Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Neoplasms

Hematologic Diseases

Neoplasms by Histologic Type

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

All Drugs and Chemicals

Tosedostat

Enzyme Inhibitors

oral, once daily administration of tosedostat to evaluate its efficacy, safety and tolerability

In Part A, approximately 70 subjects will be randomized to one of 2 dose regimens of tosedostat which will be administered orally, once daily. The dose regimens of tosedostat will be:

* 120 mg for 6 months once daily, OR
* 240 mg (induction dose) once daily for 2 months, followed by 120 mg(maintenance dose) for 4 months

In Part B a further 130 subjects will receive the dose regimen of tosedostat identified in Part A as being appropriate, based on the interim analysis during Part A.

Jorge E Cortes, MD

Karen Yee, MD

Eric Feldman, MD

David Rizzieri, MD

Joseph Jurcic, MD

Richard Larson, MD

Hanna J Khoury, MD

Harry Erba, MD

Samir Parekh, MD

Aarthi Shenoy, MD

Anjali Advani, MD

Shambavi Richard, MD

Steven Allen, MD

Ehab Attalah, MD

John Storring, MD

Gerrit J Ossenkoppele, MD

Pieter Sonneveld, MD

Gary Schiller, MD

Peter Westervelt, MD

Julio Hajdenberg, MD

Stuart Goldberg, MD

The purpose of this study is to evaluate the efficacy and safety of tosedostat in elderly patients suffering from refractory or relapsed AML.

There is an urgent need for novel compounds and treatment strategies for elderly patients with AML, particularly those with refractory or relapsed disease for whom there are few effective treatment options. Treatment options for elderly patients are further limited by co-morbidity and tolerability constraints.

Tosedostat is a new aminopeptidase inhibitor, which in preclinical experiments has shown potent activity in both in vitro and in vivo cancer models as a single agent. In early clinical studies particularly good results have been observed in refractory and relapsed AML in older patients and these observations form the basis for the current study.

This multi-center, open label phase II study will enrol approximately 70 subjects in Part A and 130 subjects in Part B.

Safety and Anti-Disease Activity of Oral Tosedostat (CHR-2797) in Elderly Subjects With Refractory or Relapsed AML

The OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects With Treatment Refractory or Relapsed Acute Myeloid Leukemia

Quintiles, Inc.

Chroma Therapeutics

Symptoms and General Pathology

Diseases and Abnormalities at or Before Birth

Immune System Diseases

Nutritional and Metabolic Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Anemia, Sickle Cell

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Anemia

Thalassemia

Anemia, Aplastic

Vitamin D Deficiency

Lymphoma

Bone Marrow Diseases

Hemolysis

Anemia, Hemolytic

Anemia, Hemolytic, Congenital

Hemoglobinopathies

Genetic Diseases, Inborn

Avitaminosis

Deficiency Diseases

Malnutrition

Nutrition Disorders

Bone Marrow Failure Disorders

Pancytopenia

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Sickle Cell Anemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Aplastic Anemia

Childhood Acute Lymphoblastic Leukemia

Lymphosarcoma

Micronutrients

Bone Density Conservation Agents

Vitamins

Vitamin D

Cholecalciferol

Hydroxycholecalciferols

Calcifediol

Ergocalciferols

Trace Elements

Hormones

Calcium

Calcium, Dietary

Vitamin D3

Calciferol

Ergocalciferol

Vitamin D2

Patients will take a single oral dose of vitamin D3 based on age and initial vitamin D level. A patient will be classified as sufficient, insufficient, or deficient at the start of therapy. Following this dose, patients will also be given standard vitamin D3 supplementation according to current Endocrine Society Guidelines.

Patients will be given standard vitamin D3 supplementation during transplant in accordance with standard of care per Endocrine Society Guidelines. This supplementation is based on a patient's initial vitamin D level.

