Study of LY573636-sodium in Essential Thrombocythemia and Acute Myeloid Leukemia

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00718159
• Collaborator: (none)
• Enrollment: 23
• Locations: 5
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine a safe dose of LY573636-sodium to be given to patients with acute myeloid leukemia and to determine any side effects that may be associated with LY573636-sodium in this patient population. Efficacy measures will also be used to assess the activity of LY573636-sodium in acute myeloid leukemia and essential thrombocythemia patients.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Essential Thrombocythemia	Drug: LY573636-sodium	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 Study of LY573636-sodium in Patients With Essential Thrombocythemia and Acute Myeloid Leukemia
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: LY573636

Drug: LY573636-sodium; Individualized dose is dependent on participant's height, weight, gender and is adjusted to target a specific exposure range corrected for a participant's laboratory parameters. Dosing will be done on Day 1 of a 35-day cycle for acute myeloid leukemia (AML) and Day 1 of a 28-day cycle for essential thrombocythemia (ET) for at least one cycle. A participant may have additional cycles of LY573636 if he or she is receiving benefit from the study drug and does not fulfill any of the criteria for study discontinuation.; Other Names: LY573636

Outcome Measures

Primary Outcome Measures

1. Recommended Phase 2 Dose of LY573636-Sodium in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Essential Thrombocythemia (ET) [Predose up to 35 days postdose in Cycle 1]

   Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD is the highest dose at which no more than 1 of 6 participants experienced a dose-limiting toxicity (DLT) and level immediately below that which had ≥2 instances of DLT. A DLT is an adverse event (AE) observed during the first cycle of treatment that is believed to be related to LY573636 and fulfills any of the following: ET only , Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity for ≥3 days; For all, ≥Gr 3 nonhematological toxicity except for nausea/vomiting or diarrhea unless it fits the next criteria; ≥Gr 3 nausea, vomiting, or diarrhea that persists >7 days despite maximal treatment; Gr 3 electrolyte disturbances that persist despite maximal measures; DLT can be declared if a participant experienced increasing toxicity during treatment. The primary outcome measure was not analyzed because the enrollment was stopped early before MTD was reached.

Secondary Outcome Measures

1. Pharmacokinetics Area Under the Curve(AUC) of LY573636 Above the Albumin-Corrected Threshold (AUCalb) [Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose]

   LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. PK sample is withdrawn at any time on days 8,14,15,21,28.

2. Number of Participants With Bone Marrow (BM) Response [Baseline to measured progressive disease up to 70 days]

   The International Working Group's revised recommendations were used to assess response in acute myeloid leukemia (AML): complete response (CR) is <5% blasts in BM and with a cell count ≥200 cells in BM, and with peripheral blood platelets ≥100x10⁹/liter (L) and absolute neutrophils ≥1x10⁹/L; CR with incomplete blood count recovery is defined as CRi; partial response (PR) is ≥5% blasts in BM but with ≥50% reduction in blast count. Number of responders for AML = CR+PR+ CRi. Result of a European Leukemia Net consensus conference was used to assess response in essential thrombocythemia (ET). CR is platelets ≤400x10⁹/L in peripheral blood, no disease-related symptoms, normal spleen size and white blood cells ≤10x10⁹/L in peripheral blood; PR has platelets ≤600x10⁹/L in peripheral blood or decrease > 50% from baseline but does not meet CR criteria. Number of responders for ET = CR+PR.

3. Pharmacokinetics: Concentration Maximum (Cmax) of LY573636 [Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose]

   PK sample is withdrawn at any time on days 8,14,15,21,28.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants who have a diagnosis of either essential thrombocythemia or acute myeloid leukemia that is relapsed or refractory to at least one prior standard treatment. If participants have acute promyelocytic leukemia, they must be resistant and/or intolerant of both all trans retinoic acid (ATRA) and arsenic trioxide.

• Are at least 18 years of age.

• Have given written informed consent approved by Lilly and the ethical review board (ERB)/institutional review board (IRB) governing the site.

• Must have adequate hepatic and renal function.

• Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 21 days for myelosuppressive agents (such as cytarabine, daunorubicin, and gemtuzumab ozogamicin) or 14 days for non-myelosuppressive agents prior to receiving study drug and recovered from the acute effects of therapy. Hydroxyurea used to control peripheral blood blast count is permitted within these respective periods, but it must be stopped at least 24 hours before study drug administration.

• Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drug.

• Females of child bearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug.

• Have a serum albumin level greater than equal to 3.0 grams/deciliter (g/L), less than or equal to 72 hour prior to dosing with LY573636-sodium.

Exclusion Criteria:

• Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a non-myelosuppressive or myelosuppressive agent, respectively.

• Participants with myeloproliferative disorders (for example, chronic myeloid leukemia (CML), polycythemia vera and primary myelofibrosis) other than essential thrombocythemia.

• Have received an autologous or allogenic stem cell transplant within 75 days of the initial dose of study drug for the dose escalation phase or within 60 days of the initial dose of study drug for the dose confirmation phase. Recipients of an allogeneic stem cell transplant must have discontinued immunosuppressive therapy at least 24 hours before study drug administration with no more than Grade 1 acute graft-versus-host disease.

• Have previously completed or withdrawn from this study or any other study investigating LY573636 sodium.

• Have serious preexisting medical conditions that in the opinion of the investigator would preclude participation in this study.

• Have serious concomitant disorders, including active bacterial, fungal, or viral infection, incompatible with the study.

• Have a second primary malignancy that could affect interpretation of results.

• Have a known coagulopathy or bleeding disorder, other than leukemic related thrombocytopenia. Participants with severe or life-threatening bleeding refractory to platelet transfusions are also excluded from this study.

• Major surgery within 4 weeks of study enrollment.

• Are receiving warfarin (Coumadin).

• Females who are pregnant or breast feeding.

• Have known positive results of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg) or hepatitis C antibodies (HCAb).

• Have received treatment within 28 days of the initial dose of study drug with an experimental agent for noncancerous indications that has not received regulatory approval for any indication.

• Participants receiving amiodarone, quinidine, propofol, or clozapine.

• Participants receiving treatment with strong or moderate inhibitors of cytochrome P450 (CYP)2C19, including proton-pump inhibitors (PPIs). Esomeprazole or pantoprazole are allowed if not administered within 72 hours before or after LY573636 administration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Los Angeles	California	United States	90095
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Aurora	Colorado	United States	80045
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baltimore	Maryland	United States	21287
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Las Vegas	Nevada	United States	89135
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Houston	Texas	United States	77030

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon -Fri 9AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00718159
• Other Study ID Numbers: 12266; H8K-MC-JZAJ
• First Posted: Jul 18, 2008
• Last Update Posted: Jan 10, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by Eli Lilly and Company: Acute Myeloid Leukemia; Myeloid Leukemia; Relapsed; Refractory
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Thrombocytosis; Thrombocythemia, Essential

Study Results

Participant Flow

Pre-assignment Detail	The reasons for discontinuation listed in the participant flow are the reasons the participant discontinued treatment. All participants who received at least 1 dose of study drug were considered to have completed the study.

Arm/Group Title	Cmax 250 μg/mL (AML)	Cmax 300 μg/mL (AML)	Cmax 350 μg/mL (AML)	Cmax 400 μg/mL (AML)	AUCalb 5500 µg*hr/mL (AML)	AUCalb 7000 µg*hr/mL (AML)	AUCalb 5500 µg*hr/mL (ET)
Arm/Group Description	Participants diagnosed with acute myeloid leukemia (AML) dosed: LY573636 targeting a maximum concentration (Cmax) of 250 micrograms per milliliter (μg/mL) as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 300 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 350 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 400 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an albumin-corrected exposure (AUCalb) 5500 micrograms*hour per milliliter (µg*hr/mL) as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an AUCalb 7000 µg*hr/mL as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with essential thrombocythemia (ET) dosed: LY573636 targeting an AUCalb 5500 µg*hr/mL as a 2-hour infusion on Day 1 of a 28-day cycle.
Period Title: Overall Study
STARTED	3	3	3	4	8	1	1
Received at Least 1 Dose of Study Drug	3	3	3	4	8	1	1
COMPLETED	0	0	0	0	0	0	0
NOT COMPLETED	3	3	3	4	8	1	1

