Ph I Study of Alvocidib and Cytarabine/Daunorubicin (7+3) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML).

• Sponsor: Sumitomo Pharma Oncology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03298984
• Collaborator: (none)
• Enrollment: 32
• Locations: 3
• Arm: 1
• Actual Duration (Months): 29.8
• Patients Per Site: 10.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this Phase I study is to determine the safety and tolerability including the maximum dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Alvocidib; Drug: Cytarabine; Drug: Daunorubicin	Phase 1

Detailed Description

Primary Objective:

• To determine the safety and tolerability including the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

Secondary Objectives:

• To observe patients for any evidence of antileukemic activity of alvocidib plus 7+3 using the 2017 ELN response criteria

• To establish the Recommended Phase 2 Dose (RP2D) for future studies with alvocidib in combination with 7+3

Exploratory Objective:

• To assess levels of minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry [MPFC] and next generation sequencing [NGS] and evaluate other potential biomarkers including, but not limited to, MCL-1 dependency.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Dose-escalation, Safety and Biomarker Prediction of Alvocidib and Cytarabine/Daunorubicin (7+3) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)
• Actual Study Start Date: Sep 25, 2017
• Actual Primary Completion Date: Mar 20, 2020
• Actual Study Completion Date: Mar 20, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Alvocidib and Cytarabine/Daunorubicin The starting dose of alvocidib will be 20 mg/m2 as a 30-minute intravenous (IV) bolus followed by 30 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3 of Induction. Patients will have a one day drug holiday (Day 4) before initiation of the 7+3 regimen. Beginning on Day 5, cytarabine will be administered as a 100 mg/m2/day continuous IV infusion for seven consecutive days (Days 5-11) plus daunorubicin administered at a dosage of 60 mg/m2 IV on Days 5-7.

Drug: Alvocidib; IV bolus followed by IV infusion; Drug: Cytarabine; continuous infusion; Drug: Daunorubicin; IV bolus

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Alvocidib [During the first cycle]

   Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

2. Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib [During the first cycle]

   Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

Secondary Outcome Measures

1. Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria [Best response during duration of study]

   CR: Measurable residual disease is positive or unknown; BM blasts (bls) <5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC >1.0 x 109/L; platelets >100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls <5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by >50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (>15% point inc required in cases w/ <30% bls at baseline or persistent BM bls % of >70% over at least 3 months; without at least 100% improvement in ANC to absolute level [>0.5 x 109/L and/or platelet count to >50 x 109/L non-transfused); or >50% inc in peripheral bls to >25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease.

2. Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3 [During Cycle 1 beginning at 1st dose of study drug through Day 50 + or - 3 days]

   The dose at which < 1 of 6 patients experience a DLT during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1

Other Outcome Measures

1. Minimal Residual Disease (MRD) Using Standardized Techniques [During duration of study]

   Percentage of participants with a CRMRD- response at the end of Cycle 1

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• To be eligible for participation in the study, patients must meet all of the following inclusion criteria:

1. Be between the ages of ≥18 and ≤65 years

2. Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria with ≥20% bone marrow blasts based on histology or flow cytometry

3. Be newly diagnosed and previously untreated

4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2

5. Have a serum creatinine level ≤1.8 mg/dL

6. Have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN)

7. Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)

8. Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

9. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate prior to study entry, for the duration of study participation, and for at least 6 months after the last dose of study drug.

10. Be able to comply with the requirements of the entire study.

11. Provide written informed consent prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)

Exclusion Criteria:

• Patients meeting any one of these exclusion criteria will be prohibited from participating in this study.

1. Received any previous treatment for AML

2. Diagnosed with APL-M3 or CBF-AML

3. Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting Induction therapy.

4. Received >200 mg/m2 equivalents of daunorubicin

5. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #3 above)

6. Have active central nervous system (CNS) leukemia

7. Have evidence of uncontrolled disseminated intravascular coagulation

8. Have an active, uncontrolled infection

9. Have other life-threatening illness

10. Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia

11. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.

12. Are pregnant and/or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287
2	Columbia University	New York	New York	United States	10032
3	University of North Carolina	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• Sumitomo Pharma Oncology, Inc.

Investigators

• Study Director: Stephen Anthony, DO, Sumitomo Pharma Oncology, Inc.

Study Documents (Full-Text)

• Study Protocol - Mar 19, 2020
• Statistical Analysis Plan - Jul 28, 2019

More Information

Publications

None provided.

