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Phase II Study of Combination of Hyper-CVAD and Dasatinib With or Without Allogeneic Stem Cell Transplant in Patients With Philadelphia (Ph) Chromosome Positive and/or Bcr-Abl Positive Acute Lymphoblastic Leukemia (ALL) (A BMT Study).


Phase 2
18 Years
60 Years
Open (Enrolling)
Both
Adult Acute Lymphoblastic Leukemia in Remission, B-cell Adult Acute Lymphoblastic Leukemia, L1 Adult Acute Lymphoblastic Leukemia, L2 Adult Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Lymphoblastic Leukemia

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Trial Information

Phase II Study of Combination of Hyper-CVAD and Dasatinib With or Without Allogeneic Stem Cell Transplant in Patients With Philadelphia (Ph) Chromosome Positive and/or Bcr-Abl Positive Acute Lymphoblastic Leukemia (ALL) (A BMT Study).


PRIMARY OBJECTIVES:

I. To test whether the relapse-free survival after allogeneic stem cell transplantation
among Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia
(ALL) patients given an intensive short-term chemotherapy regimen of hyper-CVAD in
combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant
further investigation.

SECONDARY OBJECTIVES:

I. To test whether the continuous complete remission rate for previously untreated
Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia (ALL)
patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination
with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant phase III
investigation.

II. To investigate in a preliminary manner the relative effectiveness of minimal residual
disease (MRD) detection using real-time quantitative polymerase chain reaction (PCR) for
BCR/ABL versus flow cytometry to predict the outcome of patients treated by the hyper-CVAD +
dasatinib regimen and/or allogeneic stem cell transplant.

TERTIARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the intensive short-term
chemotherapy regimen in these patients.

II. To estimate the overall survival of all patients on this study.

OUTLINE: This is a multicenter study.

Patients are stratified according to prior treatment and response (untreated vs achieved
complete remission [CR] with or without [CRi] hematopoietic recovery vs treated, refractory,
and no CR or CRi).

INDUCTION/CONSOLIDATION THERAPY: All patients receive both of the following regimens in
alternating courses:

COURSES 1, 3, 5, 7 or 3, 5, 7, 9: Patients receive cyclophosphamide intravenously (IV) over
3 hours twice daily (BID) on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4;
vincristine sulfate IV over 30 minutes on days 4 and 11; dexamethasone IV or orally (PO)
once daily (QD) on days 1-4 and 11-14; dasatinib PO QD on days 1-14; cytarabine
intrathecally (IT) on day 7; methotrexate IT on day 2; and filgrastim (G-CSF) subcutaneously
(SC) QD or BID.

COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 24 hours on day 1;
methylprednisolone IV over 30 minutes BID on days 1-3; dasatinib PO QD on days 1-14;
high-dose cytarabine IV over 2 hours BID on days 2-3; leucovorin calcium IV on days 2 or 3;
methotrexate IT on day 2; cytarabine IT on day 7; and G-CSF SC QD or BID.

Treatment repeats every 14-21 days for 8 courses in the absence of disease progression,
unacceptable toxicity, or if patient achieves CR or CRi.

MAINTENANCE THERAPY*: Patients receive vincristine sulfate IV over 30 minutes on day 1,
prednisone PO QD on days 1-5, and dasatinib PO QD on days 1-28.

Treatment repeats every month for 24 courses in the absence of disease progression or
unacceptable toxicity or until the transplant is ready.

INTENSIFICATION: For courses 6 and 13, patients receive cyclophosphamide IV over 3 hours BID
on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV
over 30 minutes on days 4 and 11; dexamethasone IV or PO QD on days 1-4 and 11-14; dasatinib
PO QD on days 1-14; and G-CSF SC QD or BID.

NOTE: *Only if transplantation is not ready after induction/consolidation therapy or
patients are not undergoing a transplant.

ALLOGENEIC STEM CELL TRANSPLANTATION (FOR PATIENTS ACHIEVING CR OR CRi):

CONDITIONING REGIMEN: Patients receive 1 of the following regimens:

REGIMEN A: Patients receive total-body irradiation (TBI) QD on days -7 to -4 and
cyclophosphamide IV on days -3 and -2.

REGIMEN B: Patients receive TBI BID on days -6 to -4 and cyclophosphamide IV on days -3 and
-2.

