Phase I Study of Lurbinectedin (PM01183) in Combination With Paclitaxel, With or Without Bevacizumab, in Selected Advanced Solid Tumors

• Sponsor: PharmaMar (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01831089
• Collaborator: (none)
• Enrollment: 69
• Locations: 3
• Arm: 1
• Duration (Months): 34
• Patients Per Site: 23
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Clinical trial of PM01183 in combination with paclitaxel, with or without bevacizumab, in patients with solid tumors

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Ovarian Cancer; Gynecological Cancer; Head and Neck Carcinoma; Non-small Cell Lung Cancer; Small Cell Lung Cancer; Non-squamous Cell Lung Cancer	Drug: PM01183 + paclitaxel +/- bevacizumab	Phase 1

Detailed Description

Clinical trial to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with weekly paclitaxel, with or without bevacizumab. Once a recommended dose is defined for the PM01183 and weekly paclitaxel combination, the feasibility of adding bevacizumab to this combination will be explored in a selected cohort of patients to characterize the safety profile and feasibility of this combination, to obtain preliminary information on antitumor activity, to obtain preliminary information on quality of life (QoL), to characterize the pharmacokinetics (PK) of this combination and to detect major drug-drug PK interactions and PK(pharmacokinetic)/PD(pharmacodynamic) correlation and to conduct an exploratory pharmacogenomic(PGx) analysis in patients with selected advanced solid tumors.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination With Weekly Paclitaxel, With or Without Bevacizumab, in Patients With Selected Advanced Solid Tumors
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment PM01183 + paclitaxel +/- bevacizumab

Drug: PM01183 + paclitaxel +/- bevacizumab; PM01183: 1 mg and 4 mg vials. Powder for concentrate for solution for infusion paclitaxel: 6 mg/ml concentrate for solution for infusion bevacizumab: 25 mg/ml concentrate for solution for infusion Once a recommended dose is defined for the PM01183 and weekly paclitaxel combination, the feasibility of adding bevacizumab to this combination will be explored in a prospectively selected cohort of patients

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) [The MTD was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks)]

   The MTD will be the lowest level at which one third or more evaluable patients experience a DLT in Cycle 1. DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1.

2. Recommended Dose (RD) [The RD was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks)]

   The RD will be the highest DL explored with less than one third of the patients experiencing a DLT during Cycle 1. DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1.

3. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [DLT was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks)]

   DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1.

Secondary Outcome Measures

1. Best Tumor Response [Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)]

   Best overall response:Best response recorded from the start of the study treatment until the end of treatment Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to<10 mm Partial Response (PR):At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression) Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum diameters while on study Treatment failure (TF):symptomatic deterioration or death due to progression

2. Progression-free Survival [Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)]

   Progression-free survival (PFS) was defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death had not occurred at the time of the analysis, the PFS was censored.

3. Duration of Response (DR) [Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)]

   Duration of response (DR) was defined as the time from the date when the response criteria (PR or CR, whichever was reached first) were fulfilled, to the first date when PD, recurrence or death was documented

4. Quality of Life (QoL) [Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)]

   Change from baseline to last cycle. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL scale scores. The EORTC QLQ-C15-PAL is an abbreviated 15-item version of the EORTC QLQ-C30 (version 3.0) developed for palliative care. Wilcoxon signed ranks test repeat-measure analyses of variance were used to measure the change value from baseline value. Data has to be analysed following the corresponding EORTC manual http://www.eortc.be/qol/files/SCManualQLQ-C15-PAL.pdf and the overall quality of life assessment is contained in 0 to 100 where a higher value represents a better state.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Voluntarily signed and dated written informed consent

• Age between 18 and 75 years old (both inclusive)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1

• Life expectancy ≥ 3 months.

• Patients with a histologically/cytologically confirmed diagnosis of advanced and/or unresectable disease of any of the following tumors:

1. Breast cancer

2. Epithelial ovarian cancer or gynecological cancer

3. Head and neck squamous cell carcinoma

4. Non-small cell lung cancer

5. Small cell lung cancer

6. Platinum-refractory germ-cell tumors.

7. Adenocarcinoma or carcinoma of unknown primary site

• Adequate bone marrow, renal, hepatic, and metabolic function

• Recovery to grade ≤ 1 or to baseline from any Adverse Event (AE) derived from previous treatment (excluding alopecia of any grade).

• Pre-menopausal women must have a negative pregnancy test before study entry and agree to use a medically acceptable method of contraception throughout the treatment period and for at least six weeks after treatment discontinuation

Exclusion Criteria:

• Prior treatment with PM01183 or weekly paclitaxel or nanoalbumin-paclitaxel

• Patients who have previously discontinued paclitaxel-based regimes due to drug related toxicity.

• Known hypersensitivity to bevacizumab or any component of its formulation

• Patients who have previously discontinued bevacizumab-containing regimes due to drug-related toxicity.

• More than three prior lines of chemotherapy

• Less than three months since last taxane-containing therapy.

• Wash-out period:

1. Less than three weeks since the last chemotherapy-containing regimen

2. Less than three weeks since the last radiotherapy dose

3. Less than four weeks since last monoclonal antibody-containing therapy

• Concomitant diseases/conditions:

Unstable angina, myocardial infarction, valvular heart disease, encephalopathy, ischemic attacks, hemorrhagic or ischemic cerebrovascular accident (CVA) or ongoing pulmonary embolism within last year, arrhythmia, hepatopathy, uncontrolled infection, hemoptysis or oxygen requiring dyspnea, known HIV infection, bleeding risk, muscular problems, peripheral neuropathy, Symptomatic or progressive brain metastases or leptomeningeal disease.

• Men or pre-menopausal women who are not using an effective method of contraception as previously described; actively breast feeding women.

