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Amphotericin B

Liposomal amphotericin B

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Antifungal Agents

Nystatin

Amphotericin B, deoxycholate drug combination

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amphotericin B deoxycholate

nystatin

David S. Gordon, MD

RATIONALE: Antifungal therapy with liposomal nystatin may reduce fever and neutropenia in patients undergoing treatment for hematologic cancer. It is not yet known whether liposomal nystatin is more effective than standard amphotericin B in treating patients with fever and neutropenia who are receiving chemotherapy for hematologic cancer or bone marrow transplantation for leukemia.

PURPOSE: Randomized phase III trial to study the effectiveness of liposomal nystatin compared with standard amphotericin B to treat fever and neutropenia in patients receiving chemotherapy for hematologic cancer or bone marrow transplantation for leukemia.

OBJECTIVES: I. Compare the efficacy of liposomal nystatin vs standard amphotericin B for the empiric treatment of persistent febrile neutropenic patients. II. Compare the incidence of drug-related toxicity or impairment and infusion-related toxicity in patients treated with liposomal nystatin vs standard amphotericin B. III. Determine the pharmacokinetics of liposomal nystatin.

OUTLINE: Randomized, double-blind study. Arm I: Antifungal Therapy. Liposomal Nystatin. Arm II: Antifungal Therapy. Amphotericin B, NSC-527017.

PROJECTED ACCRUAL: 350 evaluable patients will be studied in this multicenter trial.

Antifungal Therapy for Fever and Neutropenia in Patients Receiving Treatment for Hematologic Cancer

A PROSPECTIVE RANDOMIZED, DOUBLE-BLIND, COMPARATIVE, MULTICENTER STUDY TO EVALUATE EFFICACY AND SAFETY OF NYSTATIN AND AMPHOTERICIN B FOR EMPIRIC ANTIFUNGAL TREATMENT IN NEUTROPENIC PATIENTS

Aronex Pharmaceuticals

Antineoplastic Agents

Antirheumatic Agents

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Dermatologic Agents

Antiemetics

Neuroprotective Agents

Etoposide

Antibodies

Antibodies, Monoclonal

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Prednisone

Vincristine

Prednisolone

Etoposide phosphate

Podophyllotoxin

Immunoglobulins

Brentuximab Vedotin

Methylprednisolone

Bleomycin

Cortisone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Immunoconjugates

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Tubulin Modulators

Antimitotic Agents

Protective Agents

Immunotoxins

Keratolytic Agents

Patients receive doxorubicin hydrochloride IV over on days 1-2, bleomycin sulfate IV or SC on days 1 and 8, vincristine sulfate IV on days 1 and 8, etoposide IV on days 1-3, prednisone orally PO BID or methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive brentuximab vedotin IV on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone or methylprednisolone, and cyclophosphamide as in Arm I and vincristine sulfate IV on day 8. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity.

Bleomycin Sulfate

Doxorubicin Hydrochloride

Laboratory Biomarker Analysis

Pharmacological Study

Quality-of-Life Assessment

Questionnaire Administration

Vincristine Sulfate

Sharon M Castellino

This phase III trial studies brentuximab vedotin and combination chemotherapy to see how well they work compared to combination chemotherapy alone in treating children and young adults with stage IIB with bulk, stage IIIB, IVA, or IVB Hodgkin lymphoma. Combinations of biological substances in brentuximab vedotin may be able to carry cancer-killing substances directly to Hodgkin lymphoma cells. Chemotherapy drugs, such as doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide, 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. It is not yet known if combination chemotherapy is more effective with or without brentuximab vedotin in treating children with high-risk Hodgkin lymphoma.

PRIMARY OBJECTIVE:

I. To assess the event free survival (EFS) of a novel regimen incorporating brentuximab vedotin (Bv; Adcetris) in the chemotherapy backbone of doxorubicin hydrochloride (doxorubicin) (Adriamycin), vincristine sulfate (vincristine), etoposide, prednisone and cyclophosphamide (Bv-AVEPC) in newly diagnosed high-risk classical Hodgkin lymphoma (cHL) compared to those treated with Adriamycin, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC).

