ReLive: Efficacy and Safety Doxorubicin Transdrug Study in Patients Suffering From Advanced Hepatocellular Carcinoma

• Sponsor: Onxeo (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01655693
• Collaborator: (none)
• Enrollment: 397
• Locations: 70
• Arms: 3
• Actual Duration (Months): 83
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this phase III study is to determine whether Doxorubicin Transdrug (DT) is effective in the treatment of patients suffering from advanced Hepatocellular Carcinoma (HCC) after failure or intolerance to Sorafenib. Patients with HCC with or without cirrhosis and with good liver functions are eligible. Only those who can not benefit from treatment for which efficacy is demonstrated are eligible.

These patients are usually proposed either best standard of care (BSC) or participation to clinical trials. Patients eligible for the RELIVE study will receive either DT at 20 mg/m2 or DT at 30 mg/m2 or the BSC.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Doxorubicin 20 mg/m2; Drug: Doxorubicin 30 mg/m2; Drug: Best Standard of Care	Phase 3

Detailed Description

Doxorubicin-Transdrug™ (DT) is a nanoparticle formulation of doxorubicin.In in vitro and in vivo models, DT was shown to overcome the multidrug resistance (MDR) and to be more effective than doxorubicin on both sensitive and resistant tumour models and in particular in the X/myc bi-transgenic MDR murine model of HCC.

Study Design

• Study Type: Interventional
• Actual Enrollment: 397 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicentre, Randomised, Controlled, Open-label Study Comparing the Efficacy and Safety of Doxorubicin Transdrug™ to Best Standard of Care in Patients With Advanced Hepatocellular Carcinoma. ReLive Study.
• Actual Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: May 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doxorubicin Transdrug (DT) at 20 mg/m2 DT will be infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity	Drug: Doxorubicin 20 mg/m2; Other Names: Doxorubicin Transdrug (DT) at 20 mg/m2
Experimental: Doxorubicin Transdrug (DT) at 30 mg/m2 DT will be infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity	Drug: Doxorubicin 30 mg/m2; Other Names: Doxorubicin Transdrug (DT) at 30 mg/m2
Active Comparator: Best Standard of Care Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or unacceptable toxicity	Drug: Best Standard of Care; Other Names: BSC

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [Time from date of randomization to the date of death from any cause with initial assessment up to 24 months and follow-up assessment up to 45 months.]

   OS is defined as the time from date of randomization to the date of death from any cause.

Secondary Outcome Measures

1. Progression-free Survival (PFS) [Time from date of randomization to date of first documented progression or death from any cause, which ever came first, assessed up to 20 months.]

   PFS is defined as time from the date of randomisation to the date of the first documented progression or death from any cause. PFS determined by independent radiological review according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 is determine by at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.

2. Objective Response Rate (ORR) [Time from date of first treatment cycle to date of last cycle of treatment for the full duration of study treatment up to 24 months.]

   ORR is defined as percent of patients whose best overall response is complete response (CR) or partial response (PR) during the study treatment period and based on the evaluation of independent radiological review according to RECIST 1.1 for target lesions and assessed by MRI: CR is disappearance of all targets extra nodal lesions and the regression of all nodal lesions to < 10 mm; PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. PD is at least a 20% increase in the sum of diameters of target lesions, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.

Other Outcome Measures

1. Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, Withdrawal From Study, or Death [Time from date of initial treatment to date of death, disease progression, or participant withdrawal from the study.]

   The number of participants experiencing TEAEs considered related to treatment and categorized by severity of all related TEAEs according to National Cancer Institute/Common Toxicity Criteria (NCI-CTCAE) v4.0 and resulting in patient withdrawal from study or death.

2. Number of Participants With Cardiovascular and Respiratory Events Related to Study Drug [Time from date of initial treatment to date of death, disease progression, or patient withdrawal from the study.]

   The number of participants with cardiovascular and respiratory adverse events (AEs) were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The AE numbers reported are those considered related to treatment. Related AEs are those that are judged unlikely, possibly, probably or definitely related to the study or study drug by the investigator.

3. Number of Participants Experiencing a Reduction of Oxygen Saturation (SaO2) During and After Doxorubicin Transdrug (DT) Infusion [Time from start of infusion to resolution of reduction in oxygen saturation.]

   Number of participants experiencing an SaO2 reduction defined as a decrease =< 90% during or after DT infusion until resolution to =>93%. Participants had continuous monitoring of SaO2 saturation with pulse oximeter during 6 hour infusion and up to 24 hour after infusion start. SaO2 measures the amount of oxygen (in percent) bound to hemoglobin in red blood cells. SaO2 saturation was only monitored and reported in the DT infusion group. Reduction in SaO2 could result in modify DT dosing regimen. Decreases in SaO2 are a known and expected occurrence with DT infusions, and close monitoring of SaO2 was specified by the protocol to protect patients from potential respiratory distress during infusions.

4. Number of Participants With Clinically Significant Abnormal Change in Respiratory Function [Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.]

   Number of participants with any clinically significant abnormal change in respiratory function test over the study to include carbon monoxide diffusing capacity to measure lung function, forced expiratory volume in 1 second to measure ability to expel air from your lungs, total lung capacity to measure total amount of air in the lungs after taking the deepest breath possible, and vital capacity to measure the greatest volume of air that can be expelled from the lungs after taking the deepest breath possible. Clinically significant abnormal changes in respiratory function was determined by the investigator.

5. Number of Participants Experiencing Clinically Significant Abnormal Electrocardiogram (ECG) Changes From Baseline [Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.]

   Number of participants experiencing clinically significant abnormal ECG changes from baseline over the course of the study. ECG were completed every month before each infusion. ECG will detect changes in heart rhythm. Clinically significant abnormal changes in ECG were determined by the investigator.

6. Number of Participants Experiencing Clinically Significant Changes in Left Ventricular Ejection Fraction (LVEF) and the Severity of the Event [Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.]