The single, oral dose of vitamin D3 is based on patient's age and baseline 25-hydroxy-vitamin D level. Dosing is as follows: (1) For children under 3 years of age. 200000IU for those deficient, 150000IU for those insufficient, and 100000IU for those sufficient; (2) For children 3-12 years of age, 400000IU for those deficient, 350000IU for those insufficient, and 200000IU for those sufficient; (3) For children greater than 12 years of age, 600000IU for those deficient, 500000IU for those insufficient, and 300000IU for those sufficient. This is a single, one time oral dose given prior to the start of transplant.

Those who have sufficient vitamin D will be supplemented with 400-600IU/day of Vitamin D3 orally.

Those who have insufficient or are deficient in vitamin D will be supplemented with 50,000IU/week of Vitamin D3 orally.

Standard Vitamin D3 Supplementation

Alexander Ngwube, MD

Kayla Burgett

Research has suggested that children with sufficient vitamin D levels undergoing hematopoietic stem cell transplant (HSCT) have improved outcomes, including lower incidences of infection and graft-versus-host disease (GVHD), as well as overall improved survival. However, supplementation in children undergoing HSCT has shown to be a challenge using standard or aggressive supplementation strategies. The primary objective of this study is to determine the safety and efficacy of a single, high dose oral vitamin D (Stoss Therapy) at the start of transplant followed by maintenance supplementation in children undergoing HSCT.

Comorbidities and complications including infection, organ system toxicity, graft-versus-host disease (GVHD) and disease recurrence are some of the biggest contributors to quality of life and mortality in children undergoing hematopoietic stem cell transplant (HSCT). Research has suggested that patients with sufficient vitamin D levels during transplant have improved outcomes, including lower incidences of infection and acute GVHD, as well as overall improved survival. Prior research has shown that chronically ill children are at risk for vitamin D deficiency, including those undergoing HSCT. Data has shown populations with as many as 70% of HSCT patients have insufficient levels of vitamin D at time of transplant. While several studies have attempted methods of vitamin D supplementation in this subset of patients, there has not been success with either standard or aggressive supplementation strategies.

Single high-dose oral vitamin D therapy, known as stoss therapy, has been used in other chronically ill children where adequate levels of vitamin D are difficult to attain. Stoss therapy suggests a single high-dose followed by maintenance dosing would be adequate to replete and maintain vitamin D levels in chronically ill children. While it has been shown to be effective with no evidence of toxicity in patients with rickets and cystic fibrosis, its safety and efficacy has not been studied in the transplant setting. However, there is an urgent need to identify a modifiable factor may reduce the occurrence and/or severity of HSCT associated complications. The overall objective of this study is to determine the effectiveness of a single, high dose oral vitamin D (Stoss Therapy) followed by maintenance supplementation in children undergoing HSCT. This change will result in a new and innovative approach to maintaining adequate vitamin D levels during pediatric HSCT, with the long term goal of reducing morbidity and mortality.

Our primary goal is to assess the safety and efficacy of a single, high dose of vitamin D followed by maintenance supplementation in children undergoing HSCT. Our secondary goal is to identify the effects of adequate vitamin D levels on early clinical outcomes such as cytokine levels, graft versus host disease, immune recovery, rejection, relapse, infection rates in pediatric HSCT patients.

Patients enrolled in the study will be randomized to either a control or intervention arm prior to the start of transplant using block randomization of blocks of 6. Those randomized to the intervention arm will receive the intervention (Stoss Therapy dosing of vitamin D) at the start of transplant followed by maintenance supplementation of vitamin D according to standard of care. Those randomized into the control arm will receive only maintenance supplementation of vitamin D according to standard of care throughout transplant.

