Clinical trial NCT05032183
Conditions: Recurrent Adult Lymphoblastic Lymphoma Recurrent B Acute Lymphoblastic Leukemia Recurrent T Acute Lymphoblastic Leukemia Refractory B Acute Lymphoblastic Leukemia Refractory Lymphoblastic Lymphoma Refractory T Acute Lymphoblastic Leukemia
Sponsor: M.D. Anderson Cancer Center
Start date: 2022-02-17; Completion date: 2024-07-31
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase Ib/II trial studies the effects of tagraxofusp and low-intensity chemotherapy in treating patients with CD123 positive acute lymphoblastic leukemia or lymphoblastic lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Tagraxofusp consists of human interleukin 3 (IL3) linked to a toxic agent called DT388. IL3 attaches to IL3 receptor positive cancer cells in a targeted way and delivers DT388 to kill them. Chemotherapy drugs, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tagraxofusp with chemotherapy may help control CD123 positive relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (complete response \[CR\] + CR with inadequate count recovery \[CRi\]) of the regimen within 3 cycles.

SECONDARY OBJECTIVES:

I. Evaluate other clinical efficacy endpoints (CR rate, minimal residual disease \[MRD\] negativity, duration of response \[DOR\], relapse-free survival \[RFS\] overall survival \[OS\]).

II. Determine the proportion of patients proceeding to allogeneic stem cell transplantation (allo-SCT).

III. Determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To determine CD123 expression levels pre- and post-therapy. II. To correlate baseline CD123 expression with response rates and duration of response.

III. To evaluate change in apoptotic protein expression and alterations in cellular signaling pathways using cytometry by time of flight (CyTOF).

IV. To determine baseline gene expression profile in order to identify ALL subtypes and correlate with clinical outcomes and response to single-agent tagraxofusp-erzs (tagraxofusp).

OUTLINE:

TAGRAXOFUSP AND CHEMOTHERAPY PHASE:

CYCLE 1: Patients receive tagraxofusp-erzs intravenously (IV) over 15 minutes on days 1-5.

CYCLES 2 AND 4: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-3, cyclophosphamide IV over 3 hours twice daily (BID) and mesna IV on days 4-6, vincristine IV over 15 minutes on days 4 and 15, dexamethasone IV over 30 minutes or orally (PO) on day 4-7 and 14-17, methotrexate intrathecally (IT) on day 5, and filgrastim-sndz subcutaneously (SC) or pegfilgrastim SC on day 8, and cytarabine IT on day 10. Patients may receive rituximab IV over 4-6 hours on days 4 and 14.

CYCLES 3 AND 5: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-3, methotrexate IV over 24 hours on day 4, cytarabine IV over 3 hours BID on days 5-6, filgrastim-sndz SC or pegfilgrastim SC on day 6, methotrexate IT and cytarabine IT on day 11. Patients may receive rituximab IV over 4-6 hours on days 4 and 11. Beginning about 12 hours after the day 4 dose of methotrexate, patients may also receive leucovorin IV over 15 minutes, 4 times a day for about 8 doses.

CYCLES 6 AND 8: Patients receive cyclophosphamide IV over 3 hours BID and mesna IV on days 1-3, vincristine IV over 15 minutes on days 1 and 11, dexamethasone IV over 30 minutes or PO on day 1-4 and 11-14, and filgrastim-sndz SC or pegfilgrastim SC on day 5.

CYCLES 7 AND 9: Patients receive methotrexate IV over 24 hours on day 1, cytarabine IV over 3 hours BID on days 2-3, and filgrastim-sndz SC or pegfilgrastim SC on day 4. Beginning about 12 hours after the day 1 dose of methotrexate, patients may receive leucovorin IV over 15 minutes, 4 times a day for about 8 doses.

Cycle 1 is 21 days. Treatment repeats every 28 days for cycles 2-9 in the absence of disease progression or unacceptable toxicity.

TAGRAXOFUSP AND MAINTENANCE PHASE:

CYCLES 1-3, 5-7, 9-11, 13-15: Patients receive mercaptopurine PO three time daily (TID) on days 1-28, prednisone PO once daily (QD) on day 1-5, methotrexate PO once every week (QW) and vincristine IV over 15 minutes every 4 weeks.

CYCLES 4, 8, and 12: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-5.

Treatment repeats every 28 days for 15 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Arms: arm 1: See Detailed Description
Interventions: intervention 1: Cyclophosphamide intervention 2: Cytarabine intervention 3: Dexamethasone intervention 4: Filgrastim-sndz intervention 5: Leucovorin intervention 6: Mercaptopurine intervention 7: Mesna intervention 8: Methotrexate intervention 9: Pegfilgrastim intervention 10: Prednisone intervention 11: Rituximab intervention 12: Tagraxofusp-erzs intervention 13: Vincristine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IT intervention 3: Given IV or PO intervention 4: Given SC intervention 5: Given IV intervention 6: Given PO intervention 7: Give IV intervention 8: Given IT intervention 9: Given SC intervention 10: Given PO intervention 11: Given IV intervention 12: Given IV intervention 13: Given IV

Protocol documents:
Prot_SAP_001.pdf: 
 
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MD Anderson IND Sponsor Cover Sheet 
  
Protocol ID 
2021-0545 
Protocol Title 
Phase Ib/II Study of the Combination of Low-Intensity 
Chemotherapy and Tagraxofusp in Patients with Acute 
Lymphoblastic Leukemia (ALL)  
Phase 
Phase 1b/II 
Version 
03 
Version Date 
07/11/2022 
  
Protocol PI 
Nicholas Short, MD 
Department of Leukemia,  
University of Texas M D Anderson Cancer Center 
1515 Holcombe Boulevard Unit 428 
Houston, Texas 77030 
Tel – 713-563-4485 
Fax – 713-794-4297 
E-mail – nshort@mdanderson.org 
  
Department 
Leukemia 
Co-Principal 
Investigator: 
Elias Jabbour, MD 
Department of Leukemia,  
University of Texas M D Anderson Cancer Center 
1515 Holcombe Boulevard Unit 428 
Houston, Texas 77030 
Tel – 713-792-4764 
Fax – 713-794-4297 
E-mail – ejabbour@mdanderson.org  
  
  
IND Sponsor 
MD Anderson Cancer Center 
IND # 
157304 
 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ....................................................................... 3 
2.  
STUDY OBJECTIVES ............................................................... 6 
3. 
SELECTION OF PATIENTS ...................................................... 6 
3.1 Inclusion Criteria ..................................................................... 6 
3.2 Exclusion Criteria .................................................................... 6 
4. 
TREATMENT OF SUBJECTS ................................................... 7 
5. 
CONCOMITTANT MEDICATIONS .......................................... 14 
6. 
STUDY PROCEDURES .......................................................... 15 
7. 
EFFICACY AND SAFETY ASSESSMENTS ........................... 17 
8. 
REPORTING REQUIREMENTS .............................................. 18 
9. 
OUTSIDE PHYSICIAN PARTICIPATION ............................... 19 
10. 
STATISTICAL METHODOLOGY ............................................ 20 
 
 
 
 
 
 
 


 
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1. 
INTRODUCTION 
1.1 
Outcomes of Acute Lymphoblastic Leukemia (ALL) in Adults 
 
Significant improvements in outcome for childhood acute lymphoblastic leukemia (ALL) have been 
observed, with complete response (CR) rates exceeding 90% with modern chemotherapy 
regimens.1,2 At least 70% of children with ALL can be cured. Adult ALL however has a worse 
outcome.  Expected CR rates are 80% to 90%, and long-term event-free survival (EFS) rates are 
20% to 40%.3-7 Prognosis is influenced by age, performance status, organ function, white blood 
cell count, ALL phenotype (CALLA, T-cell, B-cell, Burkitt's or Burkitt's-like), karyotype [t(1; 19), t(4; 
11), Philadelphia (Ph) chromosome], and time to achieve CR. 
 
The longer-term results of hyper-CVAD in adult ALL have been reported8,9. Overall, the group had 
a median age of 40 years (range 15-90 years); 20% of the patients were aged 60 or older.9 The 
majority of patients were considered high-risk for systemic relapse (74%) or central nervous system 
(CNS) relapse (55%). Compared to the VAD (vincristine, doxorubicin, dexamethasone) program, 
the outcome with hyper-CVAD was significantly improved with respect to CR rate and overall 
survival.8,9 
 
The overall CR rate with hyper-CVAD for all subtypes of ALL (n=288) was 92% with an induction 
mortality of 5% (all due to infections). Eleven percent of the patients required 2 courses to achieve 
CR; only 3% of the patients failed to achieve a remission with persistence of the leukemia. Central 
nervous system relapse was low, with a 7% incidence in low-risk patients (given 4 prophylactic 
intrathecal [IT] treatments), 1% in high-risk patients (16 prophylactic ITs), and 6% in patients with 
unknown CNS relapse risk (8 prophylactic ITs).9 The 5-year continuous CR rate was 35% with a 5-
year survival of 36%. On multivariate analysis, pre-treatment factors associated with a shorter 
survival included older age, poor performance status, presence of hepatomegaly, high leukocyte 
count (≥ 50 x 109/L), low platelet count, and Ph-positive disease. When compared to other 
published standard regimens of MSKCC,5 SWOG,6 Hoelzer et al,4 and Larson et al,7 the outcome 
was comparable even though the MDACC patients were older and prognostically less favorable. 
 
 
Current outcomes of salvage chemotherapy for ALL are poor, with less than half of patients 
achieving a second CR, with rates varying based on prior therapy and duration of first remission.11,12  
CR rates are even lower for patients with multiply refractory disease.  Further intensification of 
chemotherapy has not proved to be effective.13 Novel monoclonal antibodies have been introduced 
to the armamentarium of therapies of relapsed/refractory ALL inducing responses in about 40-50% 
of patients with a median survival of 6 to 8 months. While allogeneic stem cell transplantation (allo-
SCT) offers a chance for long-term remission and cure, only a small percentage of patients could 
be bridged to allo-SCT with current therapies. Given the poor outcomes for patients with 
relapsed/refractory ALL, novel agents and combinations capable of achieving remission to allow 
for potentially curative allogeneic stem cell transplantation SCT are needed. 
 