   Number of participants that experienced a change from baseline in LVEF with severity of LVEF noted as follows: Normal: 100 - 50%, 0 - 9% drop from baseline resting ejection fraction (EF), Grade 2 = 50 - 40%, 10 - 19% drop from baseline resting EF; Grade 3 = 39 - 20%, >20% drop from baseline; Grade 4 = <20%. LVEF was monitored every other month. LVEF measures how much blood the left ventricle of the heart pumps out with each contraction and is used to assess the severity of left ventricle dysfunction in the heart. Clinical significance changes were determined by the investigator.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or non-pregnant, non-breast feeding female;

• Aged ≥ 18 years;

• Patient with:

• advanced HCC (BCLC-C according to BCLC staging classification) having progressed under Sorafenib therapy or intolerant to Sorafenib, or;

• intermediate HCC (BCLC-B) non eligible or non responders to transarterial chemoembolization (TACE), and having progressed under or intolerant to Sorafenib therapy

• Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic vein thrombosis without extension in inferior/superior vena cava, are eligible;

• HCC diagnosed according to the American Association for Study of Liver Diseases (AASLD) and/or European Association for the Study of the Liver (EASL) criteria:

• Radiological Criteria applicable in cirrhotic liver:

• Nodule ≥ 10 mm: one imaging technique among MRI and CT-scan showing typical appearances for HCC defined as arterial enhancement and rapid washout in portal venous or delayed phase;

• If appearance not typical for HCC on initial imaging: second contrast enhanced study (CT or MRI) showing typical appearances for HCC defined as arterial enhancement and rapid wash-out in portal venous or delayed phase;

• And/Or cyto-histology criteria (e.g. in case of atypical lesions for HCC at imaging, absence of cirrhosis);

• Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included);

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;

• Laboratory tests as follows:

• Platelets ≥ 50,000 /mm3

• Neutrophil count ≥ 1000/mm3

• Hemoglobin ≥ 10g/dL

• Serum transaminases < 5 upper limit normal (ULN) (NCI/common toxicity criteria (CTC) grades 0, 1, or 2)

• Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2)

• Serum bilirubin < 35 micromolar (µM)/L (or 2.0 mg/dL);

• Signed and dated written informed consent form.

Exclusion Criteria:

• Cirrhosis with a Child-Pugh score B8-C15;

• Untreated chronic hepatitis B;

• Patients eligible for curative treatments (transplantation, surgical resection, percutaneous treatment);

• Patients eligible for palliative treatments with demonstrated efficacy: TACE, Sorafenib; Patients who failed to Sorafenib treatment or intolerant to sorafenib are eligible and can be included if Sorafenib has been stopped at least 2 weeks before randomization;

• Prior history of malignancy with the exception of adequately treated basal cell carcinoma or in situ cervical cancer in complete remission since five years at least;

• HCC developed on transplanted liver;

• HIV infection;

• Risk of variceal bleeding;

• Oxygen saturation (SaO2) < 95%;

• Presence of a significant acute or chronic respiratory disease defined as NCI/CTCAE > grade 2;

• Presence of recent (< 6 months) or current cardiac failure (class III or IV New York Heart Association (NYHA) classification), recent (< 6 months) acute coronary syndrome, clinically significant ECG abnormalities or recent (less than 6 months) acute vascular diseases (stroke, myocardial infarction (MI)…);

• Prior cumulative dose of 300 mg/m² of doxorubicin or equivalent;

• Patients currently treated with immunosuppressive agents that cannot be stopped;

• Patients whose medical or surgical conditions are unstable and may not allow the study completion or compliance, and specially patients with uncontrolled diabetes;

• Uncontrolled systemic infection;

• Patients with a life expectancy of less than 2 months;

• Patients who have received an experimental drug in another clinical trial in the last 30 days prior to randomization in the present clinical trial;

• Women of child-bearing age who are unwilling or unable to use an effective contraception method during the study treatment period and for 6 months after the last administration of study drug, and their male partner(s) refusing to use a condom (if applicable);

• Men who are unwilling or unable to use a condom during the study treatment period and for 6 months after the last administration of study drug, and their female partner(s) refusing to use one of the appropriate effective contraception methods (if applicable);

