A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium (Other)
• Overall Status: Completed
• CT.gov ID: NCT01861002
• Collaborator: Gateway for Cancer Research (Other)
• Enrollment: 15
• Locations: 23
• Arms: 2
• Actual Duration (Months): 14.2
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Phase I study with a conditional cohort expansion phase to evaluate the feasibility of, and to obtain preliminary efficacy data about, pretreatment with Azacytidine (AZA) for 5 days followed by fludarabine/cytarabine chemotherapy regimen in pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients who are refractory to primary treatment or who relapsed.

Condition or Disease	Intervention/Treatment	Phase
Lymphoblastic Leukemia, Acute, Childhood; Myelogenous Leukemia, Acute, Childhood	Drug: Azacytidine; Drug: Fludarabine; Drug: Cytarabine; Drug: Intrathecal (IT) Cytarabine; Drug: Intrathecal Methotrexate (IT MTX)	Phase 1

Detailed Description

Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemia development, drug resistance, and relapse. It has been shown that pretreating leukemia cells with AZA or decitabine could partially reverse the aberrant DNA methylation, restore the expression of tumor suppressor gene important for apoptosis, and sensitize cells to subsequent killing by cytotoxic agent. Since cytarabine and decitabine share the same mechanisms of resistance, we use AZA to test the novel epigenetic "priming" approach. This is a phase I clinical study with expansion phase, using hypomethylating agent, 5-azacytidine (AZA), in sequential with chemotherapy to evaluate whether epigenetic "priming" can reverse aberrant DNA methylation, overcome drug resistance, and increase response in relapsed/refractory AML.

The chemotherapy regimen to be used in this study is fludarabine and cytarabine. This regimen has substantial activity in leukemia and has been widely used in treating pediatric patients with relapsed/refractory AML and ALL in the past several decades. In BFM relapsed AML 2001/01 study, FLAG (fludarabine, cytarabine and G-CSF) chemotherapy regimen showed significant activity in AML with 4 year OS around 36%. Since the use of G-CSF in conjunction with fludarabine/cytarabine didn't improve the overall survival of patient in a randomized trial, only fludarabine and cytarabine will be used in this study to decrease the incidence of leukocytosis related complications. This regimen is very similar to the chemotherapy regimen proposed for the next relapsed AML trial within the Children's Oncology Group (COG). If this trial proves to be safe and active, it will provide the foundation and smooth transition to larger statistically powered nationwide phase II clinical trials by COG.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML
• Actual Study Start Date: May 22, 2013
• Actual Primary Completion Date: Jul 28, 2014
• Actual Study Completion Date: Jul 28, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AML Arm Participants with Acute Myeloid Leukemia (AML) Intervention: Azacytidine (Dose Level 1 @ 75 mg/m2/day) Fludarabine 30 mg/m2/dose Cytarabine 2000 mg/m2/dose Intrathecal (IT) Cytarabine	Drug: Azacytidine; Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.; Other Names: 5 Azacytidine Vidaza ; Drug: Fludarabine; 30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses; Other Names: fludarabine phosphate Fludara 2-fluoro-ara-AMP Oforta ; Drug: Cytarabine; 2000 mg/m2/dose intravenous infusion over 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 6 to 10, total 5 doses.; Other Names: Cytosar-U Ara-C Arabinosylcytosine cytosine arabinoside ; Drug: Intrathecal (IT) Cytarabine; Intrathecally to AML patients on day 1 of course 1 and 2. Omit on day 1 of course 1 if patient received IT therapy within 7 days prior to study enrollment IT therapy may be given during the end of course 1 disease evaluation and repeated every 7 days For patients with CNS disease, IT cytarabine can be given weekly until the CSF is clear. Two additional doses of IT cytarabine should be given weekly after the initial CSF clearing. It is permitted to change to intrathecal triple therapy (ITT) if persistent blasts are present in the CSF based on the treating physician's clinical judgment. Cytarabine dose defined by age: 30 mg for patients age 1-1.99 50 mg for patients age 2-2.99 70 mg for patients >3 years of age ITT Dosing: Age (yrs) - Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC): - 1.99 MTX: 8 mg, HC: 15 mg, ARAC: 30 mg - 2.99 MTX: 10 mg, HC: 25 mg, ARAC: 50 mg 3 - MTX: 12 mg, HC: 35 mg, ARAC: 70 mg; Other Names: (See Cytarabine)
Experimental: ALL Arm Patients with Acute Lymphocytic Leukemia Intervention: Azacytidine (Dose Level 1 @ 75 mg/m2/day) Fludarabine 30 mg/m2/dose Cytarabine 2000 mg/m2/dose Intrathecal Methotrexate (IT MTX)	Drug: Azacytidine; Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.; Other Names: 5 Azacytidine Vidaza ; Drug: Fludarabine; 30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses; Other Names: fludarabine phosphate Fludara 2-fluoro-ara-AMP Oforta ; Drug: Cytarabine; 2000 mg/m2/dose intravenous infusion over 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 6 to 10, total 5 doses.; Other Names: Cytosar-U Ara-C Arabinosylcytosine cytosine arabinoside ; Drug: Intrathecal Methotrexate (IT MTX); Intrathecally to patients with ALL on day 1 of course 1 and 2. Omit IT MTX on Day 1 of course 1 if patient received IT therapy within 7 days prior to study enrollment IT therapy may be given during the end of course 1 disease evaluation and repeated every 7 days For patients with CNS 2 or 3 disease, IT MTX can be given weekly until the CSF is clear. Two additional doses of IT MTX should be given weekly after the initial clearing of the CSF. It is permitted to change to ITT if persistent blasts are present in the CSF. Methotrexate dose defined by age 8 mg for patients age 1-1.99 10 mg for patients age 2-2.99 12 mg for patients 3-8.99 years of age 15 mg for patients >9 years of age Triple IT Therapy Dosing: Age (yrs): Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC): - 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg - 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg - 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg; Other Names: Otrexup Rasuvo Rheumatrex Trexall Amethopterin Methotrexate Sodium

