Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), Acute Myeloid Leukemia (AML)
Conditions
Brief summary
This is a 4-stage, non-randomized, open-label, dose escalation and expansion, multicenter study. A cycle of therapy is 21 days. Stage 1 was a dose-escalation stage. During Stages 2-4, patients are treated at the MTD or maximum tested dose at which multiple DLTs are not observed during Stage 1.
Detailed description
Study 0114 is a multi-stage, non-randomized, open-label, multicenter study of Tagraxofusp in First line and Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) and Acute Myeloid Leukemia (AML) patients divided into 4 stages. Each study stage has its own unique objectives and patient population, with Stage 1 representing the dose escalation phase and Stage 3 the pivotal phase. In Stages 1 and 2, both patients with BPDCN (first-line and R/R) and AML were enrolled; Stage 3 enrolled previously untreated (first-line) BPDCN patients only. A separate stage, Stage 4, enrolled First-line and R/R BPDCN patients to further characterize safety and efficacy of Tagraxofusp. The primary study objectives are reported below by stage: Stage 1: to determine the Maximum Tolerated Dose (MTD) (or Maximum Tested Dose, MTeD where multiple DLTs were not observed) of Tagraxofusp administered at the following dose levels 7, 9, 12, 16 µg/kg/day Stage 2: cohort expansion to determine the efficacy and safety of Tagraxofusp at the MTD selected in Stage 1 Stage 3 (pivotal): to determine the efficacy and safety of Tagraxofusp in patients with First-line BPDCN Stage 4: to further characterize the efficacy and safety of Tagraxofusp in patients with both First-line and R/R BPDCN
Interventions
DRUGTagraxofusp
Sponsors
The Leukemia and Lymphoma Society
Stemline Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The patient has a diagnosis of AML (Protocol Stages 1 and 2) or BPDCN (Protocol Stages 1-4) according to WHO classification (AML; excluding acute promyelocytic leukemia \[APL, FAB M3\]) or confirmed by hematopathology (BPDCN) (Facchetti et al. 2008). 2. The patient must meet one of the following (a) or (b) or (c): 1. Has evidence of persistent or recurrent AML (Protocol Stages 1 and 2) in the peripheral blood and/or bone marrow that is refractory to, or has relapsed from, their most recent prior line of treatment. * A prior line of treatment is considered an induction regimen if it involves an approved or investigational cytotoxic chemotherapy agent, biological agent, and/or hypomethylating agent administered alone or in a combination regimen, with the intent to induce robust cytoreduction (i.e., CR). * The previous induction regimen may have been a SCT with intent to induce a CR. * Consolidation and/or maintenance (including SCT) may have been given in CR/CRi, but are not counted as a line of treatment. * Hydroxyurea will not be considered a prior line of treatment. 2. Has previously untreated AML (Protocol Stages 1 and 2) and is considered to be at high risk for disease progression and/or is unlikely to derive more than transient benefit from standard therapy by having at least one of the following: * Treatment-related AML, except if it is associated with favorable cytogenetics (e.g., inversion 16, t\[16;16\], t\[8;21\], t\[15;17\]), and not a candidate for SCT in their current disease state. * AML with antecedent hematological disease (e.g., MDS, myelofibrosis, polycythemia vera) and not a candidate for SCT. 3. Has histological and/or cytological evidence of BPDCN by pathologic assessment at the investigative site according to WHO classification (Facchetti et al. 2008) by a pathologist with expertise in hematologic malignancies, that can be measured for treatment response and is either: * Previously untreated (i.e., first-line) (Protocol Stages 2-4). * Persistent or recurrent in the peripheral blood, bone marrow, spleen, lymph nodes, skin, or other sites after previous treatment with at least 1 line of systemic therapy for BPDCN, e.g., stem cell transplant or chemotherapy (Protocol Stages 1, 2, and 4). A pathology specimen must be available for central pathology review for all BPDCN patients enrolled in Protocol Stages 2-4. 3. The patient is ≥ 18 years old. 4. The patient has an ECOG performance score (PS) of 0-2. 5. The patient has adequate baseline organ function, including cardiac, renal, and hepatic function: * Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal as measured by MUGA scan or 2-D ECHO within 28 days prior to start of therapy and no clinically significant abnormalities on a 12-lead ECG * Serum creatinine ≤ 1.5 mg/dl * Serum albumin ≥ 3.2 g/dl * Bilirubin ≤ 1.5 mg/dl * AST and ALT ≤ 2.5 times the upper limit of normal (ULN) 6. If the patient is a woman of child bearing potential (WOCBP), she has had a negative serum or urine pregnancy test within 1 week prior to treatment. 7. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment. 8. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment. 9. The patient (male and female) agrees to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 2 months after the last infusion of Tagraxofusp.