• Patients unwilling or unable to comply with protocol requirements and scheduled visits.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gabrail Cancer Center	Canton	Ohio	United States	44718
2	Penn State Hershey Cancer Institute	Hershey	Pennsylvania	United States	17033
3	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
4	Krankenhaus der Elisabethinen Linz GmbH	Linz		Austria	4020
5	Medical University Vienna	Vienna		Austria	1090
6	CHU Brugmann	Brussels		Belgium	1020
7	UCL Saint-Luc	Brussels		Belgium	1200
8	CHU Sart Tilman	Liège		Belgium	4000
9	CHU UCL Mont-Godinne Dinant	Yvoir		Belgium
10	Clinical Research Center/ Alexandria university hospital	Alexandria		Egypt
11	Oncology Department, Medical Research Institute, Alexandria University	Alexandria		Egypt
12	Medical Oncology department /Ain Shams University Hospitals	Cairo		Egypt
13	National hepatology and tropical medicine research institute	Cairo		Egypt
14	Medical Oncology department /Mansoura University Hospitals	Mansoura		Egypt	35516
15	National Liver Institute / Menoufyia University	Menofia		Egypt	32700
16	Hospital Amiens	Amiens		France	80054
17	Hospital Jean Minjoz	Besançon		France	25000
18	Hospital Saint André	Bordeaux		France	33075
19	Centre hospitalier P Oudot	Bourgoin-Jallieu		France	38302
20	Hospital Estaing	Clermont-Ferrand		France	63003
21	Centre Hospitalier Beaujon	Clichy		France	92110
22	Hospital Henri-Mondor	Creteil		France	94010
23	Centre Jean-François Leclerc	Dijon		France	21079
24	CHU	Dijon		France
25	Hospital Grenoble	La Tronche		France	38700
26	CHU Dupuytren	Limoges		France	87042
27	Hospital Croix Rousse	Lyon		France	69317
28	Hospital La Timone	Marseille		France	13005
29	Hospital Saint Eloi	Montpellier		France	34295
30	Hospital Brabois	Nancy		France	54511
31	Hospital Hotel Dieu	Nantes		France	44093
32	CHU - Hôpital Archet	Nice		France
33	Hospital La Source	Orleans		France	45067
34	Hospital Pitié-Salpetriere	Paris		France	75013
35	Hospital Tenon	Paris		France	75020
36	Hospital Saint Jean	Perpignan		France	66046
37	CHU de Rouen- Hôpital Charles Nicolle	Rouen		France	76031
38	IC LOIRE	Saint-Etienne		France
39	Hospital Civil	Strasbourg		France	67091
40	Hospital Paul Brousse	Villejuif		France	94804
41	Universitätsklinikum Freiburg	Freiburg		Germany	79106
42	Universitätsklinikum Halle (Saale)	Halle An Der Saale		Germany	06120
43	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
44	Universität Leipzig AöR	Leipzig		Germany	04103
45	Klinikum rechts der Isar der TU Munchen II	Munchen		Germany	81675
46	Semmelweis Egyetem Radiológiai és Onkoterápiás Klinika	Budapest		Hungary	1082
47	Egyesített Szent István és Szent László Kórház - Rendelőintézet	Budapest		Hungary	1097
48	Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet	Debrecen		Hungary	4032
49	Szegedi Tudományegyetem Onkoterápiás Klinika	Szeged		Hungary	6720
50	Irccs Centro Di Riferimento Oncologico (Cro)	Aviano		Italy	33081
51	Ospedale Civile e degli Infermi	Faenza		Italy	48018
52	Ausl 12 Livorno Ospedale Unico della Versilia	Lido di Camaiore		Italy	55041
53	IRST Istituto Romagnolo Ricerca e Cura dei Tumori	Meldola		Italy	47014
54	Granda Osp. Magg. Policlinico	Milano		Italy	20122
55	Azienda Ospedaliera Policlinico di Modena	Modena		Italy	41124
56	A.O. Ospedale Maggiore della Carità	Novara		Italy	28100
57		Rimini		Italy	47900
58	Ain Wazein Hospital	El Chouf		Lebanon
59	Hospital General Universitario de Alicante	Alicante		Spain	03010
60	Hospital Universitario Virgen de la Arrixaca	El Palmar Murcia		Spain	30120
61	Complejo Hospitalario de Jaen	Jaen		Spain	23006
62	Hospital General Universario Gregorio Maranon	Madrid		Spain	28007
63	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
64	Hospital Universitario Madrid Sanchinarro	Madrid		Spain	28050
65	Hospital Carlos Haya	Malaga		Spain	29010
66	Hospital Universario Son Espaces	Palma De Mallorca		Spain	07010
67	Hospital Universitario Marques de Valdecilla	Santander		Spain	39008
68	Hospital Universitario Río Hortega	Valladolid		Spain	47012
69	Hacettepe University Medical Faculty	Ankara		Turkey
70	Ege Univeristy Medical Faculty,	İzmir		Turkey

Sponsors and Collaborators

• Onxeo

Investigators

• Principal Investigator: Philippe Merle, MD, Croix-Rousse Hospital - Lyon-France

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 27, 2017

More Information

Publications

None provided.

• Responsible Party: Onxeo
• ClinicalTrials.gov Identifier: NCT01655693
• Other Study ID Numbers: BA2011/03/04; 2011-002843-92
• First Posted: Aug 2, 2012
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• Keywords provided by Onxeo: Intermediate/advanced hepatocellular carcinoma; After failure or intolerance to Sorafenib.
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Doxorubicin; Liposomal doxorubicin

Study Results

Participant Flow

Recruitment Details

A total of 541 patients were screened, and 397 patients were randomized a 1:1:1 allocation at 69 sites in 11 countries worldwide. The randomization was performed using an interactive web response system (IWRS) with stratification based on region. Enrollment of first patient was June 15, 2012. Data cutoff was May 28, 2017 (24 months) for initial study and May 10, 2019, for follow-up period (45 months).

Pre-assignment Detail

Of the 144 patients who failed screening, the most common reason for screen failure was meeting liver function exclusion criteria.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	130	133	134
COMPLETED	4	7	4
NOT COMPLETED	126	126	130