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) [From Day 1 to Day 42 (Cycle 1)]

   To evaluate the side effects of giving Azacytidine before and during chemotherapy using the standard drugs Fludarabine, Cytarabine, IT Cytarabine (AML patients) and IT methotrexate (ALL patients)

Secondary Outcome Measures

1. Disease Response Rate After Treatment [Between Days 36-42 of Courses 1 and 2]

   CR is defined as a bone marrow with < 5% blast by morphology, no evidence of extramedullary disease, and recovery of peripheral counts (ANC ≥ 1000/μl and platelet counts ≥ 100,000/μl). CR with incomplete count recovery (CRi) was defined as CR without recovery of ANC and/or platelets. Partial response (PR) was defined as complete disappearance of circulating blasts and a decrease of at least 50% of blasts in the bone marrow. Progressive disease (PD) was defined as an increase of at least 25% in the absolute number of bone marrow or circulating blasts, development of new sites of extramedullary disease, or other laboratory or clinical evidence of progression of disease. Stable disease (SD) referred to patient who did not satisfy the criteria for either CR, CRi, PR or PD.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients must be ≥ 1 and ≤ 21 years of age.

Diagnosis

1. Patients with AML must have ≥5% blasts (by morphology) in the bone marrow.

2. Patients with ALL must have an M2 or M3 marrow (≥5% blasts by morphology).

3. Patients may have disease in the central nervous system (CNS) or other sites of extramedullary disease. No cranial irradiation is allowed during the protocol therapy.

4. Patients with secondary AML are eligible.

5. Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age.

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

Myelosuppressive chemotherapy - the eligibility criteria is different between phase I and expansion phase

1. Phase I

• Any patient with AML in 1st or greater relapse, OR

• Any patient with ALL in 2nd or greater relapse, OR

• Patients with AML or ALL failed to go into remission after first or greater relapse, OR

• Patients with AML or ALL failed to go into remission from original diagnosis after two or more courses of induction attempts.

1. Expansion phase - will be restricted to AML patients only

2. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of azacytidine. It is recommended to use hydroxyurea in patients with significant leukocytosis (WBC > 50,000/L) to control blast count before initiation of systemic protocol therapy.

3. Patients who relapsed while they are receiving cytotoxic therapy (including AZA , decitabine, or vorinostat) At least 14 days must have elapsed since the completion of the cytotoxic therapy.

Hematopoietic stem cell transplant: Patients who have experienced their relapse after a stem cell transplant are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are at least 90 days post-transplant at the time of enrollment.

Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with filgrastim or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines.

Radiation Therapy (XRT): Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to non-CNS chloromas; ≥ 90 days must have elapsed if prior total body radiation or craniospinal radiation.

Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following laboratory values:

• Patient must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) greater than or equal to 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender.

• Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age.

Adequate Cardiac Function Defined as: Shortening fraction greater than or equal to 27% by echocardiogram, OR ejection fraction greater than or equal to 50% by radionuclide angiogram (MUGA).

Reproductive Function

• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

• Female patients with infants must agree not to breastfeed their infants while on this study.

• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria:

Patients will be excluded if they have a known allergy to any of the drugs used in the study.

Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.

Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.

Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
2	UCSF School of Medicine	San Francisco	California	United States	94143-0106
3	Children's National Medical Center	Washington	District of Columbia	United States	20010
4	Children's Healthcare of Atlanta, Emory University	Atlanta	Georgia	United States	30322
5	Johns Hopkins University	Baltimore	Maryland	United States	21287
6	Dana Farber	Boston	Massachusetts	United States	02215
7	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109-0914
8	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota	United States	55404-4597
9	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
10	Children's Hospital New York-Presbyterian	New York	New York	United States	10032
11	Levine Children's Hospital at Carolinas Medical Center	Charlotte	North Carolina	United States	28203
12	Rainbow Babies & Children's Hospital	Cleveland	Ohio	United States	44106
13	Nationwide Childrens Hospital	Columbus	Ohio	United States	43205
14	Vanderbilt Children's Hospital	Nashville	Tennessee	United States	37232
15	University of Texas at Southwestern	Dallas	Texas	United States	75235
16	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
17	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
18	Seattle Children's Hospital	Seattle	Washington	United States	98105
19	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
20	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
21	Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
22	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
23	Sainte-Justine University Hospital Center	Montreal	Quebec	Canada	H3T-1C5

Sponsors and Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium
• Gateway for Cancer Research

Investigators

• Study Chair: Weili Sun, MD, PhD, Children's Hospital Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site

Publications

None provided.

• Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
• ClinicalTrials.gov Identifier: NCT01861002
• Other Study ID Numbers: T2011-002
• First Posted: May 23, 2013
• Last Update Posted: Jun 9, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium: Relapse; Lymphoblastic; Leukemia; Azacytidine; Refractory; Myelogenous; Acute; Childhood; Pediatric; ALL; AML; Methylation; Epigenetic therapy
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Acute Disease; Vidarabine; Cytarabine; Methotrexate; Fludarabine phosphate; Azacitidine; Fludarabine

Study Results

Participant Flow

Arm/Group Title	75 mg/m2/Day Azacytidine
Arm/Group Description	Azacytidine (Dose Level @ 75 mg/m2/day),all patients will start at Dose Level 1. If 2 DLTs are observed within the first 6 patients enrolled, dose will be reduced to Dose Level 0 @ 50 mg/m2/day Fludarabine 30 mg/m2/dose Cytarabine 2000 mg/m2/dose Intrathecal (IT) Cytarabine
Period Title: Overall Study
STARTED	15
COMPLETED	14
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Dose Level 1 75 mg/m2/Day
Arm/Group Description	This arm is comprised of the AML and ALL participants that completed Dose Level 1 75 mg/m2/day
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	9.7
Sex: Female, Male (Count of Participants)
Female	6 42.9%
Male	8 57.1%
Central Nervous System (CNS) Status (Count of Participants)
CNS Negative	8 57.1%
CNS Positive	6 42.9%
Bone Marrow Status (at study entry) (Count of Participants)
M2 (5-25% Leukemic Blasts)	5 35.7%
M3 (>25% Leukemic Blasts)	9 64.3%
# Prior treatment regimens (Count of Participants)
1 prior treatment	4 28.6%
2 prior treatments	4 28.6%
3 or more prior treatments	6 42.9%
Prior Hematopoetic Stem Cell Transplantation (HSCT) (Count of Participants)
No Previous HSCT	9 64.3%
Previous HSCT	5 35.7%
White blood cell (WBC) Count (Thousand cells / mm^3) [Median (Full Range) ]
Median (Full Range) [Thousand cells / mm^3]	6.89
Peripheral blasts (Percentage of cells) [Median (Full Range) ]
Median (Full Range) [Percentage of cells]	16
Bone marrow blasts (Percentage of cells) [Median (Full Range) ]
Median (Full Range) [Percentage of cells]	68.5

