Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Dermatologic Agents

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Cytarabine

Cyclosporine

Cyclosporins

Prednisolone

Mycophenolic Acid

Thymoglobulin

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Antilymphocyte Serum

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Clotrimazole

Miconazole

Antifungal Agents

Calcineurin Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Glucocorticoids

Hormones

Hormone Antagonists

Protective Agents

Antineoplastic Agents, Hormonal

Participants achieving complete remission after consolidation therapy \& who have 5 of 6 HLA-match sibling donor to provide PBSC harvest for transplant. Pre-transplant subjects receive:

* Total lymphoid radiation (TLI) Days -11 to -7, and Days -4 to -1 (2 fractions on day -1)
* Anti-thymocyte globulin (ATG) Days -11 to -7
* Methylprednisolone Days -11 to -7
* Cyclosporine (CSP) Days -4 to +2
* 5+ of 6 HLA-matched CD34+ cells on Day 0
* Mycophenolate mofetil (MMF), Day 0 to Day +28

Regular medical care for participants who achieve complete remission after standard consolidation therapy, but do not have a 5 of 6 HLA-match sibling donor. Treatment may consist of:

* Additional consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation)
* Autologous transplantation
* Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning
* Umbilical cord blood transplantation
* Haploidentical transplantation

Allogeneic, 5+ of 6 HLA-matched PBSC transplant from sibling, mobilized to target of 5 x 10e6 CD34+ cells/kg and \< 7 x 10e8 CD3+ cells/kg.

Allogeneic HSCT

Anti-thymocyte globulin (ATG)

Cyclosporine (CSP)

Mycophenolate mofetil (MMF)

80 cGy/fraction radiotherapy in 10 fractions.

Total lymphoid irradiation (TLI)

Methylprednisolone sodium succinate

Intervention consist of:

* Consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation)
* Autologous transplantation
* Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning
* Umbilical cord blood transplantation
* Haploidentical transplantation

Best standard care

Robert Lowsky

Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.

Treatment assignment was based on availability of an HLA-matched donor.

Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML

A California Cooperative Clinical Study Comparing Allogeneic Hematopoietic Cell Transplantation Using Nonmyeloablative Host Conditioning With Total Lymphoid Irradiation and Anti-thymocyte Globulin Versus Best Standard of Care in Acute Myeloid Leukemia (AML) in First Complete Remission

Overall survival defined as the time interval between the date of attaining a first complete remission (CR) and the date of death from any cause. The outcome is reported as the number of participants alive (without dispersion).

Disease-free survival is defined as the time interval between the date of attaining a first complete remission (CR) and the date of relapse. Disease free survival (DFS) will compared to conventional therapy vs Non-myeloablative Host Conditioning (NMA HCT). The outcome is reported as the number of participants which never experienced disease relapse (without dispersion).

Non-relapse mortality is defined as death that occurs after therapy, from any cause except a cause associated with relapse. This will be reported as the number of participants experiencing non-relapse mortality (a number without dispersion).

Relapse will be determined as ≥ 5% blast cells in the bone marrow, not secondary to regeneration after myelosuppressive therapy; OR emergence of extramedullary leukemia; OR the re-emergence of blasts in the peripheral blood. The outcome will be reported as the number and percentage of participants that meet these criteria (a number without dispersion).

Transplant-related mortality will be assessed as any death occurring within 6 months post-transplant, from any cause except relapse. It will be measured at 100 day and 6 months after transplant. The outcome is expressed as at the number of participants experiencing transplant-related mortality (a number without dispersion).

Complete donor hematopoietic cell chimerism was evaluated in transplant recipients. Complete donor chimerism will be assessed as the presence of \> 95% donor T-cells (CD3+) in the blood. The outcome is reported as the percentage of participants that achieve complete donor chimerism, a number without dispersion.

Early graft loss means a failure to achieve donor T-cell chimerism of \> 5% at any time after transplant. The outcome is reported as the percentage of participants that experience early graft loss, a number without dispersion.

The assessment for completion of the intended therapy (in both arms) will be reported as the percentage of participants, a number without dispersion

Genzyme, a Sanofi Company

Stanford University

Professor of Medicine

Non-serious adverse events were not collected in this study.

Participants achieving complete remission after consolidation therapy \& who have 5 of 6 HLA-match sibling donor to provide PBSC harvest for transplant. Pre-transplant subjects receive:

* Total lymphoid radiation (TLI) Days -11 to -7, and Days -4 to -1 (2 fractions on day -1)
* Anti-thymocyte globulin (ATG) Days -11 to -7
* Methylprednisolone Days -11 to -7
* Cyclosporine (CSP) Days -4 to +2
* 5+ of 6 HLA-matched CD34+ cells on Day 0
* Mycophenolate mofetil (MMF), Day 0 to Day +28

Allogeneic HSCT: Allogeneic, 5+ of 6 HLA-matched PBSC transplant from sibling, mobilized to target of 5 x 10e6 CD34+ cells/kg and \< 7 x 10e8 CD3+ cells/kg.

