Etoposide, Prednisone, Vincristine Sulfate, Cyclophosphamide, and Doxorubicin in Treating Patients With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT03023046
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 54
• Location: 1
• Arm: 1
• Actual Duration (Months): 62.2
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia; Lymphoblastic Lymphoma	Drug: Cyclophosphamide; Drug: Dasatinib; Drug: Doxorubicin; Drug: Etoposide; Drug: Imatinib Mesylate; Other: Laboratory Biomarker Analysis; Drug: Prednisone; Biological: Rituximab; Drug: Vincristine Sulfate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Feb 23, 2017
• Actual Primary Completion Date: May 20, 2021
• Actual Study Completion Date: May 1, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy) 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.

Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Cyclophosphamide Monohydrate ; Drug: Dasatinib; Given PO; Other Names: BMS-354825 Sprycel 5-Thiazolecarboxamide Dasatinib Hydrate Dasatinib Monohydrate ; Drug: Doxorubicin; Given IV; Other Names: Adriablastin Hydroxyl Daunorubicin Hydroxyldaunorubicin ; Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside EPEG Lastet Toposar Vepesid VP 16-213 VP-16 VP-16-213 ; Drug: Imatinib Mesylate; Given PO; Other Names: CGP 57148 CGP57148B Gleevec Glivec STI 571 STI-571 STI571 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Prednisone; Given PO; Other Names: .delta.1-Cortisone 1, 2-Dehydrocortisone Adasone Cortancyl Dacortin DeCortin Decortisyl Decorton Delta 1-Cortisone Delta-Dome Deltacortene Deltacortisone Deltadehydrocortisone Deltasone Deltison Deltra Econosone Lisacort Meprosona-F Metacortandracin Meticorten Ofisolona Orasone Panafcort Panasol-S Paracort PRED Predicor Predicorten Prednicen-M Prednicort Prednidib Prednilonga Predniment Prednisonum Prednitone Promifen Servisone SK-Prednisone ; Biological: Rituximab; Given IV; Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Rituxan Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar IBI301 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 RTXM83 Rituximab ABBS ; Drug: Vincristine Sulfate; Given IV; Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Morphological Complete Response Rate [Within 4 cycles of study therapy]

   Morphological complete remission (CR) was determined by bone marrow aspirate morphology and defined as <5% blasts by morphology, absolute neutrophil count >1000/uL, and platelet count >100,000/uL.

2. Number of Participants With Complete Measurable Residual Disease (MRD) Response Rate [Within 4 cycles of study therapy]

   Response was determined by having no detectable disease by multiparameter flow cytometry (MFC-). For Ph+ subjects, complete molecular response (CMR) by BCR-ABL RT-PCR was assigned when MFC was undetectable. When no measurable residual disease was detected by MFC (MFC-) per EuroFlow criteria, high-throughput sequencing-based MRD testing (HTS; ClonoSEQ) was performed.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [Within 28 days of the last dose of the study drugs]

   Grade 1 or higher non-hematologic adverse events will be assessed by Common Terminology Criteria for Adverse Events version 5.0.

2. Overall Survival [Up to 2 years]

   Alive at 2 years after enrollment

3. Event-free Survival [Up to 2 years]

   Events were defined as any of the following: (1) unable to achieve either morphologic complete remission (CR) or MRD- by MFC, (2) relapse after CR, (3) MRD recurrence after achieving MRD-, or (4) death from any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a confirmed diagnosis of either:

• Acute lymphoblastic leukemia

• Lymphoblastic lymphoma with detectable abnormal blasts in the bone marrow

• 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

• Total bilirubin =< 2.0 x 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 =< 4.0 x ULN)

• Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5.0 x institutional ULN; (Note: patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is =< 5.0 x ULN and ALT/AST are =< 8.0 x 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)

• 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)

• 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)

• Ability to give informed consent and comply with the protocol

• Anticipated survival of at least 3 months, independent of ALL

Exclusion Criteria:

• Patients with Burkitt lymphoma/leukemia

• 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.)

• Patients with isolated extramedullary disease or with known parenchymal central nervous system (CNS) disease

• Known hypersensitivity or intolerance to any of the agents under investigation

• Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol

• May not be pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ryan D. Cassaday, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 17, 2022

More Information

Publications

None provided.

