Safety and Efficacy of Marqibo in Relapsed Acute Lymphoblastic Leukemia

• Sponsor: Spectrum Pharmaceuticals, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00495079
• Collaborator: Parexel (Industry)
• Enrollment: 65
• Locations: 33
• Arm: 1
• Duration (Months): 39.3
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a Phase 2, international, multicenter, open-label, single-arm trial evaluating Marqibo (VSLI) in adult subjects with: 1) Ph- ALL or lymphoblastic lymphoma in second or greater relapse; or 2) Ph- ALL or lymphoblastic lymphoma who failed 2 or greater treatment lines of anti-leukemia chemotherapy. The original enrollment target for this study was approximately 56 subjects. Per a protocol amendment, enrollment was increased from 56 to 65.

The primary objective of this study was to evaluate:

• The efficacy of the study treatment as determined by the rate of CR plus CR with incomplete blood count recovery (CRi) in adult subjects with Philadelphia chromosome-negative (Ph-) ALL in second relapse or adult subjects with (Ph-) ALL who failed 2 treatment lines of anti-leukemia chemotherapy. Subjects must have achieved a CR to at least 1 prior anti-leukemia therapy as defined by a leukemia-free interval of ≥ 90 days.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia (ALL)	Drug: Marqibo® (vincristine sulfate liposomes injection)	Phase 2

Detailed Description

The secondary objectives of this study were to evaluate:

• Duration of CR plus CRi

• Overall survival

• Safety and tolerability

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study to Evaluate the Safety and Efficacy of Weekly Doses of Marqibo® (Vincristine Sulfate Liposomes Injection) in Adult Patients With Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Adult Patients With Philadelphia Chromosome-negative ALL Who Failed Two Treatment Lines of Anti-leukemia Chemotherapy
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Aug 8, 2010
• Actual Study Completion Date: Aug 8, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Marqibo Eligible subjects received study drug at 2.25 mg/m^2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes).	Drug: Marqibo® (vincristine sulfate liposomes injection); Dosing was done every 7 days (± 3 days) on Days 1, 8, 15, and 22 with no less than 4 days between dosing days. Dose calculations were based on body surface area using the subject's height (from Screening) and actual weight for each course.; Other Names: VSLI, Vincristine Sulfate Liposomes Injection

Outcome Measures

Primary Outcome Measures

1. Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi) [Response assessment performed at the end of each 28 day course.]

   CR is defined as no evidence of ALL: ANC>or=1x10^9/L or platelet count>100x10^9/L, absence of leukemia blast cells in blood and marrow (<5% blasts), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery (CRi): As per CR but platelet count< 100x10^9/L or ANC< 1x10^9/L. Partial remission(PR):CR with>5-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. Reduction in EMD by at least 50%. Hematologic Improvement. Bone marrow blast(BMB) response: BMB<5% in the absence of HI. Stable disease(SD):No significant hematological and extramedullary change from baseline.

2. Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation [Response assessment at the end of each 28 days course]

   Number of subjects who achieved Complete Remission (CR)as assessed by the IRRC. CR is defined as no evidence of ALL. ANC>=1X10^9/L or Platelet count>=100x10^9/L, absence of blasts in blood and morrow (<5%), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery(CRi)is defined as per CR but platelet count <100x10^9/L or ANC<1x10^9/L.

Secondary Outcome Measures

1. Duration of CR + CRi [CR + CRi duration was calculated from the date the subject first met the definition of CR or CRi until the date of relapse]

   Duration of response for those subjects who achieved CR or CRi

2. Overall Survival [unlimited]

   Time, in days, from informed consent date until the date of death or date of last contact

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age ≥18 years.

• Had Ph- ALL or lymphoblastic lymphoma and was in second relapse, or had failed 2 treatment lines of anti-leukemia chemotherapy.

• Had histologically or cytologically proven ALL and ≥ 10% bone marrow blasts. If < 10% bone marrow blasts, subject must have had histologically or cytologically proven ALL and evaluable extramedullary disease. Sponsor approval was obtained prior to enrolling subjects who had < 10% bone marrow blasts with evaluable extramedullary disease.

