Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Recurrence

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Philadelphia Chromosome

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Translocation, Genetic

Chromosome Aberrations

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Acute Leukemia of Ambiguous Lineage

Lymphosarcoma

Antineoplastic Agents

All Drugs and Chemicals

Clofarabine

Entinostat

Histone Deacetylase Inhibitors

Antimetabolites

Enzyme Inhibitors

Patients receive entinostat PO on days 1 and 8 and clofarabine IV over 2 hours on days 3-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity (only for patients \>= 60 years of age with newly diagnosed ALL or ABL who are unable or unwilling to tolerate standard multi-agent chemotherapy and patients with relapsed or refractory ALL or ABL).

Patients 40-59 years of age with newly diagnosed ALL receive standard multi-agent induction chemotherapy beginning on day 11. Patients \>= 21 years of age in their first relapse with sensitive disease begin initiation of allogeneic transplant after one course of entinostat and clofarabine.

entinostat

clofarabine

pharmacological study

laboratory biomarker analysis

Ivana Gojo

This phase I trial studies the side effects and best dose of entinostat when given together with clofarabine in treating patients with newly diagnosed, relapsed, or refractory poor-risk acute lymphoblastic leukemia or bilineage/biphenotypic leukemia. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving entinostat with clofarabine may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the feasibility, tolerability, toxicities, and maximum tolerated dose (MTD) of entinostat plus clofarabine for: adult patients age 40 and over with newly diagnosed, poor-risk Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) or bilineage/biphenotypic leukemia (ABL) prior to traditional cyclical multi-agent chemotherapy, and adults age 21 and over with relapsed or refractory ALL/ABL.

II. To determine if entinostat plus clofarabine can induce clinical responses in adults with newly diagnosed, poor-risk ALL/ABL and in adults with relapsed/refractory ALL/ABL.

SECONDARY OBJECTIVES:

I. To determine pharmacokinetics (PK) of entinostat alone and in combination with clofarabine.

II. To obtain descriptive preliminary pharmacodynamic (PD) data regarding the effects of entinostat alone and in combination with clofarabine on histone acetylation and global and gene specific methylation in leukemic blasts.

III. To obtain descriptive preliminary data regarding the effects of entinostat alone and in combination with clofarabine on deoxyribonucleic acid (DNA) damage and apoptosis in leukemic blasts and residual disease monitored by 6-color flow cytometry.

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

Patients receive entinostat orally (PO) on days 1 and 8 and clofarabine intravenously (IV) over 2 hours on days 3-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity (only for patients at least 60 years of age with newly diagnosed ALL or ABL who are unable or unwilling to tolerate standard multi-agent chemotherapy and patients with relapsed or refractory ALL or ABL).

Patients 40-59 years of age with newly diagnosed ALL receive standard multi-agent induction chemotherapy beginning on day 11. Patients at least 21 years of age in their first relapse with sensitive disease begin initiation of allogeneic transplant after one course of entinostat and clofarabine.

After completion of study treatment, patients are followed up at 30, 60, 90, 180, and 360 days.

Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia

A Phase I Study of the Histone Deacetylase Inhibitor Entinostat (SNDX-275, NSC 706995) Plus Clofarabine for Philadelphia Chromosome-Negative, Poor Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia in Newly Diagnosed Older Adults or in Adults With Relapsed and Refractory Disease

The frequency of the observed toxicities will be tabulated by type and grade.

Will be evaluated as a continuous variable. Will be estimated including the 95% confidence interval.

Will be estimated including the 95% confidence interval.

National Cancer Institute (NCI)

Infections

Bacterial Infections

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Communicable Diseases

Neoplasm Metastasis

Mycoses

Bacteremia

Diarrhea

Neutropenia

Acute Disease

Disease Attributes

Signs and Symptoms, Digestive

Agranulocytosis

Leukopenia

Cytopenia

Leukocyte Disorders

Bacterial Infections and Mycoses

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Granulocytopenia

Childhood Acute Lymphoblastic Leukemia

Anti-Infective Agents

Levofloxacin

Ofloxacin

Anti-Bacterial Agents

Cytochrome P-450 Enzyme Inhibitors

Patients receive levofloxacin PO or IV over 60-90 minutes once or twice daily beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover.

Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I.

levofloxacin

Sarah Alexander, MD

This randomized phase III trial studies how well levofloxacin works in preventing infection in young patients with acute leukemia receiving chemotherapy or undergoing stem cell transplant. Giving antibiotics may be effective in preventing or controlling early infection in patients receiving chemotherapy or undergoing stem cell transplant for acute leukemia. It is not yet known whether levofloxacin is effective in preventing infection.

PRIMARY OBJECTIVES:

I. To determine whether levofloxacin given prophylactically during periods of neutropenia to patients being treated with chemotherapy for acute leukemia (AL) or undergoing hematopoietic stem cell transplantation (HSCT) will decrease the incidence of bacteremia.

SECONDARY OBJECTIVES:

I. To determine the effect of prophylactic levofloxacin on resistance patterns of bacterial isolates from all sterile site cultures, and the evolution of antimicrobial resistance from peri-rectal swab isolates of Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus mitis.

II. To determine the effect of levofloxacin prophylaxis on total number of days of antibiotic administration (prophylactic, empiric, and treatment) in children undergoing therapy for AL or HSCT.

III. To determine whether levofloxacin prophylaxis reduces the incidence of fever with neutropenia, severe infection, and death from bacterial infection.

IV. To assess the safety of levofloxacin prophylaxis, with specific attention to musculoskeletal disorders including tendinopathy and tendon rupture.

V. To assess the impact of prophylactic levofloxacin on the incidence of Clostridium difficile-associated diarrhea (CDAD), and the incidence of microbiologically documented invasive fungal infections (IFI).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive levofloxacin orally (PO) or intravenously (IV) over 60-90 minutes once daily (QD) or twice daily (BID) beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover.

ARM II: Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I.

After completion of study therapy, patients are followed up for 1 year.

Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation

A Randomized Trial of Levofloxacin to Prevent Bacteremia in Children Being Treated for Acute Leukemia (AL) or Undergoing Hematopoietic Stem Cell Transplantation (HSCT)

A bacteremia incidence is defined as an occurrence of at least 1 episode of true (centrally reviewed) bacteremia among Acute Leukemia (AL) and Hematopoietic stem cell transplantation (HSCT) patients.

Exposure to antibiotics was considered during the infection observation period(s) was defined a priori as follows: Gram positive agents = vancomycin, linezolid, daptomycin or quinupristin/dalfopristin; Aminoglycosides = amikacin, gentamicin or tobramycin; Third or fourth generation cephalosporins = cefepime, ceftazidime, ceftriaxone or cefotaxime; Empiric antibiotics for fever and neutropenia = imipenem, meropenem, cefepime, ceftazidime or piperacillin/tazobactam

Fever and febrile neutropenia defined as Absolute Neutrophil Count (ANC) \< 1000/mm3 with a single temperature of \>38.3 degrees C (101 degrees F) or a sustained temperature of \>= 38 degrees C (100.4 degrees F) for more than one hour.

Severe infection defined as any grade 4 or 5 CTCAE catheter-related infection, enterocolitis, lung infection, sepsis, small intestine infection and other infections or infestations

Musculoskeletal conditions included at least one occurrence of arthralgia, arthritis, gait abnormality or tendinopathy.

Clostridium Difficile Associated Disease (CDAD) is defined as a positive C. difficile toxin assay result and diarrhea, CTCAE version 4, grade 2 and higher.