Baseline Characteristics

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care	Total
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	130	133	134	397
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	50 38.5%	62 46.6%	57 42.5%	169 42.6%
>=65 years	80 61.5%	71 53.4%	77 57.5%	228 57.4%
Sex: Female, Male (Count of Participants)
Female	12 9.2%	27 20.3%	18 13.4%	57 14.4%
Male	118 90.8%	106 79.7%	116 86.6%	340 85.6%
Race/Ethnicity, Customized (Count of Participants)
White	120 92.3%	119 89.5%	125 93.3%	364 91.7%
Black	1 0.8%	3 2.3%	2 1.5%	6 1.5%
Asian	1 0.8%	3 2.3%	2 1.5%	6 1.5%
Other	1 0.8%	3 2.3%	3 2.2%	7 1.8%
Hispanic or Latino	0 0%	2 1.5%	1 0.7%	3 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
North African	6 4.6%	2 1.5%	0 0%	8 2%
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Unknown	1 0.8%	1 0.8%	1 0.7%	3 0.8%
Region of Enrollment (Count of Participants)
United States	2 1.5%	2 1.5%	3 2.2%	7 1.8%
Europe	118 90.8%	120 90.2%	119 88.8%	357 89.9%
Middle East	10 7.7%	11 8.3%	12 9%	33 8.3%
Alcohol Consumption (Count of Participants)
No Significant Alcohol Consumption	119 91.5%	127 95.5%	123 91.8%	369 92.9%
Active Alcohol Consumption	11 8.5%	6 4.5%	11 8.2%	28 7.1%
Child Pugh Class (Count of Participants)
Child Pugh A	114 87.7%	109 82%	113 84.3%	336 84.6%
Child Pugh B	15 11.5%	24 18%	21 15.7%	60 15.1%
Child Pugh C	1 0.8%	0 0%	0 0%	1 0.3%
Previous Hepatocellular Carcinoma (HCC) Treatments (Count of Participants)
Surgery/Resection	41 31.5%	49 36.8%	40 29.9%	130 32.7%
Loco-regional Treatment	84 64.6%	84 63.2%	84 62.7%	252 63.5%
Radiotherapy	14 10.8%	14 10.5%	9 6.7%	37 9.3%
Sorafenib	130 100%	133 100%	134 100%	397 100%
Other Systemic Anticancer Therapy	68 52.3%	73 54.9%	80 59.7%	221 55.7%
Medical History Active (Count of Participants)
Hypertension	73 56.2%	82 61.7%	84 62.7%	239 60.2%
Type 2 Diabetes Mellitus	28 21.5%	15 11.3%	35 26.1%	78 19.6%
Diabetes Mellitus	17 13.1%	26 19.5%	17 12.7%	60 15.1%
Hypercholestrolaemia	12 9.2%	14 10.5%	9 6.7%	35 8.8%
Varices Oesophageal	14 10.8%	24 18%	15 11.2%	53 13.4%
Chronic Obstructive Pulmonary Disease	13 10%	8 6%	9 6.7%	30 7.6%
Thrombocytopenia	7 5.4%	15 11.3%	8 6%	30 7.6%
HCC History-Cirrhosis (Count of Participants)
Yes	93 71.5%	96 72.2%	101 75.4%	290 73%
No	36 27.7%	35 26.3%	31 23.1%	102 25.7%
Unknown	1 0.8%	2 1.5%	2 1.5%	5 1.3%
HCC History - Cyto Histology (Count of Participants)
Yes	80 61.5%	87 65.4%	92 68.7%	259 65.2%
No	50 38.5%	46 34.6%	42 31.3%	138 34.8%
HCC History - Macroscopic Vascular Invasion (Count of Participants)
Macroscopic Portal Vein or Portal Branch Vascular Invasion - Yes	48 36.9%	41 30.8%	39 29.1%	128 32.2%
Macroscopic Portal Vein or Portal Branch Vascular Invasion - No	82 63.1%	92 69.2%	95 70.9%	269 67.8%
Supra-hepatic Vascular Invasion Vein - Yes	9 6.9%	8 6%	10 7.5%	27 6.8%
Supra-hepatic Vascular Invasion Vein - No	121 93.1%	125 94%	124 92.5%	370 93.2%
Vascular Invasion (Portal and/or Supra Hepatic) - Yes	50 38.5%	43 32.3%	45 33.6%	138 34.8%
Vascular Invasion (Portal and/or Supra Hepatic) - No	80 61.5%	90 67.7%	89 66.4%	259 65.2%
HCC History - Extra Hepatic Spread - Porta Hepatic Lymph Nodes (Count of Participants)
Yes	24 18.5%	19 14.3%	31 23.1%	74 18.6%
No	99 76.2%	104 78.2%	98 73.1%	301 75.8%
Unknown	7 5.4%	10 7.5%	5 3.7%	22 5.5%
HCC History - Extra Hepatic Spread - Distant Metastases (Count of Participants)
Yes	64 49.2%	68 51.1%	71 53%	203 51.1%
No	64 49.2%	61 45.9%	57 42.5%	182 45.8%
Unknown	2 1.5%	4 3%	6 4.5%	12 3%
HCC History - Aetiology of Underlying Liver Disease (Count of Participants)
Alcohol	64 49.2%	60 45.1%	68 50.7%	192 48.4%
Hepatitis C Virus	40 30.8%	40 30.1%	38 28.4%	118 29.7%
Nonalcoholic Steatohepatitis	14 10.8%	21 15.8%	23 17.2%	58 14.6%
Unknown	26 20%	14 10.5%	16 11.9%	56 14.1%
Hepatitis B Virus	7 5.4%	16 12%	14 10.4%	37 9.3%
Other	4 3.1%	12 9%	3 2.2%	19 4.8%
Hemochromatosis	3 2.3%	6 4.5%	4 3%	13 3.3%
Autoimmune	0 0%	0 0%	0 0%	0 0%
Primary Biliary Cirrhosis	0 0%	0 0%	0 0%	0 0%
HCC History - Nodule in the Liver (Count of Participants)
Single Nodule	15 11.5%	5 3.8%	8 6%	28 7.1%
Multiple Nodules	102 78.5%	106 79.7%	111 82.8%	319 80.4%
Infiltrate HCC	8 6.2%	17 12.8%	13 9.7%	38 9.6%
Unknown	5 3.8%	5 3.8%	2 1.5%	12 3%
HCC History - Disease Duration (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	28.1 (24.04)	30.5 (35.86)	31.5 (28.38)	30.1 (29.83)

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from date of randomization to the date of death from any cause.
Time Frame	Time from date of randomization to the date of death from any cause with initial assessment up to 24 months and follow-up assessment up to 45 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) Population: All randomized patients. The DT at 20 mg/m2 and 30 mg/m2 are combined into DT pooled experimental group for comparison with the BSC group. The primary analysis per protocol is DT pooled versus BSC and not individual DT groups.