Anti-thymocyte globulin (ATG): 1.5 mg/kg for 5 days by IV

Cyclosporine (CSP): 6.25 mg/kg twice daily oral

Mycophenolate mofetil (MMF): 15 mg/kg twice daily oral

Total lymphoid irradiation (TLI): 80 cGy/fraction radiotherapy in 10 fractions.

Methylprednisolone sodium succinate: 1.0 mg/kg for 5 days by IV

Allo-HSCT + TLI + ATG

Regular medical care for participants who achieve complete remission after standard consolidation therapy, but do not have a 5 of 6 HLA-match sibling donor. Treatment may consist of:

* Additional consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation)
* Autologous transplantation
* Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning
* Umbilical cord blood transplantation
* Haploidentical transplantation

Best standard care: Intervention consist of:

* Consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation)
* Autologous transplantation
* Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning
* Umbilical cord blood transplantation
* Haploidentical transplantation

Best Standard Care

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Robert Lowsky, Professor of Medicine (Blood and Marrow Transplantation)

Overall Survival (OS)

Disease-free Survival (DFS)

Non-relapse Mortality

Relapse Rate

At 100 days

At 6 months

Participants in the Best Standard Care arm did not receive transplant, and are not evaluable for transplant outcomes.

Transplant-related Mortality

Complete Donor Hematopoietic Cell Chimerism

Early Graft Loss

Patients Completing the Intended Therapy in Both Arms

Overall Study

Immune System Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hypersensitivity

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Micronutrients

Reproductive Control Agents

Hematinics

Bone Density Conservation Agents

Vitamins

Amino Acids

Leucovorin

Antibodies

Antibodies, Monoclonal

Dexamethasone

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Levoleucovorin

Methotrexate

Rituximab

Vincristine

Calcium

Dexamethasone acetate

BB 1101

Folic Acid

Immunoglobulins

Sunitinib

Dasatinib

Ponatinib

Calcium, Dietary

Idarubicin

Sorafenib

Idelalisib

Ichthammol

Vitamin B Complex

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Folic Acid Antagonists

Antiviral Agents

Antidotes

Trace Elements

Tubulin Modulators

Antimitotic Agents

Protein Kinase Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Tyrosine Kinase Inhibitors

HIV Protease Inhibitors

Protease Inhibitors

Folinic Acid

Folate

Vitamin B9

Tyrosine

Patients receive cytarabine IV continuously over 24 hours on days 1-7, and idarubicin IV over 30 minutes on days 1-3.Patients receive cyclophosphamide IV over 3 hours twice daily (BID) on days 1-3, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV on day 4, dexamethasone PO on days 1-4 and 11-14, and rituximab IV on day 1 and 11 (day 11 only of course 1). Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Based on the results of the kinase inhibitor assay (In Vitro Kinase Inhibitor Assay), patients receive either sorafenib tosylate PO BID, sunitinib malate PO daily, dasatinib PO daily, ponatinib hydrochloride PO daily, ruxolitinib phosphate or idelalisib PO BID on days 8-28 in the absence of disease progression or unacceptable toxicity.

Patients receive cytarabine IV over 2 hours BID on days 2-3, methotrexate IV over 2-22 hours on day 1, methylprednisolone sodium succinate IV BID on days 1-3, leucovorin calcium IV every 6 hours until methotrexate level is \< 0.05 uM and rituximab IV on days 1 and 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Based on the results of the kinase inhibitor assay (In Vitro Kinase Inhibitor Assay), patients receive either sorafenib tosylate PO BID, sunitinib malate PO daily, dasatinib PO daily, ponatinib hydrochloride PO daily, ruxolitinib phosphate or idelalisib PO BID on days 8-28 in the absence of disease progression or unacceptable toxicity.

Doxorubicin Hydrochloride

In Vitro Kinase Inhibitor Assay

Leucovorin Calcium

Methylprednisolone Sodium Succinate

Ponatinib Hydrochloride

Ruxolitinib Phosphate

Sorafenib Tosylate

Sunitinib Malate

Vincristine Sulfate

Stephen Spurgeon

This phase IB trial studies the feasibility of using a functional laboratory based study to determine how well the test can be used to select personalized kinase inhibitor therapy in combination with standard chemotherapy in treating patients with newly diagnosed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It also evaluates safety and potential efficacy. Kinase inhibitor is a type of substance that blocks an enzyme called a kinase. Human cells have many different kinase enzymes, and they help control important cell functions. Certain kinases are more active in some types of cancer cells and blocking them may help keep the cancer cells from growing. Testing samples of blood from patients with AML and ALL in the laboratory with kinase inhibitors may help determine which kinase inhibitor has more activity against cancer cells and which one should be combined with standard of care chemotherapy. Drugs used in chemotherapy 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. Giving a personalized kinase inhibitor therapy combined with standard chemotherapy may be a better treatment for AML and ALL.