Baseline Characteristics

Arm/Group Title	Cmax 250 μg/mL (AML)	Cmax 300 μg/mL (AML)	Cmax 350 μg/mL (AML)	Cmax 400 μg/mL (AML)	AUCalb 5500 µg*hr/mL (AML)	AUCalb 7000 µg*hr/mL (AML)	AUCalb 5500 µg*hr/mL (ET)	Total
Arm/Group Description	Participants diagnosed with acute myeloid leukemia (AML) dosed: LY573636 targeting a maximum concentration (Cmax) of 250 micrograms per milliliter (μg/mL) as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 300 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 350 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 400 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an albumin-corrected exposure (AUCalb) 5500 micrograms*hour per milliliter (µg*hr/mL) as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an AUCalb 7000 µg*hr/mL as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with essential thrombocythemia (ET) dosed: LY573636 targeting an AUCalb 5500 µg*hr/mL as a 2-hour infusion on Day 1 of a 28-day cycle.	Total of all reporting groups
Overall Participants	3	3	3	4	8	1	1	23
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55.22	52.48	66.62	55.46	58.57	81.19	65.09	56.86
Sex: Female, Male (Count of Participants)
Female	2 66.7%	2 66.7%	2 66.7%	3 75%	4 50%	0 0%	1 100%	14 60.9%
Male	1 33.3%	1 33.3%	1 33.3%	1 25%	4 50%	1 100%	0 0%	9 39.1%
Race/Ethnicity, Customized (Count of Participants)
African	0 0%	0 0%	0 0%	0 0%	1 12.5%	0 0%	0 0%	1 4.3%
Caucasian	3 100%	3 100%	3 100%	2 50%	6 75%	1 100%	1 100%	19 82.6%
East Asian	0 0%	0 0%	0 0%	2 50%	0 0%	0 0%	0 0%	2 8.7%
Missing	0 0%	0 0%	0 0%	0 0%	1 12.5%	0 0%	0 0%	1 4.3%
Region of Enrollment (Count of Participants)
United States	3 100%	3 100%	3 100%	4 100%	8 100%	1 100%	1 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Recommended Phase 2 Dose of LY573636-Sodium in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Essential Thrombocythemia (ET)
Description	Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD is the highest dose at which no more than 1 of 6 participants experienced a dose-limiting toxicity (DLT) and level immediately below that which had ≥2 instances of DLT. A DLT is an adverse event (AE) observed during the first cycle of treatment that is believed to be related to LY573636 and fulfills any of the following: ET only , Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity for ≥3 days; For all, ≥Gr 3 nonhematological toxicity except for nausea/vomiting or diarrhea unless it fits the next criteria; ≥Gr 3 nausea, vomiting, or diarrhea that persists >7 days despite maximal treatment; Gr 3 electrolyte disturbances that persist despite maximal measures; DLT can be declared if a participant experienced increasing toxicity during treatment. The primary outcome measure was not analyzed because the enrollment was stopped early before MTD was reached.
Time Frame	Predose up to 35 days postdose in Cycle 1

Outcome Measure Data

Analysis Population Description

No participants were analyzed since the MTD was not reached.

Arm/Group Title	Cmax 250 μg/mL (AML)	Cmax 300 μg/mL (AML)	Cmax 350 μg/mL (AML)	Cmax 400 μg/mL (AML)	AUCalb 5500 µg*hr/mL (AML)	AUCalb 7000 µg*hr/mL (AML)	AUCalb 5500 µg*hr/mL (ET)
Arm/Group Description	Participants diagnosed with acute myeloid leukemia (AML) dosed: LY573636 targeting a maximum concentration (Cmax) of 250 micrograms per milliliter (μg/mL) as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 300 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 350 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 400 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an albumin-corrected exposure (AUCalb) 5500 micrograms*hour per milliliter (µg*hr/mL) as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an AUCalb 7000 µg*hr/mL as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with essential thrombocythemia (ET) dosed: LY573636 targeting an AUCalb 5500 µg*hr/mL as a 2-hour infusion on Day 1 of a 28-day cycle.
Measure Participants	0	0	0	0	0	0	0

2. Secondary Outcome

Title	Pharmacokinetics Area Under the Curve(AUC) of LY573636 Above the Albumin-Corrected Threshold (AUCalb)
Description	LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. PK sample is withdrawn at any time on days 8,14,15,21,28.
Time Frame	Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose

Outcome Measure Data

Analysis Population Description

Participants who received the study drug and had pharmacokinetic (PK) data.

