PRELIMINARY CLINICAL DATA FROM A PHASE 1B STUDY OF MAVORIXAFOR AND IBRUTINIB IN PATIENTS WITH WALDENSTRÖM’S MACROGLOBULINEMIA WITH MYD88 AND CXCR4 MUTATIONS
Author(s): ,
Steven Treon
Affiliations:
Bing Center for Waldenstrom’s Macroglobulinemia Research,Harvard Medical School,Boston, MA,United States;Dana Farber Institute,Harvard Medical School,Boston, MA,United States
,
Christian Buske
Affiliations:
Comprehensive Cancer Center and Institute of Experimental Cancer Researc,University of Ulm,Ulm,Germany
,
Sheeba Thomas
Affiliations:
Deparatment of Lymphoma/Myeloma, Division of Cancer Medicine,The University of Texas MD Anderson Cancer Center,Houston, TX,United States
,
Andrew Branagan
Affiliations:
Massacusettes General Hospital Cancer Center,Boston, MA,United States
,
Meletios Dimopoulos
Affiliations:
Department of Clinical Therapeutics, National and Kapodistrian,University of Athens School of Medicine,Athens,Greece
,
Jorge Julio Castillo
Affiliations:
Bing Center for Waldenstrom’s Macroglobulinemia,Harvard Medical School,Boston, MA,United States;Dana Farber Cancer Institute,Harvard Medical School,Boston, MA,United States
,
Felix Garzon
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Weihua Tang
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Rachel Ronan
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Sean Seyffert
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Varun Garg
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Shariq Ali
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Art Taveras
Affiliations:
X4 Pharmaceuticals,Boston, MA,United States
,
Adriana Badarau
Affiliations:
X4 Pharmaceuticals,Vienna,Austria
,
Katarina Zmajkovicova
Affiliations:
X4 Pharmaceuticals,Vienna,Austria
,
Sabine Maier
Affiliations:
X4 Pharmaceuticals,Vienna,Austria
,
Barbara Maierhofer
Affiliations:
X4 Pharmaceuticals,Vienna,Austria
Jeffrey Matous
Affiliations:
Colorado Blood Cancer Institute,Sarah Cannon Research Institute,Denver, CO,United States
EHA Library. Treon S. 06/09/21; 325542; EP784
Steven Treon
Steven Treon
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP784

Type: E-Poster Presentation

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background
Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative disorder characterized by increased clonal IgM-secreting cells. Though other covalent and noncovalent BTK inhibitors (BTKi) are in development for WM, ibrutinib is the only BTKi approved by the FDA and EMA for WM. Most patients with WM (>90%) have somatic mutations in MYD88, and a subset (≤40%) also have WHIM-like activating mutations in CXCR4 (CXCR4WHIM). The presence of CXCR4WHIM impacts response to BTKi in WM, as manifested by delayed response, inferior depth of response, and/or shorter progression-free survival. Inhibition of CXCR4 has been shown to sensitize CXCR4WHIM-expressing cells to ibrutinib. Mavorixafor, an oral small-molecule antagonist of CXCR4, has been shown to inhibit CXCL12 binding and ERK hyperactivation for many CXCR4 mutations in vitro. 

Aims
This study examines the safety and efficacy of mavorixafor in combination with ibrutinib in patients with WM with MYD88 and CXCR4 mutations. 

Methods
This phase 1b, open-label, multicenter, single-arm study (NCT04274738) examines intra-patient dosing, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of mavorixafor in combination with ibrutinib. Eligibility includes age ≥18 years, clinicopathological WM diagnosis, consensus criteria indication for treatment, measurable disease, 0–3 prior therapies, confirmed MYD88L265P and CXCR4WHIM mutations, and ability to provide written informed consent. Patients are initiated on mavorixafor 200 mg and ibrutinib 420 mg, both oral and once-daily (QD). Mavorixafor escalation to 400 mg occurs after 28 days if no dose-limiting toxicities (DLTs) are observed and to 600 mg after 400 mg is deemed safe (<2/6 DLTs). Patients are followed for adverse events (AEs) and change from baseline in IgM, PK, and PD (peripheral white blood cell [WBC] counts). 

