A Phase 1 Clinical Trial of Oral Eltanexor in Patients with Relapsed or Refractory Multiple Myeloma

Background We showed a tumor-promoting and immunosuppressive role of plasmacytoid dendritic cells (pDCs; CD123/IL-3Rα+) in multiple myeloma (MM) pathogenesis (Chauhan et al. Cancer Cell, 2009;Ray et al, Leukemia, 2018). Importantly, tagraxofusp, an FDA-approved (for patients with blastic plasmacytoid dendritic cell neoplasm) novel targeted therapy directed against CD123, triggers anti-MM activity by reducing the viability of MM-promoting pDCs. These observations led to a recently completed phase 1 clinical trial of tagraxofusp and pomalidomide/dexamethasone in relapsed and refractory MM patients (NCT02661022). The treatment regimen demonstrated preliminary safety and efficacy, with 5 of 9 heavily pretreated patients achieving durable partial response (PR) (ASH 2019). Here, we report the initial results of our correlative science studies using bone marrow (BM), peripheral blood (PB), and serum from the study cohort. Materials and Methods Tagraxofusp is a bioengineered therapeutic protein developed by fusing human IL-3 to the catalytic translocation domain of truncated diphtheria toxin (DT) via a Met-His linker (Stemline Therapeutics, NY). pDCs and patient MM cells were purified from BM/PB samples after informed consent, and quantified using FACS, as described (Ray et al, Leukemia, 2018). A novel high-throughput seroproteomics platform SOMAscan was utilized to analyze 1,310 protein analytes in serum samples from MM patients (n = 9). SOMAscan data were subjected to meta-analysis to generate heatmaps, followed by hierarchical cluster analysis. SOMAscan results were validated with ELISA using supernatants from MM patient pDCs cultured with or without tagraxofusp. Results Analysis of BM/PB samples from MM patients receiving tagraxofusp therapy showed a marked reduction in the frequency of viable pDCs [average 2% at screening vs 0.75% post-tagraxofusp; n = 6; p = 0.036]. pDCs isolated from tagraxofusp-treated patients showed decreased ability to trigger MM cell growth. Seroproteomics analysis of MM patient serum before and after tagraxofusp therapy showed alterations in the levels of 100 proteins [Median Fold Change in expression: 0.39 to 4.5; n = 6; 3 each; p < 0.05]. Importantly, tagraxofusp treatment reduced pDC-related soluble proteins including IFN-α (fold change: 0.8, treated vs untreated; p < 0.05). Our earlier study showed that pDC-MM interactions triggered secretion of IL-3, which in turn promotes both pDC survival and MM cell growth. Importantly, tagraxofusp decreased serum IL-3 (fold change 0.75, treated vs untreated; p < 0.05), consistent with tagraxofusp decreasing survival of tumor-promoting pDCs. Conclusions Our current correlative science studies validate target specificity of tagraxofusp against MM pDCs in relapsed and refractory MM patients enrolled in a phase 1 clinical trial and support further evaluation for this novel therapeutic to improve the clinical outcome of patients with MM. Further combination studies are planned. Disclosures Mo: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Olguin:Stemline Therapeutics: Current Employment. Chen:Stemline Therapeutics: Current Employment. Brooks:Stemline: Current Employment. Mughal:Stemline: Current Employment. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Chauhan:consultant to Stemline Therapeutics, Inc., and Equity owner in C4 Therapeutics.: Consultancy, Other: Equity owner in C4 Therapeutics.; Oncopeptide AB: Consultancy. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees.

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Phase 1 clinical trial of marizomib (MRZ, NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 (NCT00629473) final results

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.563 ◽

2015 ◽

Vol 15 ◽

pp. e269 ◽

Cited By ~ 2

Author(s):

S.J. Harrison ◽

L. Catley ◽

T. Price ◽

M.J. Millward ◽

P. Padrik ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase 1 ◽

Phase 1 Clinical Trial ◽

Advanced Malignancies

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CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma

Blood ◽

10.1182/blood-2015-11-683854 ◽

2016 ◽

Vol 127 (26) ◽

pp. 3360-3368 ◽

Cited By ~ 58

Author(s):

James R. Berenson ◽

Alan Cartmell ◽

Alberto Bessudo ◽

Roger M. Lyons ◽

Wael Harb ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase 1 ◽

Dosing Schedule ◽

Refractory Multiple Myeloma ◽

Key Points

Key PointsThe CHAMPION-1 study is the first clinical trial to investigate carfilzomib on a once-weekly dosing schedule with dexamethasone. Once-weekly carfilzomib (30-minute infusion; 20 and 70 mg/m2) with dexamethasone is feasible and effective in relapsed/refractory MM.

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A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Patients with Relapsed/Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2019-131370 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1903-1903 ◽

Cited By ~ 1

Author(s):

James R. Berenson ◽

Jennifer To ◽

Tanya M. Spektor ◽

Daisy Martinez ◽

Armando J. Sanchez ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Research Funding ◽

Phase 1 ◽

Janus Kinase ◽

M2 Macrophage ◽

Inadequate Response ◽

Phase 1 Trial ◽

Refractory Multiple Myeloma ◽

Equity Ownership

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 (Mucin 1) is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 patients. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of March 1, 2019, 43 patients were enrolled, and 40 were evaluable for efficacy. The median age was 65 years (range, 46-81), and 25 (58%) were male. Patients received a median of 6 prior treatments including LEN and steroids to which they were all refractory. No DLTs occurred, and DL+3 was expanded. Among all 40 evaluable patients, the CBR and ORR were 47% and 37%, respectively (1 CR, 4 VGPR, 10 PR and 4 MR), and 16 and 5 patients showed SD and PD. Notably, all 19 patients achieving > MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 4 months. G3/4 AEs included anemia (16%), sepsis (14%), lymphocytopenia (14%), pneumonia (12%), neutropenia (12%) and hypokalaemia (12%). Most common SAEs included sepsis (14%) and pneumonia (12%). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to expansion of the current clinical trial to 78 patients, and represent a potential novel therapeutic approach for treating MM. Disclosures Berenson: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy; OncoTracker: Equity Ownership, Other: Officer; OncoTracker: Equity Ownership, Other: Officer; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding; Incyte Corporation.: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Eades:Celgene: Other: Stock. Boccia:Genentech: Speakers Bureau; DSI: Speakers Bureau; AMAG: Consultancy; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. OffLabel Disclosure: The goal of this clinical trial is to establish ruxolitinib in combination with lenalidomide and methylprednisolone as the therapy for relapse/refractory multiple myeloma patients.

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