Tagraxofusp (SL-401) in Participants With Chronic Myelomonocytic Leukemia (CMML) and Myelofibrosis (MF)

Phase 1

Completed

Conditions: Myelofibrosis
Chronic Myelomonocytic Leukemia

Interventions: Drug: Tagraxofusp Injection

Registration Number: NCT02268253

Lead Sponsor: Stemline Therapeutics, Inc.

Brief Summary: This multicenter, multi-arm trial evaluated the safety and efficacy of tagraxofusp, a cell division cycle protein 123 homolog-targeted therapy, in participants with either CMML or MF. There were 2 CMML cohorts, 1 enrolled participant with CMML (CMML-1 or CMML-2) who were refractory/resistant or intolerant to hypomethylating agents (HMA), hydroxyurea (HU), or intensive chemotherapy and 1 enrolled treatment-naive participants with CMML (CMML-1 or CMML-2) with molecular features associated with poor prognosis. The MF cohort enrolled participants who were resistant/refractory or intolerant to approved Janus kinase (JAK) therapy (JAK1/JAK2 or JAK2).

Detailed Description: This was a non-randomized, open-label, multicenter study, divided into 3 stages.

Stage 1: Stage 1 of the study was to enroll participants with CMML, MF, advanced systemic mastocytosis, or advanced symptomatic primary eosinophilic disorder.

Stage 2: Stage 2 was to enroll MF and CMML participants.

Stage 3A: Stage 3A was to enroll 2 populations of participants with CMML, those with CMML-1 or CMML-2 who were refractory/resistant/intolerant to HMAs, HU, or intensive chemotherapy (relapsed/refractory participants); and participants with treatment-naïve CMML-1 or CMML-2 (previously untreated participants) with molecular features associated with a poor prognosis.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 82

Inclusion Criteria

All Participants - Participants meeting all the following criteria were considered for enrollment:

The participant had a life expectancy of > 6 months.
The participant had an Eastern Cooperative Oncology Group performance status of 0-2.
The participant had adequate baseline organ function, including cardiac, renal, and hepatic function:
- Left ventricular ejection fraction 2: institutional lower limit of normal as measured by multigated acquisition scan or 2-dimensional echocardiogram within 28 days prior to the start of therapy and no clinically significant abnormalities on a 12-lead electrocardiogram.
- Serum creatinine ≤ 1.5 milligrams/deciliter (dL).
- Serum albumin ≥ 3.2 grams (g)/dL (or 32 g/liter [L]) in the absence of receipt of intravenous albumin within the previous 72 hours.
- Aspartate transaminase and alanine transaminase ≤ 2.5 times the upper limit of normal (ULN).
- Creatine phosphokinase ≤ 2.5 times the ULN.
- Absolute neutrophil count ≥ 0.5×10^9/L.
If a woman of child-bearing potential, the participant had a negative serum or urine pregnancy test within 1 week prior to tagraxofusp treatment (intervals shorter than 1 week are acceptable, if required by institutional guidelines).
The participant (either male or female) agrees to use acceptable contraceptive methods for the duration of time in the study, and to continue to use acceptable contraceptive methods for 1 week after the last tagraxofusp infusion.
The participant can adhere to the study visit schedule and other protocol requirements, including follow-up for response assessments.

Myelofibrosis (Stage 2) - Participants with MF meeting all of the following criteria, in addition to those specified for all participants, above, are eligible for enrollment in Stage 2:

