Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT03072043
• Collaborator: Aprea Therapeutics (Industry)
• Enrollment: 55
• Locations: 6
• Arms: 2
• Actual Duration (Months): 54.7
• Patients Per Site: 9.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The main purpose of this study is to determine the safe and recommended dose of APR-246 in combination with azacitidine as well as to see if this combination of therapy improves overall survival.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Neoplasm; Chronic Myelomonocytic Leukemia	Drug: APR-246; Drug: Azacitidine	Phase 1/Phase 2

Detailed Description

Participants will be treated for a total of 6 cycles. For participants responding or who have stable disease following cycle 6, treatment may continue until one of the following criteria applies:

• Inter-current illness that prevents further administration of treatment,

• Unacceptable adverse event(s),

• Participant decides to withdraw from the study, or

• General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the investigator.

• Evidence of disease progression by the International Working Group (IWG) 2006 criteria.

Participants who wish not to continue treatment at time of disease assessment at end of cycle 6 will complete their end of treatment visit upon completion of cycle 6.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Phase 1b Dose Escalation followed by Phase 2 treatment. Participants will be evaluable for inclusion in the Phase 1b and Phase 2 portions of the study if they receive at least one dose of protocol therapy.Phase 1b Dose Escalation followed by Phase 2 treatment. Participants will be evaluable for inclusion in the Phase 1b and Phase 2 portions of the study if they receive at least one dose of protocol therapy.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study to Evaluate the Safety and Efficacy of APR-246 in Combination With Azacitidine for the Treatment of TP53 Mutant Myeloid Neoplasms
• Actual Study Start Date: May 18, 2017
• Actual Primary Completion Date: Nov 15, 2019
• Actual Study Completion Date: Dec 8, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b Dose Escalation Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle.	Drug: APR-246; Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD).; Other Names: PRIMA-1MET Methylated analogue to PRIMA-1 ; Drug: Azacitidine; Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.; Other Names: Mylosar Vidaza
Experimental: Phase 2 Treatment Participants will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing schedule as in Phase 1b.	Drug: APR-246; Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD).; Other Names: PRIMA-1MET Methylated analogue to PRIMA-1 ; Drug: Azacitidine; Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.; Other Names: Mylosar Vidaza

Outcome Measures

Primary Outcome Measures

1. Phase 1b: Maximum Tolerated Dose (MTD) [Up to 12 months]

   Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in <33% of the patients.

2. Phase 2: Complete Response (CR) Rate [Up to 12 months]

   Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.

Secondary Outcome Measures

1. Phase 2: Duration of Response [Up to 24 months]

   Duration of response defined as the time between achieving response and progression of disease.

2. Overall Survival (OS) [Up to 24 months]

   OS:The length of time from the start of treatment until death by any cause.

3. Phase 2: Overall Response Rate [Up to 24 months]

   Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has signed the Informed Consent (ICF) and is able to comply with protocol requirements.

• Has adequate organ function according to study protocol guidelines.

• Age ≥18 years at the time of signing the informed consent form.

• Documented diagnosis of myelodysplastic syndrome (MDS), MDS/ myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) or oligoblastic AML (20-30% myeloblasts) by World Health Organization (WHO) criteria.

• Documentation of a TP53 gene mutation by NGS based on central or local evaluation.

• For TP53 mutant patients with lower risk MDS (i.e., low or intermediate-1 risk by the International Prognostic Scoring System (IPSS)) and isolated deletion of 5q (del(5q)), failure of prior treatment with at least 4 full cycles of lenalidomide defined as no response to treatment, loss of response at any time point, progressive disease, or intolerance to therapy.

• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 is required.

• If of childbearing potential, negative pre-treatment urine or serum pregnancy test.

• If of childbearing potential, willing to use an effective form of contraception such as hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.

Exclusion Criteria:

• Known history of HIV or active hepatitis B or active hepatitis C infection (testing not mandatory).

• Has any of the following cardiac abnormalities (as determined by treating MD): a. Symptomatic congestive heart failure; b. Myocardial infarction less than or equal to 6 months prior to enrollment; c. Unstable angina pectoris; d. Serious uncontrolled cardiac arrhythmia; e. QTc ≥ 470 msec

• Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Potential participants with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis.

• Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS, MDS/MPN, CMML or AML within 14 days of the first day of study drug treatment.

