Clinical trial NCT03023046
Conditions: Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma
Sponsor: University of Washington
Start date: 2017-02-23; Completion date: 2022-05-01
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin (DA-EPOCH) works in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin, 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.

Detailed description:

Arms: arm 1: Patients receive etoposide IV over 96 hours, doxorubicin IV over 96 hours, and vincristine sulfate IV over 96 hours on days 1-4. Patients also receive cyclophosphamide IV over 1 hour on day 5 and prednisone PO BID on days 1-5. Patients who are Ph+ also receive imatinib mesylate or dasatinib PO QD on days 1-14. Patients who are CD20+ also receive rituximab IV on day 1 or day 5. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cyclophosphamide intervention 2: Dasatinib intervention 3: Doxorubicin intervention 4: Etoposide intervention 5: Imatinib Mesylate intervention 6: Laboratory Biomarker Analysis intervention 7: Prednisone intervention 8: Rituximab intervention 9: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given IV intervention 4: Given IV intervention 5: Given PO intervention 6: Correlative studies intervention 7: Given PO intervention 8: Given IV intervention 9: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
A phase II study of dose-adjusted etoposide, prednisone, 
vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) as 
front-line therapy for adults with acute lymphoblastic 
leukemia/lymphoma 
 
 
NCT03023046 
 
 
5/17/2022 


9770 
Fred Hutchinson Cancer Center 
University of Washington 
 
PROTOCOL  
 
A phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, 
and doxorubicin (DA-EPOCH) as front-line therapy for adults with acute lymphoblastic 
leukemia/lymphoma 
 
 
 
Protocol Version 2.3 
Date:  04 May 2022 
 
Principal Investigator:                       
Ryan Cassaday, MD 
Associate Professor, UW 
Associate Professor, FHCC 
825 Eastlake Ave E, LG-700 
Seattle, WA 98109 
 
Telephone: (206) 606-1202    
 
 
IRO received 05/04/22
FHCRC IRB Approval  
05 17 2022 
Document Released Date


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SCHEMA 
Registration 
 
 
 
Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin 
(DA-EPOCH): 
Given Approximately Every 21 Days for Up to 8 Cycles 
Cytotoxic Agent Dosing Schema 
Treatment (Dose Level 1) 
 
Dosing: Days 1-5 of each Cycle# 
 
1 
2 
3 
4 
5 
Infusional Agents (over ~96 hours) 
 
 
 
 
 
Etoposide 50 mg/m2/day* 
X 
X 
X 
X 
 
Doxorubicin 10 mg/m2/day* 
X 
X 
X 
X 
 
Vincristine 0.4 mg/m2/day 
X 
X 
X 
X 
 
Bolus Agents 
 
 
 
 
 
Cyclophosphamide 750 mg/m2/day* 
 
 
 
 
X 
Prednisone 60 mg/m2/BID^ 
X 
X 
X 
X 
X 
 
* Doses of these agents will subsequently increase or decrease by 20% based on the depth of 
hematologic nadir during the previous cycle, as discussed in Section 7.0. 
^ Conversion to an IV equivalent dose of prednisone is allowable if deemed appropriate by the 
treating physician 
# Central nervous system directed therapy with intrathecal/intraventricular methotrexate will 
also be administered, as discussed in Section 6.3. 
 
 
 
 
 
Non-Cytotoxic Agent Dosing Schema 
 
 For patients with disease features that predict sensitivity to ABL kinase inhibitors (e.g., 
Philadelphia Chromosome positive (Ph+) [i.e., t(9;22)]; rearrangements involving 
PDGFRA, PDGFRB, ABL2, or other genetic lesions that activate kinase receptor signaling): 
imatinib 600 mg PO daily or dasatinib 100 mg PO daily for 14 days of each 21-day cycle.  
The decision to add imatinib or dasatinib will be left to the treating physician/PI and will be 
based on the available scientific literature to support the sensitivity of genomic alterations 
to these TKIs.  


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 For CD20+ patients, rituximab 375 mg/m2 IV on Day 1 or 5 of each 21-day cycle 
 Myeloid growth factor support: G-CSF ≥ 5 g/kg SQ daily or PEGylated G-CSF x 1 will 
be administered after each cycle, starting on Day 6-8. 
 
 


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TABLE OF CONTENTS: 
1.0 
Objectives  ................................................................................................................. 5 
2.0 
Background and Rationale ........................................................................................ 5 
3.0 
Drug Information ....................................................................................................... 6 
4.0 
Eligibility Criteria  ..................................................................................................... 7 
5.0 
Registration  ............................................................................................................... 8 
6.0 
Treatment Plan  .......................................................................................................... 8 
7.0 
Dosage Modifications  ............................................................................................... 12 
8.0 
Study Calendar  ......................................................................................................... 16 
9.0 
Criteria for Evaluation and Endpoint Definitions ..................................................... 18 
10.0 
Statistical Considerations .......................................................................................... 20 
11.0 
Study Monitoring and Reporting Procedures ............................................................ 22 
12.0 
Elements of Informed Consent  ................................................................................. 27 
13.0 
References ................................................................................................................. 27 
 
  
 


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1.0 
OBJECTIVES 
 
1.1. Primary Objectives 
1.1.1. To examine the potential efficacy of DA-EPOCH as front-line therapy 
for adults with acute lymphoblastic leukemia/lymphoma (ALL) 
1.2. Secondary Objectives 
1.2.1. To evaluate the safety and feasibility of this regimen 
1.2.2. To evaluate the progression-free (PFS) and overall survival (OS) of 
patients after receiving DA-EPOCH for newly-diagnosed ALL 
1.3. Exploratory Objectives 
1.3.1. To explore for novel genetic/genomic biomarkers of prognosis and 
response to treatment in adults with ALL 
1.3.2. To compare outcomes predicted by the presence or absence of minimal 
residual disease (MRD) as determined by either multiparameter flow 
cytometry (MFC) or high-throughput sequencing (HTS)  
 
2.0 
BACKGROUND 
 
ALL is among the most common forms of cancer in children, and in this circumstance it is 
highly curable.  However, treatment of ALL in adults is very challenging.  Outcomes with 
standard approaches remain unsatisfactory, with survival rates at 5 years with modern 
approaches for newly-diagnosed adults generally no better than 50-60%.1-4  There has been a 
trend toward using pediatric-inspired regimens in younger (i.e., < 40 years) adults with 
Philadelphia chromosome negative (Ph-) ALL, with early results from a recent US Intergroup 
trial (C10403) yielding encouraging results.5 Despite these and other improvements, however, 
the treatment still relies primarily upon remission induction with intensive multi-agent 
cytotoxic chemotherapy.  This is a particular challenge in older adults diagnosed with ALL, as 
these regimens are (in general) prohibitively toxic for these patients.6  As a consequence of 
these issues, relapsed/refractory disease is a far-too-common occurrence.  And though there is 
significant enthusiasm for new therapeutic approaches for ALL, including novel 
immunotherapies and antibody-drug conjugates, these strategies have limited indications or are 
still in development, and (in some cases) there are significant logistical and/or toxicity 
concerns.7-9 Furthermore, these new approaches are not applicable to T-cell ALL.  Therefore, 
continued improvements for the front-line treatment of ALL in adults are critically needed.  
 
ALL, like many other aggressive lymphoid malignancies, is initially quite sensitive to a number 
of agents, but resistance to these agents develops quite reliably.  This argues that an alternative 
method of delivery of these agents might yield superior outcomes.  This was the rationale that 
led to the development of dose-adjusted EPOCH (etoposide, prednisone, Oncovin [vincristine], 
cyclophosphamide, and hydroxydaunorubicin [doxorubicin]) for aggressive lymphoma.10  
What makes this approach unique is its infusional nature, providing longer exposure to 
doxorubicin, vincristine, and etoposide, which is felt to provide better anti-tumor effects than 
brief, higher-concentration exposure.11  Indeed, this regimen (along with rituximab) has proven 
to be highly effective in a number of high-grade lymphoid malignancies, including MYC+ or 
double-hit B-cell lymphoma and Burkitt lymphoma.12,13  Further, this regimen is generally 


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relatively well-tolerated, even in older adults.  Thus, it represents an attractive chemotherapy 
platform to further explore in adults with ALL. 
 