• Had achieved a CR to at least 1 prior anti-leukemia therapy as defined by a leukemia-free interval of ≥ 90 days.

• For subjects with a prior history of stem cell transplantation, had ≤ Grade 1 active skin graft-versus-host disease (GVHD). No active gastrointestinal or liver graft-versus-host disease.

• Had an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3.

• Had normal renal and liver function as defined below within 14 days, inclusive, prior to first dose of VSLI, unless the abnormality was considered attributable to leukemia:

• Total bilirubin ≤ 2.0 × institutional upper limit of normal, unless the subject had a known diagnosis of Gilbert's disease. If a subject had Gilbert's disease, he/she could have participated in this study, however must have been monitored closely during the study.

• Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal.

• Serum creatinine ≤ 2.0 g/dL or calculated estimated creatinine clearance ≥ 50 mL/minute/1.73 m2 based on Cockcroft and Gault formula, unless renal dysfunction was considered due to hematologic malignancy.

• Had never received prior VSLI treatment.

• For women of childbearing potential, had a negative serum or urine pregnancy test within 14 days prior to enrollment.

• If female, the subject was postmenopausal, surgically sterilized, or willing to use acceptable methods of birth control (e.g., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, and condom with spermicide or abstinence) from the Screening visit through 30 days after the last dose of VSLI.

• If male, the subject agreed to use an acceptable barrier method for contraception from the Screening visit through 30 days after the last dose of VSLI.

• Before enrollment, the subject was capable of understanding and complying with parameters as outlined in the protocol and able to sign a written informed consent according to ICH/GCP and national/local regulations.

Exclusion Criteria:

• Had Burkitt's lymphoma or Burkitt's leukemia.

• Had a history of Philadelphia chromosome-positive (Ph+) ALL and/or BCR/ABL rearrangements documented by fluorescent in situ hybridization or polymerase chain reaction.

• Had a history of Philadelphia chromosome-positive (Ph+) ALL and/or BCR/ABL rearrangements documented by fluorescent in situ hybridization or polymerase chain reaction.

• Had active CNS disease. History of treated CNS disease was allowable. The CNS disease must have resolved in order for the subject to be eligible.

• Was eligible for stem cell transplantation. This implied that a suitable donor was readily available, the subject was willing to undergo stem cell transplantation, and the Investigator believed this was a better treatment option than VSLI. This was at the Investigator's discretion.

• Was treated with any investigational agents or chemotherapy agents in the last 21 days before the first dose of VSLI, unless full recovery from side effects had occurred or the subject had rapidly progressing disease judged to be life threatening by the Investigator.

• Was receiving any other standard or investigational treatment for the subject's leukemia.

• Intrathecal chemotherapy for CNS prophylaxis was allowable.

• The use of hydroxyurea (Hydrea®) to control leukocytosis was allowable but must have been tapered off by Day 14 of Course 1. From Day 15 of Course 1 on through the end of study participation, hydroxyurea (Hydrea®) was not allowed.

• Systemic corticosteroids must have been tapered off, preferably before the start of study treatment, but no later than by Day 5 of Course 1. From Day 6 of Course 1 on through the end of study participation, systemic corticosteroids were not allowed.

• Had persistent chronic clinically significant toxicities from prior chemotherapy ≥ Grade 2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0).

• Had persistent ≥ Grade 2 active neuropathy (NCI CTCAE v3.0).

• Had a history of persistent ≥ Grade 2 active neurologic disorders unrelated to chemotherapy (including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition).

• Had a history of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to vincristine or components of study drug.

• Was female who was pregnant or breast-feeding.

• Had active serious infection not controlled by oral or intravenous antibiotics or antifungals.

• Had human immunodeficiency virus positive status.

• Had any medical condition which in the opinion of the investigator placed the subject at an unacceptably high risk for toxicities.