Participant meets the 2016 World Health Organization (WHO) diagnostic criteria for MF and has an International Prognostic Scoring System/Dynamic International Prognostic Scoring System (IPSS/DIPSS)/DIPSS-plus intermediate-2 or high-risk disease. Participants with IPSS/DIPSS/DIPSS-plus low or intermediate-1 risk disease who have at least 1 of the following symptoms are also eligible: MF-related anemia (hemoglobin < 10 g/dL), splenomegaly (palpable size > 10 centimeters), leukocytosis (white blood cell count [WBC] > 25×10^9/L), marked thrombocytosis (platelet count > 1,000×10^9/L), or constitutional symptoms (weight loss > 10%, during prior 6 months or fever [> 37.5 degrees Celsius or drenching night sweats for > 6 weeks]), as recommended by the European LeukemiaNet/International Working Group (ELN/IWG) 2018 criteria.
Participant was approved JAK therapy (JAK1/JAK2 or JAK2) resistant/refractory or intolerant, in accordance with the ELN/IWG 2018 criteria, and at least 4 weeks have elapsed between the last dose of any MF-directed drug treatments, excluding HU, and study enrollment (first dose). HU can be continued until 2 weeks prior to study enrollment.
Participant was not eligible for an immediate allogeneic-stem cell transplantation.

CMML (Stage 3A):
Participant had a 2016 WHO-defined diagnosis of CMML (persistent monocytosis ≥ 1×10^9/L for at least 3 months, with other causes excluded, and monocytes ≥10% of WBC in peripheral blood, no criteria and no previous history of CMML, essential thrombocythemia, polycythemia vera, and acute promyelocytic leukemia; if eosinophilic, neither platelet-derived growth factor receptor A, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1 rearrangements nor pericentriolar material 1-JAK2 translocation; < 20% blasts in peripheral blood and bone marrow aspirate; > 1 following criteria: dysplasia in > 1 myeloid lineage, acquired clonal cytogenetic or molecular abnormality in hematopoietic cells).
Participant had 2016 WHO-defined CMML-1 (2-4% blasts in peripheral blood and/or 5-9% blasts in bone marrow) and CMML-2 (5-19% blasts in peripheral blood and/or 10-19% blasts in bone marrow, and/or presence of Auer rods).
Participant was refractory/resistant/intolerant, as defined for the purposes of this study (in the absence of a standard definition for CMML) below, to HMAs, HU, or intensive chemotherapy, including:
- Resistance/intolerance to HU is defined as:
  - Uncontrolled myeloproliferation, (platelets > 400×10^9/L and WBC > 10×10^9/L after 3 months of at least 2 g/day of HU); or
  - Myelosuppression at a clinically relevant dose; or
  - Presence of unacceptable HU-related non-hematological toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis, or fever at any dose of HU.
- Conventional definition for HMA failure is defined for the purposes of this study (in the absence of a standard definition for CMML) as:
  - Disease progression following at least 4 to 6 cycles of 5-azacitidine or decitabine; or
  - Relapse after achieving response; or
  - Intolerance to 5-azacitidine or decitabine at the prescribed dose.
or

• Participant was classified as high-risk based on the presence of morphological features, as described by the 2016 WHO prognostic system, and the clinical and molecular features described in molecularly integrated prognostic systems, such as the Groupe Français des Myélodysplasies, Mayo Molecular Model, and the CMML specific prognostic model and thus is not expected to benefit from HMAs.
Participant was ineligible for an immediate allogeneic stem cell transplantation (allo-SCT).

Key

Exclusion Criteria

Participant had persistent clinically significant toxicities Grade ≥2 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue).
Participant received treatment with any disease-related therapy, including radiation therapy within 14 days of study entry.
Participant received an allo-SCT within 3 months of study entry.
Participant received treatment with another investigational agent within 14 days of study entry or concurrent treatment with another investigational agent.
Participant previously received treatment with tagraxofusp or has a known hypersensitivity to any components of the drug product.
Participant had an active malignancy and/or cancer history (excluding myeloproliferative disorders and concomitant myeloid malignancies as specified in the inclusion criteria) that could confound the assessment of the study endpoints.
Participant had clinically significant cardiovascular disease (for example, uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
Participant had uncontrolled, clinically significant pulmonary disease (for example, chronic obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator's opinion, would have put the participant at significant risk for pulmonary complications during the study.
Participant had known active or suspected disease involvement of the central nervous system (CNS). If suspected due to clinical findings, CNS disease was to be ruled out with relevant imaging and/or examination of cerebrospinal fluid.