1.2 
CD123 and Tagraxofusp in ALL 
 
CD123, the interleukin-3 (IL-3) receptor α-chain subunit binds IL-3 with high affinity when co-
expressed with the β-subunit. IL-3, mainly produced by T-lymphocytes, plays a critical role in 
leukomogenesis through enabling leukemic cells to escape programmed cell death and inhibiting 
their apoptosis.14 CD123, previously reported to have a low to absent normal hematopoietic stem 
cell expression, is expressed at various levels in hematologic malignancies, including hairy cell 


 
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leukemia, acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN) 
and others. Due to its differential overexpression on leukemic cells compared to their normal 
precursors as well as its expression on both cancer stem cells (CSCs) and leukemic blasts, the cell 
surface receptor CD123 has emerged as a promising target of therapy.15 In ALL, clinical and 
preclinical studies suggest significant overexpression of CD123 on leukemic cells. An early analysis 
by Djokic and colleagues in 2009 reported on the CD123 expression in 95 pediatric and 24 adult 
patients with B-ALL, showing 31% strong CD123 expression on B-ALL blasts, 61% moderate 
expression and 8% absent expression.16 In contrast, early B-cell precursors, intermediate B-cells 
and mature B-lymphocytes displayed only absent or low CD123 expression. Hassanein et al. 
confirmed these findings and, particularly, analyzed the normal compartment of B-cell precursors, 
as well as B-ALL leukemic blasts. They showed that early B-cell CD3+ precursors do not express 
CD123, while more mature CD34+ B-cell elements express CD123. In B-ALL, CD123 expression 
was observed in 89% of cases, 80% concomitantly with CD34 expression and 9% in the absence 
of CD34 expression. Interestingly, in the majority of B-ALL patients, CD123+/CD34+ cells were 
observed post-chemotherapy. In a recent study of 183 patients with B-ALL, CD123 was found to 
be overexpressed in 90% of patients with B-ALL, both in patients with Philadelphia-chromosome 
positive ALL (86%) and those with Philadelphia-chromosome negative ALL (97%).17 The 
pronounced CD123 expression in B-ALL offers an opportunity for possible therapeutic targeting.  
 
Tagraxofusp, formerly known as SL-401, is a novel biologic targeted therapy comprised of 
recombinant human IL-3 joined to a truncated diphtheria toxin (DT). In preclinical studies, SL-401 
has demonstrated anti-tumor activity against both leukemic blasts as well as leukemia CSCs, both 
in vitro and in vivo.18 In fact, SL-401 has been investigated in clinical trials for patients with BPDCN 
and other hematologic malignancies. In a multicenter, open-label study of 47 patients with BPDCN 
(median age, 70 years; 32 previously untreated), patients received daily infusions of tagraxofusp 
(7 or 12 µg/kg) on days 1 to 5 of each 21-day cycle until disease progression or unacceptable 
toxicity.19 At a median follow-up of 19 months, of the 29 untreated patients who received the 12 
µg/kg dose, 90% responded and 72% achieved CR; almost half of responding patients proceeded 
to allo-SCT or autologous SCT (3 patients). The 24-month overall survival for responding patients 
was 52%. Of the 15 patients with R/R disease, 67% responded and 1 patient proceeded to allo-
SCT; median overall survival was 8.5 months. Toxicities included elevated liver enzymes, 
hypoalbuminemia, edema, and thrombocytopenia. Capillary leak syndrome (CLS) occurred in 18% 
of patients, resulting in 2 deaths. In support of this, SL-401 received FDA approval for patients with 
BPDCN as a single-agent on Dec 21, 2018. In addition to BPDCN, tagraxofusp is also being 
investigated, as a single agent, in several ongoing clinical trials in AML with positive measurable 
residual disease (MRD), myelofibrosis and chronic myelomonocytic leukemia. In addition to the 
single agent experience, tagraxofusp is also being investigated in the combination setting at our 
institution such as the combination of tagraxofusp with azacitidine in AML. Thus, across multiple 
tumor types and as single agent or in combination, we have acquired extensive experience with 
the administration of tagraxofusp and have established its safety profile and efficacy in prior studies.  
 
 
1.3.4  Summary 
 
Overall, the urgent need for novel therapies in R/R ALL, the significant overexpression of CD123 
in leukemic CSCs and blasts of ALL, the promising efficacy of tagraxofusp in targeting CD123 in 
hematologic malignancies, and our extensive experience using this agent warrant further 
investigation of tagraxofusp in R/R ALL to improve on the modest outcomes currently achieved with 
salvage chemotherapy in this setting. We, therefore, propose to assess the safety and efficacy of 
tagraxofusp in combination with low-intensity chemotherapy with mini-hyper-CVD in R/R ALL. 


 
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2.  
STUDY OBJECTIVES 
2.1. Primary Objective: To evaluate the overall response rate (CR + CR with inadequate count 
recovery [CRi]) of the regimen within 3 cycles 
 
2.2 
Secondary Objectives 
• 
Evaluate other clinical efficacy endpoints (CR rate, minimal residual disease [MRD] 
negativity, duration of response [DOR], relapse-free survival [RFS] overall survival 
[OS]) 
• 
Determine the proportion of patients proceeding to allo-SCT 
• 
Determine the safety of the combination regimen. 
 
2.3 Exploratory Objectives 
• 
To determine CD123 expression levels pre- and post-therapy 
• 
To correlate baseline CD123 expression with response rates and duration of 
response 
• 
To evaluate change in apoptotic protein expression and alterations in cellular 
signaling pathways using CyTOF 
• 
To determine baseline gene expression profile in order to identify ALL subtypes and 
correlate with clinical outcomes and response to single-agent tagraxofusp 
 
See Appendix B for details of correlative study plan. 
 
3. 
SELECTION OF PATIENTS 
Patients will be selected from those referred to the Leukemia department at MD Anderson Cancer 
Center through the normal of process of referral. Eligible patients will be registered after the 
process of consenting on the MD Anderson protocol and data monitoring system. 
 
3.1 
Inclusion Criteria 
1. Patients 18-70 years of age with relapsed/refractory CD123+ B- or T-cell ALL, 
lymphoblastic lymphoma, or mixed phenotype acute leukemia or biphenotypic leukemia 
with a B-cell or T-cell immunophenotype .  
- 
CD123 positivity may be confirmed by either flow cytometry or 
immunohistochemistry. 
- 
Patients with B-cell ALL should have previously received or be ineligible for 
blinatumomab, inotuzumab ozogamicin and tisagenlecleucel 
 
2. Performance status ≤2  (ECOG Scale) 
 
3. Adequate liver and renal function as defined by the following criteria: 
a) Total serum bilirubin < 1.5 x upper limit of normal (ULN), unless due to Gilbert’s 
syndrome, in which case patients are eligible as long as direct bilirubin ≤2 x ULN 
b) Alanine aminotransferase (ALT) < 2.5 x ULN, unless due to disease involvement of 
the liver or hemolysis, in which case an ALT ≤10 x ULN is acceptable, OR 


 
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c) Aspartate aminotransferase (AST) < 2.5 x ULN, unless due to disease involvement 
of the liver or hemolysis, in which case an ALT ≤10 x ULN is acceptable 
d)   Creatinine clearance ≥ 60 mL/min 
 
4. Serum albumin ≥3.2 g/dL (32 g/L). Albumin infusions are not permitted in order to 
enable eligibility. 
 
5. For females of childbearing potential, a negative pregnancy test must be documented 
within 1 week of starting treatment 
 
6. Female and male patients who are fertile must agree to use an effective form of 
contraception (birth control methods while on study, such as birth control pills or 
injections, intrauterine devices (IUDs), or double-barrier methods (for example, a 
condom in combination with spermicide) with their sexual partners for 4 months after 
the end of treatment 
 
7. Signed informed consent  
 
8. Willingness and ability to adhere to study visit schedule and other protocol 
requirements, including follow-up for survival assessment 
 
3.2 
Exclusion Criteria 
 
1. Active serious infection not controlled by oral or intravenous antibiotics.  
 
2. Known active CNS leukemia 
 
3. Diagnosis of Philadelphia chromosome-positive ALL or Burkitt leukemia/lymphoma 
 
4. Active GVHD 
 
5. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or 
squamous cell carcinoma) that in the investigator’s opinion will shorten survival to less 
than 1 year. 
 
6. Known active hepatitis B or C infection, or active/uncontrolled HIV infection or AIDS.  
 
7. Clinically significant cardiovascular disease (e.g., 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 (diastolic blood pressure >90mmHg; systolic >140mmHg) or 
clinically significant arrhythmias not controlled by medication).  
 
8. Patients with a cardiac ejection fraction (as measured by either MUGA or 
echocardiogram) less than the lower limit of normal 
 
9. No clinically significant abnormalities on 12-lead electrocardiogram 
 
10. Concomitant use of calcineurin inhibitors in 4 weeks prior to the start of therapy 
 


 
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11. Uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive 
pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator 
would put the patient at significant risk for pulmonary complications during the study.  
 
 
12. Persistent clinically significant toxicities Grade ≥2 from previous chemotherapy 
(excluding alopecia, nausea, and fatigue).  
 
13. Treatment with any investigational antileukemic agents or chemotherapy agents in the 
last 7 days before study entry, unless full recovery from side effects has occurred or 
patient has rapidly progressive disease judged to be life-threatening by the investigator.  
Exception: Treatment with hydroxyurea and/or dexamethasone are allowed prior to 
study treatment, without window of exclusion. 
 
11. Pregnant and lactating women will not be eligible; women of childbearing potential 
should have a negative pregnancy test prior to entering on the study and be willing to 
practice methods of contraception for 4 months after last study treatment. Women do 
not have childbearing potential if they have had a hysterectomy or are postmenopausal 
without menses for 12 months. In addition, men enrolled on this study should 
understand the risks to any sexual partner of childbearing potential and should practice 
an effective method of birth control for 4 months after last study treatment. 
 