Arm/Group Title	Doxorubicin Transdrug (DT) 20 mg/m2 Group	Doxorubicin Transdrug at 30 mg/m2	Doxorubicin Transdrug Pooled	Best Standard of Care (BSC)
Arm/Group Description	DT was infused over 6 hours through the intravenous route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	The DT 20 mg/m2 and 30 mg/m2 treatment group were pooled together for OS comparison to Best Standard of Care (BCS) for initial study.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity in initial study.
Measure Participants	130	133	263	134
OS up to 24 Months	10.1	8.9	9.1	9.0
OS up to 45 Months	9.8	8.8	8.9	9.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin Transdrug (DT) 20 mg/m2 Group, Doxorubicin Transdrug at 30 mg/m2, Doxorubicin Transdrug Pooled, Best Standard of Care (BSC)
	Comments	Initial 24 month assessment: the primary aim was to demonstrate the superiority of DT pooled (20 mg/m2 and 30 mg/m2) compared to BSC treatment and not individual DT groups per protocol. OS was estimated using the Kaplan-Meier method. The comparison of treatment groups (pooled DT groups versus BSC group) was performed using a non-stratified log-rank test as the primary analysis. The Cox model and Wilcoxon test was used for sensitivity analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.991
	Comments	Treatment comparison of DT pooled with BCS used non-stratified Log-rank test at significance level p=0.05.
	Method	Log Rank
	Comments	Log rank test is used after checking the proportional hazards (PH) assumption is valid. The Wilcoxon test is used when the PH assumption fails.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was controlled for the overall type I error rate at 5% (2-sided) corresponding to 95% confidence interval (CI) and type II error rate as 15%.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin Transdrug (DT) 20 mg/m2 Group, Doxorubicin Transdrug at 30 mg/m2, Doxorubicin Transdrug Pooled, Best Standard of Care (BSC)
	Comments	Follow-up 45 month assessment: the primary aim was to demonstrate the superiority of DT pooled (20 mg/m2 and 30 mg/m2) compared to BSC treatment and not individual DT groups per protocol. OS was estimated using the Kaplan-Meier method. The comparison of treatment groups (pooled DT groups versus BSC group) was performed using a non-stratified log-rank test as the primary analysis. The Cox model and Wilcoxon test was used for sensitivity analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.796
	Comments	Treatment comparison of DT pooled with BCS used non-stratified Log-rank test at significance level p=0.05.
	Method	Log Rank
	Comments	Log rank test is used after checking the proportional hazards (PH) assumption is valid. The Wilcoxon test is used when the PH assumption fails.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was controlled for the overall type I error rate at 5% (2-sided) corresponding to 95% confidence interval (CI) and type II error rate as 15%.

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined as time from the date of randomisation to the date of the first documented progression or death from any cause. PFS determined by independent radiological review according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 is determine by at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.
Time Frame	Time from date of randomization to date of first documented progression or death from any cause, which ever came first, assessed up to 20 months.

Outcome Measure Data

Analysis Population Description

ITT population: All randomized patients. The DT at 20 mg/m2 and 30 mg/m2 are combined into DT pooled experimental group for comparison with the BSC group. The primary analysis is DT pooled versus BSC. This was only analyzed for the initial study.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Doxorubicin Transdrug Pooled	Best Standard of Care
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	The DT 20 mg/m2 and 30 mg/m2 treatment group were pooled together for PFS comparison to BCS.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Measure Participants	130	133	263	134
Median (95% Confidence Interval) [months]	2.3	2.3	2.3	2.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin Transdrug (DT) 20 mg/m2 Group, Doxorubicin Transdrug at 30 mg/m2, Best Standard of Care (BSC)
	Comments	PFS was estimated using Kaplan-Meier methods and plotted as curves by treatment group. For comparison between treatment groups (pooled DT 20 mg/m2 and 30 mg/m2 versus BSC) used Log-rank test as primary analysis. Hazard ratio, mean, and mean PFS rate were given with corresponding 95% CI.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments	Treatment comparison with BCS using non-stratified Log-rank test at significance level p=0.05.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio for treatment variable was determined by Cox model. The hazard ratio was controlled for the overall type I error rate at 5% (2-sided) and type II error rate as 15%.

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR is defined as percent of patients whose best overall response is complete response (CR) or partial response (PR) during the study treatment period and based on the evaluation of independent radiological review according to RECIST 1.1 for target lesions and assessed by MRI: CR is disappearance of all targets extra nodal lesions and the regression of all nodal lesions to < 10 mm; PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. PD is at least a 20% increase in the sum of diameters of target lesions, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.
Time Frame	Time from date of first treatment cycle to date of last cycle of treatment for the full duration of study treatment up to 24 months.

Outcome Measure Data

Analysis Population Description

ITT population: all randomized patients. The DT at 20 mg/m2 and 30 mg/m2 are combined into DT pooled experimental group for comparison with the BSC group. The primary analysis is the DT pooled versus BCS. This was only analyzed for the initial study.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Doxorubicin Transdrug Pooled	Best Standard of Care
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT will be infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity Doxorubicin	The DT 20 mg/m2 and 30 mg/m2 treatment group were pooled together for ORR comparison to BCS.	Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or unacceptable toxicity Best Standard of Care
Measure Participants	130	133	263	134
Complete Response	0 0%	0 0%	0 0%	0 0%
Partial Response	0 0%	2 1.5%	2 1.5%	1 0.3%
Stable Disease	39 30%	41 30.8%	80 59.7%	31 7.8%
Progressive Disease	58 44.6%	63 47.4%	121 90.3%	40 10.1%
Not Evaluable	33 25.4%	27 20.3%	60 44.8%	62 15.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin Transdrug (DT) 20 mg/m2 Group, Doxorubicin Transdrug at 30 mg/m2, Doxorubicin Transdrug Pooled, Best Standard of Care (BSC)
	Comments	The comparisons between groups (pooled DT 20 mg/m2 and 30mg/m2 versus BSC) used Fisher's exact test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	Treatment comparison with BCS using Fisher's exact test at significance level p=0.05.
	Method	Fisher Exact
	Comments

4. Other Pre-specified Outcome

Title	Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, Withdrawal From Study, or Death
Description	The number of participants experiencing TEAEs considered related to treatment and categorized by severity of all related TEAEs according to National Cancer Institute/Common Toxicity Criteria (NCI-CTCAE) v4.0 and resulting in patient withdrawal from study or death.
Time Frame	Time from date of initial treatment to date of death, disease progression, or participant withdrawal from the study.