SECONDARY OBJECTIVES:

I. To determine whether children/young adults with high-risk cHL treated with Bv-AVEPC have a higher rate of early response (determined by fludeoxyglucose F 18 \[FDG\]-positron emission tomography \[PET\]) and a reduction in protocol directed radiation therapy (RT) compared to those treated with ABVE-PC.

II. To compare the rate of neuropathy (\>= grade 3) among patients treated on the Bv-AVEPC (experimental arm) to patients treated on the ABVE-PC (standard arm).

EXPLORATORY OBJECTIVES:

I. To validate and compare the Childhood Hodgkin International Prognostic Score (CHIPS) to conventional Ann Arbor stage (stages II B with bulk, III B, IV A or B) in predicting outcome in high-risk childhood cHL.

II. To determine the incidence of preferentially expressed antigen in melanoma (PRAME) and testis-specific antigens in Epstein-Barr virus (EBV)- cHL tumors and the incidence of EBV antigens (Epstein-Barr nuclear antigen 1 \[EBNA1\], Epstein-Barr virus latent membrane protein 1 \[LMP1\], large multifunctional peptidase 2 \[LMP2\]) in EBV+ cHL tumors, with the goal of developing strategies to integrate cellular therapy into treatment for newly diagnosed high-risk cHL. (Biology) III. To incorporate qualitative visual FDG-PET into response-directed treatment algorithms and explore quantitative FDG-PET and computed tomography (CT) definitions of tumor burden and response for incorporation into next generation pediatric cHL risk-stratification schemes, exploring the extension of these algorithms to young adults. (Imaging) IV. To evaluate the reduction in normal tissue irradiation associated with the current treatment approach compared to the volume of historic involved field radiation therapy (IFRT) fields. (Radiation Therapy) V. To evaluate EFS and patterns of relapse following protocol-specified RT utilization and treatment volumes. (Radiation Therapy) VI. To characterize the extent of chemotherapy induced peripheral neuropathy (CIPN), as reported by patients and parent proxies, through serial administration of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX). (Patient Reported Outcomes \[PRO\] of Peripheral Neuropathy and Health-Related Quality of Life) VII. To describe the Health-Related Quality of Life (HRQL) consequences of peripheral neuropathy over time by correlating total neuropathy scale scores with the individual items with the Child Health Ratings Inventories (CHRIs)-Global scale (e.g., physical health, pain, emotional functioning). (PRO of Peripheral Neuropathy and Health-Related Quality of Life) VIII. To perform a cross validation of the FACT-GOG-NTX with the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) to determine the performance of both measures with the use of brentuximab vedotin in a limited institutional approach in children and adolescents with cHL. (PRO of Peripheral Neuropathy and Health-Related Quality of Life) IX. To assess the resource use and cost implications of Bv in combination with chemotherapy and radiotherapy (RT) for newly diagnosed high-risk cHL in children and young adults. (Economic) X. To estimate the risk of relapse among rapidly responding lesions (RRL) subjects that have at least one lesion that is Deauville 3 at PET 2. (Follow-up of Deauville score 3 lesions on FDG-PET imaging \[confirmed by central imaging review\]) XI. To characterize the pharmacokinetics of brentuximab vedotin in children \< 13 years of age.

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

ARM I (ABVE-PC): Patients receive doxorubicin hydrochloride intravenously (IV) over on days 1-2, bleomycin sulfate IV or subcutaneously (SC) on days 1 and 8, vincristine sulfate IV on days 1 and 8, etoposide IV on days 1-3, prednisone orally (PO) twice daily (BID) or methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2.

ARM II (Bv-AVEPC): Patients receive brentuximab vedotin IV on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone or methylprednisolone, and cyclophosphamide as in Arm I and vincristine sulfate IV on day 8.

In both arms, treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte simulating factor (GCSF) or equivalent is given on both arms.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 30, 36, and 48 months.

Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB, Stage IIIB, IVA, or IVB Hodgkin Lymphoma

A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults

CHIPS will be computed for all patients and summarized by descriptive statistics. Will examine the association between CHIPS and early response by cross-tabulations and Chi-square tests within each arm separately, as well as logistic regression model where early response is the outcome variable and CHIPS the predictor variable combining the 2 arms with adjustment for randomized chemotherapy.