REGIMEN C: Patients receive cyclophosphamide IV on days -7 and -6 and TBI QD on days -4 to
-1.

REGIMEN D: Patients receive cyclophosphamide IV on days -6 and -5 and TBI BID on days -3 to
-1.

REGIMEN E: Patients receive TBI QD on days -7 to -4 and etoposide IV on day -3.

REGIMEN F: Patients receive TBI BID on days -6 to -4 and etoposide IV on day -3.

ALLOGENEIC STEM CALL TRANSPLANTATION: Patients undergo allogeneic stem cell transplantation
on day 0.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive 1 of the following regimens:

REGIMEN A: Patients receive sirolimus PO and tacrolimus IV continuously (changing to PO BID)
beginning on day -3 and continuing for 6 months.

REGIMEN B: Patients receive tacrolimus IV continuously (changing to PO BID) and continuing
for 6 months, and methotrexate IV on days 1, 3, 6, and 11.

SINGLE-AGENT THERAPY: After completion of maintenance therapy or beginning on day 100
post-transplantation, patients receive dasatinib PO QD for up to 5 years.

Bone marrow and blood samples are collected periodically for cytogenetic analysis by PCR and
flow cytometry.

After completion of study therapy, patients are followed every 6 months for up to 5 years.


Inclusion Criteria:



- Patients must have a morphologic diagnosis of acute lymphoblastic leukemia (ALL),
with evidence of ALL involvement in bone marrow and/or blood; patients with only
extramedullary disease in the absence of bone marrow or blood involvement are not
eligible; patients with M0 acute myeloid leukemia (AML) or mixed lineage leukemia are
not eligible for this study; patients with L3 (Burkitts) are also not eligible

- For ALL in marrow or peripheral blood, immunophenotyping of the blood or marrow
lymphoblasts must be performed to determine lineage (B cell, T-cell, or mixed
B/T cell); NOTE: appropriate marker studies including CD19 (B cell), CD10, CD5,
and CD7 (T cell) must be performed; co-expression of myeloid antigens (CD13 and
CD33) will not exclude patients; if possible, the lineage specific markers
cytoplasmic CD22 or CD79a (B cells), cytoplasmic CD3 (T cells) and cytoplasmic
MPO (myeloid cells) must be determined

- Patients may have received no more than one course of remission induction therapy for
ALL; patients who have received any post-remission therapy for ALL or who have
relapsed from complete remission are not eligible; (patients with previously
untreated ALL can be eligible, and patients who have received one course of remission
induction therapy for ALL can be eligible, regardless of their response to therapy);
patients may have received no more than 14 days of tyrosine kinase inhibitor therapy
prior to registration; any prior induction chemotherapy must have been completed no
more than 28 days prior to registration

- NOTE: If the patient has been initiated on the protocol defined regimen (i.e.
the hyperCVAD regimen without a tyrosine kinase inhibitor) before the
Philadelphia chromosome (Ph)/breakpoint cluster region (BCR)-Abelson murine
leukemia viral oncogene (ABL) status was known, the patient may be registered on
the protocol and start dasatinib; in this first course, dasatinib will be
administered up to day 14 (i.e. if the patient is registered on day 5 and starts
therapy on day 6, only 8 days of dasatinib will be administered and dasatinib
will be completed on day 14)

- For patients who have received any prior therapy that was NOT remission induction
therapy, one of the following must be true:

- At least 6 weeks must have elapsed since any monoclonal antibodies were given,
at least 7 days must have elapsed since any other treatment was given, and all
toxicities of the remission induction therapy must have resolved to grade =< 2

- The patient must have rapidly progressive disease (per institutional guidelines)

- For previously treated patients, the Study Chair must be contacted before
registration, in order to determine the regimen to be given in the first course of
induction/consolidation therapy, based on prior therapy

- Patients must be Ph positive and/or BCR/ABL positive as confirmed by standard
cytogenetics, fluorescent in situ hybridization (FISH), and/or polymerase chain
reaction (PCR) testing performed by local laboratory; NOTE: samples will be submitted
centrally for verification of results

- Patients must have a bilirubin =< 3.0 x institutional upper limit of normal (IULN)
within 14 days prior to registration

- Patients must have serum glutamic oxaloacetic transaminase (SGOT) (aspartate
aminotransferase [AST]) =< 3.0 x IULN and/or serum glutamate pyruvate transaminase
(SGPT) (alanine aminotransferase [ALT]) =< 3.0 x IULN within 14 days prior to
registration; if both tests are done then both values must be =< 3.0 x IULN