Outcome Measure Data

Analysis Population Description

Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care (BSC)
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Measure Participants	122	120	134
TEAEs	79 60.8%	98 73.7%	58 43.3%
Severe TEAEs	26 20%	46 34.6%	31 23.1%
Serious TEAEs	13 10%	18 13.5%	13 9.7%
TEAEs Leading to Withdrawal	5 3.8%	9 6.8%	9 6.7%
TEAEs Leading to Death	1 0.8%	2 1.5%	1 0.7%

5. Other Pre-specified Outcome

Title	Number of Participants With Cardiovascular and Respiratory Events Related to Study Drug
Description	The number of participants with cardiovascular and respiratory adverse events (AEs) were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The AE numbers reported are those considered related to treatment. Related AEs are those that are judged unlikely, possibly, probably or definitely related to the study or study drug by the investigator.
Time Frame	Time from date of initial treatment to date of death, disease progression, or patient withdrawal from the study.

Outcome Measure Data

Analysis Population Description

Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care (BSC)
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Measure Participants	122	120	134
Cardiac Disorders	4 3.1%	5 3.8%	1 0.7%
Vascular Disorders	8 6.2%	8 6%	6 4.5%
Blood Pressure Increased	0 0%	1 0.8%	0 0%
Respiratory, Thoracic, and Mediastinal Disorders	17 13.1%	20 15%	13 9.7%
Oxygen Saturation Decreased	2 1.5%	7 5.3%	1 0.7%
Respiratory Rate Increased	2 1.5%	5 3.8%	0 0%
Respiratory Rate Decreased	1 0.8%	1 0.8%	0 0%
Ejection Fraction Decreased	1 0.8%	0 0%	0 0%

6. Other Pre-specified Outcome

Title	Number of Participants Experiencing a Reduction of Oxygen Saturation (SaO2) During and After Doxorubicin Transdrug (DT) Infusion
Description	Number of participants experiencing an SaO2 reduction defined as a decrease =< 90% during or after DT infusion until resolution to =>93%. Participants had continuous monitoring of SaO2 saturation with pulse oximeter during 6 hour infusion and up to 24 hour after infusion start. SaO2 measures the amount of oxygen (in percent) bound to hemoglobin in red blood cells. SaO2 saturation was only monitored and reported in the DT infusion group. Reduction in SaO2 could result in modify DT dosing regimen. Decreases in SaO2 are a known and expected occurrence with DT infusions, and close monitoring of SaO2 was specified by the protocol to protect patients from potential respiratory distress during infusions.
Time Frame	Time from start of infusion to resolution of reduction in oxygen saturation.

Outcome Measure Data

Analysis Population Description

Safety population: All patients receiving at least one infusion for DT groups.

Arm/Group Title	Doxorubicin Transdrug (DT) 20 mg/m2	Doxorubicin Transdrug 30 mg/m2
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Measure Participants	122	120
Count of Participants [Participants]	2 1.5%	4 3%

7. Other Pre-specified Outcome

Title	Number of Participants With Clinically Significant Abnormal Change in Respiratory Function
Description	Number of participants with any clinically significant abnormal change in respiratory function test over the study to include carbon monoxide diffusing capacity to measure lung function, forced expiratory volume in 1 second to measure ability to expel air from your lungs, total lung capacity to measure total amount of air in the lungs after taking the deepest breath possible, and vital capacity to measure the greatest volume of air that can be expelled from the lungs after taking the deepest breath possible. Clinically significant abnormal changes in respiratory function was determined by the investigator.
Time Frame	Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.

Outcome Measure Data

Analysis Population Description

Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care (BSC)
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Measure Participants	122	120	134
Count of Participants [Participants]	13 10%	8 6%	0 0%

8. Other Pre-specified Outcome

Title	Number of Participants Experiencing Clinically Significant Abnormal Electrocardiogram (ECG) Changes From Baseline
Description	Number of participants experiencing clinically significant abnormal ECG changes from baseline over the course of the study. ECG were completed every month before each infusion. ECG will detect changes in heart rhythm. Clinically significant abnormal changes in ECG were determined by the investigator.
Time Frame	Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.

Outcome Measure Data

Analysis Population Description

Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care (BSC)
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Measure Participants	122	120	134
Count of Participants [Participants]	4 3.1%	6 4.5%	5 3.7%

9. Other Pre-specified Outcome

Title	Number of Participants Experiencing Clinically Significant Changes in Left Ventricular Ejection Fraction (LVEF) and the Severity of the Event
Description	Number of participants that experienced a change from baseline in LVEF with severity of LVEF noted as follows: Normal: 100 - 50%, 0 - 9% drop from baseline resting ejection fraction (EF), Grade 2 = 50 - 40%, 10 - 19% drop from baseline resting EF; Grade 3 = 39 - 20%, >20% drop from baseline; Grade 4 = <20%. LVEF was monitored every other month. LVEF measures how much blood the left ventricle of the heart pumps out with each contraction and is used to assess the severity of left ventricle dysfunction in the heart. Clinical significance changes were determined by the investigator.
Time Frame	Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.

Outcome Measure Data

Analysis Population Description

Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.

Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin Transdrug at 30 mg/m2	Best Standard of Care (BSC)
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.	Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Measure Participants	122	120	134
At Least One Abnormal Value	1 0.8%	4 3%	2 1.5%
At Least One Grade 3-4 Value	1 0.8%	1 0.8%	1 0.7%

