Clinical trial NCT02573935: Clarithromycin in Multiple Myeloma Induction Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Clarithromycin
Induction Chemotherapy
Transplantation, Autologous
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Danish Myeloma Study Group
First posted: 2015-10-12
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Comparison of number of participants with very good partial response or better response after three courses of VCD combined with clarithromycin or placebo
timeFrame: 10 weeks
Secondary outcomes:
measure: 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
timeFrame: Five months
measure: Comparison of number of participants with sCR, CR, PR, PD or SD in the treatment groups after induction therapy and HDT, respectively
timeFrame: Five months
measure: Comparison of frequency of infections in patients treated VCD combined with clarithromycin or placebo
timeFrame: 9 weeks
measure: Comparison of number of stem cells harvested in patients treated with clarithromycin and placebo in combination with VCD
timeFrame: Three months
measure: Neurotoxicity assessed by FACT/GOG-Ntx, Version 4.0
timeFrame: Five months
measure: Quality of life assessed by EORTC QLQ-MY20
timeFrame: Five months
measure: Quality of life assessed by EORTC QLQ-C30
timeFrame: Five months
measure: Comparison of adverse events in patients treated VCD combined with clarithromycin or placebo assessed by CTCAE v4.0
timeFrame: Three months
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Department of Hematology, Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Department of Hematology, Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Department of Hematology, Rigshospitalet
city: Herlev
country: Denmark
facility: Department of Hematology, Herlev Hospital
city: Odense
country: Denmark
facility: Department of Hematology, Odense University Hospital
city: Roskilde
country: Denmark
facility: Department of Hematology, Roskilde Hospital
city: Vejle
country: Denmark
facility: Department of Hematology, Vejle Hospital
Study officials:
affiliation: Aalborg University Hospital
name: Henrik Gregersen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. doi: 10.1002/ajh.21777.
citation: Nielsen LK, Klausen TW, Jarden M, Frederiksen H, Vangsted AJ, Do T, Kristensen IB, Frolund UC, Andersen CL, Abildgaard N, Gregersen H. Clarithromycin added to bortezomib-cyclophosphamide-dexamethasone impairs health-related quality of life in multiple myeloma patients. Eur J Haematol. 2019 Jan;102(1):70-78. doi: 10.1111/ejh.13175. Epub 2018 Oct 29.
citation: Gregersen H, Do T, Kristensen IB, Frolund UC, Andersen NF, Nielsen LK, Andersen CL, Klausen TW, Vangsted AJ, Abildgaard N. 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. Exp Hematol Oncol. 2018 Aug 13;7:18. doi: 10.1186/s40164-018-0110-0. eCollection 2018.