4. 
TREATMENT OF SUBJECTS 
4.1    Variations in dose reductions of the individual chemotherapy or the administration of 
tagraxofusp or supportive care dose schedules other than those suggested below are 
allowed in the best interest of patients. Such patients should be discussed with the principal 
investigator. Dose escalations of chemotherapy above those outlined in the protocol; 
however, are not allowed. Variations in infusion times due to minor differences in IV bag 
overfill/underfill and institutional procedure on flushing chemotherapy lines will not result in 
protocol deviation. 
 
4.2 
Treatment Overview – The treatment will start with of an induction phase (Cycle 1) 
consisting of the administration of tagraxofusp single agent at a dose of 12 µg/kg daily for 5 
days of a 21-day cycle. Following the 21-day induction phase, the treatment cycles 
consisting of the combination of tagraxofusp and chemotherapy with mini-hyper-CVD will 
be administered (Cycles 2-5 with tagraxofusp plus chemotherapy; cycles 6-9 with 
chemotherapy without tagroxofusp). In each of these cycles, tagraxofusp will be given at 
the dose of 9 µg/kg daily for the first 3 days followed by administration of mini-hyper-CVD 
or mini-methotrexate plus cytarabine on days 4 onwards. Each of these combination cycles 
(Cycle 2+) is 28 days. The mini-hyper-CVD chemotherapy regimen consists of a total of 8 
cycles of mini-hyper-CVD [cyclophosphamide (150 mg/m2 every 12 h for 3 days), 
vincristine (2 mg flat dose for 2 doses), and dexamethasone (20 mg for 8 total doses per 
cycle) without anthracycline] alternating with high-dose methotrexate (250 mg/m2 x 1) and 
cytarabine (0.5 g/m2 given every 12 hours for 2 days) administered approximately every 28 
days (or later to allow for recovery from myelosuppression or infection). Tagraxofusp will be 
administered for a maximum of 5 cycles (Cycles 1-5) during induction/consolidation. On 
cycles containing tagraxofusp and chemotherapy (Cycles 2-5), chemotherapy will begin on 
day 4; on cycles not containing tagraxofusp (Cycles 6-9), chemotherapy will begin on day 


 
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1. Rituximab and intrathecal chemotherapy will be given for the first 4 combination cycles 
(Cycles 2-5). 
 
 
4.3 
Cycle 1 – Patients will receive tagraxofusp 12 µg/kg daily for 5 days. The patients will 
remain hospitalized up until a minimum of 24 hours after the last dose of tagraxofusp. 
Hospital stay may be prolonged in patients with infections or other issues requiring inpatient 
stay. Cycle 1 is 21 days in length.  
 
 
Use of hydroxyurea and/or dexamethasone during cycle 1 is allowed on a patient-by-
patient basis during cycle 1 if deemed in the best interest of the patient and after discussed 
with the PI. 
 
4.4 
Cycles 2-5 – Cycles 2-5 are anticipated to be 28 days in length. Tagraxofusp will be given 
at a dose of 9 µg/kg daily for the first 3 days followed by administration of mini-hyper-CVD 
or mini-methotrexate plus cytarabine on days 4 onwards. Patients will be admitted for 
tagraxofusp and for the mini-hyper-CVD / methotrexate and cytarabine regimen. The 
patients will remain hospitalized up until the completion of chemotherapy. Hospital stay 
may be prolonged in patients with infections or other issues requiring inpatient stay.  
 
4.5     Cycles 6-9 – Cycles 6-9 are anticipated to be 28 days in length. No tagraxofusp will be 
given with these cycles. Mini-hyper-CVD or mini-methotrexate plus cytarabine will begin on 
day 1. Patients will be admitted for the mini-hyper-CVD / methotrexate and cytarabine 
regimen. The patients will remain hospitalized up until the completion of chemotherapy. 
Hospital stay may be prolonged in patients with infections or other issues requiring inpatient 
stay.   
 
At anytime while enrolled in this trial, patients may be referred for SCT at the discretion of 
the treating physician.   
 
 
4.6    Alteration of regimen for patients achieving response to tagraxofusp monotherapy 
 
Patients who achieve CR or CRi with tagraxofusp monotherapy after cycle 1 will continue 
with receive tagraxofusp monotherapy (12 µg/kg daily for 5 days) rather than proceeding to 
additional cycles with tagraxofusp plus low-intensity chemotherapy. These patients will 
continue to receive cycles of tagraxofusp monotherapy (up to 5 total cycles) for as long as 
they remain in CR/CRi. Following these 5 cycles of tagraxofusp monotherapy, they will 
proceed with maintenance therapy as below. 
 
 
4.7 Tagraxofusp 
• 
See Appendix A for management of tagraxofusp 
• 
For details of tagraxofusp preparation and other pharmacologic consideration, please see the 
corresponding investigator brochure for tagraxofusp, as well as pharmacy manuals for the 
frozen and lyophilized formulations of tagraxofusp. 
• 
Expired or unused study drug will be disposed per institutional protocols 
• 
Patients will receive the following premedication approximately 60 minutes before each 
tagraxofusp infusion: 
 
Acetaminophen 650 mg orally (PO)  


 
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 
Diphenhydramine 50 mg intravenously (IV) (or equivalent dose of another H1-
histamine antagonist)  
 
Methylprednisolone 50 mg IV (or an equivalent dose of another corticosteroid)  
 
Famotidine 20 mg IV (or an equivalent dosage of another H2-histamine antagonist)  
• 
Pre-treatment Criteria for Tagraxofusp  
 
Prior to the initiation of the first dose of tagraxofusp in Cycle 1, serum albumin 
must be  ≥ 3.2 g/dL 
 
Patients with serum albumin 3.2 to 4.0 g/dL should receive 25g intravenous 
albumin prior to Cycle 1, Day 1 dose of tagraxofusp 
• 
Withhold tagraxofusp on a given treatment day if any of the following occur: 
• 
Serum albumin < 3.5 g/dL (see APPENDIX A for management of suspected 
CLS) 
• 
If serum albumin has fallen more than 0.5 g/dL below the level measured on the 
first treatment day of the cycle (see Appendix A for Management of tagraxofusp-
related toxicites,) 
• 
AST > 5x ULN or ALT > 5x ULN  
• 
Serum creatinine > 2x ULN 
• 
Signs of clinically significant capillary leak syndrome, defined as: 
• 
HR ≥ 130 or ≤ 40 bpm 
• 
SBP ≥ 160 or ≤ 80 mmHg 
• 
Body temperature ≥ 38.0 C 
• 
Increase in body weight by ≥ 1.5 kg over the weight measured prior to 
treatment on the prior day 
• 
Initiation of mini-hyper-CVD or methotrexate/cytarabine will also be delayed if 
tagraxofusp is delayed as above. Mini-hyper-CVD and methotrexate/cytarabine should 
not begin until the day following the last planned dose of tagraxofusp for a given cycle. 
• 
Tagraxofusp must be given in the inpatient setting during cycle 1, along with monitoring 
for at least 24 hours after the last infusion. For all patients receiving cycles of 
chemotherapy plus tagraxofusp, tagraxofusp will be given in the inpatient setting, along 
with 24 hour monitoring as above. For subsequent cycles of tagraxofusp monotherapy 
(e.g. patients who achieve CR/CRi with cycle 1 and continue to receive tagraxofusp 
monotherapy as consolidation, or in patients receiving tagraxofusp monotherapy in 
maintenance), tagraxofusp may be given either the inpatient setting or in a suitable 
outpatient ambulatory care setting that is equipped with appropriate monitoring for 
patients with hematopoietic malignancies undergoing treatment. These patients must be 
monitored for a minimum of 4 hours following each infusion. 
 
4.8  Mini-hyper-CVD Regimen 
 
1. General Considerations 
• 
The mini-hyper-CVD will alternate with methotrexate and cytarabine administered 
on 28 (if count recovery allows) or later day cycle (as count recovery allows).  
• 
Anti-emetic therapy with each course of intensive chemotherapy as needed.  
• 
Filgrastim product (G-CSF) will be administered with each course after the 
completion of chemotherapy.  Pegfilgrastim product may replace filgrastim product 
(G-CSF). 
• 
Next cycle may be started when granulocytes > 1.0 x 109/L and platelets ≥ 50 x 
109/L. Cycles may be started with dose reductions prior to full platelet recovery, if 
the treatment is delayed (e.g., greater than 28 days from last cycle).   


 
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• 
Prophylactic antibiotics may be given with each course until neutrophil recovery to 
500/µL or greater (or other antibiotics if being treated for active infection). 
Suggestions include:  Levaquin 500 mg po daily, trimethoprim-sulfamethoxazole 
double strength one tablet p.o. b.i.d. or other appropriate antibacterial agent. 
Caspofungin or other appropriate antifungal agent. Valacyclovir 500 mg p.o. daily 
or acyclovir 200 mg p.o. b.i.d. or other appropriate antiviral agent.  
• 
Omit azoles day -1, same day, and day after vincristine. 
• 
In general 8 cycles of chemotherapy (4 mini-hyper-CVAD, 4 methotrexate plus 
cytarabine) will be administered in approximately 4 week intervals (depending on 
the recovery of blood counts.  Modifications thought to be in the best interest of the 
patient are allowed after discussion with the principal investigator. Patients will be 
followed indefinitely for relapse and survival. 
• 
For patients with CD20 expression (≥ 20% by flow cytometry) up to 2 doses of 
rituximab 375 mg/m2 may be added in cycles 2-5 (8 doses total).  
• 
Methotrexate dose will be adjusted as indicated below for pleural effusions. 
 
