RESULTS FROM ONGOING PHASE 1/2 TRIAL OF SL-401 IN PATIENTS WITH RELAPSED/REFRACTORY CMML
Author(s): ,
Mrinal Patnaik
Affiliations:
Mayo Clinic,Rochester,United States
,
Haris Ali
Affiliations:
City of Hope,Duarte,United States
,
Vikas Gupta
Affiliations:
Princess Margaret Cancer Centre,Toronto,Canada
,
Gary Schiller
Affiliations:
UCLA,Los Angeles,United States
,
Sangmin Lee
Affiliations:
Weill Cornell Medical Center,New York,United States
,
Abdulraheem Yacoub
Affiliations:
Kansas University Cancer Center,Westwood,United States
,
Moshe Talpaz
Affiliations:
University of Michigan Health System,Ann Arbor,United States
,
Megan Sardone
Affiliations:
Stemline Therapeutics,New York,United States
,
Halyna Wysowskyj
Affiliations:
Stemline Therapeutics,New York,United States
,
Shay Shemesh
Affiliations:
Stemline Therapeutics,New York,United States
,
Janice Chen
Affiliations:
Stemline Therapeutics,New York,United States
,
Chris Brooks
Affiliations:
Stemline Therapeutics,New York,United States
,
Trishna Goswami
Affiliations:
Stemline Therapeutics,New York,United States
,
Animesh Pardanani
Affiliations:
Mayo Clinic,Rochester,United States
,
Ayalew Tefferi
Affiliations:
Mayo Clinic,Rochester,United States
,
Srdan Verstovsek
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Joseph Khoury
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
Naveen Pemmaraju
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
EHA Library. Patnaik M. 06/15/18; 215069; PF626
Mrinal Patnaik
Mrinal Patnaik
Contributions
Abstract

Abstract: PF626

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
The outcomes for chronic myelomonocytic leukemia (CMML) patients are poor, with overall response rates (ORR) of ~16% for hypomethylating agents (HMA) in first-line registration studies, and median overall survival (OS) of ~4-7 months in the relapsed/refractory setting. SL-401 is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies, including certain myeloproliferative neoplasms (MPNs) such as CMML. CD123 is also expressed on plasmacytoid dendritic cells (pDCs), which can reside in the tumor microenvironment and may play a role in promoting growth of MPN and other malignancies. Accordingly, a therapy directed at CD123-expressing malignant cells and/or their neighboring pDCs may offer a novel therapeutic approach. SL-401 has demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs, and is also being evaluated in Phase 1/2 trials of other cancers.

Aims
Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes in patients with relapsed/refractory CMML.

Methods
This multicenter, single-arm 2-stage Phase 1/2 trial is enrolling patients with MPN including relapsed/refractory CMML. In the Stage 1 dose escalation cohort (completed), SL-401 was dosed as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), the dose determined to be optimal in Stage 1 (12 mcg/kg) is being employed.

Results
As of 2/27/18, 14 CMML patients (CMML-1 [n=8]; CMML-2 [n=6]) received SL-401. 12 patients were second-line and 2 patients were third-line, with HMAs being the most commonly administered prior therapy. Median age was 70 years (range 42-80); 71% patients were male. Of the 13 patients with cytogenetic risk categories available, 5 patients (38%) were high risk, 5 patients (38%) were intermediate risk, 2 patients (15%) were low risk, and 1 patient (8%) was other. At baseline, median bone marrow (BM) blasts were 8% (range 0-18%); 57% of patients had splenomegaly (range: 2 to 20 cm palpable below costal margin (BCM) by physical exam). Most common treatment-related adverse events (TRAEs), all grades, were hypoalbuminemia and vomiting (36%), thrombocytopenia, fatigue, edema and nausea (each 29%). Most common ≥grade 3 TRAEs were thrombocytopenia (29%) and hypotension (14%). Capillary leak syndrome was reported in 3 patients (21%; all grade 2). 71% (5/7) of patients with baseline splenomegaly had 50% reduction in spleen size by physical exam: baseline 5, 4, 2, and 2 cm all reduced to 0 cm (100%) BCM; baseline 20 cm reduced to 10 cm (50%) BCM. 17% (2/12) of evaluable patients had BM complete response (BMCR), including 1 CR (15 months on treatment) and 1 BMCR (4+ months on treatment, ongoing).