• Responsible Party: Sumitomo Pharma Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT03298984
• Other Study ID Numbers: TPI-ALV-101
• First Posted: Oct 2, 2017
• Last Update Posted: Apr 6, 2022
• Last Verified: Apr 1, 2022

• 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
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Daunorubicin; Alvocidib

Study Results

Participant Flow

Recruitment Details	32 patients at 3 sites; Recruitment started 25Sep2017 Recruitment ended 20Mar2020
Pre-assignment Detail	4 dose escalation cohorts. If 1 of 3 subjects in a cohort experienced a DLT, up to 3 additional subjects were treated at that dose level. If no DLTs observed, the alvocidib dose was escalated in a new cohort of 3 subjects. At MTD level 20 additional subjects enrolled for confirmation of safety as well as additional safety analysis.

Arm/Group Title	Alvocidib 20/30 mg/m2	Alvocidib 30/40 mg/m2	Alvocidib 30/50 mg/m2	Alvocidib 30/60 mg/m2
Arm/Group Description	Alvocidib 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
Period Title: Overall Study
STARTED	3	3	3	23
COMPLETED	2	2	1	8
NOT COMPLETED	1	1	2	15

Baseline Characteristics

Arm/Group Title	Alvocidib 20/30 mg/m2	Alvocidib 30/40 mg/m2	Alvocidib 30/50 mg/m2	Alvocidib 30/60 mg/m2	Total
Arm/Group Description	Alvocidib 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours	Total of all reporting groups
Overall Participants	3	3	3	23	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	3 100%	3 100%	23 100%	32 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	2 66.7%	1 33.3%	9 39.1%	14 43.8%
Male	1 33.3%	1 33.3%	2 66.7%	14 60.9%	18 56.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 33.3%	0 0%	0 0%	0 0%	1 3.1%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 33.3%	1 33.3%	1 33.3%	2 8.7%	5 15.6%
White	1 33.3%	1 33.3%	2 66.7%	20 87%	24 75%
More than one race	0 0%	1 33.3%	0 0%	1 4.3%	2 6.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Alvocidib
Description	Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Time Frame	During the first cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least 1 dose of Alvocidib, either at 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours, 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours, 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours, or 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
Measure Participants	32
Bolus	30
IV infusion	60

2. Primary Outcome

Title	Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib
Description	Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Time Frame	During the first cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alvocidib 20/30 mg/m2	Alvocidib 30/40 mg/m2	Alvocidib 30/50 mg/m2	Alvocidib 30/60 mg/m2
Arm/Group Description	Alvocidib 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
Measure Participants	3	3	3	23
Count of Participants [Participants]	0 0%	0 0%	0 0%	1 4.3%

3. Secondary Outcome

Title	Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria
Description	CR: Measurable residual disease is positive or unknown; BM blasts (bls) <5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC >1.0 x 109/L; platelets >100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls <5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by >50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (>15% point inc required in cases w/ <30% bls at baseline or persistent BM bls % of >70% over at least 3 months; without at least 100% improvement in ANC to absolute level [>0.5 x 109/L and/or platelet count to >50 x 109/L non-transfused); or >50% inc in peripheral bls to >25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease.
Time Frame	Best response during duration of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alvocidib 20/30 mg/m2	Alvocidib 30/40 mg/m2	Alvocidib 30/50 mg/m2	Alvocidib 30/60 mg/m2
Arm/Group Description	Alvocidib 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
Measure Participants	3	3	3	23
Complete Remission MRD Negative (CRMRD-)	2 66.7%	0 0%	2 66.7%	8 34.8%
Complete Remission MRD Positive or Unknown (CR)	1 33.3%	2 66.7%	0 0%	7 30.4%
Partial Remission (PR)	0 0%	1 33.3%	0 0%	1 4.3%
Stable Disease	0 0%	0 0%	0 0%	2 8.7%
Progressive Disease (PD)	0 0%	0 0%	1 33.3%	4 17.4%
Not Evaluated	0 0%	0 0%	0 0%	1 4.3%

4. Secondary Outcome

Title	Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3
Description	The dose at which < 1 of 6 patients experience a DLT during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1
Time Frame	During Cycle 1 beginning at 1st dose of study drug through Day 50 + or - 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least 1 dose of Alvocidib, either at 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours, 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours, 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours, or 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
Measure Participants	32
Bolus	30
IV infusion	60