2. Mini-Hyper-CVD with tagraxofusp [Cycles 2 and 4]: 
• 
Tagraxofusp at a dose of 9 µg/kg daily IV on days 1-3 
• 
Cyclophosphamide (CTX) 150 mg/m2 intravenously (IV) over 3 hrs (± 1 hour) every 
12 hrs x 6 doses days 4-6 
• 
MESNA 300 mg/m2/d IV continuous infusion daily for 24 hrs (± 4 hours), starting 
approximately 1 hour prior to CTX and completing by approximately 12 hrs after 
the last dose of CTX.  
• 
Vincristine 2 mg IV on day 4 (± 3 days) and day 15 (± 3 days). Vincristine is not 
myelosuppressive and may be given while patients are receiving filgrastim product 
(G-CSF); no known adverse effects have been observed with the 2 agents given 
together. 
• 
Dexamethasone 20 mg IV or p.o. daily on days 4-7 (± 3 days) and days 14-17 (± 3 
days). 
• 
Filgrastim product (G-CSF) 10 mcg /kg (rounded) subcutaneously daily (or 5 mcg 
/kg twice daily) until post-nadir granulocytes > 1.0 x 109/L. Filgrastim product (G-
CSF) may be stopped earlier for bone pain or other related toxicity. Minimum time 
allowed between courses is 14 days.  Pegfilgrastim product may replace filgrastim 
product (G-CSF) at a dose of 6 mg SQ on Day 8 (+ 3 days). 
• 
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 
may be added on days 4 (± 3 days) and 14 (± 3 days). In patients receiving 
rituximab all therapy can be moved back 1 day if needed (i.e. day 1 starts day 2, 
day 2 starts day 3, etc.). 
• 
CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) 
on day 5 (± 3 days). Cytarabine 100 mg intrathecally on day 10 (± 3 days) for a 
total of 8 IT doses. These are generally given on cycles 2-5 but if one or more IT 
treatments is missed it can be made up on a later cycle. Administer in 3 to 5 cc of 
preservative-free normal saline. 
  
3. Mini-Hyper-CVD without tagraxofusp [Cycles 6 and 8]: 
• 
Cyclophosphamide (CTX) 150 mg/m2 intravenously (IV) over 3 hrs (± 1 hour) every 
12 hrs x 6 doses days 1-3 


 
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• 
MESNA 300 mg/m2/d IV continuous infusion daily for 24 hrs (± 4 hours), starting 
approximately 1 hour prior to CTX and completing by approximately 12 hrs after 
the last dose of CTX.  
• 
Vincristine 2 mg IV on day 1 (± 3 days) and day 11 (± 3 days). Vincristine is not 
myelosuppressive and may be given while patients are receiving filgrastim product 
(G-CSF); no known adverse effects have been observed with the 2 agents given 
together. 
• 
Dexamethasone 20 mg IV or p.o. daily on days 1-4 (± 3 days) and days 11-14 (± 3 
days). 
• 
Filgrastim product (G-CSF) 10 mcg /kg (rounded) subcutaneously daily (or 5 mcg 
/kg twice daily) until post-nadir granulocytes > 1.0 x 109/L. Filgrastim product (G-
CSF) may be stopped earlier for bone pain or other related toxicity. Minimum time 
allowed between courses is 14 days.  Pegfilgrastim product may replace filgrastim 
product (G-CSF) at a dose of 6 mg SQ on Day 5 (+ 3 days). 
 
4. Methotrexate and cytarabine with tagraxofusp [Cycles 3 and 5] 
• 
Tagraxofusp at a dose of 9 µg/kg daily IV on days 1-3 
• 
Methotrexate (MTX) 50 mg/m2 IV over 2 hrs (± 1 hour) followed by 200 mg/m2 
over 22 hrs on day 4. Total duration of administration is 24 hours (2 plus 22 
hours) (± 3 hours). 
• 
Cytarabine 0.5 g/m2 IV over 3 hrs (± 1 hour) every 12 hrs for 4 doses on days 5 
and 6. 
• 
Leucovorin rescue 50 mg IV or PO followed by 15 mg IV or PO every 6 hours for 
8 doses beginning 12 hrs (± 3 hrs) post MTX completion, i.e. approximately 36 
hours from start of MTX. 
• 
Check MTX levels around time 0h, 24h and 48h post completion of MTX unless 
methotrexate cleared: 
o 
if > 20 µM at time 0, hold cytarabine and repeat level; if continues to be > 
20 µM reduce cytarabine to 0.25 g/m2 IV over 2 hours every 12 hours for 
4 doses on days 2 and 3. Begin leucovorin rescue as described above. 
o 
if > 1 µM at 24hrs or > 0.1 µM at 48 hours, increase leucovorin rescue to 
50 mg IV or PO every 6 hrs until serum methotrexate level is < 0.1 µM. 
Clearance to levels 0.15 µM or less is acceptable in patients with normal 
renal function. 
o 
Leucovorin rescue may be increased further for elevated methotrexate 
levels or delayed clearance 
• 
Filgrastim product (G-CSF) 10 mcg/kg (rounded) subcutaneously daily (or 5 mcg 
/kg twice daily) until post-nadir granulocytes ≥ 1.0 x 109/L. Filgrastim product (G-
CSF) may be stopped earlier for bone pain or other related toxicity. Minimum 
time allowed between courses is 14 days (e.g., day 14).  Pegfilgrastim product 
may replace filgrastim product (G-CSF) at 6 mg SQ on Day 6 (± 3 days). 
• 
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 
mg/m2 may be added on days 4 (± 3 days) and 11 (± 3 days). In patients 
receiving rituximab all therapy can be moved back 1 day if needed (i.e. day 1 
starts day 2, day 2 starts day 3, etc.).  
• 
CNS prophylaxis: cytarabine 100 mg day 8 (± 3 days) and methotrexate 12 mg 
intrathecally (6 mg via Ommaya reservoir) day 11 (± 3 days) of cycle 3 and 5 for 
a total of 8 IT doses. These are generally given on cycles 2-5 but if one or more 


 
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12 
IT treatments is missed it can be made up on a later cycle.  Administer in 3 to 5 
cc of preservative-free normal saline 
 
5. Methotrexate and cytarabine without tagraxofusp [Cycles 7 and 9] 
• 
Methotrexate (MTX) 50 mg/m2 IV over 2 hrs (± 1 hour) followed by 200 mg/m2 
over 22 hrs on day 1. Total duration of administration is 24 hours (2 plus 22 
hours) (± 3 hours). 
• 
Cytarabine 0.5 g/m2 IV over 3 hrs (± 1 hour) every 12 hrs for 4 doses on days 2 
and 3. 
• 
Leucovorin rescue 50 mg IV or PO followed by 15 mg IV or PO every 6 hours for 
8 doses beginning 12 hrs (± 3 hrs) post MTX completion, i.e. approximately 36 
hours from start of MTX. 
• 
Check MTX levels around time 0h, 24h and 48h post completion of MTX unless 
methotrexate cleared: 
o 
if > 20 µM at time 0, hold cytarabine and repeat level; if continues to be > 
20 µM reduce cytarabine to 0.25 g/m2 IV over 2 hours every 12 hours for 
4 doses on days 2 and 3. Begin leucovorin rescue as described above. 
o 
if > 1 µM at 24hrs or > 0.1 µM at 48 hours, increase leucovorin rescue to 
50 mg IV or PO every 6 hrs until serum methotrexate level is < 0.1 µM. 
Clearance to levels 0.15 µM or less is acceptable in patients with normal 
renal function. 
o 
Leucovorin rescue may be increased further for elevated methotrexate 
levels or delayed clearance 
• 
Filgrastim product (G-CSF) 10 mcg/kg (rounded) subcutaneously daily (or 5 mcg 
/kg twice daily) until post-nadir granulocytes ≥ 1.0 x 109/L. Filgrastim product (G-
CSF) may be stopped earlier for bone pain or other related toxicity. Minimum 
time allowed between courses is 14 days (e.g., day 14).  Pegfilgrastim product 
may replace filgrastim product (G-CSF) at 6 mg SQ on Day 4 (± 3 days). 
 
 
 
 
 
4.9 Intrathecal Treatments 
• Patients should receive 8 total doses of intrathecal chemotherapy (2 intrathecal injections 
of methotrexate and cytarabine with cycles 2-5 until the total number reached) 
• If the patient has been previously treated, and has had prior intrathecal therapy, or prior 
CNS disease, discuss management of CNS with the principal investigator.  
• If active CNS disease: Consider methotrexate alternating with cytarabine twice weekly 
until CSF clear; then once weekly for 4 weeks, then every other week for 4 weeks, then 
monthly for 4 months. Consider radiotherapy (XRT) to the base of the skull, particularly 
with cranial nerve root involvement (cranial nerve palsies). Alternative methods of treating 
CNS disease are allowed if appropriate for the patient (e.g., intrathecal liposomal 
cytarabine, or others). Modifications to the regimen thought to be necessary for 
administration of XRT are allowed after discussion with the principal investigators.   
• Concomitant intrathecal chemotherapy should be avoided, if possible, on the days of 
administration of intravenous methotrexate and cytarabine (odd cycles). 
 
4.10 Suggested Standard Dose Reductions/Modifications: 


 
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• 
Vincristine 1 mg IV (50% reduction) if: 
o 
Bilirubin > 2 mg/dl and ≤ 3 mg/dl 
o Clinically significant grade 2 peripheral neuropathy persisting greater than 2 
weeks. 
o Eliminate vincristine for grade 3-4 peripheral neuropathy, including grade 3-4 
ileus suspected to be related to vincristine, or bilirubin > 3 mg/dL. 
• 
Methotrexate: 
o Consider reduction by 25%-50% for grade 3 or worse mucositis with previous 
methotrexate course. 
o Reduce by 50% for calculated creatinine clearance 10-50 ml/min, if < 10 ml/min, 
hold methotrexate. 
o Reduce by 25% to 75% for delayed excretion and/or nephrotoxicity with previous 
methotrexate course. 
o Reduce by 50% for pleural effusion or ascites (drain effusion if possible).  
• 
Tagraxofusp 
o 
See Appendix A for management of tagroxofusp 
• Other modifications of drug schedules may be implemented if judged to be in the best 
clinical interest of the patient after discussion with PI or at the discretion of the treating 
physician.  This includes delays in chemotherapy cycles because of persistent 
myelosuppression, other side effects, patient request, or other reasons.  
• Dose reductions exceeding those above or in other agents, e.g., leucovorin, antibiotics, 
antiemetics, etc., are allowed after discussion with the Principal Investigator. 
 