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
Description	To evaluate the side effects of giving Azacytidine before and during chemotherapy using the standard drugs Fludarabine, Cytarabine, IT Cytarabine (AML patients) and IT methotrexate (ALL patients)
Time Frame	From Day 1 to Day 42 (Cycle 1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose 75 mg/m2/Day Azacytidine Diagnosed With AML	Dose 75 mg/m2/Day Azacytidine Diagnosed With ALL
Arm/Group Description	Evaluable Participants who received azacytidine @ 75 mg/m2/day (Dose Level 1)	Evaluable ALL participants who received azacytidine @ 75 mg/m2/day (Dose Level 1)
Measure Participants	13	2
# of patients with DLT	0 0%	0 NaN
# of patients without DLT	12 85.7%	2 NaN
# of patients not evaluable	1 7.1%	0 NaN

2. Secondary Outcome

Title	Disease Response Rate After Treatment
Description	CR is defined as a bone marrow with < 5% blast by morphology, no evidence of extramedullary disease, and recovery of peripheral counts (ANC ≥ 1000/μl and platelet counts ≥ 100,000/μl). CR with incomplete count recovery (CRi) was defined as CR without recovery of ANC and/or platelets. Partial response (PR) was defined as complete disappearance of circulating blasts and a decrease of at least 50% of blasts in the bone marrow. Progressive disease (PD) was defined as an increase of at least 25% in the absolute number of bone marrow or circulating blasts, development of new sites of extramedullary disease, or other laboratory or clinical evidence of progression of disease. Stable disease (SD) referred to patient who did not satisfy the criteria for either CR, CRi, PR or PD.
Time Frame	Between Days 36-42 of Courses 1 and 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose 75 mg/m2/Day for AML Patients	Dose 75 mg/m2/Dose Azacytidine for ALL Patients
Arm/Group Description	Participants with Acute Myeloid Leukemia (AML) who are evaluable for response. A patient will be considered evaluable for response if: (1) the patient is eligible; (2) the patient receives all or part of protocol therapy; and (3) the patient is under follow-up for a sufficient period to evaluate the disease at the end of the course 2 or meets the definition of progressive disease. A patient who dies as a result of toxicity after receiving all or part of protocol therapy will be considered a non-responder. Intervention: Azacytidine (Dose Level 1 @ 75 mg/m^2/day) Fludarabine 30 mg/m^2/dose Cytarabine 2000 mg/m^2/dose Intrathecal (IT) Cytarabine	Participants with Acute Lymphoblastic Leukemia (ALL) who are evaluable for response. A patient will be considered evaluable for response if: (1) the patient is eligible; (2) the patient receives all or part of protocol therapy; and (3) the patient is under follow-up for a sufficient period to evaluate the disease at the end of the course 2 or meets the definition of progressive disease. A patient who dies as a result of toxicity after receiving all or part of protocol therapy will be considered a non-responder. Intervention: Azacytidine (Dose Level 1 @ 75 mg/m^2/day) Fludarabine 30 mg/m^2/dose Cytarabine 2000 mg/m^2/dose Intrathecal (IT) Methotrexate
Measure Participants	12	2
Complete Remission (CR)	6 42.9%	0 NaN
CR with Incomplete Count Recovery (CRi)	1 7.1%	0 NaN
Partial Remission (PR)	1 7.1%	1 NaN
Stable Disease (SD)	1 7.1%	1 NaN
Progressive Disease (PD)	3 21.4%	0 NaN