A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT

A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 (Stoss Therapy) in Pediatric Patients Undergoing HSCT to Prevent Vitamin D Deficiency and Insufficiency During Transplant

In order to monitor the safety of stoss therapy, patients will be monitored for any clinical signs or symptoms of hypervitaminosis D, including abdominal pain, dehydration, and fatigue. Patients will be monitored for hypercalcemia and hyperphosphatemia with weekly complete metabolic panels and serum phosphorus during the first 100 days of transplant. Patients will have repeat measurements of serum 25(OH)D levels will be obtained at Day +30 to ensure they do not have hypervitaminosis D at that time.

All patients will have baseline serum 25(OH)D levels obtained prior to transplant. At baseline, patient will be classified as being sufficient (\>30ng/mL), insufficient (21- 29ng/mL), or deficient (\<20ng/mL) in serum vitamin D. All patients will then undergo treatment based on their trial arm and baseline levels of vitamin D. Patients will have repeat measurements of serum 25(OH)D levels will be obtained at Day +100 of transplant. At this time they will again be classified as being sufficient (\>30ng/mL), insufficient (21- 29ng/mL), or deficient (\<20ng/mL) in serum vitamin D following therapy to assess if the therapy was efficacious in repleting and maintaining their serum vitamin D level.

All incidences of GVHD will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100

Immune recovery will be obtained at Day +100 as per standard of care and recorded in the medical record

All incidences of rejection will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100

All incidences of relapse will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100

All incidences of infection will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100

All incidences of mortality will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100

Phoenix Children's Hospital

Resident Physician

Cytopenia

Precancerous Conditions

Hematinics

Epoetin Alfa

Deferasirox

Iron

Chelating Agents

Iron Chelating Agents

Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study.

Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.

provided as dispersible tablets for oral use in 125 and 250, 500 mg

Deferasirox DFX, DT

Erythropoietin alpha

provided as film-coated tablet for oral use in 90, 180, 360 mg strengths

Deferasirox DFX, FCT

Novartis Pharmaceuticals

The primary purpose of this trial was is to assess the effect of treatment with deferasirox combined with erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1-risk myelodysplastic syndrome. The addition of deferasirox to erythropoietin can lead to a potential synergism with the reduction of reactive oxygen species, through both the NF-kB pathway and the control of free toxic iron. This may create a better environment in the bone marrow for a better response with erythropoietin.

This study was designed to test in a prospective way the combination of deferasirox with erythropoietin in terms of their effect on hematopoiesis.

This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.

Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.

An Open-label, Phase II, Randomized, Pilot Study to Assess the Effect in Term of Erythroid Improvement of Deferasirox Combined With Erythropoietin Compared to Erythropoietin Alone in Patients With low-and Int-1-risk Myelodysplastic Syndrome.

Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL. Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders

Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline \>= 1.5 g/dL (baseline \< 11 g/dL), neutrophil response: increase from baseline \>= 100% and increase \> 0.5 × 10\^9/L (baseline \<1 × 10\^9/L), platelet response: increase from baseline \>= 30 × 10\^9/L (baseline \<100 × 10\^9/L) according to modified IWG 2006 criteria

Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline \>0.5 × 10\^9/L (baseline = 1.0 × 10\^9/L ), platelet improvement: increase from baseline ≥ 30 × 10\^9/L (baseline = 100 × 10\^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline\<11 g/dL)

Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline\<11 g/dL)

Absolute change in platelets and neutrophil levels for participants showing improvement: neutrophil improvement: increase from baseline \>0.5 × 10\^9/L (baseline = 1.0 × 10\^9/L ), platelet improvement: increase from baseline ≥ 30 × 10\^9/L (baseline = 100 × 10\^9/L)

Erythroid response: hemoglobin increase from baseline \> = 1.5 g/dL (baseline \<11 g/dL)

Erythroid response: hemoglobin increase from baseline \> = 1.5 g/dL (baseline \<11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response

Absolute change in serum ferritin from baseline

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.

