Clarithromycin in Multiple Myeloma Induction Therapy (CLAIM)

• ClinicalTrials.gov Identifier: NCT02573935
• Recruitment Status: Terminated
• First Posted: October 12, 2015
• Last Update Posted: September 20, 2016
• Sponsor: Henrik Gregersen
• Collaborator: Danish Myeloma Study Group
• Information provided by (Responsible Party): Henrik Gregersen, Aalborg University Hospital

Tracking Information

• First Submitted Date: October 8, 2015
• First Posted Date: October 12, 2015
• Last Update Posted Date: September 20, 2016
• Study Start Date: January 2015
• Actual Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: October 9, 2015): Comparison of number of participants with very good partial response or better response after three courses of VCD combined with clarithromycin or placebo [ Time Frame: 10 weeks ]
• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02573935 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: October 9, 2015)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Clarithromycin
  p.o. clarithromycin 500 mg twice daily for 63 days
• Drug: Placebo
  Placebo tablet twice daily for 63 days
• Drug: VCD induction therapy
  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)

Study Arms

• Experimental: Clarithromycin
  Clarithromycin combined with VCD induction therapy
  Interventions:

  • Drug: Clarithromycin
  • Drug: VCD induction therapy
• Placebo Comparator: Placebo
  Placebo combined with VCD induction therapy
  Interventions:

  • Drug: Placebo
  • Drug: VCD induction therapy

Publications *

• 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.
• Nielsen LK, Klausen TW, Jarden M, Frederiksen H, Vangsted AJ, Do T, Kristensen IB, Frølund 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.
• Gregersen H, Do T, Kristensen IB, Frølund 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 19, 2016): 58
• Original Estimated Enrollment (submitted: October 9, 2015): 160
• Actual Study Completion Date: September 2016
• Actual Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT02573935
• Other Study ID Numbers: DMSG 03/14; 2014-002187-32 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Henrik Gregersen, Aalborg University Hospital
• Study Sponsor: Henrik Gregersen
• Collaborators: Danish Myeloma Study Group

Investigators

• Principal Investigator: Henrik Gregersen, MD; Aalborg University Hospital

• PRS Account: Aalborg University Hospital
• Verification Date: September 2016