4.11Maintenance 
• 
Patients may be moved to the maintenance phase prior to completion of 9 cycles of 
induction/consolidation if significantly intolerant to prior therapy after discussion with the 
Principal Investigator. 
• 
Maintenance chemotherapy is contained of POMP cycles (6-mercaptopurine (6-MP) + 
methotrexate (MTX) + vincristine + prednisone) and tagraxofusp cycles. A cycle of 
tagraxofusp will be given after every 3 Cycles of POMP for a total of 15 cycles of 
maintenance therapy. POMP maintenance will be given on Cycles 1-3, 5-7, 9-11, 13-15, and 
Tagraxofusp maintenance will be given on Cycles 4, 8, and 12. 
o 
POMP cycles 
 
6-MP 50 mg PO three times daily (TID), change of frequency to once 
daily dose is permitted and will not result in a deviation. 
 
MTX 20mg/m2 (rounded) PO weekly 
 
Vincristine 2 mg IV day 1 approximately every 28 days 
 
Prednisone 200 mg PO daily about days 1 to 5 approximately every 28 
days, starting with vincristine (if given). Shift of prednisone from days 1-5 
to days 2-6 is permitted and will not result in a deviation.  
o 
Tagraxofusp cycles 
 
Tagraxofusp will be given at a dose of 12 µg/kg daily IV on days 1-5. 
These cycles will be approximately 28- days in length. 
 
Suggested maintenance chemotherapy dose adjustments as below: 
 
Table 1:  Maintenance 


 
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• 
Dose adjustments for myelosuppression include MTX and 6-MP, but not vincristine or 
prednisone (the latter should remain 200 mg unless steroid myopathy or other uncontrolled 
significant toxicity occurs). Titrate to keep granulocytes ≥ 1 x 109 /L and platelet count ≥ 50 x 
109 /L.  
• 
Methotrexate 
o 
Decrease by one dose level for mucositis > grade 2. 
o 
Decrease by one dose level for bilirubin > 2.5 or elevation of transaminases ≥ 5 x 
upper limit of normal. 
o 
Hold if granulocyte count nadir < 0.5 x 109 /L or platelets < 10 x 109 /L, resume with 
decrease in one dose level or lower depending on duration of cytopenias. 
• 
Mercaptopurine (6-MP) 
o 
Decrease by one dose level for bilirubin > 2.5 mg/dL or elevation of transaminases ≥ 
5 x upper limit of normal. 
o 
Hold if granulocyte count nadir < 0.5 x 109 /L or platelets < 10 x 109 /L, resume with 
decrease in one dose level or lower depending on duration of cytopenias. 
• 
Vincristine 
o 
Decrease by one dose level for ≥ grade 2 peripheral neuropathy persisting for more 
than 2 weeks. 
o 
Discontinue for grade 3 or greater peripheral neuropathy. 
• 
Note that the dose adjustments of POMP are guidelines, and the dosing needs to be 
individualized to the patient, as differential toxicities between 6-MP and methotrexate may be 
difficult to discern. 
• 
Continued antiviral prophylaxis to prevent herpes zoster is strongly encouraged. Consider 
antifungal prophylaxis during days of prednisone. Consider PCP prophylaxis. 
 
4.12 Definition of DLT –  
 
• 
Any treatment-related death 
• 
AST or ALT >= 3 x ULN in the setting of total bilirubin >= 2 x ULN, without findings 
of cholestasis, and no other reason can be found to explain the combination of 
increased aminotransferases and total bilirubin, such as viral hepatitis A, B, or C, 
preexisting or acute liver disease, or another drug capable of causing the observed 
injury 
• 
Grade 4 neutropenia lasting ≥42 days from start of cycle in the absence of 
evidence of active leukemia, regardless of investigator attribution.  
• 
Grade ≥ 3 non-hematologic toxicity not clearly resulting from underlying leukemia 
(and unrelated to intercurrent illness, or concomitant medications) that do not 
improve to < grade 2 within 72 hours with treatment interruption and maximal 
medical therapy and that occur within the first 3 cycles (i.e., 28 days after beginning 
of cycle 3) should be considered a DLT with the following pre-specified exceptions: 


 
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- Grade 3 alopecia.  
- Grade 3 fatigue, asthenia, fever, anorexia or constipation lasting < 7 days. 
- Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization.  
- Infection, bleeding or other expected direct complication of cytopenias due 
to active underlying leukemia. 
- Grade 3 infusion reaction including cytokine release syndrome (CRS) or 
capillary leak syndrome (CLS), if successfully managed and which resolves 
within 72 hours 
- Grade 3 or 4 tumor lysis syndrome if it is successfully managed clinically 
and resolves within 7 days without end-organ damage. 
- Grade 4 electrolyte abnormalities that resolve within 72 hours 
 
 
4.13 Safety lead-in  
We will enroll 6 patients in a safety lead-in to evaluate the safety of tagraxofusp in 
combination with hyper-CVD. These patients will count toward the phase II analysis. 
The regimen will initially be explored in 6 eligible patients. If none or only one of the 6 
patients experiences DLT in the first 3 cycles attributable to the treatment components, 
this study will continue to accrue patients. If DLT attributable to the components is 
observed in 2 or more of these initial 6 patients, no further patients will be treated. A 
lower dose of the combined agents would be assessed based on the investigators’ 
decision, which will be implemented with amendment to the study. 
 
5. 
CONCOMITANT MEDICATIONS 
Concomitant medications will be documented in the subject’s electronic medical record but will 
not be entered into the case report form (Prometheus). 
 
Medications that inhibit platelet function (i.e.,aspirin, dipyridamole, epoprostenol, eptifibatide, 
clopidogrel, cilostazol, abciximab, ticlopidine, and any non-steroidal anti-inflammatory drug) or 
Anticoagulants (warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin, 
tinzaparin, enoxaparin]) should be avoided as much as possible during induction and consolidation 
due to expected thrombocytopenia.  
 
Exceptions include low-dose warfarin for prophylaxis to prevent catheter thrombosis, and for 
heparin-flushes for IV lines. If patients develop deep vein thrombosis during the course of therapy 
or are receiving anticoagulation for indications such as recent thrombosis or artificial heart valves 
these drugs may be continued with close monitoring of the patients. 
 
Irradiation of extramedullary disease may be performed at the discretion of the treating physician 
after consultation with the study PI. 
 
Concomitant hydroxyurea is allowed during cycle 1 if needed to control peripheral white blood cell 
count. Use of hydroxyurea in this period should be discussed with the PI. 
 


 
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Patients may be concurrently enrolled in supportive care clinical trials. Other investigational 
agents that are used for treatment of other cancers will not be allowed. 
 
6. STUDY PROCEDURES  
Table 2:  Study Procedures 
Chemotherapy and/or Tagraxofusp 
Maintenance 
Follow-
up 
 
Pre-Rx 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Cycles 1-15 
30 days 
after 
last 
dose 
 
Within 14  
days of 
start 
treatment  
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
EKG 
X 
 
  
  
  
  
  
  
  
  
  
  
History & physical examA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signsA 
X 
 X 
X 
X  
X  
X  
X  
X  
X  
 X 
X 
  
Performance Status 
X 
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelet countB 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X  
  
ALT or AST, Total bilirubin, 
albumin, creatinine, uric acid, 
phosphorus, LDHC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
  
Bone Marrow & cytogeneticsD 
X (within 
30days) 
X 
 
X 
 
 
 
 
 
 
 
  
Pregnancy test (If indicated) 
X (within 
7days) 
  
  
  
  
  
  
  
  
  
  
  
Echocardiogram or MUGA 
X 
  
  
  
  
  
  
  
  
  
  
  
Chest X-ray 
X 
  
  
  
  
  
  
  
  
  
  
  
Imaging Studies - Extramedullary 
DiseaseE 
X 
 
 
 
 
 
 
 
 
 
 
  
Concomitant medication and AE 
assessment 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
  
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
 
A Physical Exam and Vital Signs before start of cycles 1-9 and then before each tagraxofusp cycle during 
maintenance.  Vitals signs including weight, respiration rate, pulse, and blood pressure. 
B CBC, platelet count and differential: 1-2 weekly for cycle 1, then 1-3 weeks during intensive chemotherapy then 
every 4-8 weeks during maintenance. CBC, platelet count and differential should be checked prior to every dose of 
tagraxofusp. 
C Total bilirubin, AST or ALT, albumin, creatinine, uric acid, phosphorus, LDH weekly during cycle 1, then every 1-
3 weeks during intensive chemotherapy, then every 4-8 weeks during maintenance. Laboratory studies, including 
albumin, should be checked prior to every dose of tagraxofusp. 


 
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D  Bone marrow for correlative samples should be performed prior to starting therapy. If unable to obtain a repeat 
bone marrow prior to study entry, most recent bone marrow should have been performed within 30 days of start of 
treatment. When possible, add cytogenetics, flow minimal residual disease assessment, and mutations. Additional 
bone marrow assessment after cycles 1 at C1D21 (± 7 days) and 3 at C3D28 (± 7 days), then at the end of every 
1-3 cycles (± 7 days) during intensive chemotherapy and every 3-6 cycles (± 7 days) during maintenance, or as 
clinically indicated. Additional research samples for correlative studies will be performed at the end of cycle 1 bone 
marrow C1D21 (± 7 days) (i.e. after cycle of single-agent tagraxofusp) and at the time of relapsed. Patient who 
would have not yet achieved CR/CRi should have a bone marrow performed every cycle until response is 
documented or patient is removed from study 
E Imaging studies (chest x-ray, CT chest, and/or PET scan) at the time of maximum response and/or when 
clinically determined to be necessary (in patients with extra-medullary disease at baseline only) 
F Correlative peripheral blood samples will be collected anytime from the time of consent to prior the first dose of 
tagraxofusp (C1D1). All correlative samples (peripheral blood and bone marrow) will be sent to Dr. Kornblau’s lab. 
Correlative samples will be performed as a batch at the end of the study and no data related to these samples will 
be captured in the case report form. Failure to obtain any correlative studies will not be considered a deviation. 
 