Children's Oncology Group

Routine reporting includes all toxicities reported via AdEERs and all grade 4 \& higher non-hematologic Adverse Events

Patients receive levofloxacin PO or IV over 60-90 minutes once or twice daily beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover.

levofloxacin: Given PO or IV

Arm I (Levofloxacin)

Arm II (Standard of Care)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

India

Mexico

Ireland

Region of Enrollment

Results Reporting Coordinator

Evaluable AL patients

Evaluable HSCT patients

All evaluable, and centrally reviewed AL and HSCT patients are reported. Ineligible patients and patients who withdrew of consent prior to treatment were excluded.

Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms

Gram positive agents

Aminoglycosides

Third or fourth generation cephalosporins

Empiric antibiotics for fever and neutropenia

Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms

Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms

Comparison of the Percentage of Patients Having Severe Infection Between Arms

Evaluable patients combined from both AL and HSCT cohorts were reported. Ineligible and withdrew of Consent prior to Tx were excluded.

Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms

Evaluable AL and HSCT Patients at Baseline

Evaluable AL and HSCT Patients at 2 Months

Evaluable AL and HSCT Patients at 12 Months

Evaluable patients who submitted musculoskeletal Case Record Form (CRF) combined from both Acute Leukemia (AL) and Hematopoietic stem cell transplantation (HSCT) cohorts at enrollment. Ineligible and withdrew of Consent prior to treatment were excluded.

Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms

Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms

Overall Study

Burkitt Lymphoma

Epstein-Barr Virus Infections

Virus Diseases

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

B-cell Lymphoma

Antirheumatic Agents

Anti-Inflammatory Agents

Cyclophosphamide

Inotuzumab Ozogamicin

Prednisone

Vincristine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Antibiotics, Antitubercular

Immunotoxins

Immunoconjugates

Combination chemotherapy and inotuzumab ozogamicin - Dose level 1 Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and 0.4 mg/m2 inotuzumab ozogamicin IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Combination chemotherapy and inotuzumab ozogamicin - Dose level 2 Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.6 mg/m2 on day 1 and 0.4 mg/m2 on day 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Combination chemotherapy and inotuzumab ozogamicin - Dose level 3 Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.4 mg/m2 on day 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Combination chemotherapy and inotuzumab ozogamicin - Dose level 4 Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.4 mg/m2 on days 8 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Combination chemotherapy and inotuzumab ozogamicin - Dose level 5 Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Combination chemotherapy and inotuzumab ozogamicin - Maximum Tolerated Dose Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

cyclophosphamide

vincristine sulfate

prednisone

inotuzumab ozogamicin

Anjali Advani

This phase I trial studies the side effects and best dose of inotuzumab ozogamicin when given together with combination chemotherapy in treating patients with relapsed or refractory acute leukemia. Immunotoxins, such as inotuzumab ozogamicin, can find cancer cells that express cluster of differentiation (CD)22 and kill them without harming normal cells. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving inotuzumab ozogamicin together with combination chemotherapy may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To assess the safety of inotuzumab ozogamicin in combination with cyclophosphamide, vincristine (vincristine sulfate) and prednisone (CVP) and to determine the maximum tolerated dose (MTD) of inotuzumab ozogamicin in this regimen for patients with relapsed or refractory CD22+ acute leukemia (B-cell acute lymphoblastic leukemia \[B-ALL\], mixed phenotype, and Burkitt's).

SECONDARY OBJECTIVES:

I. To estimate the preliminary activity (response rate: complete remission \[CR\] + complete remission with incomplete count recovery \[CRi\]) of this combination in the expansion cohort.

II. To estimate the frequency and severity of toxicities of this combination in this patient population.

OUTLINE: This is a dose-escalation study of inotuzumab ozogamicin.

Patients receive cyclophosphamide intravenously (IV) on day 1, vincristine sulfate IV on day 1, prednisone orally (PO) on days 1-5, and inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 3 months for 1 year, and then every 6 months for 1 year.