Exclusion criteria
1. The patient has a diagnosis of acute promyelocytic leukemia (APL; FAB M3). 2. The patient has persistent clinically significant toxicities Grade ≥ 2 from previous chemotherapy (excluding alopecia, nausea, fatigue, and liver function tests (as mandated in the inclusion criteria)). 3. The patient has received treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of study entry. 4. The patient has received treatment with another investigational agent within 14 days of study entry. 5. The patient has previously received treatment with Tagraxofusp. 6. The patient has an active malignancy and/or cancer history (excluding AML, BPDCN, or antecedent MDS) that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the Sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease. 7. The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any NYHA Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication). 8. The patient has uncontrolled, clinically significant pulmonary disease (e.g., COPD, pulmonary hypertension) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study. 9. The patient has known active or suspected CNS leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid. 10. The patient is receiving immunosuppressive therapy - with the exception of low-dose prednisone (≤ 10 mg/day) - for treatment or prophylaxis of graft-versus-host disease (GVHD). If the patient has been on immunosuppressive treatment or prophylaxis for GVHD, the treatment(s) must have been discontinued at least 14 days prior to study treatment and there must be no evidence of Grade ≥ 2 GVHD. 11. The patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, DIC, or psychiatric illness/social situations that would limit compliance with study requirements. 12. The patient is pregnant or breast feeding. 13. The patient has known positive status for human immunodeficiency virus (HIV) active or chronic Hepatitis B or Hepatitis C. 14. The patient is oxygen-dependent. 15. The patient has any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD (Stage 1) | 21-day period after the first dose (cycle 1) | Maximum tolerated dose (MTD) in both patients with BPDCN and AML. MTD defined as the highest dose level where less than 2/3 or 2/6 patients experienced a DLT |
| CR Rate in First-line BPDCN (Stage 3, Pivotal Cohort) | at pre-defined treatment cycle intervals from randomization up to disease progression, up to 3.5 years | Complete response (CR) rate, defined as the percentage who achieved CR+ CR(clinical) with minimal residual skin abnormality (CRc) after treatment with Tagraxofusp. CR criteria according to Cheson BD et al, The International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586: Marrow: normalization of blast percentage (≤5%). Peripheral blood: normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) - absence of leukemic blasts Skin: 100% clearance of all skin lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: regression to normal size on CT Spleen, liver: not palpable, nodules disappeared CRc criteria: all the above except for skin: marked clearance of all skin lesions from baseline; residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR in First-line BPDCN, R/R BPDCN and AML | at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years | Objective response rate (ORR) defines as the percentage of patients who achieved CR (CR+CRc), CR with incomplete blood count recovery (CRi), or partial response (PR) after treatment with Tagraxofusp according to the previously reported definitions of CR, CRc and the following one of CRi and PR: CRi: CR with incomplete of neutrophil and/or platelet count and absence of leukemic blast in the peripheral blood Marrow: PR defined as decrease by ≥50% in blast percentage to 5-25% Peripheral blood: PR defined as normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) Skin: 50%-\<100% clearance of all skis lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: ≥50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes Spleen, liver: ≥50% in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen |
| CR Rate in First-line BPDCN, R/R BPDCN and AML | at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years | CR rate, defined as the percentage of patients who achieved CR+ CR with minimal residual skin abnormality (CRc) after treatment with Tagraxofusp. CR criteria according to Cheson BD et al, The International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586: Marrow: normalization of blast percentage (≤5%) Peripheral blood: normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) - absence of leukemic blasts Skin: 100% clearance of all skin lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: regression to normal size on CT Spleen, liver: not palpable, nodules disappeared CRc criteria: all the above except for skin: marked clearance of all skin lesions from baseline; residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed) |
| Bridge to SCT in First-line BPDCN, R/R BPDCN and AML | at pre-defined intervals up to achievement of outcome enabling an SCT for a period, up to 5 years | Bridge to Stem Cell Transplant (SCT) defined as the percentage of patients who received SCT subsequent to achieving an Investigator-determined outcome from Tagraxofusp that was deemed by the Investigator to enable an SCT |
| OS in First-line BPDCN, R/R BPDCN and AML | From first infusion to treatment discontinuation when survival is assessed every 90 days up to end of follow-up or death, up to 5 years | Overall survival (months) defined as the time from the date of first infusion of Tagraxofusp to the date of death from any cause |
| Duration of CR in First-line BPDCN, R/R BPDCN and AML | at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years | Duration of complete response (CR) defined as the time from when the criteria are first met for CR+CRc (whichever was recorded first) until the date that the criteria for relapse after CR+CRc are met, according to the previously reported criteria for CR and CRc and following criteria of relapse after CR+CRc (Cheson BD et al. J Clin Oncol 2007;25:579-586.): Marrow: blast percentage \>5% (if no peripheral blasts, then confirmation aspirate required ≥ 1week later) Peripheral blood: presence of leukemic blasts Skin: increase in skin score greater than the sum of nadir plus 50% baseline score Nodal masses: appearance of a new lesion(s) \>1.5 cm in any axis, ≥50% increase from nadir in SPD of more than one node, or ≥50% increase from nadir in longest diameter of a previously identified node \>1cm in short axis Spleen, liver: \>50% increase from nadir in the SPD of any previous lesions |
Countries
United States
Participant flow
Pre-assignment details
Participant flow data and safety data collected by disease, study stage, and dose only. Baseline characteristics data collected by disease and study stage only.