- Patients must have a serum creatinine =< 3.0 x IULN within 14 days prior to
registration

- Patients must not have active pericardial effusion, ascites, or pleural effusion of
any grade; exception: if the effusion is suspected to be related to the leukemia, the
patient may have pericardial effusion of =< grade 2 or pleural effusion =< grade 1

- Patients may not have any clinically significant cardiovascular disease including the
following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Prolonged corrected QT (QTc) > 480 msec (Fridericia correction)

- Ejection fraction less than institutional normal

- Major conduction abnormality (unless a cardiac pacemaker is present)

- Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of
breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with
or without stress test as needed in addition to electrocardiogram (EKG) to rule
out QTc prolongation; the patient may be referred to a cardiologist at the
discretion of the principal investigator; patients with underlying
cardiopulmonary dysfunction should be excluded from the study

- Patients must have Zubrod performance status of 0-2

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease-free for 5 years

- Collection and submission of pre-treatment cytogenetic specimens must be completed
within 28 days prior to registration on S0805

- Collection and submission of pretreatment marrow and/or peripheral blood specimens
for cellular and molecular studies, including verification of BCR/ABL status must be
completed within 28 days prior to registration

- Patients must not be pregnant or nursing because of the teratogenic potential of the
drugs used in this study; women/men of reproductive potential must have agreed to use
an effective contraceptive method; a woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months;
in addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a
side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
oophorectomy or bilateral tubal ligation; however, if at any point a previously
celibate patient chooses to become heterosexually active during the time period for
use of contraceptive measures outlined in the protocol, he/she is responsible for
beginning contraceptive measures

- Patients must not have prior history of known type I hypersensitivity or anaphylactic
reactions to doxorubicin

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- At the time of patient registration, the treating institution's name and
identification (ID) number must be provided to the Data Operations Center in Seattle
in order to ensure that the current (within 365 days) date of institutional review
board approval for this study has been entered into the data base

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Probability of relapse-free survival (RFS)

Outcome Description:

Will be estimated using the method of Kaplan-Meier.

Outcome Time Frame:

12 months

Safety Issue:

No

Principal Investigator

Farhad Ravandi-Kashani

Investigator Role:

Principal Investigator

Investigator Affiliation:

Southwest Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00800

NCT ID:

NCT00792948

Start Date:

September 2009

Completion Date:

Related Keywords:

  • Adult Acute Lymphoblastic Leukemia in Remission
  • B-cell Adult Acute Lymphoblastic Leukemia
  • L1 Adult Acute Lymphoblastic Leukemia
  • L2 Adult Acute Lymphoblastic Leukemia
  • Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • T-cell Adult Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Philadelphia Chromosome