Newer targeted agents have been successfully introduced to the therapeutic landscape of ALL, 
improving the outcomes for some subgroups of patients.  One of the most important 
developments in the treatment of Ph+ ALL over the past 15 years has been the incorporation of 
ABL tyrosine kinase inhibitors (TKIs) into treatment regimens.14-18  The number of agents in 
this class has grown since the FDA approval of imatinib in 2001, with both dasatinib and 
ponatinib having been shown to be safe and effective adjuncts to hyperCVAD in newly-
diagnosed adults with Ph+ ALL.15,18  However, there have been no studies that suggest one is 
superior to another in Ph+ ALL.17 It is becoming increasingly understood that genetic lesions 
besides the canonical Philadelphia (Ph) chromosome [BCR-ABL1; t(9;22)] may confer a worse 
prognosis but also may predict response to ABL kinase inhibitors like imatinib and dasatinib 
(e.g., rearrangements involving PDGFRA, PDGFRB, ABL2, etc.).  These include the so-called 
“Philadelphia chromosome-like” or “BCR-ABL1-like” ALL.19  There are also data supporting 
the safety and efficacy of the anti-CD20 antibody rituximab (when CD20 expression exceeds 
20% on the lymphoblasts), including when combined with hyperCVAD and TKI.18,20,21  
Therefore, TKIs and rituximab will also be incorporated into this study of DA-EPOCH to take 
advantage of their respective impacts on this disease. 
 
Several emerging biomarkers are poised to alter our approach to pre- and post-treatment 
assessments in ALL.  MRD is perhaps the most important prognostic maker in ALL.22  As 
polymerase chain reaction (PCR)-based HTS methods have evolved to identify disease-specific 
clonal sequences in the IGH or TCR genes, our ability to detect increasingly smaller amounts 
of residual disease has improved.23  Small retrospective studies have shown that MRD detection 
even to this depth may impact risk of subsequent relapse.23,24  Our hypothesis is that HTS-based 
MRD detection will identify a greater proportion of patients with persistent disease in either 
peripheral blood or bone marrow than our center’s world-class MFC, and these patients will be 
at greater risk of subsequent relapse.  This trial would be among the first to collect these data 
prospectively, allowing us to describe the results as well as the practical barriers of 
incorporating what many feel to be the future of MRD monitoring.     
 
Additionally, new insights into the genetic and genomic landscape of ALL have yielded a better 
understanding of different biologic subgroups of this disease.25,26  Chief among these to date is 
BCR-ABL1-like ALL, which is characterized by a similar gene expression profile to BCR-
ABL1/Ph+ positive ALL, but in the absence of the canonical t(9;22) that characterizes Ph+ ALL.  
The expression signature is caused by several genetic alterations, including translocations and 
mutations, which currently must be assayed by combination of FISH and PCR assays.  The 
precise genetic abnormality is important to characterize, as some are targets for tyrosine kinase 
inhibitors.19  The incidence in young adults is ≥25% of B-ALL, but little is known about its 
frequency in older adults.  Further, relatively little is known about similar genetic abnormalities 
in Ph+ ALL or in T-ALL.  We will thus use this study as a prospective platform to explore this 
previously-established subgroup but also novel genetic subtypes of ALL in adults. 
 
3.0 
DRUG INFORMATION 
 


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Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, TKIs (i.e., imatinib, 
dasatinib), rituximab, and G-CSF must be obtained from commercial sources.  Please refer to 
the current FDA-approved package inserts or the Physician Desk Reference for information 
about possible side effects and instructions for preparation, handling, dosing and storage of 
these drugs. All study medications will be administered unmodified and unblinded, as described 
in their respective, approved package inserts. 
 
4.0 
ELIGIBILITY CRITERIA 
 
4.1. 
Inclusion Criteria 
4.1.1. Patients must be ≥ 18 years of age 
4.1.2. Patients must have a confirmed diagnosis of either: 
 Acute lymphoblastic leukemia 
 Lymphoblastic lymphoma with detectable abnormal blasts in the 
bone marrow 
4.1.3. In the opinion of the treating investigator, patients must be an unsuitable 
candidate for a pediatric-inspired regimen, reasons for which may 
include (but not be limited to) older age (i.e., ≥ 40 years), 
practical/logistical barriers to or toxicity concerns from administration 
of a pediatric-inspired regimen, or Ph+ disease.  
4.1.4. Patients must have adequate organ function as defined by the following 
parameters: 
 Total bilirubin ≤ 2.0x institutional upper limit of normal (ULN; 
unless attributable to Gilbert’s disease or other causes of inherited 
indirect hyperbilirubinemia, at which point total bilirubin must be ≤ 
4.0x ULN) and AST (SGOT)/ALT (SGPT) ≤ 5.0x institutional ULN.  
(Note: Patients with liver test abnormalities attributable to hepatic 
involvement by ALL will be permitted if the total bilirubin is ≤ 5.0x 
ULN and ALT/AST are ≤ 8.0x ULN.) 
 Creatinine ≤ 2.0 mg/dL; however, patients with a creatinine > 2.0 
mg/dL but with a calculated creatinine clearance of > 30 ml/min, as 
measured by the Modification of Diet in Renal Disease (MDRD) 
equation, will be eligible. 
 As patients with ALL frequently have cytopenias, no hematologic 
parameters will be required for enrollment or to receive the first cycle 
of treatment.  However, adequate recovery of blood counts will be 
required to receive subsequent cycles, as defined below.) 
4.1.5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 
2.  (Performance status of 3 will be allowed if poor performance status 
is thought to be directly secondary to ALL.) 
4.1.6. Must agree to the use of effective contraception while on study 
treatment, unless they are highly unlikely to conceive [defined as (1) 
surgically sterilized, or (2) postmenopausal (i.e., a woman who is > 50 
years old or who has not had menses for ≥1 year), or (3) not 
heterosexually active for the duration of the study].   


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4.1.7. Ability to give informed consent and comply with the protocol.  
4.1.8. Anticipated survival of at least 3 months, independent of ALL. 
 
4.2 
Exclusion Criteria 
4.2.1 Patients with Burkitt lymphoma/leukemia. 
4.2.2 Patients must not have received any prior systemic therapy for ALL, 
except for the acute management of hyperleukocytosis or acute 
symptoms (e.g., corticosteroids, cytarabine, etc.)  
4.2.3 Patients with isolated extramedullary disease or with known 
parenchymal central nervous system (CNS) disease.   
4.2.4 Known hypersensitivity or intolerance to any of the agents under 
investigation. 
4.2.5 Other medical or psychiatric conditions that in the opinion of the 
investigator would preclude safe participation in the protocol. 
4.2.6 May not be pregnant or nursing. 
 
5.0 
REGISTRATION 
Subjects will be registered by the UW study coordinator and entered into the institutional 
clinical trials management system. A complete, signed, study consent and HIPAA consent are 
required for registration. 
 
6.0 
TREATMENT PLAN 
 
6.1 
For treatment or dose-modification related questions, please contact Dr. 
Cassaday at (206) 606-1202.  (MedCon may also be used to contact MDs at 206-
543-5300.) 
 
6.2 
Treatment will be administered in approximately 21-day cycles (± 3 days) up to 
8 total cycles.   
 
Table 1: Administration of DA-EPOCH.  Note: This schedule represents a general guideline.  
Adjustments in the schedule of ± 1 day will be permitted for administrative/scheduling 
flexibility.  
 
