Chronic Myelomonocytic Leukemia, Myelofibrosis
Conditions
Keywords
MF, CMML, CMML-1, CMML-2
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.
Interventions
DRUGTagraxofusp Injection
Tagraxofusp was administered as a 15-minute intravenous infusion once daily for the first 3 consecutive days of each dosing cycle.
Sponsors
Stemline Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: All Participants - Participants meeting all the following criteria were considered for enrollment: 1. The participant had a life expectancy of \> 6 months. 2. The participant had an Eastern Cooperative Oncology Group performance status of 0-2. 3. 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. 4. 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). 5. 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. 6. 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: 1. 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. 2. 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. 3. Participant was not eligible for an immediate allogeneic-stem cell transplantation. CMML (Stage 3A): 4. 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). 5. 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). 6. 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. 7. Participant was ineligible for an immediate allogeneic stem cell transplantation (allo-SCT). Key
Exclusion criteria
1. 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). 2. Participant received treatment with any disease-related therapy, including radiation therapy within 14 days of study entry. 3. Participant received an allo-SCT within 3 months of study entry. 4. Participant received treatment with another investigational agent within 14 days of study entry or concurrent treatment with another investigational agent. 5. Participant previously received treatment with tagraxofusp or has a known hypersensitivity to any components of the drug product. 6. 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. 7. 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). 8. 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. 9. 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 -Tagraxofusp - 7 µg/kg/Day - Chronic Myelomonocytic Leukemia Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 1 |
| Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Chronic Myelomonocytic Leukemia Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 2 |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Chronic Myelomonocytic Leukemia Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 39 |
| Dose Level 1 - Tagraxofusp - 7 µg/kg/Day - Myelofibrosis Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 2 |
| Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Myelofibrosis Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 1 |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Myelofibrosis Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 36 |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Advanced Systemic Mastocytosis Tagraxofusp was administered as a 15-minute IV infusion once daily for the first 3 consecutive days of each dosing cycle. | 1 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Stage 1 | Death | 0 | 2 | 2 | 2 | 1 | 1 | 0 |
| Stage 1 | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2 | Completion of 7 or More Cycles of Treatment | 0 | 0 | 2 | 0 | 0 | 7 | 0 |
| Stage 2 | Death | 0 | 0 | 19 | 0 | 0 | 20 | 1 |
| Stage 2 | Disease Recurrence/ Progression | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 4 | 0 |
| Stage 2 | Transferred to Hospice | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Stage 2 | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 2 | 0 |
| Stage 3A | Death | 0 | 0 | 5 | 0 | 0 | 0 | 0 |
| Stage 3A | Disease Recurrence/ Progression | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 3A | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 3A | Physician Decision | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Stage 3A | Study Terminated by Sponsor | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Stage 3A | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Advanced Systemic Mastocytosis | Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Myelofibrosis | Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Myelofibrosis | Dose Level 1 - Tagraxofusp - 7 µg/kg/Day - Myelofibrosis | Dose Level 1 -Tagraxofusp - 7 µg/kg/Day - Chronic Myelomonocytic Leukemia | Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Chronic Myelomonocytic Leukemia | Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Chronic Myelomonocytic Leukemia |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 8.81 | 63 years | 70.4 years STANDARD_DEVIATION 7.97 | 81.0 years | 65.5 years STANDARD_DEVIATION 4.95 | 42.0 years | 69.1 years STANDARD_DEVIATION 8.88 | 66.0 years STANDARD_DEVIATION 4.24 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 9 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 57 Participants | 1 Participants | 23 Participants | 1 Participants | 0 Participants | 1 Participants | 29 Participants | 2 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 16 Participants | 0 Participants | 10 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 62 Participants | 1 Participants | 25 Participants | 1 Participants | 2 Participants | 0 Participants | 32 Participants | 1 Participants |
| Sex: Female, Male Female | 29 Participants | 0 Participants | 16 Participants | 1 Participants | 1 Participants | 0 Participants | 10 Participants | 1 Participants |
| Sex: Female, Male Male | 53 Participants | 1 Participants | 20 Participants | 0 Participants | 1 Participants | 1 Participants | 29 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 2 / 2 | 26 / 39 | 2 / 2 | 1 / 1 | 21 / 36 | 1 / 1 |
| other Total, other adverse events | 1 / 1 | 2 / 2 | 39 / 39 | 2 / 2 | 1 / 1 | 35 / 36 | 1 / 1 |
| serious Total, serious adverse events | 1 / 1 | 0 / 2 | 23 / 39 | 1 / 2 | 1 / 1 | 20 / 36 | 1 / 1 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
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.
Time frame: 21 days of Cycle 1 (21 days/cycle)
Population: Safety Population: All participants who received at least 1 dose of study drug during Stage 1 only. 'Dose Level 3 - Tagraxofusp - 12 μg/kg/Day - Advanced Systemic Mastocytosis' arm enrolled during Stage 2. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure in Stage 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 - Tagraxofusp - 7 µg/kg/Day - Chronic Myelomonocytic Leukemia | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Chronic Myelomonocytic Leukemia | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Chronic Myelomonocytic Leukemia | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Dose Level 1 - Tagraxofusp - 7 µg/kg/Day - Myelofibrosis | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Myelofibrosis | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Myelofibrosis | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
Primary
Objective Response Rate (ORR)
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.
Time frame: 1145 days
Population: Modified Intent-to-Treat (mITT): Any participant who received at least 1 dose of study intervention and was evaluable for efficacy assessment. Presentation of reporting groups based upon shared criteria used for response assessment and prior treatment history (previously untreated \[treatment naive\]; previously treated \[relapsed/refractory\]). Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 - Tagraxofusp - 7 µg/kg/Day - Chronic Myelomonocytic Leukemia | Objective Response Rate (ORR) | 0 participants |
| Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Chronic Myelomonocytic Leukemia | Objective Response Rate (ORR) | 1 participants |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Chronic Myelomonocytic Leukemia | Objective Response Rate (ORR) | 0 participants |
| Dose Level 1 - Tagraxofusp - 7 µg/kg/Day - Myelofibrosis | Objective Response Rate (ORR) | 0 participants |
| Dose Level 2 - Tagraxofusp - 9 µg/kg/Day - Myelofibrosis | Objective Response Rate (ORR) | 1 participants |
| Dose Level 3 - Tagraxofusp - 12 µg/kg/Day - Myelofibrosis | Objective Response Rate (ORR) | 0 participants |