6.1 Follow-up 
 
Thirty days after last dose of the study drugs and AE assessment will be performed.  This 
may be done over the phone with a member of the study staff. The phone call should last 
about 10 minutes. Patient will be contacted every 3 months (± 1 month) until patient death or 
patient is lost to follow-up.  
 
7. EFFICACY AND SAFETY ASSESSMENTS 
7.1. CRITERIA FOR RESPONSE 
1. Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 
5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 
x 109/L or above, and platelet count of 100 x 109/L. Complete resolution of all sites of 
extramedullary disease is required for CR. 
2. Complete remission without recovery of counts (CRi): Peripheral blood and marrow 
results as for CR, but with incomplete recover of counts (platelets < 100 x 109/L; 
neutrophils < 1 x 109/L). 
3. Partial Response (PR): As above for CR except for the presence of 6-25% marrow 
blasts. 
4. Relapse and resistant disease will be defined based on morphological assessment of 
bone marrow and peripheral blood. Patients with new or recurrent CNS or 
extramedullary disease will also be considered to have relapsed disease. 
 
7.2. EVALUATION OF TOXICITY 
1. An adverse event (AE) is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have a causal 
relationship with this treatment. This includes the appearance or worsening of any 
undesirable sign, symptom, or medical condition occurring after starting the study drug 
even if the event is not considered to be related to study drug. 


 
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2. Toxicities will be graded according to the NCI Common Toxicity Criteria for Adverse 
Event Reporting Version 5 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  The 
toxicity of the regimen will be monitored continuously during the course of the study. 
 
7.3. CRITERIA FOR REMOVAL FROM THE STUDY 
1. Adverse events that are not manageable with dose adjustments and/or optimal medical 
management, or that, in the opinion of the investigator, pose an unacceptable risk for the 
patient 
2. Non-compliance by the patient with protocol requirements  
3.  Failure to achieve CR, CRi or PR after at least 3 cycles, unless the patient has derived 
clinical benefit as defined by a reduction of transfusion requirements 
4. Disease progression. 
5.  Patient death 
6.  Patient decision (e.g. withdrawal of consent) 
7.  Investigator decision, if it is deemed in the best interest of the patient 
 
 
7.4 DEFINITION OF STUDY END-POINTS 
1. Relapse-free survival is the time from documented complete response until relapse or 
death. 
 
2. Event-free survival is the time from the first day of treatment until any failure (resistant 
disease, relapse, or death). 
 
3. Overall response rate is defined as the percentage of patients achieving CR or CRi 
 
4. Overall survival is defined as the time from the first day of treatment to time of death 
from any cause. 
 
8. REPORTING REQUIREMENTS 
 
8.1 Monitoring, Recording and Reporting Adverse Events 
 
All consented subjects will be registered in the institutional database CORe.  
 
Adverse event reporting will be as per the NCI criteria and the MDACC Leukemia Specific 
Adverse Event Recording and Reporting Guidelines. 
 
              The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. For non-MD Anderson laboratory results, the principal investigator (or physician 
designee) will review laboratory results, and sign and date the results. 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. ( 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50).   


 
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Prometheus will be the electronic Case Report Form for adverse events.  Baseline events will be 
recorded in the medical history section of the case report form (Prometheus) and will include the 
terminology event name, grade, and start date of the event. AEs will be recorded from the first 
dose through 30 days after the last dose. AEs will be shared with Astellas on an annual basis. 
Abnormal laboratory values or test results will not be recorded or reported as adverse events 
unless it leads to therapeutic intervention, results in dose modification or interruption, or meets 
the protocol definition of a DLT or SAE. 
 
The Leukemia specific Adverse Event Recording and Reporting Guidelines will be followed for the 
recording and reporting of adverse event and serious adverse events on investigator-initiated trials 
within the Department of Leukemia. 
1. Baseline events will be recorded in the medical history section of the case report form 
(CRF) and will include the diagnosis, grade, and start date of the event.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the first dose of study drug 
i. Hematologic laboratory abnormalities will not be recorded as baseline 
events for patients with any type of leukemia and/or related disorders. 
b. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event or “Unknown” may be recorded. 
c. The medical history section of the CRF will serve as the source document for 
baseline events once signed and dated by the Principal Investigator.   
2. AEs will be captured starting from the first dose of the study drug to 30 days after the last 
dose of study drug or when the patient begins another treatment for the disease under 
study, whichever occurs first. Serious Adverse Events (SAEs) will be captured starting 
from the date of consent and reported according to institutional policy. 
3. The maximum grade of the adverse event (AE) will be captured per course or protocol 
defined visit date. The start date will be recorded as when the AE first began or worsened 
from baseline, regardless of when the event was at its highest grade. 
4. An AE will be recorded as intermittent if the AE is not continuous but reoccurs at an 
irregular interval within a course. 
5. Only the following AEs from the Adverse Event Record will be reported in the CRF: 
a. Any grade adverse event that is possibly, probably, or definitely related to the 
study drug(s). 
b. All serious adverse events regardless of attribution to the study drug(s). 
c. Any grade adverse event regardless of attribution to the study drug(s) that results 
in any dose modification. 
6. Hematologic adverse events will not be recorded or reported for studies in patients with 
any type of leukemia and/or related disorders, except for: 
a. Prolonged myelosuppression as defined by marrow hypocellularity on day 42 or 
later (6 weeks) from start of therapy without evidence of leukemia (< 5% blasts).  
b. Hematologic events that result in dose modifications, interruptions or meets the 
protocol definition of DLT or SAE. 
7. Other abnormal laboratory values, vital signs and test results constitute adverse events 
only if they lead to therapeutic intervention, discontinuation or delay in treatment, dose 
modification, or otherwise meet the criteria of a DLT or SAE. Lab abnormalities not 
meeting these criteria are considered not clinically significant.  


 
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8. Protocol specific language regarding the recording and reporting of adverse and serious 
adverse events will be followed in the event of discordance between the protocol and 
Leukemia-specific adverse event recording and reporting guidelines. 
 
8.2  Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsored 
Single Site IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
  
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
  
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy on Reporting Adverse Events for Drugs and Devices”. Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office.   
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 


 
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Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
  
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
Procedures for Reporting Serious Adverse Events: 
 
MDACC SAE form (eSAE) will be utilized for safety reporting to Stemline. SAEs will be 
reported to Stemline within timeframe per table 3, sec 8.3, of knowledge of any event via 
email: adverseevents@stemline.com. 
 
 
8.3 Investigator Communications with Stemline 
In addition to compliance with all FDA reporting requirements pursuant to 21 CFR 312, the 
Principal Investigator shall: 
a) Report to Stemline serious adverse events (SAEs) experienced by a study subject receiving an 
Stemline product per the timelines and requirements in the table below.  Principal Investigator 
shall make available to Stemline promptly such records as may be necessary and pertinent to 
investigate any such event, if specifically requested by Stemline, and, 
Table 3:  Investigator Communications 
Deliverables 
Timeframe & Details 
IND Safety Report 
Notifications 
Please notify Stemline of an upcoming submission to the IND. This 
notification would ideally include the following: 
• 
Timelines for IND Reporting 
• 
SAE Term(s) driving reportability 
7-Day IND Safety 
Report 
Send to Stemline as soon as it is ready, or within one (1) business day of 
completion of the eSAE Form. Please include:  
• 
Completed eSAE Form  
15-Day IND Safety 
Report 
Send to Stemline as soon as ready, but no later than five (5) business days 
of completion of the eSAE Form. Please include: 


 
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• 
Completed eSAE Form 
Fatal cases that are 
unrelated to Study 
Drug 
Please send the completed eSAE form to Stemline within seven (7) 
business days. Follow-up information should also be provided within the 
same time frame. 
Quarterly SAE 
Listings 
On a quarterly basis, please provide SAE Line Listing from the study’s 
safety database which includes: 
• 
Patient ID, Age and Gender 
• 
Study Drug start/stop dates 
• 
SAE Term 
• 
Event Onset Date 
• 
Severity Grade 
• 
Causality (Relationship to Study Drug) 
• 
Event Outcome 
 
b) Notify Stemline upon any subjects receiving an Stemline Product whose pregnancy has resulted 
in a negative outcome or untoward event during the course of pregnancy or upon delivery. 
Stemline’s contact for reporting serious adverse drug experiences, pregnancy experiences, and 
communications of FDA submissions of IND safety reports shall be 
adverseevents@stemline.com 
              Pregnancy related events will be submitted via eSAE application as “Other Important Medical 
Event”. 
 
Product Complaints:  In addition to compliance with all FDA requirements pursuant to 21 CFR 
211 and 21 CFR 820, Principal Investigator will report to Stemline within 24 hours any suspected 
quality defect in an Stemline Product or its Stemline-provided packaging, labeling, or medical 
device component (collectively, “Product Complaint”).  Principal Investigator will report Product 
Complaints that involve an Stemline Product, whether Stemline has supplied the Stemline 
Product used in the Study or not.  Stemline’s contact for reporting Product Complaints shall be 
productcomplaints@stemline.com 
9. OUTSIDE PHYSICIAN PARTICIPATION DURING TREATMENT 
 


 
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9.1. MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record. 
 
9.2. A letter to the local physician outlining the patient's participation in a clinical trial will request local 
physician agreement to supervise the patient's care 
 
9.3. Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that they 
have reviewed it. 
 
9.4. Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in the 
patient record. 
 
9.5. Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and documentation 
of any hospitalizations. 
 
9.6. The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
 
9.7. Patients should receive all induction and consolidation at MDACC but may receive maintenance 
therapy by an outside physician. However, they will need to return to MDACC monthly during 
maintenance tagraxofusp cycles. 
 
10. STATISTICAL METHODOLOGY 
 
This is a single arm, open label, phase Ib/II study to assess the safety and efficacy of tagraxofusp plus 
low-intensity chemotherapy in patients with ALL.  
 