Drug 
Dose 
Route 
Days 
Duration 
Etoposide*
50 mg/m2/day
CIV 
1-4 
~96 hours 
Doxorubicin*
10 mg/m2/day
Vincristine 
0.4 mg/m2/day 
(uncapped)
Cyclophosphamide*
750 mg/m2
IV
5
~1 hour
Prednisone†
60 mg/m2/BID
PO
1-5
5 days
Rituximab#
375 mg/m2
IV
1 or 5
Per Guidelines
TKI: Imatinib^  
OR 
Dasatinib^
600 mg/day 
 
100 mg/day
PO 
1-14 
14 days 


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Filgrastim/TBO-
filgrastim§ 
OR 
Pegfilgrastim§
~5 mcg/kg/day 
 
 
6 mg
SQ 
 
 
SQ
Day 6, 7, or 8 
 
 
Day 6, 7, or 8
Daily until ANC > 
2000/L past nadir∫ 
Once 
Notes 
* Doses of these agents will subsequently increase or decrease by 20% based on the depth of 
hematologic nadir during the previous cycle, as discussed in Section 7.0. 
† Conversion to an IV equivalent dose of prednisone is allowable if deemed appropriate by the 
treating physician 
# Rituximab will be given to patients with CD20+ (defined either qualitatively [“positive,” 
“intermediate,” “high,” etc.] or quantitatively [≥ 20%]) disease.  The rate of infusion and 
administration of premedications will be according to standard guidelines. 
^ Delays in initiating this up to the start of Cycle 2 will be permitted to account for time 
needed to identify the predictive genetic lesion and/or obtain insurance approval for TKI.  
The choice of imatinib or dasatinib will be left to the discretion of the treating investigator. 
∫ If ANC > 1000/L by the start date of the next cycle and the patient is otherwise eligible to 
proceed with next cycle, daily G-CSF should be discontinued > 24 hours before initiation 
of next cycle.  For patients receiving daily G-CSF, individual doses may be held at the 
discretion of the treating physician (e.g., for high ANC).  
§ In the event that a patient starts daily G-CSF but is unable to continue until recovery (e.g., 
intolerant of daily injections, financial issues, etc.), a single dose of pegfilgrastim may be 
given as a substitute, provided it is given no later than Day 8 of the chemotherapy cycle. 
Abbreviations: ANC = absolute neutrophil count; CIV = continuous intravenous infusion; IV 
= intravenous; PO = by mouth; SQ = subcutaneous
6.3 CNS-Directed Therapy 
6.3.1 As CNS prophylaxis is a standard part of treating ALL, all patients should 
receive intra-CSF chemotherapy either via lumbar puncture (intrathecal [IT]) or 
Ommaya reservoir. 
6.3.2 For patients with active CNS disease at the time of enrollment or unable to 
undergo multiple lumbar punctures, placement of an Ommaya reservoir and 
consultation/co-management 
with 
Neuro-Oncology 
will 
be 
strongly 
encouraged. 
6.3.3. The details regarding the dosing and timing of intra-CSF chemotherapy 
will not be stipulated by this protocol. Instead, this will be left to the discretion 
of the treating investigator.  That said, the following is a recommendation, based 
on prior experience with DA-EPOCH in adults with Burkitt lymphoma12: 
6.3.3.1 If CNS negative at screening, methotrexate 12 mg IT or 6 mg 
intra-Ommaya on Days 1 and 5 of each chemotherapy cycle beginning 
with cycle 1 for 8 total doses. For patients with a high white blood cell 
count and/or LDH at diagnosis, consider increasing to 10 total doses. 
6.3.3.2 If CNS positive at screening, methotrexate 12 mg IT or 6 mg 
intra-Ommaya twice weekly for 4 weeks, then once weekly for 6 weeks, 
then once monthly for 4 months. 
 
6.4 Supportive Care 


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6.4.1    Nausea/vomiting prophylaxis: Antiemetic prophylaxis is recommended 
during administration of EPOCH chemotherapy on Days 1-5, at the 
discretion of the treating investigator.  Other antiemetics (e.g., 
lorazepam, promethazine, etc.) should be prescribed according to the 
discretion of the prescribing physician. 
 
6.4.2 Infection prophylaxis: Gram negative bacterial prophylaxis (e.g., 
levofloxacin) is highly recommended once a patient’s absolute neutrophil count 
(ANC) is < 1,000 cells/L.  Herpes virus prophylaxis (e.g., acyclovir) and 
Pneumocystis prophylaxis (e.g., trimethoprim-sulfamethoxazole) are also 
strongly recommended during protocol treatment. 
 
6.4.3 Tumor lysis syndrome (TLS) prophylaxis/treatment: TLS is a relatively 
common complication of treating ALL.  Active prevention and treatment of TLS 
with hypouricemic agents and/or aggressive IV hydration is highly 
recommended during the first cycle of study treatment.  The details of this will 
be left to the discretion of the treating investigator based on individual patient 
risk factors. 
 
6.4.4 Monitoring for consumptive coagulopathy/disseminated intravascular 
coagulation (DIC):  DIC can be observed during the treatment of ALL.  
Laboratory monitoring and management of abnormal laboratory parameters, 
including clotting factor replacement, will be left to the discretion of the treating 
physician based on individual patient risk factors. 
 
6.4.5 Miscellaneous: Treatment can be administered on either an inpatient or 
outpatient basis.  However, it is required that cycle 1 be administered while 
inpatient for the first 5-6 days, per the usual care with these drugs, to monitor 
for early toxicities. The remaining days of Cycle 1 may be administered either 
inpatient or outpatient, based on treating physician decision.  Concurrent IV 
hydration during the infusional portion of EPOCH should be strongly 
considered, particularly in patients who are not considered able to maintain 
sufficient oral hydration to generate adequate urine output; details of this will be 
deferred to treating physicians. 
 
6.5 Post-Protocol Therapy 
6.5.1 Allogeneic HCT: Patients that are deemed to be appropriate candidates 
may proceed to HCT at the discretion of the treating investigator.  However, 
patients should receive > 2 cycles of study therapy to adequately assess toxicity 
and response before being referred for HCT.  Following HCT, patients will be 
followed only for survival and relapse/progression of disease. 
 
6.5.2 Maintenance Therapy: For patients who are not referred for HCT, 
maintenance therapy will be highly encouraged, as is routinely offered to 
patients with ALL.  The specifics of maintenance therapy will be left to the 
discretion of the treating investigator, but ideally should include monthly cycles 


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of vincristine and a corticosteroid (plus TKI if disease characteristics at 
diagnosis predict sensitivity, such as Ph+, PDGFRA, PDGFRB, ABL2, etc.) and 
should be continued for approximately 2 years.  Maintenance therapy should 
only be considered after patients have received > 2 cycles of study therapy to 
adequately assess toxicity and response.  Following initiation of maintenance 
therapy, patients will be followed only for survival and relapse/progression of 
disease.  
 
6.5.3 Radiation Therapy: Patients may receive consolidative radiation 
therapy (e.g., mediastinal mass, testicular involvement, additional CNS-
directed therapy) at the discretion of the treating physician.  However, 
this should only be considered after patients have received > 2 cycles of 
study therapy to adequately assess toxicity and response.  Furthermore, 
study treatment with DA-EPOCH will NOT resume once radiation 
therapy has commenced. 
 