• Responsible Party: Ryan D. Cassaday, Associate Professor, Division of Hematology, University of Washington
• ClinicalTrials.gov Identifier: NCT03023046
• Other Study ID Numbers: 9770; NCI-2016-02050; 9770; P30CA015704; RG1016012
• First Posted: Jan 18, 2017
• Last Update Posted: Jul 13, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Prednisone; Cortisone; Cyclophosphamide; Rituximab; Doxorubicin; Liposomal doxorubicin; Etoposide; Vincristine; Etoposide phosphate; Imatinib Mesylate; Daunorubicin; Dasatinib; Podophyllotoxin; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Treatment (Chemotherapy)
Arm/Group Description	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. Cyclophosphamide: Given IV Dasatinib: Given PO Doxorubicin: Given IV Etoposide: Given IV Imatinib Mesylate: Given PO Laboratory Biomarker Analysis: Correlative studies Prednisone: Given PO Rituximab: Given IV Vincristine Sulfate: Given IV
Period Title: Overall Study
STARTED	54
COMPLETED	53
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy)
Arm/Group Description	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. Cyclophosphamide: Given IV Dasatinib: Given PO Doxorubicin: Given IV Etoposide: Given IV Imatinib Mesylate: Given PO Laboratory Biomarker Analysis: Correlative studies Prednisone: Given PO Rituximab: Given IV Vincristine Sulfate: Given IV
Overall Participants	53
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	49
Sex: Female, Male (Count of Participants)
Female	28 52.8%
Male	25 47.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 11.3%
Not Hispanic or Latino	47 88.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 5.7%
Asian	2 3.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 3.8%
White	46 86.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
High white blood cell count (Count of Participants)
Count of Participants [Participants]	11 20.8%
Lineage (Count of Participants)
B-cell	49 92.5%
T-cell	4 7.5%
Philadelphia chromosome (Count of Participants)
Philadelphia chromosome: positive	28 52.8%
Philadelphia chromosome: negative	25 47.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Morphological Complete Response Rate
Description	Morphological complete remission (CR) was determined by bone marrow aspirate morphology and defined as <5% blasts by morphology, absolute neutrophil count >1000/uL, and platelet count >100,000/uL.
Time Frame	Within 4 cycles of study therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ph+ Subjects	Ph- Subjects
Arm/Group Description	Subjects who have Philadelphia chromosome mutation	Subjects who do not have Philadelphia chromosome mutation
Measure Participants	28	25
Count of Participants [Participants]	27 50.9%	20 NaN

2. Primary Outcome

Title	Number of Participants With Complete Measurable Residual Disease (MRD) Response Rate
Description	Response was determined by having no detectable disease by multiparameter flow cytometry (MFC-). For Ph+ subjects, complete molecular response (CMR) by BCR-ABL RT-PCR was assigned when MFC was undetectable. When no measurable residual disease was detected by MFC (MFC-) per EuroFlow criteria, high-throughput sequencing-based MRD testing (HTS; ClonoSEQ) was performed.
Time Frame	Within 4 cycles of study therapy

Outcome Measure Data

Analysis Population Description

HTS- percentages were calculated after excluding patients (Ph+, n = 4; Ph-, n = 3) that were unable to have HTS testing performed for technical reasons.

Arm/Group Title	Ph+ Subjects	Ph- Subjects
Arm/Group Description	Subjects who have Philadelphia chromosome mutation	Subjects who do not have Philadelphia chromosome mutation
Measure Participants	28	25
Achieve within 4 cycles	20 37.7%	16 NaN
Not achieved within 4 cycles	8 15.1%	9 NaN
Achieve within 4 cycles	11 20.8%
Not achieved within 4 cycles	17 32.1%
Achieve within 4 cycles	8 15.1%	6 NaN
Not achieved within 4 cycles	16 30.2%	16 NaN

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Grade 1 or higher non-hematologic adverse events will be assessed by Common Terminology Criteria for Adverse Events version 5.0.
Time Frame	Within 28 days of the last dose of the study drugs

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy)
Arm/Group Description	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. Cyclophosphamide: Given IV Dasatinib: Given PO Doxorubicin: Given IV Etoposide: Given IV Imatinib Mesylate: Given PO Laboratory Biomarker Analysis: Correlative studies Prednisone: Given PO Rituximab: Given IV Vincristine Sulfate: Given IV
Measure Participants	53
Count of Participants [Participants]	44 83%