• No concurrent use of erythroid stimulating agents, G-CSF, GM-CSF is allowed during study except in cases of febrile neutropenia where G-CSF can be used for short term. Growth factors must be stopped 14 days prior to study.

• Women who are pregnant or breastfeeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
4	Weill Medical College of Cornell University	New York	New York	United States	10065
5	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
6	University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Aprea Therapeutics

Investigators

• Principal Investigator: David Sallman, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 30, 2019

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT03072043
• Other Study ID Numbers: MCC-18973
• First Posted: Mar 7, 2017
• Last Update Posted: Jan 24, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: myelodysplastic syndrome (MDS); TP53 mutant myelodysplastic syndrome; MDS/myeloproliferative neoplasm (MPN); chronic myelomonocytic leukemia (CMML); acute myeloid leukemia (AML)
• Additional relevant MeSH terms: Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Myeloproliferative Disorders; Syndrome; Azacitidine

Study Results

Participant Flow

Arm/Group Title	Phase 1b Dose Level 1	Phase 1B Dose Level 2	Phase 1B Dose Level 3 / Phase 2 MTD
Arm/Group Description	Participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	Participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	Participants treated at dose level 3/Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2
Period Title: Overall Study
STARTED	3	3	49
COMPLETED	3	3	40
NOT COMPLETED	0	0	9

Baseline Characteristics

Arm/Group Title	Phase 1B Dose Level 1	Phase 1B Dos Level 2	Phase 1B Dose Level 3/ MTD	Total
Arm/Group Description	Participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	Participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	Participants treated at dose level 3/MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	Total of all reporting groups
Overall Participants	3	3	49	55
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 33.3%	1 33.3%	20 40.8%	22 40%
>=65 years	2 66.7%	2 66.7%	29 59.2%	33 60%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	3 100%	24 49%	29 52.7%
Male	1 33.3%	0 0%	25 51%	26 47.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 66.7%	2 4.1%	4 7.3%
Not Hispanic or Latino	3 100%	1 33.3%	45 91.8%	49 89.1%
Unknown or Not Reported	0 0%	0 0%	2 4.1%	2 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	2 4.1%	2 3.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	2 4.1%	2 3.6%
White	2 66.7%	3 100%	42 85.7%	47 85.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 33.3%	0 0%	3 6.1%	4 7.3%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	49 100%	55 100%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Maximum Tolerated Dose (MTD)
Description	Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in <33% of the patients.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1b Dose Escalation
Arm/Group Description	Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. APR-246: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). Azacitidine: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.
Measure Participants	12
Number [mg/day]	4500

2. Primary Outcome

Title	Phase 2: Complete Response (CR) Rate
Description	Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

45 participants were evaluable for response

Arm/Group Title	Phase 2: Participants in Dose Level 3/MTD
Arm/Group Description	All participants who received at least one dose at level 3: 100 mg/kg LBW APR-246 + 75 mg Azacitidine
Measure Participants	45
Number (95% Confidence Interval) [percentage of patients]	53

3. Secondary Outcome

Title	Phase 2: Duration of Response
Description	Duration of response defined as the time between achieving response and progression of disease.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

45 participants were evaluable for response.

Arm/Group Title	Evaluable Participants
Arm/Group Description	All evaluable participants
Measure Participants	45
Median (Full Range) [months]	8

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS:The length of time from the start of treatment until death by any cause.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug

Arm/Group Title	Phase 1B Dose Level 1	Phase 1B Dose Level 2	Phase 1B: Dose Level 3 / Phase 2 MTD
Arm/Group Description	All participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	All participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2	All participants treated at dose level 3/ Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m^2
Measure Participants	3	3	49
Median (Full Range) [months]	14.6	11.6	10.4

5. Secondary Outcome

Title	Phase 2: Overall Response Rate
Description	Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

45 participants were evaluable for response

Arm/Group Title	All Participants
Arm/Group Description	All participants
Measure Participants	45
Number (95% Confidence Interval) [percent of participants]	87 2900%

