Dasatinib Followed by Stem Cell Transplant in Treating Older Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This phase II clinical trial studies how well dasatinib followed by stem cell transplant works in treating older patients with newly diagnosed acute lymphoblastic leukemia. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Monoclonal antibodies, such as alemtuzumab, may interfere with the ability of cancer cells to grow and spread. Giving more than one drug (combination chemotherapy) and giving dasatinib together with chemotherapy may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Estimate the disease-free survival (DFS) and overall survival (OS) profiles in newly diagnosed patients 18 years or older who have Philadelphia chromosome positive (Ph+) (BCR/(v-abl Abelson murine leukemia viral oncogene homolog [ABL]+) acute lymphoblastic leukemia (ALL) receiving sequential dasatinib followed by allogeneic or autologous hematopoietic cell transplant (HCT) or chemotherapy followed by dasatinib maintenance. SECONDARY OBJECTIVES: I. Compare the OS and DFS profiles for each of the three cohorts to those from similar populations from other studies. II. Determine the ability of dasatinib to produce or maintain a BCR/ABL-negative status, as judged by quantitative-polymerase chain reaction (Q-PCR) following sequential dasatinib, chemotherapy, and HCT. III. Determine the feasibility of collecting adequate peripheral blood stem cells for autologous HCT following dasatinib therapy and assess for residual Ph+ (BCR/ABL+) cells by Q-PCR. IV. Study the safety and efficacy of autologous HCT following therapy with dasatinib. V. Study the safety and efficacy of reduced-intensity preparatory regimen followed by an allogeneic HCT following induction therapy with dasatinib. VI. Study the safety and efficacy of dasatinib maintenance administered after allogeneic or autologous HCT or chemotherapy. VII. Correlate plasma and cerebrospinal fluid (CSF) levels of dasatinib when given orally during induction. OUTLINE: As of 8/21/2014, no new patients may be enrolled on E3903. REMISSION INDUCTION THERAPY (RIT): Patients receive dasatinib orally (PO) daily continuously and dexamethasone PO or intravenously (IV) on days 1-7. EARLY INTENSIFICATION THERAPY: Patients with bone marrow =< 20% blasts are assigned to cohort A and patients with bone marrow > 20% blasts are assigned to cohort B. COHORT A: Patients receive dasatinib and dexamethasone as in RIT. COHORT B: Patients receive dasatinib and dexamethasone as in RIT, and vincristine sulfate IV and daunorubicin hydrochloride IV on days 1, 8, and 15. Patients who do NOT achieve a complete response (CR) or CR with incomplete hematologic recovery based on bone marrow continue on to second induction therapy; patients who achieve a hematologic and morphologic CR continue on to CNS prophylaxis therapy. SECOND INDUCTION THERAPY: Patients receive dasatinib and dexamethasone as in RIT, cyclophosphamide IV on day 1, daunorubicin hydrochloride IV and vincristine sulfate IV on days 1 and 8, and filgrastim subcutaneously (SC) beginning on day 9 and continuing for >= 7 days or one dose of pegfilgrastim on day 9. CNS PROPHYLAXIS THERAPY: Patients receive dasatinib PO daily continuously during CNS prophylaxis therapy; methotrexate intrathecally (IT), vincristine sulfate IV, and methotrexate IV over 3 hours on days 1, 15, and 29; methotrexate PO every 6 hours for a total of 4 doses each on days 1-2, 15-16, and 29-30; leucovorin calcium IV on days 2, 16, and 30; and leucovorin PO calcium every 6 hours for a total of 8 doses each on days 3-4, 17-18, and 31-32. TRANSPLANTATION OR ALTERNATIVE CHEMOTHERAPY AND MAINTENANCE THERAPY: Patients aged 50-70 years with an HLA-matched related or unrelated donor are assigned to allogeneic transplantation, patients aged 50-70 years without an HLA-matched related or unrelated donor are assigned to autologous transplantation, and patients aged > 70 years or who are not transplantation candidates are assigned to alternative chemotherapy. ALLOGENEIC TRANSPLANTATION: Patients receive fludarabine phosphate IV over 30 minutes and alemtuzumab IV over 30 minutes on days -7 through -3 and melphalan IV over 30 minutes on day -2. Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0. Patients then receive filgrastim SC beginning on day 1 and continuing until count recovery and tacrolimus IV or PO beginning on day -2 and beginning to taper on day 100 (for matched related donors) or day 180 (for mismatched related or unrelated donors). Beginning on day 30, patients receive dasatinib PO daily as maintenance therapy. Treatment continues for >= 12 months in the absence of disease progression. AUTOLOGOUS TRANSPLANTATION: MOBILIZATION: Patients receive etoposide phosphate IV continuously on days 1-4, high-dose cytarabine IV over 2 hours every 12 hours for a total of 8 doses on days 1-4, and filgrastim SC once or twice daily beginning on day 14 and continuing until peripheral blood stem cell collection is complete or WBC > 50,000/μL. LEUKAPHERESIS: Patients undergo leukapheresis beginning when WBC > 10,000/μL for a target collection of >= 5 x 10^6 CD34+ cells/kg. After completion of stem cell collection, patients receive dasatinib PO twice daily until 3 days before transplantation. TRANSPLANTATION: Beginning >= 4 weeks after recovery from toxicity related to previous treatment, patients receive melphalan IV over 30 minutes on days -2 and -1. Patients undergo autologous PBSCT on day 0. Patients then receive filgrastim SC beginning on day 0 and continuing until count recovery. MAINTENANCE THERAPY: Beginning on day 30, patients receive dasatinib PO once daily. Treatment continues for >= 12 months in the absence of disease progression. ALTERNATIVE CHEMOTHERAPY: Beginning 3-10 days after completion of CNS prophylaxis therapy, patients receive etoposide phosphate IV continuously on days 1-4, high-dose cytarabine IV over 2 hours every 12 hours for a total of 8 doses on days 1-4, and filgrastim SC once or twice daily beginning on day 14 and continuing until count recovery. MAINTENANCE THERAPY: Patients receive dasatinib PO once daily beginning on day 30. Patients also receive vincristine sulfate IV every 4 weeks, dexamethasone for 5 days every 4 weeks, mercaptopurine PO once daily, and methotrexate PO once weekly. Treatment continues for >= 12 months in the absence of disease progression. NOTE: Patients with CNS leukemia or testicular disease may receive additional treatment. After completion of study treatment, patients are followed up every month for 1 year, every 3 months for 2 years, every 6 months for 2 years, and every year for 5 years.