Conclusion
Single agent SL-401 was well-tolerated and demonstrated 71% (5/7) rate of spleen reductions and a 17% (2/12) rate of BMCR (1 CR and 1 BMCR) in relapsed/refractory CMML, an area of unmet medical need. Given CD123 expression on certain myeloid neoplastic cells and pDCs in the tumor microenvironment, SL-401 may offer a novel targeted approach for CMML patients. Enrollment continues, and updated safety and efficacy data will be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Chronic myelomonocytic leukemia, Microenvironment, Targeted therapy

Abstract: PF626

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
The outcomes for chronic myelomonocytic leukemia (CMML) patients are poor, with overall response rates (ORR) of ~16% for hypomethylating agents (HMA) in first-line registration studies, and median overall survival (OS) of ~4-7 months in the relapsed/refractory setting. SL-401 is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies, including certain myeloproliferative neoplasms (MPNs) such as CMML. CD123 is also expressed on plasmacytoid dendritic cells (pDCs), which can reside in the tumor microenvironment and may play a role in promoting growth of MPN and other malignancies. Accordingly, a therapy directed at CD123-expressing malignant cells and/or their neighboring pDCs may offer a novel therapeutic approach. SL-401 has demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs, and is also being evaluated in Phase 1/2 trials of other cancers.

Aims
Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes in patients with relapsed/refractory CMML.

Methods
This multicenter, single-arm 2-stage Phase 1/2 trial is enrolling patients with MPN including relapsed/refractory CMML. In the Stage 1 dose escalation cohort (completed), SL-401 was dosed as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), the dose determined to be optimal in Stage 1 (12 mcg/kg) is being employed.

Results
As of 2/27/18, 14 CMML patients (CMML-1 [n=8]; CMML-2 [n=6]) received SL-401. 12 patients were second-line and 2 patients were third-line, with HMAs being the most commonly administered prior therapy. Median age was 70 years (range 42-80); 71% patients were male. Of the 13 patients with cytogenetic risk categories available, 5 patients (38%) were high risk, 5 patients (38%) were intermediate risk, 2 patients (15%) were low risk, and 1 patient (8%) was other. At baseline, median bone marrow (BM) blasts were 8% (range 0-18%); 57% of patients had splenomegaly (range: 2 to 20 cm palpable below costal margin (BCM) by physical exam). Most common treatment-related adverse events (TRAEs), all grades, were hypoalbuminemia and vomiting (36%), thrombocytopenia, fatigue, edema and nausea (each 29%). Most common ≥grade 3 TRAEs were thrombocytopenia (29%) and hypotension (14%). Capillary leak syndrome was reported in 3 patients (21%; all grade 2). 71% (5/7) of patients with baseline splenomegaly had 50% reduction in spleen size by physical exam: baseline 5, 4, 2, and 2 cm all reduced to 0 cm (100%) BCM; baseline 20 cm reduced to 10 cm (50%) BCM. 17% (2/12) of evaluable patients had BM complete response (BMCR), including 1 CR (15 months on treatment) and 1 BMCR (4+ months on treatment, ongoing).

Conclusion
Single agent SL-401 was well-tolerated and demonstrated 71% (5/7) rate of spleen reductions and a 17% (2/12) rate of BMCR (1 CR and 1 BMCR) in relapsed/refractory CMML, an area of unmet medical need. Given CD123 expression on certain myeloid neoplastic cells and pDCs in the tumor microenvironment, SL-401 may offer a novel targeted approach for CMML patients. Enrollment continues, and updated safety and efficacy data will be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Chronic myelomonocytic leukemia, Microenvironment, Targeted therapy

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