PRIMARY OBJECTIVES:

I. Determine feasibility of using an in vitro small molecule inhibitor screen to select kinase inhibitors to add to standard chemotherapy induction in AML or ALL.

SECONDARY OBJECTIVES:

I. Determine the safety and tolerability of the addition of the kinase inhibitors when added to standard chemotherapy induction.

II. Evaluate overall objective response rates at completion of induction therapy.

III. Evaluate need for re-induction at day 14 (+/- 3 days) for AML. IV. Evaluate sensitivity to kinase inhibitors using our in vitro small molecule inhibitor screen in newly diagnosed AML/ALL.

V. Determine twelve-month overall survival.

TERTIARY OBJECTIVES:

I. Perform next-generation mutational analysis in primary leukemia samples from study subjects at baseline to establish a panel of known mutations for each subject and at the time of bone marrow recovery after induction chemotherapy to measure residual disease and evaluate utility of next-generation sequencing as a method compared to flow cytometry for minimal residual disease (MRD).

II. Evaluate pharmacokinetics for each individual kinase inhibitor. III. Determine if there is a cytogenetic or other risk group that has a higher rate of treatment failure or inability to obtain results from the small molecule inhibitor screen.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (AML): Patients receive cytarabine intravenously (IV) continuously over 24 hours on days 1-7, and idarubicin IV over 30 minutes on days 1-3.

ARM II (ALL) CYCLE A: Patients receive cyclophosphamide IV over 3 hours twice daily (BID) on days 1-3, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV on day 4, dexamethasone PO on days 1-4 and 11-14, and rituximab IV on day 1 and 11 (day 11 only of course 1). Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II (ALL) CYCLE B: Patients receive cytarabine IV over 2 hours BID on days 2-3, methotrexate IV over 2-22 hours on day 1, methylprednisolone sodium succinate IV BID on days 1-3, leucovorin calcium IV every 6 hours until methotrexate level is \< 0.05 uM and rituximab IV on days 1 and 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

In all arms, based on the results of the kinase inhibitor assay, patients receive either sorafenib tosylate PO BID, sunitinib malate PO daily, dasatinib PO daily, ponatinib hydrochloride PO daily, ruxolitinib phosphate or idelalisib PO BID on days 8-28 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-6 weeks, and then for a minimum of 1 year.

Personalized Kinase Inhibitor Therapy Combined With Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia

A Phase Ib Feasibility Study of Personalized Kinase Inhibitor Therapy Combined With Induction in Acute Leukemias Who Exhibit In Vitro Kinase Inhibitor Sensitivity

A proportion of subjects whose targeted drug is identified and who start the kinase-inhibitor drug on day 8 will be estimated among all screened subjects along with the 95% confidence interval using the feasibility analysis set.

DLT events will be tabulated and summarized. The incidence of DLT and its 95% confidence interval will be provided for the entire safety analysis set as well as for each targeted drug separately.

The proportion and its 95% confidence interval will be provided for morphologic CR rate, cytogenetic CR rate, and molecular CR rate at the end of induction period. The descriptive statistics (mean, standard deviation, median, minimum and maximum) will be provided for % blasts at day 14 (+/- 3 days) for acute myeloid leukemia or show signs of disease progression requiring alternative treatment (re-induction) during the 21 day targeted treatment period (days 8-28) for acute lymphoblastic leukemia. The proportion and its 95% confidence interval will be provided for the proportion of patients who show sensitivity to each of the study drugs (i.e., IC50 \< 20% of median IC50).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML	NCT00568633	Leukemia, Myelo... Leukemia Acute Myeloid L...	Allogeneic HSCT Anti-thymocyte ... Cyclosporine (C... Mycophenolate m... Total lymphoid ... Methylprednisol... Best standard c...	50 Years - 75 Years	Stanford University
Personalized Kinase Inhibitor Therapy Combined With Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia	NCT02779283	Acute Lymphobla... Acute Myeloid L...	Cyclophosphamid... Cytarabine Dasatinib Dexamethasone Doxorubicin Hyd... Idarubicin Idelalisib In Vitro Kinase... Leucovorin Calc... Methotrexate Methylprednisol... Ponatinib Hydro... Rituximab Ruxolitinib Pho... Sorafenib Tosyl... Sunitinib Malat... Vincristine Sul...	18 Years - 64 Years	OHSU Knight Cancer Institute
Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML	NCT00568633	Leukemia, Myelo... Leukemia Acute Myeloid L...	Allogeneic HSCT Anti-thymocyte ... Cyclosporine (C... Mycophenolate m... Total lymphoid ... Methylprednisol... Best standard c...	50 Years - 75 Years	Stanford University

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