Phase Ib 
 
A safety lead-in design with 6 patients will be used to determine the MTD for the combination regimen. 
These patients will count toward the phase II part. If none or 1 out of the 6 patients experience a DLT, 
then the phase II will commence. If 2 or more patients experience a DLT, in which case the MTD has 
been exceeded, then a lower dose of the combination regimen could be assessed based on the 
investigators’ decision, which will be implemented with amendment to the study. 
 
Phase II 
   
The primary endpoint of the phase II is overall response rate (ORR) of the combination regimen. A total 
40 patients will be enrolled in the phase II part including the 6 patients of the phase Ib. The ORR and 
toxicity within 3 cycles of treatment initiation will be monitored simultaneously using the Bayesian 
approach of Thall, Simon, Estey (1995, 1996) as extended by Thall and Sung (1998). The design 
software Multc Lean Desktop (version 2.1) developed by the Department of Biostatistics at M D Anderson 


 
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Cancer Center was used to generate the stopping boundaries and operating characteristics for futility and 
toxicity monitoring. Toxicities are defined as grade 3/4/5 adverse events that are at least possibly related 
to study drug (with the exception of any adverse events that constitute exceptions to DLTs as above).  
 
The historical ORR for ALL patients is 25%. It is expected for the current trial that the combination 
regimen will improve the ORR by 10%, while the toxicity rate is maintained at or below 20%. A sample 
size of 40 patients ensures that, if the trial is not terminated early, a posterior 95% credible interval for 
ORR will be (0.21, 0.49) under the assumption of a 35% of ORR and a prior of Beta (0.5, 1.5). The prior 
probabilities of ORR and toxicity for the experimental combination regimen are modeled by beta 
distributions Beta (0.5, 1.5) and Beta (0.4, 1.6), respectively. Denoting the historical proportion of overall 
response rate and toxicity rate by {p(ORR, H) = 0.25, p(TOX, H) = 0.20}, the following decision criteria will 
be applied:  
1) Stop if Prob{p(ORR, H) + δORR > p(ORR, E) | data} > 0.975, where δORR = 0 
2) Stop if Prob{p(TOX, H) + δTOX < p(TOX, E) | data} > 0.80, where δTOX = 0 
 
Patients will be monitored in cohorts of 5 according to the following stopping boundaries for response and 
toxicity. 
 
Table 4:  Stopping Boundaries for Response and Toxicity 
# Patients 
Evaluated 
Stop this cohort if ≤ this # ORR 
Stop if ≥ this # toxicities 
5 
Never stop with this many patients 
3-5 
10 
0 
4-10 
15 
0 
5-15 
20 
0-1 
6-20 
25 
0-2 
7-25 
30 
0-3 
9-30 
35 
0-4 
10-35 
40 
Always stop with this many patients 
Always stop with this many patients 
 
 
The operating characteristics are summarized in the following table (based on simulations from 10,000 
trials). 
 
Table 5:  Operating Characteristics  
 
True Toxicity Rate 
True ORR  
Prob(Stop Early) 
0.10 
0.25 
0.1287 
0.30 
0.0704 
0.35 
0.0468 
0.40 
0.0373 
0.45 
0.0334 
0.20 
0.25 
0.3967 
0.30 
0.3564 


 
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25 
0.35 
0.3400 
0.40 
0.3334 
0.45 
0.3307 
0.30 
0.25 
0.8005 
0.30 
0.7872 
0.35 
0.7817 
0.40 
0.7796 
0.45 
0.7787 
0.40 
0.25 
0.9736 
0.30 
0.9719 
0.35 
0.9711 
0.40 
0.9709 
0.45 
0.9707 
0.50 
0.25 
0.9988 
0.30 
0.9987 
0.35 
0.9987 
0.40 
0.9986 
0.45 
0.9986 
 
Statistical Analysis Plan 
 
All patients who received at least one dose of study drug will be included in the intent-to-treat analysis for 
efficacy and safety. We will follow standard reporting guidelines for adverse events. Safety data will be 
summarized by category, severity and frequency using frequency tables. Demographic/clinical 
characteristics (such as duration of response) will be summarized using descriptive statistics such as 
mean, standard deviation, median and range. Overall response rate, and CR rate within 3 cycles of 
treatment initiation will be estimated along with 95% credible intervals. Chi-square tests or Fisher’s exact 
test will be used to evaluate the association between patient’s prognostic factor and response. Kaplan-
Meier method will be used to estimate the relapsed-free survival (RFS), and overall survival. RFS is 
defined as the time from the of response to relapsed or death, whichever happens earlier. It will be 
censored at last follow-up. Paired t-tests will be used to determine the gene expressions and other clinical 
variables changes from pre-therapy to the predefined time-points. 
 
The Investigator is responsible for completing an efficacy/safety summary report, and submitting it to the 
IND Office Medical Affairs and Safety Group, for review and approval  
 
• 
Lead-In Phase: 
After the first 3 evaluable patients, complete 3 cycles of study treatment, and every 3 evaluable patients 
complete 3 cycles thereafter, IND Office approval must be obtained prior to expanding/changing dose 
levels. 
 
• 
 Phase II: 
After the first 5 evaluable patients complete 3 cycles of study treatment, and every 5 patients complete 3 
cycles of treatment thereafter.  


 
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A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under “sponsor 
correspondence”. 
 
11. 
REFERENCES 
1. 
Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 1998; 339(9): 605-15. 
2. 
Rivera GK, Raimondi SC, Hancock ML, et al. Improved outcome in childhood acute lymphoblastic 
leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 1991; 337(8733): 61-6. 
3. 
Kantarjian HM, Walters RS, Keating MJ, et al. Results of the vincristine, doxorubicin, and dexamethasone 
regimen in adults with standard- and high-risk acute lymphocytic leukemia. J Clin Oncol 1990; 8(6): 994-1004. 
4. 
Hoelzer D, Thiel E, Loffler H, et al. Prognostic factors in a multicenter study for treatment of acute 
lymphoblastic leukemia in adults. Blood 1988; 71(1): 123-31. 
5. 
Gaynor J, Chapman D, Little C, et al. A cause-specific hazard rate analysis of prognostic factors among 
199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 1988; 
6(6): 1014-30. 
6. 
Hussein KK, Dahlberg S, Head D, et al. Treatment of acute lymphoblastic leukemia in adults with intensive 
induction, consolidation, and maintenance chemotherapy. Blood 1989; 73(1): 57-63. 
7. 
Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive 
consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995; 
85(8): 2025-37. 
8. 
Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive 
regimen, in adult acute lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2000; 18(3): 547-61. 
9. 
Kantarjian H, Thomas D, O'Brien S, et al. Long-term follow-up results of hyperfractionated 
cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult 
acute lymphocytic leukemia. Cancer 2004; 101(12): 2788-801. 
10. 
O'Brien S, Thomas DA, Ravandi F, Faderl S, Pierce S, Kantarjian H. Results of the hyperfractionated 
cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic 
leukemia. Cancer 2008; 113(8): 2097-101. 
11. 
Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse in adults with acute 
lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia 2007; 21(9): 1907-14. 
12. 
Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood 2013; 
121(7): 1077-82. 
13. 
Faderl S, Thomas DA, O'Brien S, et al. Augmented hyper-CVAD based on dose-intensified vincristine, 
dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clinical lymphoma, 
myeloma & leukemia 2011; 11(1): 54-9. 
14. 
Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic 
malignancies. Biomarker research 2014; 2(1): 4. 
15. 
Short NJ, Konopleva M, Kadia TM, et al. Advances in the Treatment of Acute Myeloid Leukemia: New 
Drugs and New Challenges. Cancer discovery 2020; 10(4): 506-25. 
16. 
Djokic M, Björklund E, Blennow E, Mazur J, Söderhäll S, Porwit A. Overexpression of CD123 correlates 
with the hyperdiploid genotype in acute lymphoblastic leukemia. Haematologica 2009; 94(7): 1016-9. 
17. 
Bras AE, de Haas V, van Stigt A, et al. CD123 expression levels in 846 acute leukemia patients based on 
standardized immunophenotyping. Cytometry Part B, Clinical cytometry 2019; 96(2): 134-42. 
18. 
Testa U, Pelosi E, Castelli G. CD123 as a Therapeutic Target in the Treatment of Hematological 
Malignancies. Cancers 2019; 11(9). 
19. 
Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. 
The New England journal of medicine 2019; 380(17): 1628-37. 


 
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Appendix A:  Updated Tagroxfusp (SL-401) Capillary Leak Syndrome (CLS) Management and 
Guidelines. 
Dose Delays/Modifications and Management Procedures for Toxicities Associated with 
tagraxofusp 
During the dosing period for each cycle, individual tagroxofusp infusions may be delayed to allow for 
toxicity resolution. Details are presented in the Table A-1 below: 
Monitor vital signs/weight and check albumin, transaminases, and creatinine prior to preparing each dose 
of tagraxofusp.  See Table below for CLS management guidance. 
 
Table A-1 Recommended Tagraxofusp Dose Modifications 
Parameter 
Severity Criteria 
Dose Modification 
Serum albumin  
Serum albumin < 3.5 g/dL or reduced ≥ 
0.5 g/dL from value measured prior to 
initiation of the current cycle 
See CLS Management Guidelines 
(Table A-2) 
Body weight  
Body weight increase ≥ 1.5 kg over 
pretreatment weight on prior treatment 
day 
See CLS Management Guidelines 
(Table A-2) 
Aspartate 
aminotransferase 
(AST) or alanine 
aminotransferase 
(ALT)  
ALT or AST increase > 5 times the upper 
limit of normal  
Withhold tagraxofusp until 
transaminase elevations are ≤ 2.5 
times the upper limit of normal. 
Serum creatinine  
Serum creatinine > 1.8 mg/dL (159 
micromol/L) or creatinine clearance < 60 
mL/minute 
Withhold tagraxofusp until serum 
creatinine resolves to ≤ 1.8 mg/dL 
(159 micromol/L) or creatinine 
clearance ≥ 60 mL/minute. 
Systolic blood 
pressure 
Systolic blood pressure ≥ 160 mmHg or 
≤ 80 mmHg 
Withhold tagraxofusp until systolic 
blood pressure is < 160 mmHg or > 
80 mmHg. 
Heart rate  
Heart rate ≥ 130 bpm or ≤ 40 bpm 
Withhold tagraxofusp until heart 
rate is < 130 bpm or > 40 bpm. 
Body temperature  
Body temperature ≥ 38°C 
Withhold SL-401 until body 
temperature is < 38°C. 
Hypersensitivity 
reactions 
Mild or moderate 
Withhold tagraxofusp until 
resolution of any mild or moderate 
hypersensitivity reaction. Resume 
SL-401 at the same infusion rate. 
Severe or life-threatening 
Discontinue tagraxofusp 
permanently. 
Dose reductions should be discussed with the medical monitor or PI on a case by case basis.  