Note: Other inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Level 1 - Tagraxofusp - 7 micrograms/kilogram (µg/kg)/day - Chronic Myelomonocytic Leukemia	Tagraxofusp Injection	-
Dose Level 1 - Tagraxofusp - 7 µg/kg/day - Myelofibrosis	Tagraxofusp Injection	-
Dose Level 2 - Tagraxofusp - 9 µg/kg/day - Chronic Myelomonocytic Leukemia	Tagraxofusp Injection	-
Dose Level 2 - Tagraxofusp - 9 µg/kg/day - Myelofibrosis	Tagraxofusp Injection	-
Dose Level 3 - Tagraxofusp - 12 µg/kg/day - Chronic Myelomonocytic Leukemia	Tagraxofusp Injection	-
Dose Level 3 - Tagraxofusp - 12 µg/kg/day - Myelofibrosis	Tagraxofusp Injection	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-limiting Toxicities (DLTs)	21 days of Cycle 1 (21 days/cycle)	During Stage 1, DLT was defined as any of the following occurring during the first cycle of therapy: any treatment-emergent Grade 4 transaminase or creatine phosphokinase (CPK) elevation (confirmed within 24 hours of initial identification), regardless of duration or relationship to SL-401; any Grade ≥3 non-hematologic toxicity (unrelated to underlying MPN), with the exception of Grade 3 laboratory toxicities that resolve to Grade ≤1 or baseline ≤28 days after the last infusion of SL-401, or the following Grade 3 toxicities if they resolve to Grade ≤1 or baseline ≤21 days after the last infusion of SL-401, arthralgia, myalgia, fever responding to treatment, nausea and/or vomiting (excluding cases that require tube feeding, total parenteral nutrition, or hospitalization) or diarrhea associated with suboptimal prophylaxis or treatment; Grade 4 neutropenia or Grade 4 thrombocytopenia with a duration (at Grade 4) of ≥28 days.
Objective Response Rate (ORR)	1145 days	ORR was defined as the percentage of participants (responders) who achieved disease-specific complete response (CR) or partial response (PR) after treatment. For response assessment of myelofibrosis during both Stage 1 and Stage 2, the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet (IWG-MRT/ELN 2013) criteria were used. For chronic myelomonocytic leukemia, during both Stage 1 and Stage 2, the International Working Group 2006 response criteria for myelodysplastic syndromes (IWG MDS 2006) were used for response assessment while the Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) 2015 criteria were used for response assessment during Stage 3A.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (24): University of California, San Francisco
🇺🇸
Clovis, California, United States
Stanford Cancer Institute
🇺🇸
Stanford, California, United States
Mayo Clinic Florida
🇺🇸
Jacksonville, Florida, United States
Georgia Cancer Center at Augusta University
🇺🇸
Augusta, Georgia, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
Indiana Blood and Bone Marrow Transplantation
🇺🇸
Indianapolis, Indiana, United States
Dana Farber Cancer Institute (DFCI)
🇺🇸
Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
University of Michigan Health System
🇺🇸
Ann Arbor, Michigan, United States
John Theurer Cancer Center
🇺🇸
Hackensack, New Jersey, United States
University of New Mexico
🇺🇸
Albuquerque, New Mexico, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
The Ohio State University
🇺🇸
Columbus, Ohio, United States
Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
City of Hope
🇺🇸
Duarte, California, United States
University of California, Los Angeles
🇺🇸
Los Angeles, California, United States
University of Kansas Cancer Center
🇺🇸
Westwood, Kansas, United States
Norton Cancer Institute
🇺🇸
Louisville, Kentucky, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Weill Cornell Medical Center
🇺🇸
New York, New York, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Alberta
🇨🇦
Edmonton, Alberta, Canada
Princess Margaret Cancer Centre
🇨🇦
Toronto, Ontario, Canada