• Had any condition or circumstance which in the opinion of the investigator would significantly interfere with the subject's protocol compliance and put the subject at increased risk.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC - Norris Cancer Center	Los Angeles	California	United States	90033
2	UCLA Medical Center	Los Angeles	California	United States	90095
3	University of California Medical Center	San Francisco	California	United States	94143
4	Stanford Hospitals and Clinics	Stanford	California	United States	94305
5	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
6	Emory University - Winship Cancer Institute	Atlanta	Georgia	United States	30322
7	Loyola University Medical Center	Chicago	Illinois	United States	60153
8	Rush University Medical Center	Chicago	Illinois	United States	60612
9	University of Chicago Medical Center	Chicago	Illinois	United States	60637
10	Univesity of Iowa - Hospitals and Clinica	Iowa City	Iowa	United States	52242
11	Henry Ford Health System	Detroit	Michigan	United States	48202
12	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
13	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
14	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
15	New York Medical College	Valhalla	New York	United States	10595
16	Western Pennsylvania Allegheny Health System	Pittsburgh	Pennsylvania	United States	15224
17	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15232
18	University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030
19	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
20	Dresden University Hospital	Dresden		Germany	01307
21	University of Essen	Essen		Germany	45122
22	J.W. Goethe University	Frankfurt		Germany	60325
23	University of Leipzig	Leipzig		Germany
24	University of Muenster	Muenster		Germany	48149
25	University of Rostock	Rostock		Germany	18057
26	Diakonie-Klinikum Stuttgart	Stuttgart		Germany	70176
27	Robert Bosch Hospital	Stuttgart		Germany
28	University of Ulm	Ulm		Germany	89070
29	Rambam Medical Center	Haifa		Israel	31096
30	Hadassah Medical Center - Ein Karem	Jerusalem		Israel	91120
31	Rabin Medical Center Campus	Petah-Tikva		Israel	49100
32	The Chaim Sheba Medical Center	Tel Hashomer		Israel
33	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH

Sponsors and Collaborators

• Spectrum Pharmaceuticals, Inc
• Parexel

Investigators

• Principal Investigator: Susan O'Brien, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Spectrum Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT00495079
• Other Study ID Numbers: HBS407
• First Posted: Jul 2, 2007
• Last Update Posted: Mar 5, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Spectrum Pharmaceuticals, Inc: acute; lymphoblastic; lymphocytic; leukemia; leukaemia; lukemia; leukimia; ALL; Marqibo; Hana Biosciences; vincristine; liposomal; liposome; optisome; hematology; malignancy; hematological; relapsed; anti-leukemia; adult; chemotherapy
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Vincristine

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled and treated at 22 sites in United States, Canada, Germany, Israel and United Kingdom. The first subject was infused on August 2, 2007. The last subject completed study on August 8, 2010.
Pre-assignment Detail	2.25 mg/m^2 Marqibo administered intravenously via peripheral or central venous access over 60 minutes (+-10 minutes)

Arm/Group Title	Marqibo
Arm/Group Description	Eligible subjects received study drug at 2.25 mg/m2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes).
Period Title: Overall Study
STARTED	65
COMPLETED	65
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Marqibo
Arm/Group Description	Eligible subjects received study drug at 2.25 mg/m2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes).
Overall Participants	65
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	59 90.8%
>=65 years	6 9.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.3 (16.37)
Sex: Female, Male (Count of Participants)
Female	32 49.2%
Male	33 50.8%
Region of Enrollment (participants) [Number]
United States	53 81.5%
Canada	2 3.1%
Israel	6 9.2%
Germany	4 6.2%

Outcome Measures

1. Primary Outcome

Title	Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi)
Description	CR is defined as no evidence of ALL: ANC>or=1x10^9/L or platelet count>100x10^9/L, absence of leukemia blast cells in blood and marrow (<5% blasts), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery (CRi): As per CR but platelet count< 100x10^9/L or ANC< 1x10^9/L. Partial remission(PR):CR with>5-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. Reduction in EMD by at least 50%. Hematologic Improvement. Bone marrow blast(BMB) response: BMB<5% in the absence of HI. Stable disease(SD):No significant hematological and extramedullary change from baseline.
Time Frame	Response assessment performed at the end of each 28 day course.

Outcome Measure Data

Analysis Population Description

Subjects who had CR plus CRi by the PI and the IRRC assessments using the International Working Group Criteria. The Intent-to-Treat Analysis, n=65, minimum 1 dose. The IRRC, n=53, 1 dose, assess response as determined by the IRRC. Analyses, a Simon's 2-stage minimax design where the type I error alpha was set at 0.10 and the power was 80%.