Results
At data cutoff (January 22, 2021), 7 patients have enrolled; all continue on study. All 7 patients were escalated to 400 mg, with 6 remaining at 400 mg and 1 de-escalated to 200 mg (median exposure, 90 days). None have yet escalated to 600 mg. A total of 56 AEs were observed (84% grade 1 severity). Of 50 AEs with complete assessment for causal relationship to study drugs, 4 were deemed related to mavorixafor only, 7 to ibrutinib only, and 18 to the combination. A single patient experienced all events attributed to mavorixafor only (all grade ≤2 GI events). Only 1 DLT was observed, consisting of grade 3 hypertension with definitive attribution to ibrutinib and possible attribution to mavorixafor. No AEs led to study discontinuation, and no serious AEs were observed. Six out of 7 patients showed decrease in IgM after 1 cycle. Four patients were treated for ≥3 cycles; all had decrease in serum IgM, with 2 achieving a ≥50% decrease from baseline consistent with partial response after 3 cycles (median decrease, 51.0%; range, 4.4%–84.5%). Mavorixafor and ibrutinib exposures were consistent with previous reports, and combination treatment increased peripheral lymphocytes, neutrophils, and monocytes. 

Conclusion
Our findings to date in patients with WM carrying both MYD88 and CXCR4 mutations show that mavorixafor in combination with ibrutinib is well tolerated at doses up to 400 mg QD. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM levels, suggesting that mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.

Keyword(s): CXCR4, Ibrutinib, Monoclonal gammopathy, Waldenstrom's macroglobulinemia

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP784

Type: E-Poster Presentation

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background
Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative disorder characterized by increased clonal IgM-secreting cells. Though other covalent and noncovalent BTK inhibitors (BTKi) are in development for WM, ibrutinib is the only BTKi approved by the FDA and EMA for WM. Most patients with WM (>90%) have somatic mutations in MYD88, and a subset (≤40%) also have WHIM-like activating mutations in CXCR4 (CXCR4WHIM). The presence of CXCR4WHIM impacts response to BTKi in WM, as manifested by delayed response, inferior depth of response, and/or shorter progression-free survival. Inhibition of CXCR4 has been shown to sensitize CXCR4WHIM-expressing cells to ibrutinib. Mavorixafor, an oral small-molecule antagonist of CXCR4, has been shown to inhibit CXCL12 binding and ERK hyperactivation for many CXCR4 mutations in vitro. 

Aims
This study examines the safety and efficacy of mavorixafor in combination with ibrutinib in patients with WM with MYD88 and CXCR4 mutations. 

Methods
This phase 1b, open-label, multicenter, single-arm study (NCT04274738) examines intra-patient dosing, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of mavorixafor in combination with ibrutinib. Eligibility includes age ≥18 years, clinicopathological WM diagnosis, consensus criteria indication for treatment, measurable disease, 0–3 prior therapies, confirmed MYD88L265P and CXCR4WHIM mutations, and ability to provide written informed consent. Patients are initiated on mavorixafor 200 mg and ibrutinib 420 mg, both oral and once-daily (QD). Mavorixafor escalation to 400 mg occurs after 28 days if no dose-limiting toxicities (DLTs) are observed and to 600 mg after 400 mg is deemed safe (<2/6 DLTs). Patients are followed for adverse events (AEs) and change from baseline in IgM, PK, and PD (peripheral white blood cell [WBC] counts). 

Results
At data cutoff (January 22, 2021), 7 patients have enrolled; all continue on study. All 7 patients were escalated to 400 mg, with 6 remaining at 400 mg and 1 de-escalated to 200 mg (median exposure, 90 days). None have yet escalated to 600 mg. A total of 56 AEs were observed (84% grade 1 severity). Of 50 AEs with complete assessment for causal relationship to study drugs, 4 were deemed related to mavorixafor only, 7 to ibrutinib only, and 18 to the combination. A single patient experienced all events attributed to mavorixafor only (all grade ≤2 GI events). Only 1 DLT was observed, consisting of grade 3 hypertension with definitive attribution to ibrutinib and possible attribution to mavorixafor. No AEs led to study discontinuation, and no serious AEs were observed. Six out of 7 patients showed decrease in IgM after 1 cycle. Four patients were treated for ≥3 cycles; all had decrease in serum IgM, with 2 achieving a ≥50% decrease from baseline consistent with partial response after 3 cycles (median decrease, 51.0%; range, 4.4%–84.5%). Mavorixafor and ibrutinib exposures were consistent with previous reports, and combination treatment increased peripheral lymphocytes, neutrophils, and monocytes. 

Conclusion
Our findings to date in patients with WM carrying both MYD88 and CXCR4 mutations show that mavorixafor in combination with ibrutinib is well tolerated at doses up to 400 mg QD. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM levels, suggesting that mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.

Keyword(s): CXCR4, Ibrutinib, Monoclonal gammopathy, Waldenstrom's macroglobulinemia

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