Descriptive statistics will be used to summarize RT doses received by normal tissues on this study. Two-sample t-test will be used to compare the doses received on this study to those on prior studies.

EFS for patients on each arm as well as those receiving ISRT or those with slow early response (SER) on each arm will be estimated. One-sample log rank test will be used to compare the observed EFS to the assumed baseline of 82% at 3 years to see if the observed EFS is significantly lower than the projection in these subsets.

The risk of relapse for cases that are RRL, but have Deauville 3 lesions, will be compared to those that are classified as complete metabolic response at PET2 with solely Deauville 1 or 2 lesions with K-sample test.

PK concentration time profile will be evaluated.

Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle. Progression is defined as an ≥50% increase of in the product of the perpendicular diameters of any of the involved nodes or nodal masses or focal organ lesions in sites that were persistently PET positive; or recurrent PET positive lesions (Deauville 4, 5) in sites that had previously been PET negative regardless of change of size, as was the development of new PET avid measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Relapse is defined in patients who achieved a prior CR but subsequently has an increase of ≥50% of the PPD in prior nodal or extranodal sites in a recurrently PET positive lesion(s), or the development of new measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Second malignancy is defined based on report of a cancer that is not considered to be classic Hodgkin Lymphoma.

The percentages of patients (with available PET scan) with no SRL and no PD will be compared between the two randomized arms to see if brentuximab vedotin in the chemotherapy backbone of doxorubicin hydrochloride, vincristine sulfate, etoposide, prednisone and cyclophosphamide (Bv-AVEPC) arm has a higher rate of early response compared to doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC) arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons.

The percentages of patients experiencing grade 3+ peripheral neuropathy assessed by the treating clinician using the modified Balis scale. The "Modified Balis scale of Pediatric Neuropathy" allows clinicians to assign a score for sensory or motor neuropathy symptoms separately. Scores range from 1 to 4 with 1 being the least symptomatic state and 4 indicating a severe debility. The percentages of patients (with a score \>/=3) will be compared between the 2 arms by two-sample Z test at 1-sided alpha level of 0.05.

National Cancer Institute (NCI)

Adverse Events are collected using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). Per the protocol, SAE reporting requirements and expedited reporting of AEs did differ for the Bv-AVEPC arm, given that Bv was under IND. All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table.

Arm I (ABVE-PC)

ARM II (Bv-AVEPC)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Region of Enrollment

Results Reporting Coordinator

Assuming a 3-year EFS of 82% (5-year EFS of 78.4%, long term EFS of 76%) for standard arm, the study will have approximately 86% power for detecting an 8% improvement in 3-year EFS in the Bv-AVEPC arm (3-year EFS of 90%, 5-year EFS of 88.0%, long term EFS of 86.7%) in log rank test.

All the eligible patients who had undergone randomization

Event Free Survival (EFS), Where Events Include Disease Progression or Relapse, Second Malignancy, or Death

All the eligible patients who had undergone randomization and had PET result by central review after completed cycle 2

Percentages of Patients With Early Response Defined as no Slow Responding Lesions (SRL) and no Progressive Disease (PD) at Any Disease Sites Determined by Positron Emission Tomography (PET) Per Deauville Criteria Through Central Review

Percentages of Patients Experiencing Grade 3+ Peripheral Neuropathy Assessed by Modified Balis Scale

Childhood International Prognostic Score (CHIPS) Score

Dose of Radiation Received by Normal Tissues Following Chemotherapy on Either Study Arm

Efficacy of Involved Site Radiotherapy (ISRT) by Analyzing the Event-free Survival of Patients Treated With Response-adapted ISRT and by Evaluating Patterns of Relapse Following ISRT

Risk of Relapse Among RRL Subjects That Have at Least One Lesion That is Deauville 3 at PET 2

Pharmacokinetic (PK) Analyses

Overall Study

Behaviors and Mental Disorders

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Myelomonocytic, Juvenile

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Neoplasm Metastasis

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Quality of Life

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

cognitive assessment

management of therapy complications

psychosocial assessment and care

quality-of-life assessment

Jean E. Sanders, MD

RATIONALE: Studying quality of life in cancer survivors may help determine the long-term effects of hematologic cancer and may help improve the quality of life for future cancer survivors.