Arm/Group Title	Marqibo
Arm/Group Description	Eligible subjects received study drug at 2.25 mg/m2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes).
Measure Participants	65
Number [participants]	13 20%

2. Secondary Outcome

Title	Duration of CR + CRi
Description	Duration of response for those subjects who achieved CR or CRi
Time Frame	CR + CRi duration was calculated from the date the subject first met the definition of CR or CRi until the date of relapse

Outcome Measure Data

Analysis Population Description

Based on the first date of CR or CRi to the date of the last available histologic assessment of the same response (n=8)

Arm/Group Title	Marqibo
Arm/Group Description	Duration of response derived using the IRRC determined response dates for subjects who achieved CR or CRi (n=8). The K-M product limit method was used to estimate the median event time. Eligible subjects received Marqibo at 2.25mg^m2 intravenously via peripheral or central venous access over 60 minutes (+- 10 minutes)every 7 days (+/- 3 days)
Measure Participants	8
Median (95% Confidence Interval) [days]	28

3. Secondary Outcome

Title	Overall Survival
Description	Time, in days, from informed consent date until the date of death or date of last contact
Time Frame	unlimited

Outcome Measure Data

Analysis Population Description

Based on the first date of CR or CRi to date of documented relapse, death, or subsequent chemotherapies including hematopoietic stem cell transplant (HSCT)(n=10)

Arm/Group Title	Marqibo
Arm/Group Description	The population analyzed included all subjects who received at least one dose of Marqibo. Subjects who did not die had their survival times censored on the date of last contact. The K-M method was used to estimate the distribution of overall survival. Eligible subjects received study drug at 2.25 mg/m2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes)every 7 days (+/- 3 days)
Measure Participants	10
Median (95% Confidence Interval) [days]	56

4. Primary Outcome

Title	Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation
Description	Number of subjects who achieved Complete Remission (CR)as assessed by the IRRC. CR is defined as no evidence of ALL. ANC>=1X10^9/L or Platelet count>=100x10^9/L, absence of blasts in blood and morrow (<5%), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery(CRi)is defined as per CR but platelet count <100x10^9/L or ANC<1x10^9/L.
Time Frame	Response assessment at the end of each 28 days course

Outcome Measure Data

Analysis Population Description

The IRRC evaluable population included all subjects who received at least 1 dose of study drug and who has reviewable data to assess and determine response or lack of response as determined by the IRRC.

Arm/Group Title	Marqibo
Arm/Group Description	Proportion if subjects who achieved CR+CRi as determined by the IRRC using the International Working Group (IWG)Criteria. The IRRC Evaluable analysis set(n=53) included subjects who received at least 1 dose of study drug and reviewable data. Eligible subjects received Marqibo at 2.25mg^m2 intravenously via peripheral or central venous access over 60 minutes (+/-10 minutes) every 7 days (+/-3days)
Measure Participants	53
Number [participants]	11 16.9%

