Phase I dose-escalation study of F50067, a humanized anti-CXCR4 monoclonal antibody alone and in combination with lenalidomide and low-dose dexamethasone, in relapsed or refractory multiple myeloma

Article

Author: Gruchet, Cécile ; Vedovato, Jean-Claude ; Syshenko, Thomas ; Franques, Paul ; Macro, Margaret ; Karlin, Lionel ; Ferre, Pierre ; Sabirou, Florence ; Pavlyuk, Mariya ; Levy, Anthony ; Facon, Thierry ; Stoppa, Anne-Marie ; Gardeney, Hélène ; Le Tourneau, Christophe ; Ouali, Monia ; Bobin, Arthur ; Richez, Valentine ; Moya, Niels ; Attal, Michel ; Benboubker, Lotfi ; Guidez, Stéphanie ; Leleu, Xavier ; Fouquet, Guillemette

PURPOSEMultiple myeloma (MM) remains an incurable disease as tumor cells ultimately resist to all available drugs. Homing of tumor cells to the bone marrow microenvironment, involving especially the CXCR4/SDF-1 axis, allows them to survive, proliferate and resist to therapy. F50067, a humanized anti-CXCR4 IgG1 antibody, has promising preclinical activity in MM.We present a phase I multicenter escalation study in relapsed/refractory MM (RRMM) to determine the maximum tolerated dose (MTD) for F50067 alone and in combination with lenalidomide and low dose dexamethasone (Len-Dex).EXPERIMENTAL DESIGN14 end-stage RRMM patients received F50067 single agent (n = 10) or in combination with Len-Dex (n = 4).RESULTSOne dose-limiting toxicity was observed, a grade 4 neutropenia lasting more than 7 days in combination arm. MTD could not be established. Thrombocytopenia was observed in 100% and neutropenia in 92.9% of patients with no cases of febrile neutropenia and no severe bleeding or hematoma. Non-hematological adverse events were of mild to moderate severity.Nine patients (6 in single arm and 3 in combination arm) were evaluable for response, with 66.7% overall response rate (≥PR) in combination arm, and 33.3% of disease control (≥SD) in single agent arm. At the time of study termination, 55.6% had progressed.CONCLUSIONThis study suggests that egression of tumor cells to the blood stream can represent a novel therapeutic strategy for MM. However, because of significant hematological toxicity, this study had to be discontinued. Further studies are needed to validate the feasibility of this approach in clinical practice.

01 Aug 2016·Molecular Cancer TherapeuticsQ2 · MEDICINE

A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells

Q2 · MEDICINE

Article

Author: Klinguer-Hamour, Christine ; Akla, Barbara ; Goetsch, Liliane ; Bailly, Christian ; Robert, Alain ; Berger, Sven ; Beau-Larvor, Charlotte ; Matthes, Thomas ; Champion, Thierry ; Dumontet, Charles ; Haeuw, Jean-François ; Broussas, Matthieu ; Corvaia, Nathalie ; Beck, Alain ; Boute, Nicolas

AbstractThe type IV C-X-C-motif chemokine receptor (CXCR4) is expressed in a large variety of human cancers, including hematologic malignancies, and this receptor and its ligand, stromal cell–derived factor-1 (SDF-1), play a crucial role in cancer progression. We generated a humanized immunoglobulin G1 mAb, hz515H7, which binds human CXCR4, efficiently competes for SDF-1 binding, and induces a conformational change in CXCR4 homodimers. Furthermore, it inhibits both CXCR4 receptor–mediated G-protein activation and β-arrestin-2 recruitment following CXCR4 activation. The binding of the hz515H7 antibody to CXCR4 inhibits the SDF-1–induced signaling pathway, resulting in reduced phosphorylation of downstream effectors, such as Akt, Erk1/2, p38, and GSK3β. Hz515H7 also strongly inhibits cell migration and proliferation and, while preserving normal blood cells, induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against neoplastic cells. In mouse xenograft models, hz515H7 displays antitumor activities with multiple hematologic tumor cell lines, with its Fc-mediated effector functions proving essential in this context. Furthermore, hz515H7 binds to primary tumor cells from acute myeloid leukemia and multiple myeloma patients. Collectively, our results demonstrate two major mechanisms of action, making hz515H7 unique in this regard. Its potential as a best-in-class molecule is currently under investigation in a phase I clinical trial. Mol Cancer Ther; 15(8); 1890–9. ©2016 AACR.

Antibodies

Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development

Review

Author: Rosko, Nathaniel ; Sandeep, Sonia ; Iftikhar, Ahmad ; Hassan, Hamza ; Sohail, Atif ; Chakraborty, Rajshekhar ; Anwer, Faiz ; Kanate, Abraham Sebastian ; Valent, Jason Neil ; Iftikhar, Nimra ; Mushtaq, Adeela ; Razzaq, Faryal

Background: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. Conclusions: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.

100 Deals associated with hz-515H7

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	FR	Pierre Fabre SA	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2019	Not Applicable	Multiple Myeloma	1,917	Isatuximab	(sywacxawft) = fqrqwygvaf zgpwspcjwu (euelsroxxj ) View more	-	26 May 2019
				F50067	(svtblwwhyh) = jtsibkopvo wqipdczuio (pgirfrkgfj )

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