6.6 Patients will be assessed for response as specified in section 9.0.  Criteria for 
removal from protocol treatment are as follows: 
6.6.1   Treatment failure, which will be defined as any of the following: 
6.6.1.1 Documented progression/relapse of disease. 
6.6.1.2 Inadequate response, as defined by any of the criteria below: 
 Persistent morphologic disease after 2 cycles of treatment 
 Progressive/refractory disease by imaging as defined in 
section 9.3.5.2 
 MRD persistence after 6 cycles of treatment 
6.6.2   Any related grade 4 non-hematologic toxicity (excluding asymptomatic 
laboratory abnormalities). 
6.6.3   Development of any unacceptable toxicities unless prophylactic measures 
can be taken for subsequent cycles.   
6.6.4    Delay of treatment for more than 3 weeks due to adverse events.   
6.6.5 Completion of protocol treatment (maximum of 8 cycles or 
patient/investigator preference to refer for HCT or begin maintenance therapy).  
6.6.6    If none of the above criteria are explicitly met but a change in treatment 
is felt to be appropriate, patients may be removed from protocol treatment at the 
discretion of the treating physician.  
6.6.7    The patient may withdraw from the treatment at any time for any reason.   
 
7.0 
DOSAGE MODIFICATIONS 
 
Standard dose adjustments for etoposide, prednisone, vincristine, cyclophosphamide, 
doxorubicin, and TKIs may be made based on changes in hepatic and renal function 
during treatment.  The following parameters for retreatment and treatment modifications 
are suggested; however, these represent general guidelines and can be adjusted based 
on the discretion of the treating physician and PI.  
 
7.1 Modifications for Hematologic Toxicity   


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7.1.1 Subsequent cycles of therapy will not begin until the ANC is  1000/L 
and the platelet count is  50,000/L.  
7.1.1.1 Therapy will be delayed a maximum of 3 weeks until these values 
are achieved.  Patients who fail to recover adequate counts within 
3 weeks will be removed from study treatment.  
7.1.1.2 If the ANC and platelet counts have recovered to these thresholds 
and the investigator feels it beneficial, patients will be given the 
option to admit for the next cycle earlier than the 21-day mark, 
provided the start of the next cycle is ≥ 14 days since the start of 
the previous cycle and enough time is allowed to complete any 
necessary assessments of toxicity and/or response. 
7.1.2 Beginning with cycle 2, the doses of etoposide, doxorubicin, and 
cyclophosphamide will be adjusted based on the depth of the 
hematologic nadir from the preceding cycle.10   
7.1.2.1 If ANC nadir > 500/L, increase doses by 1 dose level above last 
cycle 
7.1.2.2 If ANC nadir < 500/L on 1 or 2 measurements, maintain the 
same dose level as last cycle 
7.1.2.3 If ANC nadir < 500/L on > 3 measurements, OR if platelet nadir 
< 25,000/L at any time, decrease doses by 1 dose level below 
last cycle.  
 
Table 2: Drug doses per dose levels 
Drugs 
-2 
-1 
1 
“starting 
dose”
2 
3 
4 
5 
6 
Doxorubicin 
(mg/m2/day)
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
Etoposide  
(mg/m2/day)
50 
50 
50 
60 
72 
86.4 103.7
124.4
Cyclophosphamide
(mg/m2/day)
480 
600 
750 
900
1080
1296
1555 
1866 
 
For the purposes of this protocol, this range of dose levels is not absolute.  
Decreasing below Dose Level -2 or above Dose Level 6 will be permitted 
based on the discretion of the treating physician.  Further, if the depth of 
the nadir would necessitate a decrease below Level -2 or above Level 6, 
these dose levels can be maintained if a patient is deriving benefit from 
this chemotherapy regimen.  This provides an alternative option beyond 
further adjustment outside this range or removal from the protocol. 
 
Adjustments will be made based on results of complete blood counts 
(CBCs) checked approximately 3 days apart, +/- 1 day for 
logistical/administrative flexibility.  If patients undergo more frequent 
laboratory monitoring for routine clinical purposes, only labs that meet 
this definition will be used for dose-adjustment purposes.  For example, 


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if a patient has a CBC checked daily, the results from only Monday and 
Thursday or Tuesday and Friday will be considered.  Dose re-escalation 
will be permitted if the above criteria are met following a dose reduction.  
 
In the event that a patient has significant cytopenias that are felt to be 
primarily due to marrow involvement by ALL, dose reductions for the 
subsequent cycle should NOT be performed unless there is a > 7-day 
delay to adequate hematologic recovery to begin the subsequent cycle or 
unless a dose reduction is felt to be medically appropriate at the 
discretion of the treating physician.  Based on the study design, this will 
primarily impact dosing for Cycle 2, as patients with extensive marrow 
involvement after 2 cycles of treatment will not likely be eligible to 
continue to Cycle 3 (see Section 6.6 above).  
 
 
7.2 
Modifications for Impaired Renal Function 
7.2.1 Serum creatinine must be < 2.0 mg/dl or an estimated or measured 
creatinine clearance must be > 30 ml/minute by the MDRD equation on 
Day 1 of each cycle (lab may be drawn up to 3 days prior to day 1).  If 
these values are not met, treatment may be delayed for up to 3 weeks.  If 
these values do not recover within 3 weeks, the patient will be removed 
from protocol treatment.   
 
7.3 
Modifications for Impaired Liver Function 
7.3.1 Total bilirubin must be < 2.0x ULN (or < 4.0x ULN for patients with 
Gilbert’s 
disease 
or 
other 
causes 
of 
inherited 
indirect 
hyperbilirubinemia), and ALT/AST < 5.0x ULN on Day 1 of each cycle 
(lab may be drawn up to 3 days prior to day 1). If these values are not 
met, treatment may be delayed for up to 3 weeks.  If these values do not 
recover within 3 weeks, the patient will be removed from protocol 
treatment.     
 
7.4 
Modifications for Rituximab-Associated Toxicities 
7.4.1 For patients who receive rituximab and experience grade 3 or higher 
infusion related reactions, subsequent doses of rituximab may be omitted 
at the discretion of the treating investigator 
7.4.2 Patients in whom this occurred may remain on study, receiving treatment 
without rituximab, provided other rules governing treatment delays, etc. 
are met. 
 
7.5 
Modifications for TKI-Associated Toxicities 
7.5.1 The following instructions represent recommendations for treating 
physicians; deviations from these instructions are permissible at the 
discretion of the treating investigator. 
7.5.2 If a patient receiving TKI experiences hematologic toxicity requiring 
dose reduction of etoposide, doxorubicin, and cyclophosphamide on 2 


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consecutive cycles, the dose of TKI for that patient can be reduced: if on 
imatinib, the dose can be reduced to 400 mg PO daily on Days 1-14 of 
all subsequent cycles; if on dasatinib, the dose can be reduced to 70 mg 
PO daily on Days 1-14.  If a dose reduction of etoposide, doxorubicin, 
and cyclophosphamide is required for a 3rd consecutive cycle, then the 
dose of TKI can be reduced again for all subsequent cycles: for imatinib, 
200 mg PO daily on Days 1-14; for dasatinib, 50 mg PO daily on Days 
1-14.  If this issue persists, contact the Study Chair to discuss further 
dose adjustments. 
7.5.3 For non-hematologic toxicity attributable to TKI (e.g., diarrhea, edema): 
7.5.3.1 If moderate (i.e., Grade 2) and unable to be controlled with 
additional supportive care, therapy may continue but with the 
dose reduced (imatinib 400 mg PO daily or dasatinib 70 mg PO 
daily on Days 1-14).  If symptoms do not improve to Grade 1 or 
less, further reduction can occur (imatinib 200 mg PO daily or 
dasatinib 50 mg PO daily on Days 1-14).  If the issue persists, 
contact the Study Chair to discuss further dose adjustments. 
7.5.3.2 If severe (i.e., Grade 3), TKI can be held until symptoms 
attributable to the event have improved and/or severity has 
resolved to Grade 1 or less, then resumed at a reduced dose 
(imatinib 400 mg PO daily or dasatinib 70 mg PO daily on Days 
1-14).  If the same Grade 3 event recurs at the reduced dose, TKI 
can again be held and resumed as above, but reduced further 
(imatinib 200 mg PO daily or dasatinib 50 mg daily on Days 1-
14).  If the issue persists, contact the Study Chair to discuss 
further dose adjustments. 
7.5.3.3 If life-threatening (i.e., Grade 4), TKI can be discontinued. 
7.5.4 Additionally, TKI may be discontinued at the discretion of the treating 
investigator in the event of any other clinically-significant adverse event 
attributable to this drug that is unlikely to recur or worsen with 
discontinuation of the drug  
7.5.5 For patients who experience toxicities as above that warrant dose-
reduction or discontinuation of the initial TKI used, they may be 
switched to an alternative TKI at the discretion of the treating 
investigator. 
7.5.6 Patients in whom TKI has been stopped may remain on study, receiving 
treatment without TKI, provided other rules governing treatment delays, 
etc. are met. 
 