Adverse Events

Time Frame	From date of first dose of study drug until 30 days after last Marqibo dose (+ 5 days)
Arm/Group Title	Marqibo
Arm/Group Description	Eligible subjects received study drug at 2.25 mg/m2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes).
All Cause Mortality
	Marqibo
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Marqibo
	Affected / at Risk (%)	# Events
Total	21/65 (32.3%)
Blood and lymphatic system disorders
Febrile neutropenia	12/65 (18.5%)	12
Neutropenia	1/65 (1.5%)	1
Anaemia	1/65 (1.5%)	1
Pancytopenia	1/65 (1.5%)	1
Thrombocytopenia	2/65 (3.1%)	2
Cardiac disorders
Cardiac arrest	1/65 (1.5%)	1
Cardiac Arrest	3/65 (4.6%)	3
Cardio-Respiratory Arrest	2/65 (3.1%)	2
Cardiogenic Shock	1/65 (1.5%)	1
Cardiomyopathy	1/65 (1.5%)	1
Endocrine disorders
Inappropriate antidiuretic hormone secretion	1/65 (1.5%)	1
Gastrointestinal disorders
Abdominal pain	1/65 (1.5%)	1
Constipation	2/65 (3.1%)	2
Diarrhoea	3/65 (4.6%)	3
Gastrointestinal haemorrhage	1/65 (1.5%)	1
Ileus	1/65 (1.5%)	1
Nausea	1/65 (1.5%)	1
Subileus	1/65 (1.5%)	1
Vomiting	1/65 (1.5%)	1
General disorders
Pyrexia	1/65 (1.5%)	1
Gait Disturbance	1/65 (1.5%)	1
Multi-Organ Failure	1/65 (1.5%)	1
Pain	1/65 (1.5%)	1
Hepatobiliary disorders
Cholecystitis, chronic	1/65 (1.5%)	1
Immune system disorders
Graft versus host disease	1/65 (1.5%)	1
Infections and infestations
Bacteraemia	1/65 (1.5%)	1
Staphylococcal bacteraemia	1/65 (1.5%)	1
Pneumonia	1/65 (1.5%)	1
Sepsis	2/65 (3.1%)	2
Septic Shock	2/65 (3.1%)	2
Acute Sinusitis	1/65 (1.5%)	1
Bronchiectasis	1/65 (1.5%)	1
Bronchopulmonary Aspergillosis	1/65 (1.5%)	1
Cellulitis	1/65 (1.5%)	1
Entrocococcal Bacteraemia	1/65 (1.5%)	1
Escherichia Sepsis	1/65 (1.5%)	1
Klebsiella Sepsis	1/65 (1.5%)	1
Neutropenic Sepsis	1/65 (1.5%)	1
Parainfluenzae Virus Infection	1/65 (1.5%)	1
Pneumonia Bacterial	1/65 (1.5%)	1
Rhinitis	1/65 (1.5%)	1
Sinusitis	1/65 (1.5%)	1
Injury, poisoning and procedural complications
Subdural Haematoma	1/65 (1.5%)	1
Investigations
Csf Bacteria Identified	1/65 (1.5%)	1
Metabolism and nutrition disorders
Tumor lysis syndrome	3/65 (4.6%)	3
Decreased appetite	1/65 (1.5%)	1
Hyponatraemia	1/65 (1.5%)	1
Dehydration	1/65 (1.5%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/65 (1.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphocytic leukaemia	1/65 (1.5%)	1
Acute Lymphocytic Leukemia	9/65 (13.8%)	9
Acute Lymphocytic Leukaemia Recurrent	1/65 (1.5%)	1
Leukaemia	1/65 (1.5%)	1
Leukaemia Infiltration Brain	1/65 (1.5%)	1
Nervous system disorders
Neuropathy, peripheral	4/65 (6.2%)	4
Facial palsy	1/65 (1.5%)	1
Peripheral sensory neuropath	1/65 (1.5%)	1
Cerebral Infarction	1/65 (1.5%)	1
Convulsion	1/65 (1.5%)	1
Heamorrhage Intracranial	1/65 (1.5%)	1
Peripheral Motor Neuropathy	1/65 (1.5%)	1
Psychiatric disorders
Mental Status Changes	2/65 (3.1%)	2
Renal and urinary disorders
Cystitis Haemorrhagic	1/65 (1.5%)	1
Renal Failure	1/65 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Organising pneumonia	1/65 (1.5%)	1
Respiratory distress	3/65 (4.6%)	3
Respiratory Failure	3/65 (4.6%)	3
Dyspnoea	1/65 (1.5%)	1
