Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma

Chari, Ajai; Larson, Sarah; Holkova, Beata; Cornell, Robert F.; Gasparetto, Cristina; Karanes, Chatchada; Matous, Jeffrey; Niesvizky, Rubén; Valent, Jason; Lunning, Matthew A.; Usmani, Saad Z.; Anderson, Larry D.; Chang, Lipo; Lee, Yihua; Pak, Yvonne; Salman, Zeena; Graef, Thorsten; Bilotti, Elizabeth; Chhabra, Saurabh

doi:10.1080/10428194.2018.1443337

Cited by 24 publications

(31 citation statements)

References 14 publications

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“…However, it should be noted that a higher dose of ibrutinib (840 mg once daily) was used in the current study compared with other haematological malignancies (420 mg or 560 mg once daily). The ibrutinib dose used in the current study was chosen based on clinical activity and a favourable safety profile observed at the 840 mg dose level of ibrutinib in combination with carfilzomib with or without dexamethasone and in combination with dexamethasone in two early phase studies in MM . Plasma exposures to ibrutinib and bortezomib were consistent with those previously reported, suggesting that drug‐drug interactions may not be contributing factors to the safety observations.…”

Section: Discussionsupporting

confidence: 59%

“…This phase 2 study evaluated the efficacy and safety of ibrutinib in combination with bortezomib plus dexamethasone in patients with R/R MM who had received one to three previous lines of therapy. After 74 patients had received at least one dose of study treatment, study enrolment was suspended as a risk‐minimisation measure to address concerns over an increased incidence of serious and fatal infections compared with other studies of ibrutinib in R/R MM . While the incidence of infection of any grade in this study (80%) was similar to rates reported with ibrutinib in other haematological malignancies (68%‐78%) over median follow‐up durations of 9.4 to 33.4 months, the incidence of grade ≥3 infections (43%) was higher than rates previously reported with ibrutinib (7%‐29%) .…”

Section: Discussionmentioning

confidence: 62%

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A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Pour

Özcan

Sánchez

et al. 2020

European J of Haematology

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Objective:We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/ refractory multiple myeloma who had received 1-3 prior therapies. Methods:This was a phase 2, single-arm, open-label, multicentre study (NCT02902965).The primary endpoint was progression-free survival (PFS). Results:Seventy-six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2-10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6).Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients.Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk-minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs. Conclusion: Ibrutinib combined with bortezomib and dexamethasone elicited clinicalresponses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated. K E Y W O R D S bortezomib, dexamethasone, ibrutinib, multiple myelomaThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 62%

A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Pour

Özcan

Sánchez

et al. 2020

European J of Haematology

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“…In osteoclasts or bone marrow stromal cells from patients with MM, ibrutinib downregulated the secretion of carcinogen-initiated chemokines and cytokines, including CCL3, TNFβ, APRIL, and CXCL12, blocked CXCL12induced adhesion and migration of MM cells and reduced IL6-induced cell growth [101]. In clinical trials, ibrutinib plus dexamethasone or ibrutinib-carfilzomib-dexamethasone demonstrated encouraging responses with a manageable safety profile [102,103].…”

Section: Btk Inhibitors In MMmentioning

confidence: 99%

Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

et al. 2020

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Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

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“…Additionally, the treatment using ibrutinib in combination with carfilzomib ± dexamethasone was first evaluated in patients with relapsed or relapsed/refractory MM by Chari et al (2018) [75] in a phase 1 dose-finding trial. The outcomes demonstrated the combination therapy of ibrutinib (840 mg) and carfilzomib (36 mg/m 2 ) with dexamethasone showed the most promising result as it has the shortest median duration of response for patients who achieved above partial response which was 7.2 months.…”

Section: Ibrutinib For Multiple Myeloma (Mm)mentioning

confidence: 99%

A review on the potential of Bruton’s tyrosine kinase (Btk) inhibitor – Ibrutinib for treatment of Multiple Myeloma (MM)

Bong¹,

Law²,

Law³

2019

Prog Micobes Mol Biol

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Multiple myeloma (MM) is characterized by the over-production of monoclonal plasma cells that eventually become malignant in the bone marrow. MM remains as an incurable cancer, but it can be treated through chemotherapy. Nonetheless, research on novel therapies for effective treatment of MM is ongoing and in this case the involvement of Bruton’s tyrosine kinase (Btk) in B-cell malignancies has made it one of the new therapeutic targets. In MM patients, it has been reported that the expression of Btk was elevated and this could potentially contribute to chemoresistance indirectly via enhancement of cell proliferation and survival. Ibrutinib is a highly selective irreversible Btk inhibitor commonly used as treatment for B-cell malignancies such as Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). With reference to the potential involvement of Btk in MM and current treatment of MCL and CLL using ibrutinib, researchers have begun to examine the effect of ibrutinib treatment on MM. This review provides information on the association of MM and Btk in conjunction with the treatment using ibrutinib. To date, clinical trials of ibrutinib as therapeutic alternative for MM have produced promising results, particularly as combination therapy with other agents such as dexamethasone and carfilzomib. However, there is limited evidence on the Btk mechanisms involved in MM, hence, it is important to further investigate the Btk oncogenic signalling pathway(s) in MM cells in order to establish successful and improved treatment of MM.

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Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma

Cited by 24 publications

References 14 publications

A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

A review on the potential of Bruton’s tyrosine kinase (Btk) inhibitor – Ibrutinib for treatment of Multiple Myeloma (MM)

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