 
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Table A-2: CLS Management Guidance 
Time of 
Presentation 
CLS 
Sign/Symptom 
Recommended 
Action 
SL-401 Dosing 
Management 
Prior to first dose of 
SL-401 in Cycle 1  
Serum albumin < 3.2 
g/dL  
Administer SL-401 when serum albumin ≥ 3.2 g/dL. 
During SL-401 
dosing 
Serum albumin < 3.5 
g/dL  
Administer 25g intravenous albumin 
(q12h or more frequently as 
practical) until serum albumin is ≥ 3.5
g/dL AND not more than 0.5 g/dL 
lower than the value measured prior 
to dosing initiation of the current 
cycle. 
Interrupt SL-
401 dosing until 
the relevant 
CLS 
sign/symptom 
has resolved1. 
Serum albumin 
reduced by ≥ 0.5 g/dL 
from the albumin value 
measured prior to SL-
401 dosing initiation of 
the current cycle 
A predose body weight 
that is increased by ≥ 
1.5 kg over the 
previous day’s predose 
weight 
Administer 25g intravenous albumin 
(q12h or more frequently as 
practical), and manage fluid status 
as indicated clinically (e.g., 
generally with intravenous fluids 
and vasopressors if hypotensive 
and with diuretics if normotensive or 
hypertensive), until body weight 
increase has resolved (i.e. the 
increase is no longer ≥ 1.5 kg 
greater than the previous day’s 
predose weight). 
Edema, fluid overload 
and/or hypotension 
Administer 25g intravenous albumin 
(q12h, or more frequently as 
practical) until serum albumin is ≥ 
3.5 g/dL. 
 
Administer 1 mg/kg of 
methylprednisolone (or an 
equivalent) per day, until resolution 
of CLS sign/symptom or as 
indicated clinically. 
 
Aggressive management of fluid 
status and hypotension if present, 
which could include intravenous 
fluids and/or diuretics or other blood 
pressure management, until 
resolution of CLS sign/symptom or 
as clinically indicated.   
1  SL-401 administration may resume in the same cycle if all CLS signs/symptoms have resolved and the patient did not require 
measures to treat hemodynamic instability. SL-401 administration should be held for the remainder of the cycle if CLS 
signs/symptoms have not resolved or the patient required measures to treat hemodynamic instability (e.g. required administration of 
intravenous fluids and/or vasopressors to treat hypotension) (even if resolved), and SL-401 administration may only resume in the 
next cycle if all CLS signs/symptoms have resolved, and the patient is hemodynamically stable. 


 
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Appendix B 
 
Correlative plan for genomic profiling of ALL cases. 
 
Background and objectives: 
 
Acute lymphoblastic leukemia (ALL) is a highly heterogeneous disease driven by various genetic lesions1. 
Recent years, with the effort of large scale transcriptome sequencing (RNA-seq) of ALL, multiple novel 
subtypes had been identified by analyzing the distinct gene expression profile and the causal genetic 
lesions2-9. RNA-seq has been shown with high reliability of evaluating the gene expression profile and high 
sensitivity of identifying the driver genetic lesions including gene rearrangements, large scale copy number 
alterations, and even sequence mutations, which position RNA-seq as an ideal platform to assist the 
molecular diagnosis and profiling of ALL10,11. Based on our previous research8,10, here we will apply an 
RNA-seq based analysis pipeline to study the gene expression profile and genetic lesions of the enrolled 
ALL cases to achieve the following Specific Aims:  
 
1. Classify the leukemic samples (collected at pre- and post- tagraxofusp treatment) into different 
ALL subtypes according to the driver genetic lesions and gene expression profiles 
2. Identify drug response relevant gene sets and biological pathways through differential gene 
expression analysis between good vs poor responders 
3. Validate the connection of reported CD123 and DPH1 (encoding a diphthamide pathway 
enzyme) expression levels12 and drug responses in ALL 
4. Identify clonal evolution and key genetic lesions introduced through tagraxofusp treatment from 
diagnosis to relapse through RNA-seq and whole genome sequencing (WGS). 
 
Materials and research approaches: 
For diagnosis and relapsed samples, at least 5 million blast cells are required to perform genomic profiling 
(RNA-seq for all the leukemic samples; WGS for ALL missing driver genetic lesion by RNA-seq or for 
mutational spectrum analysis), genetic alteration validation, and following functional characterization of 
leukemic cells. For samples with low blast percentage (<70%), which is common in relapsed cases, the 
leukemic cells will be enriched through fluorescence-activated cell sorting (FACS) or magnetic beads 
enrichment before extracting DNA and RNA for sequencing. With 2-3 million cells, at least 1µg RNA can 
be extracted and submitted for RNA-seq. The rest amount of RNA will be secured for validating the genetic 
lesions identified by RNA-seq through RT-PCR and sanger sequencing. Although most of ALL cases can 
be classified into distinct subtypes using RNA-seq10, around 5~10% are missing driver lesions, thus WGS 
(≥1µg DNA, from 1-2 million cells) of tumor and matched germline samples will be used to further assist the 
disease classification. To minimize the patient sample requirement, the RNA/DNA extraction and 
sequencing library preparation will be carefully carried out within Dr. Gu’s laboratory at City of Hope by a 
senior lab member through consistent sample processing pipelines and protocols, then the libraries will be 
submitted for Illumina high-throughput sequencing. To achieve sufficient sensitivity and accuracy of calling 
fusions and detect genetic lesions from RNA-seq, 50 million 2X150bp reads will be generated. For WGS, 
500 million 2X150bp reads are required for each sample. 
 
Specific Aim 1: The RNA-seq data will be analyzed to call gene rearrangements (e.g. BCR-ABL1), gene 
expression profiles, digital karyotypes10, key sequence mutations (e.g., NRAS, KRAS, PAX5, IL7R, etc.), 
and key intragenic copy number alterations (e.g., IKZF1, ERG, PAX5, etc.). The genetic and transcriptomic 
information will be integrated to assign ALL samples into distinct disease subtypes7,10,13. Should there be  
a small number of ALL cases fail the RNA-seq based disease classification, WGS will be applied to call 
sequencing mutations, granular copy number alterations, and large-scale structure variations, and the 
results will be integrated with RNA-seq to clarify the genetic background of these cases. 


 
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Specific Aim 2: From RNA-seq, the gene expression level will be evaluated and normalized for the enrolled 
ALL cohort to identify differentially expressed genes between good and poor tagraxofusp responders. Gene 
set enrichment and pathway analysis will be performed to identify signature genes and biological pathways 
which can potentially explain and/or predict drug response. With the promising candidate genes and 
pathways identified, patient-derived xenograft mouse models could be used to verify the results. 
 
Specific Aim 3: Tagraxofusp is a CD123-targeted agent, but the factors influencing the response other 
than CD123 expression are largely unknown. A study from Togami et al.12 showed that expression of DPH1, 
which encodes a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant acute 
myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm. With the whole transcriptome 
information acquired from RNA-seq, the connection between drug resistance and expression level of 
CD123/DPH1 will be specifically assessed in the context of ALL. 
 
Specific Aim 4: For the ALL cases with both diagnosis and relapsed samples available, WGS will be 
complemented to RNA-seq to call genetic alterations including sequencing mutation, copy number 
alteration and structure variation. The progression of genetic lesions and gene expression profiles from 
diagnosis to release will be characterized to identify the genetic lesions and deregulated gene expression 
pathways introduced by the selective pressure from tagraxofusp treatment, which will bring insights of 
developing synergistic regimens to further dwindle the risk of relapse.  
In summary, through the proposed genomic profiling of ALL cases enrolled in the tagraxofusp clinical trial, 
the genomic and transcriptomic background of each patient will be thoroughly characterized, which will 
facilitate the interpretation of the treatment response, identify molecular markers to stratify the risk groups, 
and inspire the development of combined treatments to advance the  efficacy of tagraxofusp in curing ALL. 
 
References 
1 
Pui, C. H., Relling, M. V. & Downing, J. R. Acute lymphoblastic leukemia. The New England 
journal of medicine 350, 1535-1548, doi:10.1056/NEJMra023001 (2004). 
2 
Mullighan, C. G. et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. The New 
England journal of medicine 360, 470-480, doi:10.1056/NEJMoa0808253 (2009). 
3 
Den Boer, M. L. et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment 
outcome: a genome-wide classification study. The lancet oncology 10, 125-134, 
doi:10.1016/s1470-2045(08)70339-5 (2009). 
4 
Yasuda, T. et al. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents 
and young adults. Nature genetics, doi:10.1038/ng.3535 (2016). 
5 
Zhang, J. et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nature genetics 
48, 1481-1489, doi:10.1038/ng.3691 (2016). 
6 
Seki, M. et al. Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic 
leukemia. Nature genetics 49, 1274-1281, doi:10.1038/ng.3900 (2017). 
7 
Liu, Y. et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic 
leukemia. Nature genetics, doi:10.1038/ng.3909 (2017). 
8 
Gu, Z. et al. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic 
leukaemia. Nature communications 7, 13331, doi:10.1038/ncomms13331 (2016). 
9 
Lilljebjorn, H. et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in 
paediatric B-cell precursor acute lymphoblastic leukaemia. Nature communications 7, 11790, 
doi:10.1038/ncomms11790 (2016). 
10 
Gu, Z. et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nature 
genetics, doi:10.1038/s41588-018-0315-5 (2019). 


 
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11 
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