Participants by arm
| Arm | Count |
|---|---|
| First-line BPDCN- Stage 1 Dose Escalation, 7 or 12 µg/kg/day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 6 |
| First-line BPDCN - Stage 2 Administration of 12 µg/kg/day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 13 |
| First-line BPDCN - Stage 3 Administration of 12 µg/kg/day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 13 |
| First-line BPDCN - Stage 4 Administration of 12 µg/kg/day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 36 |
| R/R BPDCN - Stage 1 Dose Escalation, 12 µg/kg/ day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 3 |
| R/R BPDCN - Stage 2 Administration of 12 µg/kg/day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 10 |
| R/R BPDCN - Stage 4 Administration of 12 µg/kg/day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 6 |
| AML - Stage 1 Dose Escalation 7, 9,12 or 16 µg/kg/ day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 14 |
| AML - Stage 2 Administration of 12 µg/kg/ day of Tagraxofusp as IV over 15 minutes for up to 5 consecutive days of a 21-day cycle | 35 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Stage 1: Dose Escalation | Adverse Event | 0 | 0 | 2 | 4 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1: Dose Escalation | Complicating Disease | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1: Dose Escalation | Other Therapy | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1: Dose Escalation | Progressive Disease | 3 | 1 | 0 | 2 | 2 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1: Dose Escalation | Transplant | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1: Dose Escalation | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Other Therapy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Patient Preference | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 7 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 19 | 0 | 5 | 7 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Transplant | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 2 | 0 | 0 | 0 |
| Stage 2: Cohort Expansion | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 3: Efficacy Cohort | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Stage 3: Efficacy Cohort | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 |
| Stage 3: Efficacy Cohort | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 0 | 0 |
| Stage 3: Efficacy Cohort | Transplant | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 0 | 0 |
| Stage 4: First-line and R/R BPDCN | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 0 |
| Stage 4: First-line and R/R BPDCN | Patient Preference | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 4: First-line and R/R BPDCN | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 7 | 2 |
| Stage 4: First-line and R/R BPDCN | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 14 | 3 |
| Stage 4: First-line and R/R BPDCN | Radiation Consolidation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Stage 4: First-line and R/R BPDCN | Transplant | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 0 |
| Stage 4: First-line and R/R BPDCN | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 2 |
Baseline characteristics
| Characteristic | Total | AML - Stage 2 | AML - Stage 1 | R/R BPDCN - Stage 4 | First-line BPDCN- Stage 1 | R/R BPDCN - Stage 2 | R/R BPDCN - Stage 1 | First-line BPDCN - Stage 4 | First-line BPDCN - Stage 3 | First-line BPDCN - Stage 2 |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 14.64 | 61.2 years STANDARD_DEVIATION 16.01 | 58.6 years STANDARD_DEVIATION 11.17 | 67.5 years STANDARD_DEVIATION 15.32 | 67 years STANDARD_DEVIATION 10.49 | 69.7 years STANDARD_DEVIATION 9.31 | 72 years STANDARD_DEVIATION 7.94 | 64.1 years STANDARD_DEVIATION 14.71 | 61.7 years STANDARD_DEVIATION 17.15 | 62.5 years STANDARD_DEVIATION 17.72 |
| ECOG Performance Status Scale ECOG 0 | 51 Participants | 6 Participants | 5 Participants | 2 Participants | 3 Participants | 4 Participants | 1 Participants | 16 Participants | 8 Participants | 6 Participants |
| ECOG Performance Status Scale ECOG 1 | 78 Participants | 26 Participants | 8 Participants | 4 Participants | 3 Participants | 6 Participants | 2 Participants | 17 Participants | 5 Participants | 7 Participants |