S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

S1312, A Phase I Study of Inotuzumab Ozogamicin (NSC-772518) in Combination With CVP (Cyclophosphamide, Vincristine, Prednisone) for Patients With Relapsed/Refractory CD22-Positive Acute Leukemia (Including B-ALL, Mixed Phenotypic Leukemia, and Burkitt's Leukemia)

To determine the maximum tolerated dose (MTD) of inotuzumab ozogamicin in this regimen for patients with relapsed or refractory CD22+ acute leukemia (B-cell acute lymphoblastic leukemia \[B-ALL\], mixed phenotype, and Burkitt's). The MTD is defined as the highest dose studied in which the incidence of dose-limiting toxicities is \< 33% using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

The response rate (CR + CRi) is defined as the rate of complete remission (CR) + complete remission with incomplete count recovery (CRi). Complete remission (CR) is defined as \< 5% marrow aspirate blasts, neutrophils ≥ 1000/uL, platelets \> 100,000/uL, no blasts in peripheral blood, and C1 Extramedullary disease status. C1 Extramedullary disease status is characterized by complete disappearance of all measurable and non-measurable extramedullary disease with the exception of lesions for which the following must be true: for participants with at least one measurable lesion, all lesions must have reduced by 75% in sum of products of greatest diameters (SPD), have no new lesions, and the spleen and other previously enlarged organs must have regressed in size. Complete remission with incomplete platelet recovery (CRi) is defined the same as CR, except absolute neutrophil count may be \<1000/uL and/or platelet count may be ≤ 100,000/uL.

Number of participants with Grade 3-5 adverse events that are possibly, probably or definitely related to study drug are reported by given type of adverse event.

SWOG Cancer Research Network

All adverse events, regardless of attribution and grade, are reported.

Combination chemotherapy and inotuzumab ozogamicin � Dose level 1

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and 0.4 mg/m2 inotuzumab ozogamicin IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab Dose Level 1

Combination chemotherapy and inotuzumab ozogamicin - Dose level 2

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.6 mg/m2 on day 1 and 0.4 mg/m2 on day 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab Dose Level 2

Combination chemotherapy and inotuzumab ozogamicin - Dose level 3

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.4 mg/m2 on day 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab Dose Level 3

Combination chemotherapy and inotuzumab ozogamicin - Dose level 4

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.4 mg/m2 on days 8 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab Dose Level 4

Combination chemotherapy and inotuzumab ozogamicin - Dose level 5

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab Dose Level 5

Combination chemotherapy and inotuzumab ozogamicin - Maximum Tolerated Dose

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour at 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab MTD

SWOG Statistician

Day 1 Dose

Day 8 Dose

Day 15 Dose

Combination chemotherapy and inotuzumab ozogamicin

Patients receive cyclophosphamide IV on day 1, vincristine sulfate IV on day 1, prednisone PO on days 1-5, and inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

CVP + Inotuzumab

Includes eligible patients who received treatment among all arms.

MTD of Inotuzumab Ozogamicin With CVP for Patients With Relapsed or Refractory CD22+ Acute Leukemia

MTD arm only, including eligible patients who received treatment and were evaluable for response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia	NCT01132573	Acute Leukemias... Philadelphia Ch... Recurrent Adult... Untreated Adult...	entinostat clofarabine pharmacological... laboratory biom...	21 Years -	National Cancer Institute (NCI)
Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation	NCT01371656	Acute Leukemias... Bacterial Infec... Diarrhea Fungal Infectio... Musculoskeletal... Neutropenia Recurrent Child... Recurrent Child... Secondary Acute... Untreated Child...	levofloxacin	6 Months - 21 Years	Children's Oncology Group
S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia	NCT01925131	Acute Leukemias... B-cell Adult Ac... Philadelphia Ch... Recurrent Adult... Recurrent Adult...	cyclophosphamid... vincristine sul... prednisone inotuzumab ozog... laboratory biom...	18 Years -	SWOG Cancer Research Network
AT9283 in Treating Young Patients With Relapsed or Refractory Acute Leukemia	NCT01431664	Leukemia	multikinase inh... laboratory biom... pharmacological...	- 18 Years	Cancer Research UK

Spots Global Cancer Trial Database for acute leukemias of ambiguous lineage