Arm/Group Title	LY573636
Arm/Group Description	LY573636 dose was based on an albumin-corrected exposure (AUCalb) to target a specific exposure range. Intravenous dosing is done on Day 1 of Cycle 1. Data are pooled together from all treatment groups.
Measure Participants	23
Geometric Mean (Geometric Coefficient of Variation) [micrograms*hour/milliliter (µg*hr/mL)]	6911 (86.8)

3. Secondary Outcome

Title	Number of Participants With Bone Marrow (BM) Response
Description	The International Working Group's revised recommendations were used to assess response in acute myeloid leukemia (AML): complete response (CR) is <5% blasts in BM and with a cell count ≥200 cells in BM, and with peripheral blood platelets ≥100x10⁹/liter (L) and absolute neutrophils ≥1x10⁹/L; CR with incomplete blood count recovery is defined as CRi; partial response (PR) is ≥5% blasts in BM but with ≥50% reduction in blast count. Number of responders for AML = CR+PR+ CRi. Result of a European Leukemia Net consensus conference was used to assess response in essential thrombocythemia (ET). CR is platelets ≤400x10⁹/L in peripheral blood, no disease-related symptoms, normal spleen size and white blood cells ≤10x10⁹/L in peripheral blood; PR has platelets ≤600x10⁹/L in peripheral blood or decrease > 50% from baseline but does not meet CR criteria. Number of responders for ET = CR+PR.
Time Frame	Baseline to measured progressive disease up to 70 days

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of the study drug.

Arm/Group Title	Cmax 250 μg/mL (AML)	Cmax 300 μg/mL (AML)	Cmax 350 μg/mL (AML)	Cmax 400 μg/mL (AML)	AUCalb 5500 µg*hr/mL (AML)	AUCalb 7000 µg*hr/mL (AML)	AUCalb 5500 µg*hr/mL (ET)
Arm/Group Description	Participants diagnosed with acute myeloid leukemia (AML) dosed: LY573636 targeting a maximum concentration (Cmax) of 250 micrograms per milliliter (μg/mL) as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 300 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 350 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 400 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an albumin-corrected exposure (AUCalb) 5500 micrograms*hour per milliliter (µg*hr/mL) as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with AML dosed: LY573636 targeting an AUCalb 7000 µg*hr/mL as a 2-hour infusion on Day 1 of a 35-day cycle.	Participants diagnosed with essential thrombocythemia (ET) dosed: LY573636 targeting an AUCalb 5500 µg*hr/mL as a 2-hour infusion on Day 1 of a 28-day cycle.
Measure Participants	3	3	3	4	8	1	1
Count of Participants [Participants]	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Pharmacokinetics: Concentration Maximum (Cmax) of LY573636
Description	PK sample is withdrawn at any time on days 8,14,15,21,28.
Time Frame	Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose

Outcome Measure Data

Analysis Population Description

Participants who received the study drug and had pharmacokinetic (PK) data.

Arm/Group Title	LY573636
Arm/Group Description	LY573636 dose was based on an albumin-corrected exposure (AUCalb) to target a specific exposure range. Intravenous dosing is done on Day 1 of Cycle 1. Data are pooled together from all treatment groups.
Measure Participants	23
Geometric Mean (Geometric Coefficient of Variation) [micrograms per milliliter (µg/mL)]	317 (21.0)