Adverse Events

Time Frame	From date of first dose of AZA until 30 days following the last dose of protocol therapy (approximately from Day 0 to Day 112)
Adverse Event Reporting Description	The definitions of AE and SAE do not differ from the clinicaltrials.gov definitions.
Arm/Group Title	AML Cohort: 75 mg/m2/Day		ALL Cohort: 75 mg/m2/Day
Arm/Group Description	Any patients in the AML arm who are evaluable for toxicity. Any patient who experiences a DLT after receiving at least one dose of AZA on study will be considered evaluable for toxicity of AZA. Patients who do not experience a DLT must receive at least 80% of the prescribed course of AZA in the first cycle (i.e., must receive at least 4 of the planned 5 doses of AZA between days 1 to 5) to be evaluable for toxicity of AZA. Patients not evaluable for toxicity of AZA will be replaced.		Any patients in the ALL arm who are evaluable for toxicity. Any patient who experiences a DLT after receiving at least one dose of AZA on study will be considered evaluable for toxicity of AZA. Patients who do not experience a DLT must receive at least 80% of the prescribed course of AZA in the first cycle (i.e., must receive at least 4 of the planned 5 doses of AZA between days 1 to 5) to be evaluable for toxicity of AZA. Patients not evaluable for toxicity of AZA will be replaced.
All Cause Mortality
	AML Cohort: 75 mg/m2/Day		ALL Cohort: 75 mg/m2/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/2 (0%)
Serious Adverse Events
	AML Cohort: 75 mg/m2/Day		ALL Cohort: 75 mg/m2/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)		1/2 (50%)
Blood and lymphatic system disorders
Febrile neutropenia	2/13 (15.4%)		1/2 (50%)
General disorders
Fever	1/13 (7.7%)		0/2 (0%)
Infections and infestations
Infections and infestations - Other, specify	2/13 (15.4%)		0/2 (0%)
Sepsis	1/13 (7.7%)		0/2 (0%)
Metabolism and nutrition disorders
Hypokalemia	1/13 (7.7%)		0/2 (0%)
Vascular disorders
Hypotension	0/13 (0%)		1/2 (50%)
Other (Not Including Serious) Adverse Events
	AML Cohort: 75 mg/m2/Day		ALL Cohort: 75 mg/m2/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		2/2 (100%)
Blood and lymphatic system disorders
Anemia	10/13 (76.9%)		2/2 (100%)
Febrile neutropenia	9/13 (69.2%)		2/2 (100%)
Lymphocyte count decreased	4/13 (30.8%)		0/2 (0%)
Neutrophil count decreased	11/13 (84.6%)		1/2 (50%)
Platelet count decreased	12/13 (92.3%)		2/2 (100%)
Cardiac disorders
Sinus bradycardia	3/13 (23.1%)		0/2 (0%)
Sinus tachycardia	3/13 (23.1%)		0/2 (0%)
Eye disorders
Conjunctivitis	1/13 (7.7%)		0/2 (0%)
Dry eye	1/13 (7.7%)		0/2 (0%)
Eye disorders - Other, specify	1/13 (7.7%)		0/2 (0%)
Eye pain	1/13 (7.7%)		0/2 (0%)
Photophobia	1/13 (7.7%)		0/2 (0%)
Gastrointestinal disorders
Abdominal distension	1/13 (7.7%)		0/2 (0%)
Abdominal pain	6/13 (46.2%)		0/2 (0%)
Anal pain	1/13 (7.7%)		0/2 (0%)
Constipation	7/13 (53.8%)		0/2 (0%)
Dental caries	1/13 (7.7%)		0/2 (0%)
Diarrhea	5/13 (38.5%)		0/2 (0%)
Mucositis oral	4/13 (30.8%)		0/2 (0%)
Nausea	12/13 (92.3%)		0/2 (0%)
Oral hemorrhage	1/13 (7.7%)		1/2 (50%)
Anal Fissure	1/13 (7.7%)		0/2 (0%)
Gum Bleeding	1/13 (7.7%)		0/2 (0%)
Stomach pain	1/13 (7.7%)		0/2 (0%)
Toothache	1/13 (7.7%)		0/2 (0%)
Vomiting	8/13 (61.5%)		0/2 (0%)
General disorders
Chills	1/13 (7.7%)		0/2 (0%)
Edema face	1/13 (7.7%)		0/2 (0%)
Fatigue	2/13 (15.4%)		0/2 (0%)
Fever	10/13 (76.9%)		0/2 (0%)
Non-cardiac chest pain	3/13 (23.1%)		0/2 (0%)
