Placebo tablet twice daily for 63 days<br>Drug: VCD induction therapy<br>* Three courses of VCD (sc bortezomib 1.3 mg/sqm days 1, 4, 8, 11, iv cyclophosphamide 500 mg/sqm on days 1 and 8, and p.o. dexamethasone 40 mg days 1, 2, 4, 5, 8, 9, 11, 12 in each 21-days course)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of number of participants with very good partial response or better response after three courses of VCD combined with clarithromycin or placebo |  | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of number of participants with very good partial response or better response after HDT in patients treated with three courses of VCD combined with clarithromycin or placebo |  | Five months | 
| Comparison of number of participants with sCR, CR, PR, PD or SD in the treatment groups after induction therapy and HDT, respectively |  | Five months | 
| Comparison of frequency of infections in patients treated VCD combined with clarithromycin or placebo |  | 9 weeks | 
| Comparison of number of stem cells harvested in patients treated with clarithromycin and placebo in combination with VCD |  | Three months | 
| Neurotoxicity assessed by FACT/GOG-Ntx, Version 4.0 |  | Five months | 
| Quality of life assessed by EORTC QLQ-MY20 |  | Five months | 
| Quality of life assessed by EORTC QLQ-C30 |  | Five months | 
| Comparison of adverse events in patients treated VCD combined with clarithromycin or placebo assessed by CTCAE v4.0 |  | Three months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Clarithromycin, Induction Chemotherapy, Transplantation, Autologous