| ECOG Performance Status Scale ECOG 2 | 5 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status Scale Missing | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 16 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 120 Participants | 31 Participants | 12 Participants | 5 Participants | 5 Participants | 10 Participants | 2 Participants | 30 Participants | 13 Participants | 12 Participants |
| Sex: Female, Male Female | 36 Participants | 13 Participants | 7 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 7 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 100 Participants | 22 Participants | 7 Participants | 5 Participants | 5 Participants | 8 Participants | 3 Participants | 29 Participants | 11 Participants | 10 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 | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 2 | 4 / 6 | 1 / 3 | 0 / 3 | 1 / 3 | 3 / 34 | 0 / 1 | 1 / 13 | 0 / 10 | 1 / 13 | 3 / 37 | 2 / 7 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 2 / 2 | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 34 / 34 | 1 / 1 | 13 / 13 | 10 / 10 | 13 / 13 | 37 / 37 | 7 / 7 |
| serious Total, serious adverse events | 2 / 3 | 3 / 3 | 2 / 2 | 6 / 6 | 1 / 3 | 1 / 3 | 3 / 3 | 19 / 34 | 1 / 1 | 7 / 13 | 6 / 10 | 4 / 13 | 20 / 37 | 5 / 7 |
Outcome results
Primary
CR Rate in First-line BPDCN (Stage 3, Pivotal Cohort)
Complete response (CR) rate, defined as the percentage who achieved CR+ CR(clinical) with minimal residual skin abnormality (CRc) after treatment with Tagraxofusp. CR criteria according to Cheson BD et al, The International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586: Marrow: normalization of blast percentage (≤5%). Peripheral blood: normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) - absence of leukemic blasts Skin: 100% clearance of all skin lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: regression to normal size on CT Spleen, liver: not palpable, nodules disappeared CRc criteria: all the above except for skin: marked clearance of all skin lesions from baseline; residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed)
Time frame: at pre-defined treatment cycle intervals from randomization up to disease progression, up to 3.5 years
Population: Pre-defined efficacy primary end point assessed in Stage 3, standalone, pivotal efficacy cohort of only patients with first-line BPDCN exposed to 12 μg/kg/day were enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First-line BPDCN | CR Rate in First-line BPDCN (Stage 3, Pivotal Cohort) | 53.8 percentage of participants |
Primary
MTD (Stage 1)
Maximum tolerated dose (MTD) in both patients with BPDCN and AML. MTD defined as the highest dose level where less than 2/3 or 2/6 patients experienced a DLT
Time frame: 21-day period after the first dose (cycle 1)
Population: Patients with First-line Blastic Plasmacytoid Dendritic Cell Neoplasm, R/R Blastic Plasmacytoid Dendritic Cell Neoplasm and Acute Myeloid Leukemia participating to stage 1 (dose-escalation)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First-line BPDCN | MTD (Stage 1) | 12 µg/kg/day |
| R/R BPDCN | MTD (Stage 1) | 12 µg/kg/day |
| Acute Myeloid Leukemia | MTD (Stage 1) | 16 µg/kg/day |
Secondary
Bridge to SCT in First-line BPDCN, R/R BPDCN and AML
Bridge to Stem Cell Transplant (SCT) defined as the percentage of patients who received SCT subsequent to achieving an Investigator-determined outcome from Tagraxofusp that was deemed by the Investigator to enable an SCT
Time frame: at pre-defined intervals up to achievement of outcome enabling an SCT for a period, up to 5 years
Population: Efficacy population including evaluable patients treated at 12 μg/kg/day in the first-line BPDCN, R/R BPDCN and AML
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First-line BPDCN | Bridge to SCT in First-line BPDCN, R/R BPDCN and AML | 32.3 percentage of evaluable patients |
| R/R BPDCN | Bridge to SCT in First-line BPDCN, R/R BPDCN and AML | 5.3 percentage of evaluable patients |
| Acute Myeloid Leukemia | Bridge to SCT in First-line BPDCN, R/R BPDCN and AML | 3 percentage of evaluable patients |
Secondary
CR Rate in First-line BPDCN, R/R BPDCN and AML
CR rate, defined as the percentage of patients who achieved CR+ CR with minimal residual skin abnormality (CRc) after treatment with Tagraxofusp. CR criteria according to Cheson BD et al, The International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586: Marrow: normalization of blast percentage (≤5%) Peripheral blood: normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) - absence of leukemic blasts Skin: 100% clearance of all skin lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: regression to normal size on CT Spleen, liver: not palpable, nodules disappeared CRc criteria: all the above except for skin: marked clearance of all skin lesions from baseline; residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed)