Adverse Events

Time Frame	Adverse events (AEs) were collected until 1 month after last treatment. Treatment continued until patient experienced disease progression, aggravation of liver dysfunction, death, serious AE (SAE), or intolerable AE; or the patient withdrew consent or was withdrawn from study by investigator for reasons listed in the protocol. Median treatment durations were 1.9, 2.7, and 2.4 months in the Doxorubicin Transdrug (DT) 20 mg/m2, DT 30 mg/m2, and best standard of care (BSC) groups, respectively.
Adverse Event Reporting Description	The incidence and severity of all AEs and SAEs were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The cutoff for AE reporting was May 28, 2017.
Arm/Group Title	Doxorubicin Transdrug (DT) at 20 mg/m2		Doxorubicin Transdrug at 30 mg/m2		Best Standard of Care
Arm/Group Description	DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.		DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.		Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
All Cause Mortality
	Doxorubicin Transdrug (DT) at 20 mg/m2		Doxorubicin Transdrug at 30 mg/m2		Best Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/122 (96.7%)		119/120 (99.2%)		113/134 (84.3%)
Serious Adverse Events
	Doxorubicin Transdrug (DT) at 20 mg/m2		Doxorubicin Transdrug at 30 mg/m2		Best Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/122 (30.3%)		37/120 (30.8%)		48/134 (35.8%)
Blood and lymphatic system disorders
Neutropenia	0/122 (0%)	0	1/120 (0.8%)	2	1/134 (0.7%)	1
Leukopenia	0/122 (0%)	0	2/120 (1.7%)	2	0/134 (0%)	0
Anaemia	1/122 (0.8%)	1	1/120 (0.8%)	1	4/134 (3%)	4
Thrombocytopenia	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Cardiac disorders
Atrial fibrillation	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Atrioventricular block complete	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Atrioventricular block second degree	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Cardiac failure	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Ischaemic cardiomyopathy	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Supraventricular tachycardia	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Atrial thrombosis	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Gastrointestinal disorders
Ascites	3/122 (2.5%)	3	1/120 (0.8%)	1	3/134 (2.2%)	3
Abdominal pain	3/122 (2.5%)	4	0/120 (0%)	0	1/134 (0.7%)	1
Peritoneal haemorrhage	1/122 (0.8%)	1	2/120 (1.7%)	2	0/134 (0%)	0
Dysphagia	3/122 (2.5%)	3	0/120 (0%)	0	1/134 (0.7%)	1
Gastrooesophageal reflux disease	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Melaena	2/122 (1.6%)	2	0/120 (0%)	0	1/134 (0.7%)	1
Oesophageal varices haemorrhage	1/122 (0.8%)	1	3/120 (2.5%)	3	7/134 (5.2%)	7
Upper gastrointestinal haemorrhage	1/122 (0.8%)	1	0/120 (0%)	0	2/134 (1.5%)	2
Abdominal pain upper	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Haematemesis	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Vomiting	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Peptic ulcer haemorrhage	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Retroperitoneal haematoma	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
General disorders
Fatigue	0/122 (0%)	0	3/120 (2.5%)	3	0/134 (0%)	0
General physical health deterioration	3/122 (2.5%)	3	2/120 (1.7%)	2	8/134 (6%)	8
Pyrexia	2/122 (1.6%)	2	0/120 (0%)	0	2/134 (1.5%)	2
Chills	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Mucosal inflammation	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Oedema	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Oedema peripheral	0/122 (0%)	0	2/120 (1.7%)	2	0/134 (0%)	0
Asthenia	1/122 (0.8%)	1	1/120 (0.8%)	1	2/134 (1.5%)	2
Pain	1/122 (0.8%)	1	0/120 (0%)	0	1/134 (0.7%)	1
Complications associated with device	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Generalised oedema	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Hypothermia	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Multiple organ dysfunction syndrome	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Hepatobiliary disorders
Hepatic encephalopathy	1/122 (0.8%)	1	5/120 (4.2%)	6	7/134 (5.2%)	9
Hepatic failure	1/122 (0.8%)	1	2/120 (1.7%)	2	0/134 (0%)	0
Hepatorenal syndrome	0/122 (0%)	0	2/120 (1.7%)	2	1/134 (0.7%)	1
Portal vein thrombosis	0/122 (0%)	0	0/120 (0%)	0	2/134 (1.5%)	2
Biliary dilatation	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Cholelithiasis	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Coma hepatic	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Jaundice	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Immune system disorders
Drug hypersensitivity	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Infections and infestations
Catheter site infection	3/122 (2.5%)	3	0/120 (0%)	0	2/134 (1.5%)	2
Pneumonia	0/122 (0%)	0	2/120 (1.7%)	2	2/134 (1.5%)	2
Sepsis	2/122 (1.6%)	2	0/120 (0%)	0	2/134 (1.5%)	2
Endocarditis	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Escherichia sepsis	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Liver abscess	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Lower respiratory tract infection	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Lung infection	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Septic shock	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Staphylococcal sepsis	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Subcutaneous abscess	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Peritonitis	1/122 (0.8%)	1	1/120 (0.8%)	1	1/134 (0.7%)	1
Urinary tract infection	0/122 (0%)	0	1/120 (0.8%)	1	1/134 (0.7%)	1
Campylobacter infection	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Enterobacter pneumonia	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Erysipelas	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Peritonitis bacterial	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Lumbar vertebral fracture	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Post procedural bile leak	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Spinal fracture	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Investigations
Oxygen saturation decreased	0/122 (0%)	0	2/120 (1.7%)	2	0/134 (0%)	0