Name

Location

Albert Einstein College of Medicine Bronx, New York  10461
Louisiana State University New Orleans, Louisiana  70112-2282
Johns Hopkins University Baltimore, Maryland  21205
Cleveland Clinic Foundation Cleveland, Ohio  44195
Roswell Park Cancer Institute Buffalo, New York  14263
Mayo Clinic Rochester, Minnesota  55905
Washington University School of Medicine Saint Louis, Missouri  63110
Medical University of South Carolina Charleston, South Carolina  29425-0721
University of Washington Medical Center Seattle, Washington  98195-6043
Abramson Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania  19104-4283
Avera Cancer Institute Sioux Falls, South Dakota  57105
Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Loyola University Medical Center Maywood, Illinois  60153
LDS Hospital Salt Lake City, Utah  84143
Via Christi Regional Medical Center Wichita, Kansas  67214
Wesley Medical Center Wichita, Kansas  67214
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
Group Health Cooperative Seattle, Washington  98112
Great Falls Clinic Great Falls, Montana  59405
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109
Montefiore Medical Center Bronx, New York  10467-2490
Lewistown Hospital Lewistown, Pennsylvania  17044
Mount Nittany Medical Center State College, Pennsylvania  16803
Cancer Center of Kansas - Chanute Chanute, Kansas  66720
Cancer Center of Kansas - Dodge City Dodge City, Kansas  67801
Cancer Center of Kansas - Newton Newton, Kansas  67114
Cancer Center of Kansas - Salina Salina, Kansas  67042
Cancer Center of Kansas - Wellington Wellington, Kansas  67152
Associates in Womens Health Wichita, Kansas  67203
Cancer Center of Kansas - Winfield Winfield, Kansas  67156
Munson Medical Center Traverse City, Michigan  49684
Bozeman Deaconess Hospital Bozeman, Montana  59715
Kalispell Regional Medical Center Kalispell, Montana  59901
Avera McKennan Hospital and University Health Center Sioux Falls, South Dakota  57105
American Fork Hospital American Fork, Utah  84003
Logan Regional Hospital Logan, Utah  84321
McKay-Dee Hospital Center Ogden, Utah  84403
Harborview Medical Center Seattle, Washington  98104
Cancer Care Northwest - Spokane South Spokane, Washington  99202
Welch Cancer Center Sheridan, Wyoming  82801
Baylor University Medical Center Dallas, Texas  75246
City of Hope Medical Center Duarte, California  91010
Hematology and Oncology Associates Chicago, Illinois  60611
Salina Regional Health Center Salina, Kansas  67401
Mecosta County Medical Center Big Rapids, Michigan  49307
Grandview Hospital Dayton, Ohio  45405
Hematology Oncology Associates of Illinois-Highland Park Highland Park, Illinois  60035
Miami Valley Hospital Dayton, Ohio  45409
Cancer Center of Kansas - Fort Scott Fort Scott, Kansas  66701
Cancer Center of Kansas-Independence Independence, Kansas  67301
Lawrence Memorial Hospital Lawrence, Kansas  66044
Bozeman Deaconess Cancer Center Bozeman, Montana  59715
Wayne Hospital Greenville, Ohio  45331
Clinton Memorial Hospital Wilmington, Ohio  45177
Wenatchee Valley Medical Center Wenatchee, Washington  98801-2028
Rocky Mountain Oncology Casper, Wyoming  82609
Greene Memorial Hospital Xenia, Ohio  45385
Memorial Medical Center Springfield, Illinois  62781
Metro Health Hospital Grand Rapids, Michigan  49506
University of North Carolina Chapel Hill, North Carolina  27599
Northwestern University Chicago, Illinois  60611
University of Florida Gainesville, Florida  32610-0277
Saint Louis University Hospital St. Louis, Missouri  63110-0250
University of Rochester Rochester, New York  14642
Emory University Atlanta, Georgia  30322
Wayne State University Detroit, Michigan  48202
University of Arizona Health Sciences Center Tucson, Arizona  85724
University of Kentucky Lexington, Kentucky  40536-0098
Wichita CCOP Wichita, Kansas  67214-3882
Montana Cancer Consortium CCOP Billings, Montana  59101
Huntsman Cancer Institute/University of Utah Salt Lake City, Utah  84112
UC Davis Comprehensive Cancer Center Sacramento, California  95817
Tulane University Health Sciences Center New Orleans, Louisiana  70112
Montana Cancer Specialists Missoula, Montana  59807-7877
Florida Hospital Orlando, Florida  32803
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470
M D Anderson Cancer Center Houston, Texas  77030
Penn State Milton S Hershey Medical Center Hershey, Pennsylvania  17033
Hays Medical Center Hays, Kansas  67601
Froedtert and the Medical College of Wisconsin Milwaukee, Wisconsin  53226
North Shore Hematology Oncology Libertyville, Illinois  60048