Hypoxia	1/65 (1.5%)	1
Pulmonary Haemorrhage	1/65 (1.5%)	1
Vascular disorders
Venoocclusive disease	1/65 (1.5%)	1
Hypotension	2/65 (3.1%)	2
Other (Not Including Serious) Adverse Events
	Marqibo
	Affected / at Risk (%)	# Events
Total	65/65 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	24/65 (36.9%)	24
Anaemia	17/65 (26.2%)	17
Neutropenia	15/65 (23.1%)	15
Thrombocytopenia	15/65 (23.1%)	15
Leukopenia	5/65 (7.7%)	5
Cardiac disorders
Tachycardia	11/65 (16.9%)	11
Gastrointestinal disorders
Nausea	35/65 (53.8%)	35
Constipation	34/65 (52.3%)	34
Diarrhoea	22/65 (33.8%)	22
Vomiting	17/65 (26.2%)	17
Abdominal pain	13/65 (20%)	13
Stomatitis	9/65 (13.8%)	9
Abdominal distension	7/65 (10.8%)	7
Gingival bleeding	6/65 (9.2%)	6
Dry mouth	4/65 (6.2%)	4
Dysphagia	4/65 (6.2%)	4
Flatulence	4/65 (6.2%)	4
General disorders
Pyrexia	25/65 (38.5%)	25
Fatigue	19/65 (29.2%)	19
Asthenia	15/65 (23.1%)	15
Pain	15/65 (23.1%)	15
Oedema, peripheral	10/65 (15.4%)	10
Chills	8/65 (12.3%)	8
Chest pain	7/65 (10.8%)	7
Infections and infestations
Pneumonia	9/65 (13.8%)	9
Oral candidiasis	4/65 (6.2%)	4
Septic shock	4/65 (6.2%)	4
Urinary tract infection	4/65 (6.2%)	4
Investigations
Weight decreased	10/65 (15.4%)	10
Alanine aminotransferase increased	7/65 (10.8%)	7
Aspartate aminotransferase increased	7/65 (10.8%)	7
Blood lactate dehydrogenase increased	7/65 (10.8%)	7
Blood alkaline phosphatase increased	4/65 (6.2%)	4
Metabolism and nutrition disorders
Decreased appetite	24/65 (36.9%)	24
Hypokalaemia	17/65 (26.2%)	17
Hypomagnesaemia	9/65 (13.8%)	9
Hypocalcaemia	7/65 (10.8%)	7
Hypophosphataemia	7/65 (10.8%)	7
Hyperglycaemia	6/65 (9.2%)	6
Dehydration	5/65 (7.7%)	5
Hyponatraemia	5/65 (7.7%)	5
Tumor lysis syndrome	5/65 (7.7%)	5
Cachexia	4/65 (6.2%)	4
Musculoskeletal and connective tissue disorders
Back pain	13/65 (20%)	13
Arthralgia	12/65 (18.5%)	12
Bone pain	9/65 (13.8%)	9
Pain in extremity	8/65 (12.3%)	8
Muscular weakness	6/65 (9.2%)	6
Myalgia	5/65 (7.7%)	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukemia	9/65 (13.8%)	9
Nervous system disorders
Neuropathy, peripheral	20/65 (30.8%)	20
Headache	17/65 (26.2%)	17
Hypoaesthesia	16/65 (24.6%)	16
Paraesthesia	14/65 (21.5%)	14
Dizziness	10/65 (15.4%)	10
Areflexia	6/65 (9.2%)	6
Hyporeflexia	5/65 (7.7%)	5
Cranial neuropathy	4/65 (6.2%)	4
Facial neuralgia	4/65 (6.2%)	4
Neuralgia	4/65 (6.2%)	4
Psychiatric disorders
Insomnia	16/65 (24.6%)	16
Confusional state	10/65 (15.4%)	10
Anxiety	6/65 (9.2%)	6
Depression	5/65 (7.7%)	5
Agitation	4/65 (6.2%)	4
Renal and urinary disorders
Urinary incontinence	4/65 (6.2%)	4
Respiratory, thoracic and mediastinal disorders
Dyspnoea	16/65 (24.6%)	16
Epistaxis	10/65 (15.4%)	10
Oropharyngeal pain	10/65 (15.4%)	10
Cough	7/65 (10.8%)	7
Hypoxia	4/65 (6.2%)	4
Skin and subcutaneous tissue disorders
Rash	8/65 (12.3%)	8
Petechiae	4/65 (6.2%)	4
Pruritis	4/65 (6.2%)	4
Vascular disorders
Hypertension	11/65 (16.9%)	11
Hypotension	10/65 (15.4%)	10
Orthostatic hypotension	4/65 (6.2%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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