Time frame: at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years
Population: Efficacy population including evaluable patients treated at 12 μg/kg/day in the first-line BPDCN, R/R BPDCN and AML.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First-line BPDCN | CR Rate in First-line BPDCN, R/R BPDCN and AML | 56.9 percentage of evaluable patients |
| R/R BPDCN | CR Rate in First-line BPDCN, R/R BPDCN and AML | 15.8 percentage of evaluable patients |
| Acute Myeloid Leukemia | CR Rate in First-line BPDCN, R/R BPDCN and AML | 3 percentage of evaluable patients |
Secondary
Duration of CR in First-line BPDCN, R/R BPDCN and AML
Duration of complete response (CR) defined as the time from when the criteria are first met for CR+CRc (whichever was recorded first) until the date that the criteria for relapse after CR+CRc are met, according to the previously reported criteria for CR and CRc and following criteria of relapse after CR+CRc (Cheson BD et al. J Clin Oncol 2007;25:579-586.): Marrow: blast percentage \>5% (if no peripheral blasts, then confirmation aspirate required ≥ 1week later) Peripheral blood: presence of leukemic blasts Skin: increase in skin score greater than the sum of nadir plus 50% baseline score Nodal masses: appearance of a new lesion(s) \>1.5 cm in any axis, ≥50% increase from nadir in SPD of more than one node, or ≥50% increase from nadir in longest diameter of a previously identified node \>1cm in short axis Spleen, liver: \>50% increase from nadir in the SPD of any previous lesions
Time frame: at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years
Population: Efficacy population including evaluable patients treated at 12 μg/kg/day in the first-line BPDCN, R/R BPDCN and AML
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First-line BPDCN | Duration of CR in First-line BPDCN, R/R BPDCN and AML | 24.9 months |
| R/R BPDCN | Duration of CR in First-line BPDCN, R/R BPDCN and AML | 3.6 months |
| Acute Myeloid Leukemia | Duration of CR in First-line BPDCN, R/R BPDCN and AML | 8.6 months |
Secondary
ORR in First-line BPDCN, R/R BPDCN and AML
Objective response rate (ORR) defines as the percentage of patients who achieved CR (CR+CRc), CR with incomplete blood count recovery (CRi), or partial response (PR) after treatment with Tagraxofusp according to the previously reported definitions of CR, CRc and the following one of CRi and PR: CRi: CR with incomplete of neutrophil and/or platelet count and absence of leukemic blast in the peripheral blood Marrow: PR defined as decrease by ≥50% in blast percentage to 5-25% Peripheral blood: PR defined as normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) Skin: 50%-\<100% clearance of all skis lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: ≥50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes Spleen, liver: ≥50% in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen
Time frame: at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years
Population: Efficacy population including evaluable patients treated at 12 μg/kg/day in the first-line BPDCN, R/R BPDCN and AML
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First-line BPDCN | ORR in First-line BPDCN, R/R BPDCN and AML | 75.4 percentage of evaluable patients |
| R/R BPDCN | ORR in First-line BPDCN, R/R BPDCN and AML | 57.9 percentage of evaluable patients |
| Acute Myeloid Leukemia | ORR in First-line BPDCN, R/R BPDCN and AML | 3 percentage of evaluable patients |
Secondary
OS in First-line BPDCN, R/R BPDCN and AML
Overall survival (months) defined as the time from the date of first infusion of Tagraxofusp to the date of death from any cause
Time frame: From first infusion to treatment discontinuation when survival is assessed every 90 days up to end of follow-up or death, up to 5 years
Population: Efficacy population including evaluable patients treated at 12 μg/kg/day in the first-line BPDCN, R/R BPDCN and AML
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First-line BPDCN | OS in First-line BPDCN, R/R BPDCN and AML | 15.8 Months |
| R/R BPDCN | OS in First-line BPDCN, R/R BPDCN and AML | 8.2 Months |
| Acute Myeloid Leukemia | OS in First-line BPDCN, R/R BPDCN and AML | 5.7 Months |