Adverse Events

Arm/Group Title	Cmax 250 μg/mL (AML)		Cmax 300 μg/mL (AML)		Cmax 350 μg/mL (AML)		Cmax 400 μg/mL (AML)		AUCalb 5500 µg*hr/mL (AML and ET)		AUCalb 7000 µg*hr/mL (AML)
Arm/Group Description	Participants diagnosed with acute myeloid leukemia (AML) dosed: LY573636 targeting a maximum concentration (Cmax) of 250 micrograms per milliliter (μg/mL) as a 24-hour infusion on Day 1 of a 35-day cycle.		Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 300 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.		Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 350 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.		Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 400 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle.		Participants diagnosed with AML dosed: LY573636 targeting an albumin-corrected exposure (AUCalb) 5500 micrograms*hour per milliliter (µg*hr/mL) as a 2-hour infusion on Day 1 of a 35-day cycle. Participants diagnosed with essential thrombocythemia (ET) dosed: LY573636 targeting an AUCalb 5500 µg*hr/mL as a 2-hour infusion on Day 1 of a 28-day cycle.		Participants diagnosed with AML dosed: LY573636 targeting an AUCalb 7000 µg*hr/mL as a 2-hour infusion on Day 1 of a 35-day cycle.
All Cause Mortality
	Cmax 250 μg/mL (AML)		Cmax 300 μg/mL (AML)		Cmax 350 μg/mL (AML)		Cmax 400 μg/mL (AML)		AUCalb 5500 µg*hr/mL (AML and ET)		AUCalb 7000 µg*hr/mL (AML)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cmax 250 μg/mL (AML)		Cmax 300 μg/mL (AML)		Cmax 350 μg/mL (AML)		Cmax 400 μg/mL (AML)		AUCalb 5500 µg*hr/mL (AML and ET)		AUCalb 7000 µg*hr/mL (AML)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		2/3 (66.7%)		1/3 (33.3%)		4/4 (100%)		6/9 (66.7%)		1/1 (100%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Febrile neutropenia	2/3 (66.7%)	2	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	3/9 (33.3%)	3	1/1 (100%)	1
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Thrombocytopenia	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Cardiac failure congestive	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Caecitis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Oesophageal pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Oral pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/9 (22.2%)	2	0/1 (0%)	0
Stomatitis	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	2/9 (22.2%)	2	0/1 (0%)	0
General disorders
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Pyrexia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Infections and infestations
Cellulitis orbital	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Infection	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	1/1 (100%)	1
Pneumonia	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Sepsis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Septic shock	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Staphylococcal sepsis	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Injury, poisoning and procedural complications
Subdural haematoma	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/9 (22.2%)	2	0/1 (0%)	0
Nervous system disorders
Somnolence	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Renal and urinary disorders
Renal failure acute	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Hypoxia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Respiratory failure	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	Cmax 250 μg/mL (AML)		Cmax 300 μg/mL (AML)		Cmax 350 μg/mL (AML)		Cmax 400 μg/mL (AML)		AUCalb 5500 µg*hr/mL (AML and ET)		AUCalb 7000 µg*hr/mL (AML)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	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%)		4/4 (100%)		9/9 (100%)		1/1 (100%)
Blood and lymphatic system disorders
Anaemia	2/3 (66.7%)	2	2/3 (66.7%)	2	1/3 (33.3%)	1	2/4 (50%)	2	1/9 (11.1%)	1	0/1 (0%)	0
Febrile neutropenia	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/9 (0%)	0	1/1 (100%)	1
Leukopenia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Splenomegaly	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Thrombocytopenia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Cardiac disorders
Arrhythmia supraventricular	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Atrial fibrillation	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	2	1/9 (11.1%)	1	0/1 (0%)	0
Cardiac failure congestive	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Pericarditis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Tachycardia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	1/1 (100%)	1
Eye disorders
Eye pain	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Abdominal pain	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Anal inflammation	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Constipation	0/3 (0%)	0	2/3 (66.7%)	2	1/3 (33.3%)	1	4/4 (100%)	5	2/9 (22.2%)	3	1/1 (100%)	1
Diarrhoea	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Gingival bleeding	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Haemorrhoids	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Intestinal obstruction	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Mouth haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Nausea	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	4/4 (100%)	4	2/9 (22.2%)	2	0/1 (0%)	0
Oral pain	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Proctalgia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	1/1 (100%)	1
Stomatitis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Vomiting	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/4 (75%)	3	2/9 (22.2%)	2	0/1 (0%)	0
General disorders
Chest discomfort	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Chest pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Chills	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Fatigue	0/3 (0%)	0	1/3 (33.3%)	1	2/3 (66.7%)	2	1/4 (25%)	1	2/9 (22.2%)	2	0/1 (0%)	0
Inflammatory pain	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	3/9 (33.3%)	3	0/1 (0%)	0
Oedema	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Oedema peripheral	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	2	1/4 (25%)	1	2/9 (22.2%)	2	1/1 (100%)	1
Pyrexia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Therapeutic response unexpected	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Ulcer	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Infections and infestations