7.6 
Modifications for Other Adverse Events 
7.6.1 Except for those drug-specific events described above, any other grade 
4 non-hematologic toxicity possibly, probably or definitely related to the 
drug combination (excluding asymptomatic laboratory abnormalities) as 
defined in Section 10 will result in the patient being removed from 
protocol treatment.  


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7.6.2 Patients should receive appropriate medical management for adverse 
events.  Treatment may be delayed up to 3 weeks for clinically 
significant grade 2 or 3 adverse events and unrelated grade 4 adverse 
events at the discretion of the treating physician.  If treatment is delayed 
for 3 weeks, the patient will be removed from protocol treatment. 
 
 
 
7.7 
Concomitant Therapy 
7.7.1 Prohibited Concomitant Therapy: The administration of concurrent 
medications intended to treat the primary cancer is not allowed during 
protocol therapy.  This includes any chemotherapy, investigational 
agent, biologic agent or other anti-tumor agents.  Concomitant radiation 
therapy is also prohibited, though it is permitted as post-protocol therapy 
as per Section 6.5.3.  CNS directed chemotherapy per section 6.3 is 
allowed. 
7.7.2 Patients should be strongly discouraged from taking any “alternative” or 
“naturopathic” medications since these agents may interact with study 
treatment.  Any use of these medications should be at the judgment of 
the treating investigator and should be documented in the patient’s 
medical record. 
 


9770 
 8.0 
STUDY CALENDAR (Table 3) 
 
Required Studies 
Pre-Entry1 
Within 3 Days 
Prior to Each 
Cycle7 
Monitoring Between 
Cycles: ≥ 2x/Week8 
Interim Response 
Assessment9 
Post 
Therapy11 
Follow-up12 
Physical 
 
 
 
 
 
 
History and Physical 
X* 
X7 
 
 
X11 
X12 
Performance Status 
X 
X7 
 
 
X11 
 
Clinical Disease Assessment 
X 
X7 
 
 
X11 
 
Adverse Event Assessment 
Adverse Events will be continuously monitored from time of consent to 30 days post discontinuation of all study 
treatment, or until the patient receives an alternative anti-cancer therapy, whichever date comes first. Treatment 
related toxicities last > 30 days will be followed until a satisfactory resolution has been achieved.  
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
CBC, Diff, platelets  
X7 
X7 
 
 
X11 
X12 
CBC, ANC, platelets 
 
 
X8 
 
 
 
Creatinine, electrolytes, 
glucose, total bilirubin, ALT, 
AST, alk phos, LDH, 
albumin
X 
X7 
 
 
X11 
 
Pregnancy test 
X2 
 
 
 
 
 
Bone Marrow Studies 
X3,4 
 
 
X3,9 
X3,11 
 
Radiology 
 
 
 
 
 
 
CT Chest, abdomen and 
pelvis; CT neck if cervical 
adenopathy present
X5 
 
 
X5,9 
X5,11 
 
Correlative Studies 
 
 
 
 
 
 
Peripheral Blood 
X6 
 
 
 
 
 
Bone Marrow 
X6 
 
 
X10 
X10,11 
 
 
 * Height will be assessed once at the pre-entry visit 
1 Pre-entry studies should be obtained ≤ 2 weeks from enrollment, unless otherwise indicated by protocol or provider. 


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2 Pregnancy test is only required in women, unless they are highly unlikely to conceive [defined as (1) surgically sterilized, or (2) postmenopausal (i.e., a woman 
who is > 50 years old or who has not had menses for ≥1 year), or (3) not heterosexually active]. 
3 Bone marrow studies should include unilateral aspirate or (if inaspirable) biopsy.  All bone marrow samples should be sent for morphology, flow cytometry, and 
(for Ph+ patients) BCR-ABL quantitative PCR; additional studies (e.g., based on known molecular or cytogenetic abnormalities) may be performed at the discretion 
of the treating investigator.  In cases where a genetic abnormality is identified that predicts response to TKIs, imatinib or dasatinib will be added at the discretion 
of the PI and/or treating physician based on the specific genetic lesion identified and the available scientific literature to support sensitivity to these TKIs.  These 
results should be obtained from clinically/commercially-available assays performed in a CAP/CLIA-certified laboratory.  In general, these assays utilize either 
FISH or RT-PCR based methods to identify specific gene fusions.  As the turnaround time can exceed one week, enrollment will not be dictated by these results; 
they will only be acted upon in the event that they become available after study treatment has commenced. 
4 Pre-entry bone marrow exam may be omitted in patients with circulating leukemia in the peripheral blood in adequate amounts to perform flow cytometry and 
routine cytogenetics. 
5 Imaging studies should be performed only if extramedullary disease is suspected. While CT-based imaging is preferred, other imaging studies will be leveraged 
if performed for clinical reasons and they provide sufficient description of disease status for response-assessment purposes. 
6 For patients with a sufficient amount of circulating leukemia, necessary samples for pre-entry correlative studies will be obtained via peripheral blood draw.  
Alternatively, we may attempt to obtain adequate material from the bone marrow studies performed for clinical purposes to establish the diagnosis (either freshly 
obtained or archived material). 
7 For Cycle 1 Day 1, pre-entry H&P, performance status, laboratory studies, disease assessment and adverse event assessment may be used (i.e., these do not 
need to be repeated within 3 days). CBC with differential should be performed within three days of subsequent cycle starts.  
8 These represent recommended laboratory monitoring guidelines between cycles of treatment for the purposes of dose adjustments of etoposide, doxorubicin, 
and cyclophosphamide (Section 7.1.2); more frequent monitoring should be considered on an individual patient basis at the discretion of the treating physician.  
Once hematologic recovery from the prior cycle of chemotherapy is observed, laboratory monitoring can be reduced in frequency at the discretion of the treating 
physician.    
9 Bone marrow response will be assessed prior to Cycle 2 and repeated (if necessary) no less often than after every 3 subsequent cycles until either a complete MRD 
response or progressive disease (PD) is observed, or study treatment is completed.  For patients with persistent disease by bone marrow morphology after Cycle 1, 
a bone marrow exam must be repeated after Cycle 2, as persistent morphologic disease after 2 cycles will lead to discontinuation of study therapy.  For patients 
who achieve a complete MRD response, subsequent interim-response bone marrow assessments should be performed again between 2-4 calendar months of 
documentation of complete MRD response to confirm persistence of response.  Patients with PD based on imaging or a rising peripheral lymphoblast count may 
forego a bone marrow exam.  For patients with measurable extramedullary disease on the “pre-entry” CT, an interim response CT is recommended at some point 
between the start of cycles 2 and 5, particularly for patients deemed by the treating physician to have a significant burden of extramedullary disease at enrollment.   
10 Concurrently with the bone marrow samples obtained for clinical response assessment (e.g., prior to Cycle 2, end of treatment, and an intermediate assessment 
[e.g., prior to Cycle 5]), material will be collected for HTS-based MRD detection. 
11 Post therapy studies should be done at least 3 weeks after the start of the patient’s last cycle of study therapy, unless otherwise specified.  Post-therapy CT may 
be omitted in patients without extramedullary disease at enrollment.  For patients with a significant burden of extramedullary disease by CT at enrollment, PET/CT 
is recommended to confirm CR. 
12 The timing of follow-up visits will not be explicitly stated.  A recommended schedule is every 3 months for 2 years then every 6 months for 3 years (total follow-
up time 5 years).  These visits may be performed by outside physicians, provided medical records documenting patient status are available.  Furthermore, the 
specific assessments performed at these visits will not be required by the protocol: history, physical examination, and CBC with diff and platelets are the minimum 
RECOMMENDED assessments; bone marrow studies are NOT REQUIRED.  For the purposes of data collection, patients will be followed for up to 5 years after 
enrollment for subsequent therapy, relapse, and survival. 


