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

Henrik Gregersen*, Trung Do, Ida Bruun Kristensen, Ulf Christian Frølund, Niels Frost Andersen, Lene Kongsgaard Nielsen, Christen Lykkegaard Andersen, Tobias Wirenfeldt Klausen, Annette Juul Vangsted, Niels Abildgaard

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Resumé

Background: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.

Methods: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.

Results: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.

Conclusion: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy. Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).

OriginalsprogEngelsk
Artikelnummer18
TidsskriftExperimental Hematology & Oncology
Vol/bind7
Antal sider8
DOI
StatusUdgivet - 13. aug. 2018

Fingeraftryk

Melphalan
Clarithromycin
Placebos
Neutropenic Enterocolitis
Intestinal Pseudo-Obstruction
Safety
Poisons

Citer dette

Gregersen, Henrik ; Do, Trung ; Kristensen, Ida Bruun ; Frølund, Ulf Christian ; Andersen, Niels Frost ; Nielsen, Lene Kongsgaard ; Andersen, Christen Lykkegaard ; Klausen, Tobias Wirenfeldt ; Vangsted, Annette Juul ; Abildgaard, Niels. / 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. I: Experimental Hematology & Oncology. 2018 ; Bind 7.
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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",
abstract = "Background: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.Methods: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.Results: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36{\%} of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4{\%}, 95{\%} CI 25.5-64.7) and in 16 patients (51.6{\%}, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9{\%}) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.Conclusion: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy. Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).",
keywords = "Adverse drug event, Bortezomib, Clarithromycin, Double blind study, Induction chemotherapy, Multiple myeloma",
author = "Henrik Gregersen and Trung Do and Kristensen, {Ida Bruun} and Fr{\o}lund, {Ulf Christian} and Andersen, {Niels Frost} and Nielsen, {Lene Kongsgaard} and Andersen, {Christen Lykkegaard} and Klausen, {Tobias Wirenfeldt} and Vangsted, {Annette Juul} and Niels Abildgaard",
year = "2018",
month = "8",
day = "13",
doi = "10.1186/s40164-018-0110-0",
language = "English",
volume = "7",
journal = "Experimental Hematology & Oncology",
issn = "2162-3619",
publisher = "BioMed Central",

}

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. / Gregersen, Henrik; Do, Trung; Kristensen, Ida Bruun; Frølund, Ulf Christian; Andersen, Niels Frost; Nielsen, Lene Kongsgaard; Andersen, Christen Lykkegaard; Klausen, Tobias Wirenfeldt; Vangsted, Annette Juul; Abildgaard, Niels.

I: Experimental Hematology & Oncology, Bind 7, 18, 13.08.2018.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - 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

AU - Gregersen, Henrik

AU - Do, Trung

AU - Kristensen, Ida Bruun

AU - Frølund, Ulf Christian

AU - Andersen, Niels Frost

AU - Nielsen, Lene Kongsgaard

AU - Andersen, Christen Lykkegaard

AU - Klausen, Tobias Wirenfeldt

AU - Vangsted, Annette Juul

AU - Abildgaard, Niels

PY - 2018/8/13

Y1 - 2018/8/13

N2 - Background: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.Methods: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.Results: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.Conclusion: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy. Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).

AB - Background: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.Methods: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.Results: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.Conclusion: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy. Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).

KW - Adverse drug event

KW - Bortezomib

KW - Clarithromycin

KW - Double blind study

KW - Induction chemotherapy

KW - Multiple myeloma

U2 - 10.1186/s40164-018-0110-0

DO - 10.1186/s40164-018-0110-0

M3 - Journal article

VL - 7

JO - Experimental Hematology & Oncology

JF - Experimental Hematology & Oncology

SN - 2162-3619

M1 - 18

ER -