5. Other Pre-specified Outcome

Title	Minimal Residual Disease (MRD) Using Standardized Techniques
Description	Percentage of participants with a CRMRD- response at the end of Cycle 1
Time Frame	During duration of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alvocidib 20/30 mg/m2	Alvocidib 30/40 mg/m2	Alvocidib 30/50 mg/m2	Alvocidib 30/60 mg/m2
Arm/Group Description	Alvocidib 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours	Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
Measure Participants	3	3	3	23
Number [percentage of participants]	66.7 2223.3%	0 0%	66.7 2223.3%	34.8 151.3%

Adverse Events

Time Frame	Beginning at 1st dose of study drug through 30 days of the last administration of study drug
Adverse Event Reporting Description	Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
Arm/Group Title	Alvocidib 20/30 mg/m2 (N=3)		Alvocidib 30/40 mg/m2 (N=3)		Alvocidib 30/50 mg/m2 (N=3)		Alvocidib 30/60 mg/m2 (N=23)
Arm/Group Description	Alvocidib 20mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours		Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours		Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours		Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours
All Cause Mortality
	Alvocidib 20/30 mg/m2 (N=3)		Alvocidib 30/40 mg/m2 (N=3)		Alvocidib 30/50 mg/m2 (N=3)		Alvocidib 30/60 mg/m2 (N=23)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Serious Adverse Events
	Alvocidib 20/30 mg/m2 (N=3)		Alvocidib 30/40 mg/m2 (N=3)		Alvocidib 30/50 mg/m2 (N=3)		Alvocidib 30/60 mg/m2 (N=23)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		5/23 (21.7%)
Cardiac disorders
Cardiogenic shock	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Immune system disorders
Cytokine release syndrome	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Infections and infestations
Fungaemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Pneumonia	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Pneumonia fungal	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Sepsis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Septic shock	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Investigations
Blood bilirubin increased	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Blood creatinine increased	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Metabolism and nutrition disorders
Tumour lysis syndrome	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Nervous system disorders
Haemorrhage intracranial	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Renal and urinary disorders
Acute kidney injury	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Alvocidib 20/30 mg/m2 (N=3)		Alvocidib 30/40 mg/m2 (N=3)		Alvocidib 30/50 mg/m2 (N=3)		Alvocidib 30/60 mg/m2 (N=23)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		3/3 (100%)		23/23 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	3/3 (100%)		2/3 (66.7%)		3/3 (100%)		19/23 (82.6%)
Lymphadenopathy	0/3 (0%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Anaemia	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		0/23 (0%)
Lymph node pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Cardiac disorders
Sinus tachycardia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		4/23 (17.4%)
Cardiac failure	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Cardiogenic shock	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Palpitations	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Eye disorders
Dry eye	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		7/23 (30.4%)
Eyelid ptosis	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Keratitis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Vision blurred	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/23 (4.3%)
Eye inflammation	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Lacrimation increased	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Ocular hyperaemia	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Photophobia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Gastrointestinal disorders
Diarrhoea	2/3 (66.7%)		3/3 (100%)		3/3 (100%)		23/23 (100%)
Nausea	1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		17/23 (73.9%)
Vomiting	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		14/23 (60.9%)
Abdominal pain	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		10/23 (43.5%)
Dyspepsia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		6/23 (26.1%)
Constipation	0/3 (0%)		2/3 (66.7%)		3/3 (100%)		5/23 (21.7%)
Dry mouth	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		5/23 (21.7%)
Gastrooesophageal reflux disease	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		5/23 (21.7%)
Haemorrhoids	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		5/23 (21.7%)
Stomatitis	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		4/23 (17.4%)
Colitis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Ascites	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Enterocolitis	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Haematochezia	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Haemorrhoidal haemorrhage	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Abdominal distension	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Enteritis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Oral pain	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/23 (4.3%)
Proctalgia	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Lower gastrointestinal haemorrhage	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/23 (0%)
Proctitis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
General disorders
Oedema peripheral	1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		12/23 (52.2%)
Fatigue	2/3 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		8/23 (34.8%)
Chills	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		4/23 (17.4%)
Pyrexia	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		4/23 (17.4%)
Catheter site pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		3/23 (13%)
Chest pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		3/23 (13%)
Mucosal inflammation	0/3 (0%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Oedema	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Pain	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Localised oedema	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Infections and infestations
Device related infection	1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		7/23 (30.4%)
Lung infection	0/3 (0%)		2/3 (66.7%)		0/3 (0%)		4/23 (17.4%)
Escherichia bacteraemia	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Oral candidiasis	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Pneumonia fungal	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Urinary tract infection	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Bacteraemia	2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Clostridium difficile infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Enterococcal bacteraemia	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Enterococcal infection	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/23 (4.3%)