9770 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – bone marrow 
response will be defined by standard morphologic and MRD criteria for acute 
leukemia,27,28 while sites of extramedullary disease will be assessed according to the 
National Comprehensive Cancer Network (NCCN) response criteria.29 Response 
assessments via imaging will be taken from clinical reports.  While CT ± PET are the 
preferred imaging modalities, these same principles will be applied to results of other 
imaging studies used if the clinical situation warrants their use in specific circumstances. 
 
For the purposes of study eligibility, evaluable disease will be defined as positive bone 
marrow morphology or MRD assessment (as defined below). Patients will be 
considered evaluable for the primary objective of the study if they complete 4 cycles of 
study treatment, or one of the following occurs: (1) complete MRD response is 
documented prior to the end of cycle 4, (2) removal from protocol treatment prior to 
completing 4 cycles for any of the criteria listed in Section 6.6 EXCEPT 6.6.7, or (3) 
death from any cause prior to completing 4 cycles.  Patients who discontinue protocol 
treatment before completing 4 cycles for other reasons (e.g., unable to continue 
receiving treatment at our center, withdrawal of consent, etc.) will not be considered 
evaluable. Data will still be collected from these patients as available and as 
circumstances allow to address secondary study objectives.  
 
 
9.1  Bone Marrow Status: Bone marrow status is evaluated as follows:  
 
9.1.1 Positive by morphology: ≥ 5% blasts  
9.1.2 Negative by morphology: < 5% blasts  
9.1.2.1 MRD positive: negative by morphology but detectable disease 
using more sensitive assays (e.g., MFC) 
9.1.2.2 MRD negative: negative by morphology and MFC.  (Note: For 
patients who have genetic abnormalities that can be measured by 
quantitative PCR (e.g., BCR-ABL1), MRD status will be 
assessed by PCR if available, in addition to MFC. These results 
may be used clinically at the discretion of the treating physician, 
but they will not contribute to the primary endpoint of the study 
to allow for a more consistent assessment of MRD across all 
patients via MFC.) 
 
9.2  Measurability of Extramedullary Lesions: 
 
9.2.1 Measurable Disease: Lesions that can be accurately measured in two 
dimensions by CT, MRI, medical photograph (skin or oral lesion), plain 
x-ray, or other conventional technique and a greatest transverse diameter 
of 1.5 cm or greater; or palpable lesions with both diameters ≥ 2 cm.  
Note: CT scans remain the standard for evaluation of nodal disease. 


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9.2.2 Non-measurable Disease: All other lesions including unidimensional 
lesions, lesions too small to be considered measurable, pleural or 
pericardial effusion, ascites, bone disease, lymphangitis, pneumonitis, 
abdominal masses not confirmed or followed by imaging techniques, or 
disease documented by indirect evidence only (e.g., lab values).  
 
9.3 
Objective Disease Status:  Objective status is to be recorded at each evaluation. 
As patients may have evaluable disease by bone marrow evaluation, imaging, or 
both, response definitions for bone marrow will supersede those for 
extramedullary disease unless imaging demonstrates progressive/refractory 
disease, as defined below. 
 
9.3.1 Complete Response (CR):   
9.3.1.1 Bone Marrow: < 5% blasts by morphology, ANC > 1000/L, 
platelets > 100,000/L 
9.3.1.1.1 CR with incomplete hematologic recovery (CRi): < 
5% blasts by morphology but either ANC < 1000/L 
or platelets < 100,000/L 
9.3.1.1.2 Complete MRD response: morphologic CR/CRi and 
no detectable disease by MFC 
9.3.1.1.3 MRD 
persistence: 
morphologic 
CR/CRi 
but 
detectable disease using MFC 
9.3.1.2 Imaging: Complete resolution of lymphomatous enlargement.  
For patients with a previous positive PET scan, a post-treatment 
residual mass of any size is considered a CR as long as it is PET 
negative.  
 
9.3.2 Partial Response (PR):   
9.3.2.1 Bone Marrow: Decrease of at least 50% in the proportion of 
blasts by morphology to 5-25% of the total marrow cellularity, 
ANC > 1000/L, platelets > 100,000/L 
9.3.2.2 Imaging: >50% decrease in the sum of the product of the greatest 
perpendicular diameters (SPD) of the lymphomatous enlargement.  For 
patients with a previous positive PET scan, post-treatment PET must 
be positive in at least one previously involved site.  
 
9.3.3 Stable disease (SD):  Does not qualify for CR, PR, or 
Relapsed/Progressive Disease.  All disease must be assessed using the 
same technique as baseline.  
 
9.3.4 Relapsed Disease:   
9.3.4.1 Bone Marrow: Re-appearance of > 5% blasts by morphology 
after having previously achieved a CR. 
9.3.4.1.1 MRD reappearance: Conversion to MRD positivity 
after having previously met the criteria to be defined 
as MRD negative. 


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9.3.4.2 Imaging: Recurrence of the lymphomatous enlargement after 
achieving CR.  For patients with a previous positive PET scan, 
post-treatment PET must be positive in at least one previously 
involved site. 
 
9.3.5 Progressive/Refractory Disease (PD):  
9.3.5.1 Bone Marrow: Survival > 7 days after completion of study 
treatment with disease present by morphology in the most recent 
bone marrow evaluation. 
9.3.5.2 Imaging: >25% increase in the SPD of the lymphomatous 
enlargement.  For patients with a previous positive PET scan, 
post-treatment PET must be positive in at least one previously 
involved site.  
9.3.6 Assessment inadequate, objective status unknown: Progression has not 
been documented and one or more target lesions or other sites of disease 
have not been assessed or inconsistent methods of assessment were used. 
 
10.0 STATISTICAL CONSIDERATIONS 
 
10.1 Primary Objective: To examine the potential efficacy of DA-EPOCH as front-
line therapy for adults with ALL   
 
Efficacy will be examined by evaluating the response rates in  two subgroups, 
independent of each other: Ph+ patients and Ph- patients.  As our eligibility 
criteria will relatively enrich for Ph+ patients, enrollment into this subgroup is 
expected to be higher.  We will attempt to take advantage of this by 
implementing a statistical design to more precisely estimate the response rate in 
Ph+ ALL.  This will also help place our results into a clearer context of other, 
lower-intensity strategies for Ph+ ALL which have emerged.30,31  Alternatively, 
the design used for the Ph- subgroup will be less statistically rigorous, intended 
more to ensure that DA-EPOCH is not clearly inferior to a historical standard.   
 