Official Title
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A Phase II Study of Dasatinib (Sprycel&#174;) (NSC #732517) as Primary Therapy Followed by Transplantation for Adults &gt;/= 18 Years With Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia by CALGB, ECOG and SWOG

Conditions
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Acute Lymphoblastic Leukemia, Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1

Intervention / Treatment
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* Biological: Alemtuzumab
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dasatinib
* Drug: Daunorubicin Hydrochloride
* Drug: Dexamethasone
* Drug: Etoposide Phosphate
* Biological: Filgrastim
* Drug: Fludarabine Phosphate
* Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
* Other: Laboratory Biomarker Analysis
* Drug: Leucovorin Calcium
* Drug: Melphalan
* Drug: Mercaptopurine
* Drug: Methotrexate
* Biological: Pegfilgrastim
* Other: Pharmacological Study
* Drug: Tacrolimus
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unequivocal histologic diagnosis of ALL Detection of the t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL positive status by molecular analysis (Q-PCR or fluorescent in situ hybridization [FISH]) in a Cruise Lines International Association (CLIA)-approved laboratory No prior therapy except up to one week of corticosteroids and/or hydroxyurea to enable time for the detection of t(9;22)(q34;q11) or BCR/ABL Non-pregnant and non-nursing; treatment under this protocol would expose an unborn child to significant risks; women and men of reproductive potential should agree to use an effective means of birth control and contraception should continue for three months after the last dose of dasatinib to allow complete clearance of drug and its principal metabolites from the body; in women of childbearing potential, a pregnancy test will be required at study entry Left ventricular ejection fraction >= lower limit of institutional normal No myocardial infarction within 6 months No ventricular tachyarrhythmia within 6 months No major conduction abnormality (unless a cardiac pacemaker is present)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, transplant)<br>See Detailed Description | Biological: Alemtuzumab<br>* Given IV<br>* Other names: Monoclonal Antibody Campath-1H;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo peripheral blood allogeneic HCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo peripheral blood autologous HCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation<br>* Undergo peripheral blood autologous or allogeneic HCT<br>* Other names: in vitro-treated peripheral blood progenitor cell transplantation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given IV or PO<br>* Other names: Wellcovorin;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT, IV, or PO<br>* Other names: WR-19039;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: Ziextenzo;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival Defined From the Date of First Induction Complete Response (CR) to Relapse or Death Due to Any Cause | Estimated using the Kaplan-Meier estimator. Proportions will be estimated using point as well as interval estimators. All interval estimators will be constructed using the finite sample size sampling distribution at the unadjusted two-sided level of 0.05. | At 3 years after CR | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Being BCR-ABL Negative in the Bone Marrow and Peripheral Blood at the Completion of the CNS Prophylaxis Course (Restricted to Those Patients Achieving a CR) | Proportions will be estimated based on the combined and individual cohorts. | 10 years | 
| Feasibility of Maintenance Therapy in This Patient Population (Restricted to Those Patients Achieving a CR). Feasibility Will be Defined as the Number of Deaths Ocuring. | Proportions will be estimated based on the combined and individual cohorts. | 10 years | 
| Overall Survival (OS) | Estimated using the Kaplan-Meier estimator. Proportions will be estimated using point as well as interval estimators. All interval estimators will be constructed using the finite sample size sampling distribution at the unadjusted two-sided level of 0.05. | 10 years | 
| Disease Free Survival (DFS) | Estimated using the Kaplan-Meier estimator. Proportions will be estimated using point as well as interval estimators. All interval estimators will be constructed using the finite sample size sampling distribution at the unadjusted two-sided level of 0.05. | 10 years | 
| Response | Proportion of patients reaching a CR. A CR requires the following: an absolute neutrophil count (segs and bands) >1000/μL, no circulating blasts, platelets >100,000/μL; adequate bone marrow cellularity with trilineage hematopoiesis, and <5% marrow leukemia blast cells. All previous extramedullary manifestations of disease must be absent (e.g., lymphadenopathy, splenomegaly, skin or gum infiltration, testicular masses, or CNS involvement). | 10 years |