PURPOSE: This clinical trial is studying the quality of life of adult cancer survivors who have undergone a previous bone marrow or peripheral stem cell transplant for a childhood hematologic cancer.

OBJECTIVES:

* Determine the extent to which adult cancer survivors who have undergone prior bone marrow or peripheral blood stem cell transplantation for a pediatric hematologic malignancy require ongoing health care and whether these needs change with increasing time after transplantation.
* Correlate physical capabilities, body image, physical limitations, including sexuality issues which alter or influence lifestyle, with time after transplantation in these patients.
* Determine whether cognitive abilities relative to memory and neurobehavioral ratings change with increasing time after transplantation in these patients.
* Correlate social and relationship abilities with length of time after transplantation in these patients.

OUTLINE: Patients and siblings complete a self-report quality of life questionnaire, including outcome assessments of neuroendocrine function, cognitive abilities, physical capability, and psychosocial behavior.

PROJECTED ACCRUAL: Approximately 750 patients (375 adult cancer survivors \[case group\] and 375 siblings \[control group\]) will be accrued for this study within 7 years.

Quality of Life of Adult Cancer Survivors Who Have Undergone a Previous Bone Marrow or Peripheral Stem Cell Transplant for a Childhood Hematologic Cancer

The Quality of Life of Adult Survivors Who Received a Marrow Transplant as a Child

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Antifungal Therapy for Fever and Neutropenia in Patients Receiving Treatment for Hematologic Cancer	NCT00002742	Chronic Myelopr... Infection Leukemia Lymphoma Multiple Myelom... Myelodysplastic...	amphotericin B ... nystatin	2 Years -	National Cancer Institute (NCI)
Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB, Stage IIIB, IVA, or IVB Hodgkin Lymphoma	NCT02166463	Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Childhood Hodgk... Classic Hodgkin...	Bleomycin Sulfa... Brentuximab Ved... Cyclophosphamid... Doxorubicin Hyd... Etoposide Laboratory Biom... Methylprednisol... Pharmacological... Prednisone Quality-of-Life... Questionnaire A... Vincristine Sul...	2 Years - 22 Years	National Cancer Institute (NCI)
Quality of Life of Adult Cancer Survivors Who Have Undergone a Previous Bone Marrow or Peripheral Stem Cell Transplant for a Childhood Hematologic Cancer	NCT00126477	Leukemia Lymphoma Myelodysplastic... Quality of Life	cognitive asses... management of t... psychosocial as... quality-of-life...	18 Years -	Fred Hutchinson Cancer Center
Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT	NCT02728700	Adult Hodgkin L... Adult Myelodysp... Blast Phase Chr... Childhood Chron... Childhood Hodgk... Childhood Myelo... Chronic Phase C... Myelofibrosis Primary Myelofi... Recurrent Adult... Recurrent Adult... Recurrent Adult... Recurrent Child... Recurrent Child... Recurrent Child... Recurrent Chron... Refractory Chro... Refractory Non-...	Allogeneic Hema... Laboratory Biom... Mycophenolate M... Sirolimus	3 Years - 30 Years	Stanford University
Biomarkers in Blood and Tissue Samples From Patients With Epstein-Barr Virus-Positive Hodgkin Lymphoma	NCT01490801	Lymphoma Nonneoplastic C...	DNA analysis RNA analysis cytogenetic ana... in situ hybridi... mutation analys... polymerase chai... western blottin... flow cytometry immunohistochem... medical chart r...	- 9 Years	Children's Oncology Group
Biomarkers in Blood and Tissue Samples From Patients With Epstein-Barr Virus-Positive Hodgkin Lymphoma	NCT01490801	Lymphoma Nonneoplastic C...	DNA analysis RNA analysis cytogenetic ana... in situ hybridi... mutation analys... polymerase chai... western blottin... flow cytometry immunohistochem... medical chart r...	- 9 Years	Children's Oncology Group

Spots Global Cancer Trial Database for childhood hodgkin lymphoma