If either group closes due to the efficacy stopping rules outlined below (see 
sections 10.1.1 and 10.1.2), the other group may continue to enroll patients, 
provided it has not met its protocol-defined efficacy stopping rule.  The stopping 
rules for safety (see section 10.4.2) will be applied to both Ph+ and Ph- 
subgroups in aggregate.  Patients that lack t(9;22) but receive a TKI for BCR-
ABL1-like ALL will be evaluated in the Ph- group; it is not known if TKIs 
augment the efficacy of chemotherapy to the same degree in this subgroup of 
patients.19   
 
10.1.1 Efficacy in Ph+ Patients 
For newly-diagnosed adults with ALL, the probability of achieving a complete 
MRD response by MFC within 90 days of initiation of hyperCVAD at our 
institution is 50%.32  We will consider DA-EPOCH successful in Ph+ patients  
if we observe a complete MRD response rate by MFC after 4 cycles (i.e., 


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approximately 90 days) of at least 70%.  A Simon two-stage minimax design 
will be used to assess the potential efficacy of this treatment.  After 15 patients 
have been enrolled, if 7 or fewer responses (47% or less) have been observed 
the study will be placed on an enrollment hold to review potential corrective 
actions for lack of sufficient efficacy.  The probability of this occurrence is 0.50 
if the true response rate is 50%.  If 8 or more responses are seen among the first 
15 patients, enrollment will continue until 28 patients, at which point the study 
will be considered to be potentially efficacious if at least 18 responses are seen 
among the 28 patients (64% or higher estimated response rate).  The expected 
number of patients to be enrolled under this design and these assumptions is 
21.5, and the type I error rate is 0.09 and the power is 80%.   
 
10.1.2 Efficacy in Ph- Patients 
The historical rate of complete MRD response by MFC within 90 days (i.e., after 
4 cycles) for Ph- patients receiving hyperCVAD is 59%.32  For Ph- patients who 
receive DA-EPOCH, we will calculate the rate of complete MRD responses after 
the first 10 patients, then again in cohorts of 5 patients.  We will determine a 
90% confidence interval of the response rate for each of these cohorts.  As long 
as the upper bound of this confidence interval is not < 59% (which would 
indicate a high probability that DA-EPOCH is in fact less effective than 
hyperCVAD), we will continue to enroll up to a maximum of 25 patients.  This 
would mean we would need to see complete MRD responses at the following 
rates to continue enrollment into this cohort: ≥ 4 of the first 10 patients, ≥ 6 of 
the first 15 patients, and ≥ 9 of the first 20 patients. 
 
10.2   Secondary Objectives 
Reporting of secondary objectives will be primarily descriptive, with comparisons 
using established statistical methods.  Binary outcomes will be estimated with 
proportions and associated confidence intervals, time-to-event outcomes will be 
estimated using Kaplan-Meier or cumulative incidence estimates, as appropriate.  
Although the sample size will be small, outcomes will be compared between those 
with and those without MRD.  The chi-square test (or Fisher’s exact test) will be 
used for binary outcomes; the log-rank test will be used for time-to-event 
outcomes.  More emphasis will be placed on the magnitude of differences rather 
than the resultant p-values from these comparisons, and the estimated effects will 
be used in the design of subsequent studies.  
 
  
10.2.1 To evaluate the safety and feasibility of this regimen 
 
To quantify this, the following events will be noted:  
 Any non-hematologic grade 3 or higher NCI CTCAE adverse event 
(excluding asymptomatic grade 3 laboratory abnormalities) that is 
possibly, probably or definitely related to the drug combination until 
30 days after discontinuation of all study treatment or the start of an 
alternative therapy.   


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 Any patients that do not complete one full cycle of therapy due to 
toxicity from the treatment.  Patients choosing to stop study 
medication for adverse events that are not considered medically 
significant by the Investigator will not be included.  
 Any serious adverse event that is possibly, probably or definitely 
related to the drug combination, but does not meet the above criteria. 
 
10.2.2 To evaluate the PFS and OS of patients after receiving DA-EPOCH for 
newly-diagnosed ALL 
 
10.3   Exploratory Objectives 
Reporting of exploratory objectives will be primarily descriptive, with 
comparisons using established statistical methods.  Binary outcomes will be 
estimated with proportions and associated confidence intervals, time-to-event 
outcomes will be estimated using Kaplan-Meier or cumulative incidence 
estimates, as appropriate.  Although the sample size will be small, outcomes will 
be compared between those with and those without MRD.  The chi-square test (or 
Fisher’s exact test) will be used for binary outcomes; the log-rank test will be used 
for time-to-event outcomes.  More emphasis will be placed on the magnitude of 
differences rather than the resultant p-values from these comparisons, and the 
estimated effects will be used in the design of subsequent studies.  
 
10.3.1 To explore for novel genetic/genomic biomarkers of prognosis and 
response to treatment in adults with ALL 
10.3.2 To compare outcomes predicted by the presence or absence of MRD as 
determined by either MFC or HTS 
 
 
 
10.4 Anticipated accrual: Based on the design above, we will enroll up to 53 patients.  
Patients who enroll and receive study treatment but do not meet the definition of 
“evaluable for the primary objective” as outlined in Section 9.0 will not count 
toward the enrollment goals and will be replaced. 
   
 
10.5 Stopping Rules: Patients will not be enrolled until adequate follow-up is available 
to satisfy these rules.  The Principal Investigator is responsible for reviewing 
patient data in real-time to ensure adherence to these stopping rules. 
 
10.5.1 To limit the number of patients exposed to a potentially-ineffective 
therapy, the study will be placed on an enrollment hold to review potential 
corrective actions for futility as detailed above.  Moreover, the study will pause 
prior to enrolling 15 patients (the first stage of the minimax design) if 8 
responses are not possible among the first 15 patients (e.g., if no responses occur 
within the first 8 patients). 


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10.5.1.1 For those who do not achieve a complete MRD response with 
DA-EPOCH, it is worth emphasizing that outcomes incorporating HCT 
after complete MRD response following subsequent/salvage therapy are 
comparable to HCT while in first complete MRD remission for ALL.33  
For those subjects who do not achieve a complete MRD response to DA-
EPOCH, second-line therapy (with hyperCVAD or others) shall be given 
with this goal in mind. 
10.5.2 The study will be placed on an enrollment hold to review potential 
corrective actions for safety using 2 different rules, based on recent published 
experience with hyperCVAD.15,18  These will be assessed in cohorts of 5 
patients: 
10.5.2.1The lower bound of the 80% confidence interval of the incidence 
of grade 3 or higher non-hematologic toxicity occurring during the first 
2 cycles of treatment possibly, probably or definitely related to the drug 
combination (excluding neutropenic fever and asymptomatic Grade 3 
laboratory abnormalities) exceeds 60%.  Thus, this rule would be enacted 
if 5 of the first 5 patients, ≥ 8 of the first 10 patients, ≥ 12 of the first 15 
patients, ≥ 15 of the first 20 patients, ≥ 18 of the first 25 patients, ≥ 22 of 
the first 30 patients, ≥ 25 of the first 35 patients, ≥ 28 of the first 40 
patients, ≥ 31 of the first 45 patients, or ≥ 35 of the first 50 patients 
experience such an event.   
10.5.2.2. The lower bound of the 80% confidence interval of the 
incidence of treatment-related death exceeds 10%.  Thus, this rule would 
be enacted if ≥ 2 of the first 5 patients, ≥ 3 of the first 10 patients, ≥ 3 of 
the first 15 patients, ≥ 4 of the first 20 patients, ≥ 5 of the first 25 patients, 
≥ 6 of the first 30 patients, ≥ 7 of the first 35 patients, ≥ 8 of the first 40 
patients, ≥ 8 of the first 45 patients, or ≥ 9 of the first 50 patients 
experience such an event 
 
 
10.6 Estimated distribution of study population by gender and race and ethnicity (Table 
4): 
 
 
Ethnic Category 
Females
Males
American Indian/Alaska Native
1
Asian
2
1
Native Hawaiian or Other Pacific Islander
Black or African American
1
2
White
16
16
Hispanic or Latino
7
7
More than one race
Unknown or not reported 
 
 
Racial Categories: Total of all subjects 
26
27
 
 
11.0  STUDY MONITORING AND REPORTING PROCEDURES 
 


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11.1 
Adverse Event Reporting  
 
AEs of Grade 3 and above, and Serious Adverse Events (SAEs) occurring at 
any grade will be monitored and recorded in study-specific case report forms 
(CRFs) from the time the patient signs consent through 30 days following 
discontinuation of study treatment, or until the patient receives an alternative 
anti-cancer therapy, whichever date comes first. Treatment related toxicities 
will be followed until a satisfactory resolution has been achieved.  AEs 
related to biopsies that are done solely for research study screening purposes 
will be monitored, recorded, and reported according to the same standards, 
with the exception that assessment of study drug attribution will be 
excluded from reporting criteria.  
 