N-terminal prohormone brain natriuretic peptide increased	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Respiratory rate decreased	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/122 (0%)	0	1/120 (0.8%)	2	0/134 (0%)	0
Decreased appetite	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Dehydration	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Hypoglycaemia	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Musculoskeletal and connective tissue disorders
Osteitis	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Back pain	0/122 (0%)	0	2/120 (1.7%)	2	0/134 (0%)	0
Bone pain	2/122 (1.6%)	2	0/120 (0%)	0	0/134 (0%)	0
Pain in extremity	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Flank pain	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Osteoarthritis	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Trismus	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage	0/122 (0%)	0	1/120 (0.8%)	1	1/134 (0.7%)	1
Malignant neoplasm progression	2/122 (1.6%)	2	0/120 (0%)	0	1/134 (0.7%)	1
Lung neoplasm malignant	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Metastases to adrenals	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Metastases to bone	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Metastases to central nervous system	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Neoplasm progression	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Peritumoural oedema	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Squamous cell carcinoma of lung	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Nervous system disorders
Cerebral haematoma	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Neuralgia	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Psychiatric disorders
Completed suicide	1/122 (0.8%)	1	1/120 (0.8%)	1	0/134 (0%)	0
Depression	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Mental status changes	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/122 (0%)	0	0/120 (0%)	0	3/134 (2.2%)	3
Proteinuria	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/122 (0%)	0	1/120 (0.8%)	1	1/134 (0.7%)	1
Bronchopneumopathy	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Interstitial lung disease	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Pleural effusion	1/122 (0.8%)	2	2/120 (1.7%)	2	0/134 (0%)	0
Pulmonary embolism	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Restrictive pulmonary disease	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Dyspnoea	1/122 (0.8%)	2	1/120 (0.8%)	1	0/134 (0%)	0
Lung disorder	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Skin and subcutaneous tissue disorders
Skin ulcer	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Venous ulcer pain	0/122 (0%)	0	1/120 (0.8%)	1	0/134 (0%)	0
Social circumstances
Impaired quality of life	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Vascular disorders
Hypotension	0/122 (0%)	0	2/120 (1.7%)	2	0/134 (0%)	0
Arterial occlusive disease	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Superior vena cava syndrome	1/122 (0.8%)	1	0/120 (0%)	0	0/134 (0%)	0
Vena cava thrombosis	0/122 (0%)	0	0/120 (0%)	0	1/134 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Doxorubicin Transdrug (DT) at 20 mg/m2		Doxorubicin Transdrug at 30 mg/m2		Best Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	110/122 (90.2%)		112/120 (93.3%)		97/134 (72.4%)
Blood and lymphatic system disorders
Thrombocytopenia	2/122 (1.6%)	2	14/120 (11.7%)	26	24/134 (17.9%)	40
Anaemia	15/122 (12.3%)	24	22/120 (18.3%)	30	22/134 (16.4%)	28
Neutropenia	4/122 (3.3%)	16	18/120 (15%)	41	7/134 (5.2%)	9
Leukopenia	1/122 (0.8%)	6	11/120 (9.2%)	23	3/134 (2.2%)	3
Lymphopenia	5/122 (4.1%)	6	7/120 (5.8%)	16	3/134 (2.2%)	4
Gastrointestinal disorders
Nausea	26/122 (21.3%)	44	33/120 (27.5%)	62	24/134 (17.9%)	28
Diarrhoea	21/122 (17.2%)	39	23/120 (19.2%)	31	20/134 (14.9%)	26
Vomiting	15/122 (12.3%)	19	20/120 (16.7%)	28	10/134 (7.5%)	13
Constipation	18/122 (14.8%)	22	15/120 (12.5%)	18	12/134 (9%)	14
Abdominal pain	13/122 (10.7%)	15	15/120 (12.5%)	18	13/134 (9.7%)	17
Abdominal pain upper	10/122 (8.2%)	13	12/120 (10%)	15	5/134 (3.7%)	5
General disorders
Asthenia	41/122 (33.6%)	65	57/120 (47.5%)	82	39/134 (29.1%)	48
Fatigue	9/122 (7.4%)	11	14/120 (11.7%)	18	14/134 (10.4%)	15
Pyrexia	9/122 (7.4%)	13	23/120 (19.2%)	32	8/134 (6%)	8
Oedema peripheral	9/122 (7.4%)	10	25/120 (20.8%)	27	24/134 (17.9%)	26
Mucosal inflammation	2/122 (1.6%)	2	6/120 (5%)	7	4/134 (3%)	4
Hepatobiliary disorders
Hyperbilirubinaemia	2/122 (1.6%)	2	7/120 (5.8%)	17	3/134 (2.2%)	3
Jaundice	2/122 (1.6%)	2	8/120 (6.7%)	9	1/134 (0.7%)	1
Infections and infestations
Bronchitis	7/122 (5.7%)	10	7/120 (5.8%)	7	4/134 (3%)	4
Investigations
Weight decreased	5/122 (4.1%)	5	13/120 (10.8%)	13	5/134 (3.7%)	5
Blood bilirubin increased	8/122 (6.6%)	9	2/120 (1.7%)	3	7/134 (5.2%)	12
Gamma-glutamyltransferase increased	3/122 (2.5%)	3	6/120 (5%)	6	3/134 (2.2%)	5
Metabolism and nutrition disorders
Decreased Appetite	16/122 (13.1%)	16	19/120 (15.8%)	19	21/134 (15.7%)	23
Hypokalaemia	4/122 (3.3%)	5	11/120 (9.2%)	13	5/134 (3.7%)	6
Hypoalbuminaemia	3/122 (2.5%)	9	6/120 (5%)	13	6/134 (4.5%)	11
Musculoskeletal and connective tissue disorders
Back pain	11/122 (9%)	13	15/120 (12.5%)	23	6/134 (4.5%)	6
Muscle spasms	0/122 (0%)	0	7/120 (5.8%)	7	5/134 (3.7%)	5
Nervous system disorders
Paraesthesia	4/122 (3.3%)	5	2/120 (1.7%)	2	20/134 (14.9%)	35
Headache	11/122 (9%)	12	16/120 (13.3%)	23	6/134 (4.5%)	8
Neuropathy peripheral	0/122 (0%)	0	0/120 (0%)	0	9/134 (6.7%)	9
Dizziness	7/122 (5.7%)	8	1/120 (0.8%)	2	1/134 (0.7%)	1
Psychiatric disorders
Anxiety	3/122 (2.5%)	3	8/120 (6.7%)	8	5/134 (3.7%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea	12/122 (9.8%)	20	12/120 (10%)	16	9/134 (6.7%)	9
Cough	13/122 (10.7%)	19	9/120 (7.5%)	10	10/134 (7.5%)	12
Skin and subcutaneous tissue disorders
Alopecia	3/122 (2.5%)	3	7/120 (5.8%)	7	2/134 (1.5%)	2
Palmar-plantar erythrodysaesthesia syndrome	0/122 (0%)	0	1/120 (0.8%)	1	7/134 (5.2%)	11
Pruritus	7/122 (5.7%)	10	9/120 (7.5%)	10	7/134 (5.2%)	7
Dry skin	3/122 (2.5%)	3	7/120 (5.8%)	7	3/134 (2.2%)	3
Vascular disorders
Hypertension	8/122 (6.6%)	10	5/120 (4.2%)	5	3/134 (2.2%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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