Adverse Events

Time Frame	2 years, 10 months
Adverse Event Reporting Description	All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Arm/Group Title	Phase 1b Dose Level 1		Phase 1B Dose Level 2		Phase 1B Dose Level 3/Phase 2 MTD
Arm/Group Description	All participants treated at dose level 1: APR-246 50 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m^2		All participants treated at dose level 2: APR-246 75 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m^2		All participants treated at dose level 3 & Phase 2: APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m^2
All Cause Mortality
	Phase 1b Dose Level 1		Phase 1B Dose Level 2		Phase 1B Dose Level 3/Phase 2 MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		1/3 (33.3%)		36/49 (73.5%)
Serious Adverse Events
	Phase 1b Dose Level 1		Phase 1B Dose Level 2		Phase 1B Dose Level 3/Phase 2 MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/3 (33.3%)		30/49 (61.2%)
Blood and lymphatic system disorders
Blood and Lymphatic system disorders -Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Febrile neutropenia	1/3 (33.3%)	1	0/3 (0%)	0	17/49 (34.7%)	34
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Chest pain -cardiac	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Pericardial effusion	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Ear and labyrinth disorders
Ear and labyrinth disorders -Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Gastrointestinal disorders
Gastrointestinal disorders -Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Vomiting	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
General disorders
Death NOS	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Infusion related reaction	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Multi organ failure	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Pain	1/3 (33.3%)	1	0/3 (0%)	0	0/49 (0%)	0
Infections and infestations
Abdominal infection	1/3 (33.3%)	1	0/3 (0%)	0	0/49 (0%)	0
Bladder infection	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Infection and Infestations - Other	0/3 (0%)	0	1/3 (33.3%)	1	7/49 (14.3%)	9
Lung infection	0/3 (0%)	0	0/3 (0%)	0	7/49 (14.3%)	7
Sepsis	1/3 (33.3%)	1	0/3 (0%)	0	5/49 (10.2%)	5
Skin inefection	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Injury, poisoning and procedural complications
Ankle fracture	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Investigations
Creatinine increased	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Musculoskeletal and connective tissue disorders
Bone pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Chest wall pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Generalized muscle weakness	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Nervous system disorders
Encephalopathy	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Stroke	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Renal and urinary disorders
Acute kidney injury	1/3 (33.3%)	1	0/3 (0%)	0	0/49 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Aspiration	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Bronchopulmonary hemorrhage	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Respiratory failure	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Respiratory, thoracic and mediastinal disorders - Other	2/3 (66.7%)	2	0/3 (0%)	0	3/49 (6.1%)	3
Vascular disorders
Hypotension	0/3 (0%)	0	1/3 (33.3%)	1	0/49 (0%)	0
Thromboembolic event	1/3 (33.3%)	1	0/3 (0%)	0	3/49 (6.1%)	3
Vascular disorders -Other	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Vascular disorders - Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Other (Not Including Serious) Adverse Events
	Phase 1b Dose Level 1		Phase 1B Dose Level 2		Phase 1B Dose Level 3/Phase 2 MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		47/49 (95.9%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	2	0/3 (0%)	0	4/49 (8.2%)	5
Blood and lymphatic system disorders - Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Bone marrow hypocellular	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Lymph node pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Cardiac disorders
Chest pain - cardiac	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Heart palpitations	0/3 (0%)	0	1/3 (33.3%)	1	4/49 (8.2%)	4
Sinus tachycardia	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	5
Cardiac disorders - Other	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	6
Atrial fibrillation	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Ventricular tachycardia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Sinus bradycardia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Restrictive cardiomyopathy	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pericarditis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Myocardial infarction	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Ear and labyrinth disorders
Ear pain	1/3 (33.3%)	1	0/3 (0%)	0	0/49 (0%)	0
Ear and labyrinth disorders -Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Vertigo	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Endocrine disorders
Endocrine disorders -other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Eye disorders
Blurry vision	0/3 (0%)	0	1/3 (33.3%)	1	0/49 (0%)	0
Eye disorders - Other	1/3 (33.3%)	1	0/3 (0%)	0	2/49 (4.1%)	2
Dry eye	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Eye pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Gastrointestinal disorders
Nausea	1/3 (33.3%)	2	2/3 (66.7%)	8	32/49 (65.3%)	57
Constipation	1/3 (33.3%)	1	0/3 (0%)	0	21/49 (42.9%)	24
Diarrhea	1/3 (33.3%)	1	1/3 (33.3%)	1	15/49 (30.6%)	24
Dry mouth	0/3 (0%)	0	2/3 (66.7%)	2	0/49 (0%)	0