The NCI Common Terminology Criteria for Adverse Events v5.0 (CTCAE) will 
be used to classify and grade toxicities.  The CTC can be found on the Cancer 
Therapy Evaluation Program (CTEP) homepage at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CT
CAE_v5_Quick_Reference_8.5x11.pdf. 
 
11.2  Definitions and descriptions of terms used in adverse event reporting. 
 
Adverse Event (AE) 
An AE is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be 
related to the study. 
 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they 
induce clinical signs or symptoms or require treatment or further diagnostic 
tests. 
 
Serious Adverse Event (SAE) or Adverse Drug Reaction (ADR) 
A Serious Adverse Event or Adverse Drug Reaction means any AE/ADR 
occurring at any dose that results in: 
 
 Death; 
 
 A life-threatening AE/ADR (i.e., the patient/subject was, in the view of 
the initial reporter/investigators, at immediate risk of death from the AE 
as it occurred.  It does not refer to an AE that hypothetically might have 
caused death if more severe); 
. 
 Inpatient hospitalization or prolongation of existing hospitalization 
(Hospitalization itself will not be considered a serious adverse event if 
required for complications of ALL or comorbid conditions. 


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Hospitalization will be considered an SAE if it fulfills the criteria for a 
serious and unexpected adverse event as otherwise described); 
 
 A persistent or significant disability or incapacity (disability here means 
that there is a substantial disruption of a person's ability to conduct 
normal life functions); 
 
 A congenital anomaly/birth defect; 
 
 An important medical event (i.e., AEs/ADRs that might not be 
immediately life-threatening, or result in death or hospitalization might 
be considered serious when, based upon appropriate medical and 
scientific judgment, they might jeopardize the patient/subject or might 
require medical or surgical intervention to prevent one of the other 
serious outcomes listed above); 
 
 Any suspected transmission via a medicinal product of an infectious 
agent. 
 
Investigator shall use his/her judgment to determine the relationship between the 
Serious Adverse Drug Experience and the Study Drug. 
 
 
Grade 
Grade is defined as the severity of the adverse event.  The CTCAE Version 5.0 
must be used to determine the grade of the adverse event. If toxicity is not listed 
in the CTCAE use the following general criteria for grading.   
 
0 – No adverse event or within normal limits 
1 – Mild adverse event 
2 – Moderate adverse event 
3 – Severe adverse event 
4 – Life-threatening or disabling adverse event 
5 – Fatal adverse event 
 
Attribution 
Attribution is defined as the determination of whether an adverse event is related 
to a medical treatment or procedure.  Attribution categories are as follows: 
 
 Unrelated The adverse event is doubtfully or clearly NOT related to therapy 
 Related 
The adverse event is possibly, probably, or definitely related to 
therapy 
 
Suspected Adverse Reaction  
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event. 


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Unexpected Adverse Event 
An unexpected adverse event is any adverse event for which the specificity or 
severity is not listed in the package insert or the specificity or severity of which 
is not consistent with the package insert.   
 
11.3 
Routine Reporting 
 
Grade ≥3 adverse events other than hematologic toxicities will be recorded, 
graded, and reported as appropriate. AEs will be collected from the time the 
patient signs consent until 30 days after discontinuation of all study treatment, 
or until the patient receives an alternative anti-cancer therapy, whichever date 
comes first. AEs that do not meet the requirement for expedited reporting will 
be reported to the IRB as part of the annual renewal of the protocol. 
Myelosuppression and associated complications are expected events during 
leukemia therapy; therefore, myelosuppression and associated simple 
complications such as fever, infections, bleeding, lab abnormalities, and related 
hospitalizations will not be reported as individual AE but will be summarized in 
the annual report to the IRB as needed.  
11.4  Expedited Reporting  
 
In accordance with FHCC/UW Cancer Consortium IRB policy, all adverse 
events (AEs; whether occurring on-site or off-site), which in the opinion of the 
principal investigator (PI)  are (1) unexpected, and (2) related or possibly related 
to the research, and (3) serious or suggests that the research places research 
participants or others at a greater risk of physical or psychological harm than 
was previously known or recognized, will be submitted to the IRB within ten 
(10) calendar days of learning of the problem. Both the “Expedited Reporting 
Form for Unanticipated Problems or Noncompliance” and the “Adverse Event 
Reporting Form”, or equivalent forms, will be completed for this reporting.  
 
 
11.5 
Data Safety and Monitoring Plan 
 
The Principal Investigator will carry out ongoing trial oversight and will meet 
frequently with the study team to review recently acquired data and adverse 
events. The data recorded within the research charts and protocol database is 
compared with the actual data that is available from the medical record and/or 
clinical histories. All investigators on the protocol have received formal 
training in the ethical conduct of human research. The Principal Investigator 
will receive monitoring support as described below. Institutional support of 
trial monitoring will be in accordance with the FHCC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. 
Under the provisions of this plan, FHCC Clinical Research Support 
coordinates data and compliance monitoring conducted by consultants, 
contract research organizations, or FHCC employees unaffiliated with the 
conduct of the study. Independent monitoring visits occur at specified intervals 


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determined by the assessed risk level of the study and the findings of previous 
visits per the institutional DSMP. In addition, protocols are reviewed at least 
annually and as needed by the Consortium Data and Safety Monitoring 
Committee (DSMC), FHCC Scientific Review Committee (SRC) and the 
FHCC/University of Washington Cancer Consortium Institutional Review 
Board (IRB). The review committees evaluate accrual, adverse events, 
stopping rules, and adherence to the applicable data and safety monitoring plan 
for studies actively enrolling or treating patients. The IRB reviews the study 
progress and safety information to assess continued acceptability of the risk-
benefit ratio for human subjects. Approval of committees as applicable is 
necessary to continue the study. The trial will comply with the standard 
guidelines set forth by these regulatory committees and other institutional, state 
and federal guidelines. 
 
 
11.6 
Required Records and Materials 
 
 Under the supervision of the investigators, research staff will maintain case 
report forms and secured databases on the relevant clinical and laboratory 
data.   Records maintained in investigators' offices will be secured with access 
limited to study personnel.  Authorization for access to medical records will 
be obtained from all patients in accordance with provisions of the Health 
Insurance Portability and Accountability Act (HIPAA). 
 
Original signed informed consent forms will be kept within the secured study 
team office, access is limited to study personnel. A copy of the signed informed 
consent form is given to the participant.  Data will be collected on patient 
characteristics, disease characteristics, protocol therapy, response to treatment, 
adverse events and follow-up for relapse and survival.  Copies of the patient’s 
medical record including history and physical exams, documentation of protocol 
therapy, labs, scans, x-rays, hospitalizations, operative reports, pathology 
reports etc. are required.  
 
 
 
 
  
 
12.0 
ELEMENTS OF INFORMED CONSENT 
 
All Institutional, NCI, State and Federal regulations concerning informed consent and peer 
judgment will be fulfilled.  Written consent will be obtained from all patients entering the study. 
 
 
 
13.0 
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