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Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Poly(ADP-ribose) Polymerase Inhibitors

Veliparib

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Patients receive veliparib PO QD on day 1 and twice daily on days 4-12 and temozolomide PO QD on days 3-9 of course 1.

Beginning at least 30 days after the start of treatment, patients receive veliparib PO BID on days 1-8 and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients achieving complete remission receive 5 more courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Ivana Gojo

This phase I clinical trial is studies the side effects and best dose of giving veliparib together with temozolomide in treating patients with acute leukemia. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving veliparib together with temozolomide may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To define the maximum-tolerated dose (MTD) and recommended phase II dose of ABT-888 (veliparib) administered in combination with temozolomide in patients with acute leukemias.

II. To evaluate the feasibility, safety, and toxicity of administering ABT-888 in combination with temozolomide in patients with acute leukemias.

SECONDARY OBJECTIVES:

I. To document response in acute leukemias. II. To observe the pharmacokinetics of both ABT-888 and temozolomide when administered alone and in combination.

III. To study the pharmacodynamics to determine the levels of poly(ADP-ribose) (PAR) before and after administration of ABT-888 and temozolomide in patient leukemia blasts, to analyze methyl-guanine methyl-transferase (MGMT) protein levels in primary leukemia blasts, and to quantify the induction of gamma-H2A histone family, member X (y-H2AX) and RAD51 recombinase (RAD51) foci in patient leukemia blasts after treatment.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive veliparib orally (PO) once daily (QD) on day 1 and twice daily on days 4-12 and temozolomide PO QD on days 3-9 of course 1.

Beginning at least 30 days after the start of treatment, patients receive veliparib PO twice daily (BID) on days 1-8 and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients achieving complete remission receive 5 more courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Veliparib and Temozolomide in Treating Patients With Acute Leukemia

A Phase I Study of the PARP Inhibitor ABT-888 in Combination With Temozolomide in Acute Leukemias

The proportion of responders will be estimated and reported with the corresponding 90% confidence interval.

The proportion of subjects with significant inhibition will be estimated for each dose level. Summary statistics and results of the statistical tests for contingency tables will be reported.

Average expression of MGMT will be measured and classified as positive versus negative (less than 20% of mean value) for all patients regardless of the administered drug dose. We will use the Fisher's exact test for 2 x 2 tables to assess whether the lack of MGMT expression correlates with the response.

The average change from baseline level in γ-H2AX and RAD51 foci will be estimated for all patients to assess whether increase in foci and response to treatment are associated. Assessed using a single group repeated measures analysis of variance (ANOVA) with 0.05 significance level.

The average change from baseline level in γ-H2AX and RAD51 foci will be estimated for all patients to assess whether increase in foci and response to treatment are associated. Assessed using a single group repeated measures ANOVA with 0.05 significance level.

Repeated measures data structure will provide adequate power to estimate intra- and inter-patient variability.

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.

National Cancer Institute (NCI)

Childhood Acute Lymphoblastic Leukemia

Anti-Infective Agents

Antirheumatic Agents

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Micronutrients

Dermatologic Agents

Reproductive Control Agents

Hematinics

Neuroprotective Agents

Bone Density Conservation Agents

Vitamins

Amino Acids

Etoposide

Cytarabine

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Dexamethasone

Leucovorin

Levoleucovorin

Methotrexate

Prednisone

Vincristine

Prednisolone

Calcium

Lenograstim

Tacrolimus

Dexamethasone acetate

BB 1101

Sirolimus

Folic Acid

Etoposide phosphate

Podophyllotoxin

Dasatinib

Methylprednisolone

Cortisone

Calcium, Dietary

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Ichthammol

Temsirolimus

MTOR Inhibitors

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Immunosuppressive Agents

Immunologic Factors

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

HIV Protease Inhibitors

Protease Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antimetabolites

Folic Acid Antagonists

Antiviral Agents

Adjuvants, Immunologic

Antidotes

Protective Agents

Trace Elements

Calcineurin Inhibitors

Tubulin Modulators

Antimitotic Agents

Clotrimazole

Miconazole

Antifungal Agents

Protein Kinase Inhibitors

Tyrosine Kinase Inhibitors

Keratolytic Agents

Folinic Acid

Folate

Vitamin B9

Tyrosine

Allogeneic Hematopoietic Stem Cell Transplantation

Doxorubicin Hydrochloride

Filgrastim

Leucovorin Calcium

Peripheral Blood Stem Cell Transplantation

Total-Body Irradiation

Vincristine Sulfate

Farhad Ravandi-Kashani

This phase II trial is studying the side effects of giving combination chemotherapy together with or without donor stem cell transplant and to see how well it works in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect).