4. Secondary Outcome

Title	Overall Survival
Description	Alive at 2 years after enrollment
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy)
Arm/Group Description	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. Cyclophosphamide: Given IV Dasatinib: Given PO Doxorubicin: Given IV Etoposide: Given IV Imatinib Mesylate: Given PO Laboratory Biomarker Analysis: Correlative studies Prednisone: Given PO Rituximab: Given IV Vincristine Sulfate: Given IV
Measure Participants	53
Number [Percentage of Participants]	70 132.1%

5. Secondary Outcome

Title	Event-free Survival
Description	Events were defined as any of the following: (1) unable to achieve either morphologic complete remission (CR) or MRD- by MFC, (2) relapse after CR, (3) MRD recurrence after achieving MRD-, or (4) death from any cause.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy)
Arm/Group Description	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. Cyclophosphamide: Given IV Dasatinib: Given PO Doxorubicin: Given IV Etoposide: Given IV Imatinib Mesylate: Given PO Laboratory Biomarker Analysis: Correlative studies Prednisone: Given PO Rituximab: Given IV Vincristine Sulfate: Given IV
Measure Participants	53
Number [Percentage of Participants]	32 60.4%

Adverse Events

Time Frame	From the time patient signs consent through 30 days following discontinuation of study treatment, or until patient receives alternative anti-cancer therapy, whichever date comes first, up to 2 years.
Arm/Group Title	Treatment (Chemotherapy)
Arm/Group Description	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. Cyclophosphamide: Given IV Dasatinib: Given PO Doxorubicin: Given IV Etoposide: Given IV Imatinib Mesylate: Given PO Laboratory Biomarker Analysis: Correlative studies Prednisone: Given PO Rituximab: Given IV Vincristine Sulfate: Given IV
All Cause Mortality
	Treatment (Chemotherapy)
	Affected / at Risk (%)	# Events
Total	18/53 (34%)
Serious Adverse Events
	Treatment (Chemotherapy)
	Affected / at Risk (%)	# Events
Total	32/53 (60.4%)
Blood and lymphatic system disorders
Febrile neutropenia	14/53 (26.4%)	19
Cardiac disorders
Atrial fibrillation	1/53 (1.9%)	2
Myocardial infarction	1/53 (1.9%)	1
Sinus bradycardia	1/53 (1.9%)	1
Gastrointestinal disorders
Enterocolitis	2/53 (3.8%)	2
Lower gastrointestinal hemorrhage	1/53 (1.9%)	1
Mucositis oral	2/53 (3.8%)	2
Small intestinal obstruction	1/53 (1.9%)	1
Typhlitis	1/53 (1.9%)	1
Upper gastrointestinal hemorrhage	2/53 (3.8%)	2
Gastric hemorrhage	1/53 (1.9%)	1
General disorders
Multi-organ failure	1/53 (1.9%)	1
Infections and infestations
Endophthalmitis	1/53 (1.9%)	1
Fungemia	1/53 (1.9%)	1
Kidney infection	1/53 (1.9%)	1
Sepsis	9/53 (17%)	9
Investigations
Fibrinogen decreased	1/53 (1.9%)	1
Nervous system disorders
Intracranial hemorrhage	2/53 (3.8%)	2
Peripheral motor neuropathy	1/53 (1.9%)	1
Psychiatric disorders
Delirium	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/53 (1.9%)	1
Hypoxia	1/53 (1.9%)	1
Vascular disorders
Hypotension	1/53 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy)
	Affected / at Risk (%)	# Events
Total	14/53 (26.4%)
Blood and lymphatic system disorders
Febrile neutropenia	3/53 (5.7%)	3
Gastrointestinal disorders
Abdominal pain	1/53 (1.9%)	1
Diarrhea	1/53 (1.9%)	1
Mucositis oral	5/53 (9.4%)	6
General disorders
Edema limbs	1/53 (1.9%)	1
Infections and infestations
Sepsis	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/53 (1.9%)	1
Vascular disorders
Hypertension	2/53 (3.8%)	2
Hypotension	2/53 (3.8%)	2

Limitations/Caveats

The sample sizes in this study are relatively small, making it difficult to draw definitive conclusions regarding response rate and survival with this regimen.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.