There was no washout period during the study before switch of treatment. Therefore effects (including AEs) from long lasting treatment like EPO can potentially still be observed after the switch, e.g. from EPO+DFX to DFX alone. Thus the resulting includes both treatments (DFX-EPO category). The same applies for staring EPO alone and switching to EPO plus DFX.

Patients receiving EPO during the first 12 weeks and no switching to EPO+DFX arm

EPO A

Patients receiving EPO+DFX from week 1 and continuing with EPO+DFX after 12 weeks or with DFX alone after 12 weeks

EPO+DFX DT

Patients receiving EPO alone and switched to EPO+DFX after 12 weeks of treatment

EPO+DFX FCT

Switched to DFX+EPO After 12 Weeks

Starting dose was erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were switched to the combination arm. At any time when erythroid response was achieved, erythropoietin treatment was stopped until end of study.

Erythropoietin Alpha

Starting dose was deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, erythropoietin dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were discontinued from the study. At any time when erythroid response was achieved, erythropoietin treatment was stopped study and Deferasirox treatment was continued until end of study

Deferasirox + Erythropoietin Alpha

Total

Age, Continuous

Sex: Female, Male

Caucasian

Asian

Race/Ethnicity, Customized

Study Director

Difference in Percentage of Patients Achieving Erythroid Response Within 12 Weeks, by Treatment Group (Full Analysis Set)

Absolute Change From Baseline to Post-baseline Value for Hemoglobin(g/dL)(Full Analysis Set)

Hematologic improvement

Neutropil improvement

Platelet improvement

Hemoglobin improvement

Number of patients who met criteria varied across parameters

Summary of Hematologic Improvement in Patients Randomized to EPO+DFX and EPO Alone, Within 24 Weeks of Treatment (Full Analysis Set)

Absolute Change in Hemoglobin Values up to 24 Weeks

Platelets

Neutrophils

Absolute Change in Platelets and Neutrophil Levels up to 24 Weeks

Patients randomized to EPO alone with inadequate response at 12 weeks who had been switched over to combination EPO+DFX

EPO+DFX (12 Weeks)

Summary of Erythroid Response in Participants Randomized to EPO Alone at Baseline and Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)

Patients who were in EPO alone group and were not switched to EPO+DFX after 12 weeks,

EPO (24 Weeks)

Summary of Erythroid Response Within 24 Weeks in Participants Randomized to EPO at Baseline and Not Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)

Responders - Week 5

Responders - Week 9

Responders - Week 13

Responders - Week 17

Responders - Week 21

Non-responders - Week 5

Non-responders - Week 9

Non-responders - Week 13

Number of patients analyzed varied by visit

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Anti-Disease Activity of Oral Tosedostat (CHR-2797) in Elderly Subjects With Refractory or Relapsed AML	NCT00780598	Acute Myeloid L... AML	Tosedostat	60 Years -	Chroma Therapeutics
A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT	NCT03176849	Vitamin D Defic... Stem Cell Trans... Pediatric Cance... Blood Disorder Pediatric Acute... Pediatric Acute... Myelodysplastic... Sickle Cell Ane... Aplastic Anemia Thalassemia in ...	Vitamin D3 Standard Vitami...	1 Year - 25 Years	Phoenix Children's Hospital
Safety and Anti-Disease Activity of Oral Tosedostat (CHR-2797) in Elderly Subjects With Refractory or Relapsed AML	NCT00780598	Acute Myeloid L... AML	Tosedostat	60 Years -	Chroma Therapeutics
A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT	NCT03176849	Vitamin D Defic... Stem Cell Trans... Pediatric Cance... Blood Disorder Pediatric Acute... Pediatric Acute... Myelodysplastic... Sickle Cell Ane... Aplastic Anemia Thalassemia in ...	Vitamin D3 Standard Vitami...	1 Year - 25 Years	Phoenix Children's Hospital
Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.	NCT01868477	Low and Int 1-r...	Deferasirox DFX... Erythropoietin ... Deferasirox DFX...	18 Years -	Novartis

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