Hematology Oncology Associates of Illinois - Skokie Skokie, Illinois  60076
Saint Francis Hospital and Health Centers Beech Grove, Indiana  46107
Fort Wayne Medical Oncology and Hematology Inc - State Boulevard Fort Wayne, Indiana  46845
Reid Hospital and Health Care Services Richmond, Indiana  47374
Mercy Medical Center-Sioux City Sioux City, Iowa  51104
Saint Luke's Regional Medical Center Sioux City, Iowa  51104
Cancer Center of Kansas - El Dorado El Dorado, Kansas  67042
Cancer Center of Kansas-Kingman Kingman, Kansas  67068
Cancer Center of Kansas - Parsons Parsons, Kansas  67357
Cancer Center of Kansas - Pratt Pratt, Kansas  67124
Saint Francis Hospital and Medical Center - Topeka Topeka, Kansas  66606
Cancer Center of Kansas-Wichita Medical Arts Tower Wichita, Kansas  67208
Cancer Center of Kansas - Main Office Wichita, Kansas  67214
Grand Rapids Clinical Oncology Program Grand Rapids, Michigan  49503
Saint Mary's Health Care Grand Rapids, Michigan  49503
Spectrum Health at Butterworth Campus Grand Rapids, Michigan  49503
Mercy Health Partners-Mercy Campus Muskegon, Michigan  49443
Truman Medical Center Kansas City, Missouri  64108
Hematology-Oncology Centers of the Northern Rockies PC Billings, Montana  59101
Saint Vincent Healthcare Billings, Montana  59101
Billings Clinic Billings, Montana  59107-7000
Saint James Community Hospital and Cancer Treatment Center Butte, Montana  59701
Benefis Healthcare- Sletten Cancer Institute Great Falls, Montana  59405
Saint Peter's Community Hospital Helena, Montana  59601
Glacier Oncology PLLC Kalispell, Montana  59901
Saint Patrick Hospital - Community Hospital Missoula, Montana  59802
Good Samaritan Hospital - Dayton Dayton, Ohio  45406
Dayton CCOP Dayton, Ohio  45429
Samaritan North Health Center Dayton, Ohio  45415
Blanchard Valley Hospital Findlay, Ohio  45840
Atrium Medical Center-Middletown Regional Hospital Franklin, Ohio  45005-1066
Kettering Medical Center Kettering, Ohio  45429
Saint Rita's Medical Center Lima, Ohio  45801
Upper Valley Medical Center Troy, Ohio  45373
Harrison Bremerton Hematology and Oncology Bremerton, Washington  98310
Columbia Basin Hematology and Oncology PLLC Kennewick, Washington  99336
Minor and James Medical PLLC Seattle, Washington  98104
The Polyclinic Seattle, Washington  98122
Swedish Medical Center-First Hill Seattle, Washington  98122-4307
West Virginia University Morgantown, West Virginia  26506
University of Maryland Greenebaum Cancer Center Baltimore, Maryland  21201
Kansas City Cancer Centers - North Kansas City, Missouri  64154
Cancer Center of Kansas-Liberal Liberal, Kansas  67901
University of Michigan University Hospital Ann Arbor, Michigan  48109
Sandra L Maxwell Cancer Center Cedar City, Utah  84720
Intermountain Medical Center Murray, Utah  84157
Utah Valley Regional Medical Center Provo, Utah  84603
Dixie Medical Center Regional Cancer Center Saint George, Utah  84770
Utah Cancer Specialists-Salt Lake City Salt Lake City, Utah  84106
Skagit Valley Hospital Mt. Vernon, Washington  98273
Evergreen Hematology and Oncology PS Spokane, Washington  99218
Kansas City Cancer Centers-Southwest Overland Park, Kansas  66210
Arizona Cancer Center at University Medical Center North Tucson, Arizona  85719
Kansas City Cancer Center-West Kansas City, Kansas  66112
Kansas City Cancer Center-Shawnee Mission Shawnee Mission, Kansas  66204
Kansas City Cancer Center - South Kansas City, Missouri  64131
Kansas City Cancer Center-Lee's Summit Lee's Summit, Missouri  64064
Cancer Care Center at Island Hospital Anacortes, Washington  98221
Highline Medical Center-Main Campus Burien, Washington  98166
United General Hospital Sedro-Woolley, Washington  98284
The Jewish Hospital Cincinnati, Ohio  45236
Stanford University Hospitals and Clinics Stanford, California  94305
Siouxland Hematology Oncology Associates Sioux City, Iowa  51101
Swedish Cancer Institute-Issaquah Issaquah, Washington  98029
Southwest Oncology Group San Antonio, Texas  78245
Southwest Oncology Group (SWOG) Research Base San Antonio, Texas  78245
Via Christi Hospital-Pittsburg Pittsburg, Kansas  66762
PeaceHealth Saint Joseph Medical Center Bellingham, Washington  98225
Illinois Cancer Specialists-Niles Niles, Illinois  60714
Bronson Battle Creek Battle Creek, Michigan  49017
Promise Regional Medical Center-Hutchinson Hutchinson, Kansas  65702
Harrison Poulsbo Hematology and Oncology Poulsbo, Washington  98370
Presence Saint Mary's Hospital Kankakee, Illinois  60901
Hematology/Oncology Clinic LLP Baton Rouge, Louisiana  70809
Swedish Medical Center-Edmonds Edmonds, Washington  98026