Enterocolitis	0/3 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Fecal incontinence	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Mucositis oral	0/3 (0%)	0	2/3 (66.7%)	2	8/49 (16.3%)	10
Vomiting	1/3 (33.3%)	1	1/3 (33.3%)	5	22/49 (44.9%)	37
Abdominal pain	0/3 (0%)	0	0/3 (0%)	0	8/49 (16.3%)	8
Toothache	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Abdominal distension	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Anal pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dental carries	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dyspepsia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Esophagitis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Gastric hemorrhage	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Gastroesophageal reflux disease	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Stomach pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Rectal pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Rectal hemorrhage	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Oral pain	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	6
Oral hemorrhage	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Ileal ulcer	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hemorrhoids	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hemorrhoidal hemorrhage	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Gastrointestinal disorders -Other	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	4
General disorders
Fever	0/3 (0%)	0	0/3 (0%)	0	12/49 (24.5%)	16
Flu like symptoms	0/3 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Gait disturbance	0/3 (0%)	0	0/3 (0%)	0	7/49 (14.3%)	18
Generalized edema	1/3 (33.3%)	1	0/3 (0%)	0	1/49 (2%)	4
Pain -Side pain	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Pain -Hip	1/3 (33.3%)	1	0/3 (0%)	0	4/49 (8.2%)	4
Pain- Jaw	0/3 (0%)	0	1/3 (33.3%)	1	0/49 (0%)	0
Pain -Shoulder	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Pain -Muscle	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pain -Chest	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Edema- limbs	0/3 (0%)	0	0/3 (0%)	0	18/49 (36.7%)	21
Chills	0/3 (0%)	0	0/3 (0%)	0	8/49 (16.3%)	9
Injection site reaction	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	4
Fatigue	0/3 (0%)	0	0/3 (0%)	0	23/49 (46.9%)	38
Edema face	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Edema trunk	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Malaise	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	4
Diffuse body pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/3 (33.3%)	1	0/3 (0%)	0	0/49 (0%)	0
Port vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Cholecystitis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Immune system disorders
Allergic reaction including pruritis	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Allergic Reaction - swollen tongue	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Allergic Reaction	1/3 (33.3%)	1	0/3 (0%)	0	1/49 (2%)	2
Infections and infestations
Infections and Infestations - Other	3/3 (100%)	3	1/3 (33.3%)	4	12/49 (24.5%)	17
Lung infection	1/3 (33.3%)	1	0/3 (0%)	0	4/49 (8.2%)	4
Rhinitis, infective	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Sinusitis	1/3 (33.3%)	1	0/3 (0%)	0	2/49 (4.1%)	2
Skin infection	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Tooth infection	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Upper respiratory infection	0/3 (0%)	0	1/3 (33.3%)	1	4/49 (8.2%)	4
Urinary tract infection	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Eye Infection	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Cecal infection	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Papulopustular rash	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Kidney infection	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Injury, poisoning and procedural complications
Fall	1/3 (33.3%)	1	1/3 (33.3%)	1	7/49 (14.3%)	8
Injury, poisoning and procedural complications - other	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Brusing	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Investigations
Leukopenia	2/3 (66.7%)	5	2/3 (66.7%)	7	12/49 (24.5%)	14
Alanine aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	10/49 (20.4%)	14
Alkaline phosphatase increased	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Aspartate aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	8
Blood bilirubin increased	0/3 (0%)	0	0/3 (0%)	0	6/49 (12.2%)	11
Creatinine increased	0/3 (0%)	0	0/3 (0%)	0	8/49 (16.3%)	13
Electrocardiogram QT corrected interval prolonged	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	5
Neutrophil count decreased	2/3 (66.7%)	4	3/3 (100%)	12	10/49 (20.4%)	27
Hypokalemia	1/3 (33.3%)	1	0/3 (0%)	0	7/49 (14.3%)	11
Hypomagnesemia	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Weight loss	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Platelet count decreased	1/3 (33.3%)	1	2/3 (66.7%)	6	12/49 (24.5%)	23
Investigations - Other	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	3
Metabolism and nutrition disorders
Hyperglycemia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hypoalbuminemia	1/3 (33.3%)	2	0/3 (0%)	0	3/49 (6.1%)	3
Hyponatremia	1/3 (33.3%)	1	0/3 (0%)	0	2/49 (4.1%)	3
Anorexia	0/3 (0%)	0	0/3 (0%)	0	14/49 (28.6%)	15
Dehydration	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Alkalosis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Metabolism and nutrition disorders - Other	1/3 (33.3%)	1	0/3 (0%)	0	5/49 (10.2%)	6
Iron overload	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hypophosphatemia	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	5