PRIMARY OBJECTIVES:

I. To test whether the relapse-free survival after allogeneic stem cell transplantation among Philadelphia chromosome positive and/or breakpoint cluster region (BCR)/Abelson murine leukemia viral oncogene (ABL) positive acute lymphoblastic leukemia (ALL) patients given an intensive short-term chemotherapy regimen of fractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (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:

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 complete remission (CR) or complete remission with incomplete platelet recovery (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.

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

Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

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)

OS will be estimated using the method of Kaplan-Meier.

Correlation between the two measures of MRD measured on the same remission specimens will be examined using scatterplots and correlation analysis. The prognostic effect for relapse of each measure will be illustrated using cumulative incidence plots, and estimated using Cox regression models. This outcome will be reported as funding allows.

Will be estimated using the method of Kaplan-Meier.

Will be testing using an exact binomial test

Analysis includes eligible patients who were assessed for adverse events.

Patients receive up to 8 courses, alternating between hyper-CVAD plus dasatinib and high dose methotrexate and cytarabine plus dasatinib. There are nine possible induction/consolidation courses.

Induction/Consolidation

Patients receive vincristine IV on day 1, prednisone PO on days 1 to 5, and dasatinib PO on days 1 to 28 for up to 24 courses or until transplant is available.

Vincristine/Prednisone/Dasatinib

Patients who have an available sibling donor or a 10/10 matched unrelated donor will be removed from therapy and proceed directly to allogeneic stem cell transplant after achieving CR or CRi.

Allogeneic Stem Cell Transplant

Patients receive Single-Agent Dasatinib therapy PO every day for up to five years from original registration.

Treatment

Age, Continuous

Sex: Female, Male

Analysis includes eligible patients who received treatment.

Leukemia Committee Statistician

See Detailed Description

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic stem cell transplant

Cyclophosphamide: Given IV

Cytarabine: Given IT

Dasatinib: Given PO

Dexamethasone: Given IV or PO

Doxorubicin Hydrochloride: Given IV

Etoposide: Given IV

Filgrastim: Given SC

Laboratory Biomarker Analysis: Correlative studies

Leucovorin Calcium: Given IV

Methotrexate: Given IV or IT

Methylprednisolone: Given IV

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic stem cell transplant

Prednisone: Given PO

Sirolimus: Given PO

Tacrolimus: Given IV

Total-Body Irradiation: Undergo TBI

Vincristine Sulfate: Given IV

Patients who received allogeneic stem cell transplant

Relapse-free Survival (RFS) After Allogeneic Stem Cell Transplantation

Patients who had not received prior ALL therapy

Continuous Complete Remission (CCR) Rate

Overall Survival (OS)

MRD as Assessed Using Real-time Quantitative Polymerase Chain Reaction and Flow Cytometry

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Veliparib and Temozolomide in Treating Patients With Acute Leukemia	NCT01139970	Acute Lymphobla... Acute Myeloid L... Acute Myeloid L... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Pro... Adult B Acute L... Adult B Acute L... Adult T Acute L... Alkylating Agen... Chronic Myelomo... Recurrent Adult... Recurrent Adult... Secondary Acute...	Laboratory Biom... Pharmacological... Temozolomide Veliparib	18 Years -	National Cancer Institute (NCI)
Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia	NCT00792948	Acute Lymphobla... Adult B Acute L... Adult B Acute L... Adult L1 Acute ... Adult L2 Acute ... Adult T Acute L... Recurrent Adult...	Allogeneic Hema... Cyclophosphamid... Cytarabine Dasatinib Dexamethasone Doxorubicin Hyd... Etoposide Filgrastim Laboratory Biom... Leucovorin Calc... Methotrexate Methylprednisol... Peripheral Bloo... Prednisone Sirolimus Tacrolimus Total-Body Irra... Vincristine Sul...	18 Years - 60 Years	National Cancer Institute (NCI)
Veliparib and Temozolomide in Treating Patients With Acute Leukemia	NCT01139970	Acute Lymphobla... Acute Myeloid L... Acute Myeloid L... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Pro... Adult B Acute L... Adult B Acute L... Adult T Acute L... Alkylating Agen... Chronic Myelomo... Recurrent Adult... Recurrent Adult... Secondary Acute...	Laboratory Biom... Pharmacological... Temozolomide Veliparib	18 Years -	National Cancer Institute (NCI)
Veliparib and Temozolomide in Treating Patients With Acute Leukemia	NCT01139970	Acute Lymphobla... Acute Myeloid L... Acute Myeloid L... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Pro... Adult B Acute L... Adult B Acute L... Adult T Acute L... Alkylating Agen... Chronic Myelomo... Recurrent Adult... Recurrent Adult... Secondary Acute...	Laboratory Biom... Pharmacological... Temozolomide Veliparib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for adult t acute lymphoblastic leukemia