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Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma

Annals of Hematology volume 102, pages 369–383 (2023)Cite this article

Abstract

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

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Fig. 1
Fig. 2

Data availability

The data that support the findings of this study are available on request from the corresponding author. Certain data are not publicly available due to privacy or ethical restrictions.

Abbreviations

AE:

Adverse event

BID:

Twice a day

CAR:

Chimeric antigen receptor

CTCAE:

Common Terminology Criteria for Adverse Events

DCEP:

Dexamethasone, cyclophosphamide, etoposide, and cisplatin

DLT:

Dose-limiting toxicity

ECOG PS:

Eastern Cooperative Oncology Group performance status

IMiD:

Immunomodulatory drug

IMWG:

International Myeloma Working Group

MM:

Multiple myeloma

MTD:

Maximal tolerated dose

NDMM:

Newly diagnosed multiple myeloma

PD:

Pharmacodynamic

PFS:

Progression-free survival

PI:

Proteasome inhibitor

PK:

Pharmacokinetic

PrD:

Progressive disease

RRMM:

Relapsed/refractory multiple myeloma

SAE:

Serious adverse event

SD:

Stable disease

SK:

Sphingosine kinase

VD-PACE:

Velcade, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide

VGPR:

Very good partial response

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Acknowledgements

We thank patients and their families for their support and participation in this study.

Funding

This work was supported by NCI R44CA199767 (SBIR award to CS), NCI R01CA197792 (YK), NCI R21CA234701 (YK), NCI P01CA203628 (BO) and Duke Cancer Center Start-up fund (YK). RedHill Biopharma Limited is the IND holder and sponsored the trial including data monitoring and CRO activities.

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Authors and Affiliations

  1. Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA

    Yubin Kang, Pasupathi Sundaramoorthy, Cristina Gasparetto, Daniel Feinberg, Shengjun Fan, Gwynn Long, Emily Sellars & Anderson Garrett

  2. Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Sascha A. Tuchman & Brandi N. Reeves

  3. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    Zhiguo Li

  4. Division of Hematology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Bei Liu

  5. Department of Biochemistry and Molecular Biology, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    Besim Ogretmen

  6. Apogee Biotechnology Corporation, Hummelstown, PA, USA

    Lynn Maines & Charles Smith

  7. RedHill Biopharma, Tel Aviv, Israel

    Vered Katz Ben-Yair & Terry Plasse

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  1. Yubin Kang
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Contributions

YK: designed the experiments and wrote the manuscript; PS, DF, and SF: performed the correlative studies; CG, GL, ES, AG, SAT, and BNR: accrued patients for the studies; ZL: provided biostatistical support; BL and BO: provided important inputs; LM and VKB-Y: supported the clinical studies; CS: designed the clinical study, wrote and edited the manuscript, and the awardee of the NCI SBIR grant; TP: Medical Director for RedHill Biopharma, the sponsor of the clinical study, wrote and edited the manuscript, and provided input on the protocol and analysis of results.

Corresponding author

Correspondence to Yubin Kang.

Ethics declarations

Ethics approval and consent to participate

The study was conducted according to the Declaration of Helsinki and the International Council on Harmonization. The Duke Institutional Review Board (IRB) approved the protocol. All patients provided written informed consent.

Consent for publication

All authors approved the manuscript and the submission.

Competing interests

Yubin Kang received research funding from InCyte Corporation and a consultancy fee from Takeda Oncology USA and Sanofi Genzyme Corp. Charles Smith is the CEO and President, and Lynn Maines is employed by Apogee Biotechnology Corporation. Vered Katz Ben-Yair and Terry Plasse are consultants to RedHill Biopharma Limited. All other authors declare no competing conflicts of interest.

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Kang, Y., Sundaramoorthy, P., Gasparetto, C. et al. Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma. Ann Hematol 102, 369–383 (2023). https://doi.org/10.1007/s00277-022-05056-7

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Keywords

  • Phase I trial
  • Multiple myeloma
  • Opaganib
  • ABC294640
  • Sphingosine kinase inhibitor
  • Maximal tolerated dose
  • Response