Hypernatremia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Acidosis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	1/3 (33.3%)	1	9/49 (18.4%)	10
Generalized muscle weakness	2/3 (66.7%)	2	0/3 (0%)	0	8/49 (16.3%)	14
Arthralgia	0/3 (0%)	0	0/3 (0%)	0	7/49 (14.3%)	11
Arthritis	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	5
Myalgia	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	5
Pain in extremity	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	9
Neck pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Musculoskeletal and connective tissue disorders - other	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Muscle weakness - lower limb	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Bone pain	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	6
Nervous system disorders
Ataxia	2/3 (66.7%)	2	0/3 (0%)	0	4/49 (8.2%)	11
Dizziness	1/3 (33.3%)	1	2/3 (66.7%)	5	18/49 (36.7%)	31
Peripheral sensory neuropathy	0/3 (0%)	0	2/3 (66.7%)	8	12/49 (24.5%)	13
Headache	1/3 (33.3%)	2	1/3 (33.3%)	2	14/49 (28.6%)	16
Intracranial hemorrhage	1/3 (33.3%)	1	0/3 (0%)	0	1/49 (2%)	1
Syncope	0/3 (0%)	0	1/3 (33.3%)	1	2/49 (4.1%)	3
Presyncope	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Amnesia	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Tremor	1/3 (33.3%)	1	0/3 (0%)	0	10/49 (20.4%)	21
Allodynia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Nervous system disorders -Other	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	6
Concentration impairment	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dysarthria	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	3
Dysesthesia	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	7
Dysgeusia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Vasovagal reaction	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dysphasia	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Somnolence	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Sinus pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Paresthesia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Memory impairment	1/3 (33.3%)	1	0/3 (0%)	0	0/49 (0%)	0
Psychiatric disorders
Anxiety	1/3 (33.3%)	1	0/3 (0%)	0	3/49 (6.1%)	3
Insomnia	0/3 (0%)	0	1/3 (33.3%)	1	6/49 (12.2%)	7
Confusion	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	6
Delirium	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Depression	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Hallucinations	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Renal and urinary disorders
Dysuria	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Urinary incontinence	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Urinary frequency	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Acute kidney injury	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Chronic kidney disease	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Urinary urgency	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hematuria	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	4
Urinary retention	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Renal calculi	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Renal and urinary disorders - Other	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Urinary tract pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)	0	1/3 (33.3%)	1	14/49 (28.6%)	19
Allergic rhinitis	0/3 (0%)	0	0/3 (0%)	0	6/49 (12.2%)	7
Atelectasis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Wheezing	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Voice alteration	0/3 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Dyspnea	0/3 (0%)	0	0/3 (0%)	0	16/49 (32.7%)	17
Epistaxis	1/3 (33.3%)	1	0/3 (0%)	0	7/49 (14.3%)	11
Sore throat	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Sinus disorder	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Respiratory, thoracic and mediastinal disorders -Other	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Post nasal drip	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Pleuritic pain	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Nasal congestion	0/3 (0%)	0	0/3 (0%)	0	6/49 (12.2%)	6
Adult respiratory distress syndrome	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hypoxia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pneumonitis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other	0/3 (0%)	0	1/3 (33.3%)	1	10/49 (20.4%)	14
Alopecia	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Bullous dermatitis	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Dry skin	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Erythema multiforme	0/3 (0%)	0	0/3 (0%)	0	5/49 (10.2%)	6
Skin induration	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Rash maculo-papular	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Rash acneiform	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Purpura	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	2
Pruritus	1/3 (33.3%)	1	0/3 (0%)	0	12/49 (24.5%)	12
Palmar-plantar ethryodysesthesia syndrome	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hyperhidrosis	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Vascular disorders
Flushing	0/3 (0%)	0	2/3 (66.7%)	3	1/49 (2%)	1
Hematoma	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Vasculitis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Thromboembolic event	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Superficial thrombophlebitis	0/3 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hypotension	0/3 (0%)	0	1/3 (33.3%)	1	4/49 (8.2%)	5
Hypertension	0/3 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	8
Hot flashes	0/3 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

There IS 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.