Pain	6/13 (46.2%)		0/2 (0%)
Immune system disorders
Allergic reaction	3/13 (23.1%)		0/2 (0%)
Infections and infestations
Infections and infestations - Other, specify	4/13 (30.8%)		1/2 (50%)
Mucosal infection	0/13 (0%)		1/2 (50%)
Nail infection	1/13 (7.7%)		0/2 (0%)
Injury, poisoning and procedural complications
Bruising	5/13 (38.5%)		0/2 (0%)
Fall	1/13 (7.7%)		0/2 (0%)
Infusion related reaction	1/13 (7.7%)		0/2 (0%)
Infusion site extravasation	2/13 (15.4%)		0/2 (0%)
Injury, poisoning & proc complications - Other	1/13 (7.7%)		0/2 (0%)
Investigations
Activated partial thromboplastin time prolonged	2/13 (15.4%)		0/2 (0%)
Alanine aminotransferase increased	11/13 (84.6%)		1/2 (50%)
Alkaline phosphatase increased	2/13 (15.4%)		0/2 (0%)
Aspartate aminotransferase increased	11/13 (84.6%)		1/2 (50%)
Blood bilirubin increased	4/13 (30.8%)		0/2 (0%)
Cholesterol high	1/13 (7.7%)		0/2 (0%)
Creatinine increased	1/13 (7.7%)		0/2 (0%)
Fibrinogen decreased	1/13 (7.7%)		0/2 (0%)
GGT increased	3/13 (23.1%)		0/2 (0%)
INR increased	2/13 (15.4%)		0/2 (0%)
Investigations - Other, specify	2/13 (15.4%)		0/2 (0%)
Serum amylase increased	1/13 (7.7%)		0/2 (0%)
White blood cell decreased	11/13 (84.6%)		2/2 (100%)
Metabolism and nutrition disorders
Anorexia	5/13 (38.5%)		0/2 (0%)
Hypercalcemia	2/13 (15.4%)		0/2 (0%)
Hyperglycemia	6/13 (46.2%)		0/2 (0%)
Hypermagnesemia	3/13 (23.1%)		0/2 (0%)
Hypernatremia	1/13 (7.7%)		0/2 (0%)
Hypertriglyceridemia	3/13 (23.1%)		0/2 (0%)
Hypoalbuminemia	10/13 (76.9%)		0/2 (0%)
Hypercalcemia	7/13 (53.8%)		0/2 (0%)
Hypoglycemia	1/13 (7.7%)		0/2 (0%)
Hypokalemia	13/13 (100%)		0/2 (0%)
Hypomagnesemia	6/13 (46.2%)		0/2 (0%)
Hyponatremia	6/13 (46.2%)		1/2 (50%)
Hypophosphatemia	5/13 (38.5%)		0/2 (0%)
Metabolism and nutrition disorders - Other	1/13 (7.7%)		0/2 (0%)
Weight gain	1/13 (7.7%)		0/2 (0%)
Weight loss	2/13 (15.4%)		0/2 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/13 (15.4%)		0/2 (0%)
Bone pain	1/13 (7.7%)		0/2 (0%)
Joint range of motion decreased	1/13 (7.7%)		0/2 (0%)
Myositis	1/13 (7.7%)		0/2 (0%)
Pain in extremity	2/13 (15.4%)		0/2 (0%)
Nervous system disorders
Dizziness	3/13 (23.1%)		0/2 (0%)
Headache	4/13 (30.8%)		0/2 (0%)
Nervous system disorders - Other, specify	3/13 (23.1%)		0/2 (0%)
Psychiatric disorders
Anxiety	1/13 (7.7%)		0/2 (0%)
Irritability	1/13 (7.7%)		0/2 (0%)
Renal and urinary disorders
Hematuria	1/13 (7.7%)		0/2 (0%)
Urinary tract infection	1/13 (7.7%)		0/2 (0%)
Reproductive system and breast disorders
Menorrhagia	1/13 (7.7%)		0/2 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	1/13 (7.7%)		0/2 (0%)
Cough	2/13 (15.4%)		0/2 (0%)
Epistaxis	2/13 (15.4%)		0/2 (0%)
Lung infection	1/13 (7.7%)		1/2 (50%)
Respiratory, thoracic & mediastinal disorder-Other	1/13 (7.7%)		0/2 (0%)
Sore throat	1/13 (7.7%)		0/2 (0%)
Upper respiratory infection	1/13 (7.7%)		0/2 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/13 (7.7%)		0/2 (0%)
Dry skin	1/13 (7.7%)		0/2 (0%)
Erythema multiforme	1/13 (7.7%)		0/2 (0%)
Erythema & Swelling	1/13 (7.7%)		0/2 (0%)
Pruritus	4/13 (30.8%)		0/2 (0%)
Rash maculo-papular	1/13 (7.7%)		0/2 (0%)
Skin & subcutaneous tissue disorder-Other	6/13 (46.2%)		0/2 (0%)
Skin hypopigmentation	1/13 (7.7%)		0/2 (0%)
Skin induration	1/13 (7.7%)		0/2 (0%)
Skin infection	2/13 (15.4%)		0/2 (0%)
Vascular disorders
Hypertension	1/13 (7.7%)		0/2 (0%)
Hypotension	1/13 (7.7%)		1/2 (50%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.