Anal infection	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Enterococcal bacteraemia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Gastrointestinal infection	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Gingival infection	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Lobar pneumonia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Oral candidiasis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Pneumonia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Systemic candida	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Tooth abscess	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Urinary tract infection	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Fall	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Laceration	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Alanine aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Aspartate aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/9 (22.2%)	2	0/1 (0%)	0
Blood alkaline phosphatase increased	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Blood creatinine	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Blood creatinine increased	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	2/9 (22.2%)	2	0/1 (0%)	0
Blood magnesium decreased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	1/1 (100%)	1
Cardiac murmur	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Ejection fraction decreased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Fibrin d dimer increased	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Haemoglobin decreased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	1/1 (100%)	1
Neutrophil count decreased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Platelet count decreased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	1/1 (100%)	1
Prothrombin time prolonged	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
White blood cell count decreased	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Fluid overload	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	1/9 (11.1%)	1	0/1 (0%)	0
Hyperglycaemia	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Hypernatraemia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Hypoalbuminaemia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	3/9 (33.3%)	3	1/1 (100%)	1
Hypocalcaemia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	4/9 (44.4%)	4	0/1 (0%)	0
Hypoglycaemia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Hypokalaemia	1/3 (33.3%)	1	2/3 (66.7%)	3	1/3 (33.3%)	1	0/4 (0%)	0	4/9 (44.4%)	5	1/1 (100%)	2
Hypomagnesaemia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Hyponatraemia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Hypophosphataemia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	2/9 (22.2%)	2	0/1 (0%)	0
Metabolic acidosis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Joint swelling	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	2	0/9 (0%)	0	0/1 (0%)	0
Kyphosis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Musculoskeletal chest pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Musculoskeletal pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Pain in extremity	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Nervous system disorders
Headache	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/4 (50%)	2	2/9 (22.2%)	2	0/1 (0%)	0
Psychiatric disorders
Anxiety	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Confusional state	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Depression	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Hallucination	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Insomnia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Mental status changes	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Renal and urinary disorders
Dysuria	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Haematuria	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Pollakiuria	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	1/1 (100%)	1
Renal failure acute	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/9 (0%)	0	0/1 (0%)	0
Urinary retention	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	1/1 (100%)	1
Reproductive system and breast disorders
Vaginal inflammation	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1	0/5 (0%)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	4/9 (44.4%)	4	0/1 (0%)	0
Dysphonia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Dyspnoea	0/3 (0%)	0	1/3 (33.3%)	1	2/3 (66.7%)	2	2/4 (50%)	2	4/9 (44.4%)	4	0/1 (0%)	0
Epistaxis	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Haemoptysis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1	0/1 (0%)	0
Hypoxia	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Oropharyngeal pain	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Pleural effusion	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Pulmonary alveolar haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Pulmonary hypertension	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Wheezing	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Skin and subcutaneous tissue disorders
Blister	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Blood blister	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Dermatitis acneiform	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	1/1 (100%)	1
Exfoliative rash	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Petechiae	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Pruritus	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	1/9 (11.1%)	1	0/1 (0%)	0
Rash erythematous	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Rash generalised	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Subcutaneous nodule	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0
Urticaria	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1	0/1 (0%)	0
Vascular disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Hypotension	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	1	0/9 (0%)	0	0/1 (0%)	0
Thrombophlebitis superficial	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/9 (0%)	0	0/1 (0%)	0

Limitations/Caveats

The primary outcome measure in this trial was not reached because the enrollment was stopped early before the maximum tolerated dose was reached.

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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.