Sepsis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Abdominal infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Bacterial infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Cellulitis orbital	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Escherichia infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Fungaemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Klebsiella bacteraemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Mucosal infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Oral infection	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Periodontitis	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Upper respiratory tract infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Injury, poisoning and procedural complications
Transfusion reaction	0/3 (0%)		0/3 (0%)		0/3 (0%)		4/23 (17.4%)
Fall	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Procedural pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/23 (4.3%)
Infusion related reaction	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Lip injury	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Investigations
White blood cell count decreased	0/3 (0%)		2/3 (66.7%)		2/3 (66.7%)		9/23 (39.1%)
Platelet count decreased	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		4/23 (17.4%)
Aspartate aminotransferase increased	0/3 (0%)		1/3 (33.3%)		3/3 (100%)		3/23 (13%)
Blood bilirubin increased	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		3/23 (13%)
Blood creatinine increased	1/3 (33.3%)		2/3 (66.7%)		1/3 (33.3%)		3/23 (13%)
International normalised ratio increased	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Lymphocyte count decreased	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		3/23 (13%)
Weight decreased	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		3/23 (13%)
Alanine aminotransferase increased	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		1/23 (4.3%)
Neutrophil count decreased	2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Blood alkaline phosphatase increased	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/23 (0%)
Ejection fraction decreased	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Liver function test increased	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Sputum culture positive	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Metabolism and nutrition disorders
Hypokalaemia	3/3 (100%)		2/3 (66.7%)		3/3 (100%)		16/23 (69.6%)
Hypomagnesaemia	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		10/23 (43.5%)
Hypophosphataemia	1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		10/23 (43.5%)
Tumour lysis syndrome	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		10/23 (43.5%)
Hypocalcaemia	0/3 (0%)		2/3 (66.7%)		1/3 (33.3%)		7/23 (30.4%)
Hyperkalaemia	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		5/23 (21.7%)
Decreased appetite	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		4/23 (17.4%)
Hyperglycaemia	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		3/23 (13%)
Hypoalbuminaemia	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		3/23 (13%)
Fluid overload	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Hyponatraemia	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		2/23 (8.7%)
Hyperuricaemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Hypoglycaemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Acidosis	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/23 (0%)
Hypermagnesaemia	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Hyperphosphataemia	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Hypervolaemia	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		5/23 (21.7%)
Back pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/23 (8.7%)
Cytarabine syndrome	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Musculoskeletal chest pain	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Musculoskeletal pain	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Arthralgia	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Myalgia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/23 (4.3%)
Muscle spasms	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Nervous system disorders
Headache	2/3 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		10/23 (43.5%)
Dizziness	2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		8/23 (34.8%)
Dysgeusia	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		3/23 (13%)
Hypoaesthesia	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Paraesthesia	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Somnolence	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Syncope	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Disturbance in attention	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Psychiatric disorders
Insomnia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		6/23 (26.1%)
Anxiety	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Depression	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Hallucination	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Renal and urinary disorders
Acute kidney injury	2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		4/23 (17.4%)
Haematuria	0/3 (0%)		0/3 (0%)		0/3 (0%)		4/23 (17.4%)
Chromaturia	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Urinary retention	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/23 (4.3%)
Pollakiuria	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Reproductive system and breast disorders
Scrotal pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		5/23 (21.7%)
Dyspnoea	2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		4/23 (17.4%)
Cough	1/3 (33.3%)		3/3 (100%)		1/3 (33.3%)		3/23 (13%)
Oropharyngeal pain	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Pleural effusion	0/3 (0%)		0/3 (0%)		0/3 (0%)		3/23 (13%)
Pulmonary oedema	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Wheezing	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Nasal congestion	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/23 (0%)
Upper-airway cough syndrome	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		7/23 (30.4%)
Pruritus	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		3/23 (13%)
Alopecia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Rash	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Rash generalised	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Dermatitis	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/23 (4.3%)
Petechiae	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Blood blister	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)
Vascular disorders
Hypotension	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		7/23 (30.4%)
Hypertension	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		3/23 (13%)
Embolism	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/23 (8.7%)
Flushing	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/23 (4.3%)
Jugular vein distension	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/23 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.