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Title Phase II Study of Combination of Hyper-CVAD and Dasatinib (NSC-732517) 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)

IRB S0805

CC 12-208

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Acute Lymphoblastic (ALL)

Drug Dasatinib, Hyper-CVAD

Description

1. 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.
2. 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.
3. To investigate in a preliminary manner the relative effectiveness of MRD detection using real-time quantitative 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.
4. To estimate the frequency and severity of toxicities of the intensive short-term chemotherapy regimen in these patients.
5. To estimate the overall survival of all patients on this study.

Inclusion Criteria

1. INDUCTION/CONSOLIDATION REGISTRATION (Registration Step 1):
   • Patients must have a morphologic diagnosis of acute lymphoblastic leukemia (ALL), as defined in Section 4.1b, 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 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. Coexpression 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, providing this induction course was given prior to the results of the cytogenetics testing for Ph/BCR/ABL status being known. 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.) Any prior induction chemotherapy must have been completed within 28 days prior to registration.
   • 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; or
     • The patient must have rapidly progressive disease (per institutional guidelines).
   • For previously treated patients, the Study Coordinator 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 Philadelphia (Ph) chromosome positive and/or BCR/ABL positive as confirmed by standard cytogenetics, FISH, and/or polymerase chain reaction (PCR) testing performed by local laboratory. NOTE: Samples will be submitted centrally for verification of results (see Section 5.1o).
   • Patients must have a bilirubin ≤ 3.0 x Institutional Upper Limit of Normal (IULN) within 14 days prior to registration.
   • Patients must have SGOT (AST) ≤ 3.0 x IULN and/or SGPT (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 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.
   • Patients must be ≥ 18 and ≤ 60 years of age.
   • 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. Specimens must be submitted as outlined below:
     
     SWOG and BMT CTN Sites and other sites not affiliated with ECOG or CALGB: Pretreatment specimens of bone marrow (or peripheral blood if the marrow aspirate is a dry tap) must be submitted to an approved SWOG Cytogenetics Laboratory for cytogenetics analysis per the instructions on the SWOG Leukemia Cytogenetics website. The website can be accessed at www.swog.org/Members/ClinicalTrials/Specimens/Cytogenetics.asp.
     
     ECOG Sites: Cytogenetic studies are performed locally. Prior to registration on S0805 ECOG patients must be registered on E3903, Ancillary laboratory protocol for collecting diagnostic material on patients considered for ECOG treatment trials for leukemia or related hematologic disorders. Karyotypes and FISH reports must be submitted for central review, via E3903, to the Mayo Clinic Cytogenetics Laboratory in Rochester (Section 15.2). Note that Note that S0805 also requires the submission of follow-up cytogenetics.
     
     CALGB Sites: Patients must be registered on CALGB-8461 ("Cytogenetic Studies in Acute Leukemia"). Pretreatment specimens must be submitted as outlined in CALGB-8461 and Section 15.3 for cytogenetic analysis. Note that protocol CALGB-8461 also requires submission of remission and relapse specimens.
   • Collection and submission of pretreatment marrow and/or peripheral blood specimens for cellular and molecular studies, including verification of BCR/ABL status (see Section 7.8a) must be completed within 28 days prior to registration as outlined below:
     
     SWOG, BMT CTN and CALGB Sites: Patients must submit specimens to the Southwest Oncology Group Lymphoid and CML Repository in Seattle, Washington. Specimens will be collected and submitted as outlined on the SWOG Specimens Submission web page (https://swog.org/members/clinicaltrials/specimens/). The web page can be accessed via the link above, or from the link provided on the S0805 protocol abstract page on the Southwest Oncology Group website (swog.org). Note that specimens not used for study-specific testing will be stored in the repository only if the patient consents separately to that optional storage (see "Consent Form for Use of Specimens for Research"). Note that S0805 also requires submission of follow-up specimens.
     
     ECOG Sites: Patients must be registered on E3903, Ancillary laboratory protocol for collecting diagnostic material on patients considered for ECOG treatment trials for leukemia or related hematologic disorders. Specimens must be submitted to the Leukemia Translational Research Laboratory (LTRL) at Our Lady of Mercy Cancer Center, New York (Section 15.2). Note that E3903 also requires the submission of follow-up specimens.
     
     CALGB Sites: Patients must be offered participation in the CALGB Leukemia Tissue Bank via CALGB-9665. With patient consent, pretreatment specimens must be submitted as outlined in CALGB-9665 and Section 15.3. Note that CALGB-S9665 also requests submission of remission and relapse specimens.
   • 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. Women of reproductive potential must have a negative pregnancy test performed within 14 days prior to registration.
   • Patients must not have prior history of known Type I hypersensitivity or anaphylactic reactions to doxorubicin.
   • All patients 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 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.
2. MAINTENANCE/INTENSIFICATION REGISTRATION (Registration Step 2):
   
   After completing induction/consolidation therapy, patients who have not received transplant will be registered for maintenance treatment, provided that they were eligible for the initial remission induction registration and satisfy the following additional criteria.
   • Patient must have achieved CR or CRi within 2 courses of Induction/Consolidation Chemotherapy. Patient must remain in CR or CRi until beginning Maintenance Chemotherapy and this must be re-documented by bone marrow and peripheral blood examination within 28 days prior to registration to Step 2.
   • All treatment related toxicities must have resolved to ≤ Grade 2.
   • Patients must not have received allogeneic stem cell transplant.
3. TRANSPLANT REGISTRATION (Registration Step 3):
   
   All patients should be considered and referred for potential allogeneic stem cell transplant. All transplants must be performed by a transplant facility which has been approved by either the BMT CTN, CALGB, ECOG or SWOG, regardless of group affiliation (see Section 7.5). For patients receiving treatment at non-transplant facilities who are candidates for transplant, arrangements for transfer to an approved facility should begin as soon as possible. Patients may be registered to Step 3 at any point during protocol therapy provided they have a donor who satisfies the eligibility criteria 5.3a and 5.3e-5.3r, and that arrangements for transplant are completed prior to registration. Patients may be registered for allogeneic stem cell transplant, provided that they were eligible for induction/consolidation and satisfy the following additional criteria.
   • Patients must have an available completely matched sibling donor or a 10/10 matched non-sibling donor.
   • Patients must have allogeneic stem cell transplant arranged prior to registration to Step 3.
   • Patients must have documented CR or CRi within 14 days prior to registration to Step 3.
   • Patients must not be HIV + (human immunodeficiency virus). A negative HIV test must be obtained within 14 days prior to registration (see Section 2.0 for justification).
4. POST-TRANSPLANT/POST-MAINTENANCE SINGLE-AGENT DASATINIB THERAPY REGISTRATION (Registration Step 4):
   • Patients must have reached Day 100 post transplant or must have completed protocol maintenance/intensification (or must have been approved by the Study Coordinator after early removal from maintenance/intensification).
   • Patients must be in CR or CRi based on bone marrow and peripheral blood examination within 28 days prior to registration to Step 4.
   • Patients must have recovered to ≤ Grade 2 from all treatment related toxicity.

Exclusion Criteria

Exclusion Criteria Not Available