• Patients who have pelvic irradiation with doses ≥ 45 Grays (Gy).

• History of previous bone marrow and/or stem cell transplantation.

• Confirmed bone marrow involvement

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		New York	New York	United States
2		Madrid		Spain
3		Bellinzona		Switzerland

Sponsors and Collaborators

• PharmaMar

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT01831089
• Other Study ID Numbers: PM1183-A-007-13
• First Posted: Apr 15, 2013
• Last Update Posted: Apr 10, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Paclitaxel; Bevacizumab

Study Results

Participant Flow

Recruitment Details	A total of 69 patients were enrolled at 3 investigational sites: 55 Group A (paclitaxel plus PM01183) and 14 Group B (paclitaxel+PM01183 and BEV). Patients participated in this trial between 15/Oct/2013 and 14/Jul/2016 (last FU). The first dose of the first cycle was given on 23/Oct/2013 and the last dose of the last cycle was given on 23/Jun/2016
Pre-assignment Detail	Signed IC,Age 18-75,ECOG PS≤1,Life expectancy≥3 months,Histologically/cytologically confirmed diagnosis of advanced and/or unresectable disease according to the groups,adequate status patient,no AEs,negative pregnancy test.

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
Period Title: Cohort I: Dose Level 1
STARTED	3	0	0	0	0	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	3	0	0	0	0	0
Period Title: Cohort I: Dose Level 1
STARTED	0	3	0	0	0	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	0	3	0	0	0	0
Period Title: Cohort I: Dose Level 1
STARTED	0	0	6	0	0	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	0	0	6	0	0	0
Period Title: Cohort I: Dose Level 1
STARTED	0	0	0	6	0	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	0	0	0	6	0	0
Period Title: Cohort I: Dose Level 1
STARTED	0	0	0	0	37	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	37	0
Period Title: Cohort I: Dose Level 1
STARTED	0	0	0	0	0	14
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	14

Baseline Characteristics

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg	Total
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Total of all reporting groups
Overall Participants	3	3	6	6	37	14	69
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	3 100%	6 100%	5 83.3%	23 62.2%	12 85.7%	51 73.9%
>=65 years	1 33.3%	0 0%	0 0%	1 16.7%	14 37.8%	2 14.3%	18 26.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57	50	53.5	46.5	61.0	57	57
Sex: Female, Male (Count of Participants)
Female	2 66.7%	3 100%	4 66.7%	5 83.3%	26 70.3%	8 57.1%	48 69.6%
Male	1 33.3%	0 0%	2 33.3%	1 16.7%	11 29.7%	6 42.9%	21 30.4%
Region of Enrollment (Count of Participants)
Switzerland	1 33.3%	2 66.7%	1 16.7%	1 16.7%	6 16.2%	1 7.1%	12 17.4%
Spain	2 66.7%	1 33.3%	3 50%	4 66.7%	12 32.4%	6 42.9%	28 40.6%
United States	0 0%	0 0%	2 33.3%	1 16.7%	19 51.4%	7 50%	29 42%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	The MTD will be the lowest level at which one third or more evaluable patients experience a DLT in Cycle 1. DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1.
Time Frame	The MTD was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks)

Outcome Measure Data

Analysis Population Description

Three patients at the RD were not evaluable because they did not receive a complete Cycle 1 due to disease-related grade 3 vomiting and early PD, disease-related grade 3 confusional state, and because not enough information for DLT evaluation was collected during Cycle 1.

Arm/Group Title	Group A (Paclitaxel/PM01183)
Arm/Group Description	All participants who received at least 1 dose of Paclitaxel/PM01183, either at 60/3.0, 60/4.0, 60/5.0, 80/5.0, 80/4.0 mg/m2 / mg FD.
Measure Participants	52
Number [mg/m2 / mg FD]	NA

2. Primary Outcome

Title	Recommended Dose (RD)
Description	The RD will be the highest DL explored with less than one third of the patients experiencing a DLT during Cycle 1. DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1.
Time Frame	The RD was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks)

Outcome Measure Data

Analysis Population Description

Three patients at the RD were not evaluable because they did not receive a complete Cycle 1 due to disease-related grade 3 vomiting and early PD, disease-related grade 3 confusional state, and because not enough information for DLT evaluation was collected during Cycle 1.

Arm/Group Title	Group A (Paclitaxel/PM01183)
Arm/Group Description	All participants who received at least 1 dose of Paclitaxel/PM01183, either at 60/3.0, 60/4.0, 60/5.0, 80/5.0, 80/4.0 mg/m2 / mg FD.
Measure Participants	52
Number [mg/m2 / mg FD]	NA

3. Primary Outcome

Title	Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
Description	DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1.
Time Frame	DLT was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
Measure Participants	3	3	6	6	34	12
Count of Participants [Participants]	0 0%	0 0%	2 33.3%	3 50%	6 16.2%	3 21.4%

4. Secondary Outcome

Title	Best Tumor Response
Description	Best overall response:Best response recorded from the start of the study treatment until the end of treatment Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to<10 mm Partial Response (PR):At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression) Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum diameters while on study Treatment failure (TF):symptomatic deterioration or death due to progression
Time Frame	Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
Measure Participants	3	3	6	6	33	10
CR	0 0%	0 0%	0 0%	0 0%	1 2.7%	1 7.1%
PR	1 33.3%	0 0%	2 33.3%	4 66.7%	12 32.4%	4 28.6%
SD ≥3 months	1 33.3%	2 66.7%	1 16.7%	1 16.7%	6 16.2%	4 28.6%
SD <3 months	0 0%	0 0%	1 16.7%	0 0%	1 2.7%	0 0%
PD	1 33.3%	1 33.3%	2 33.3%	1 16.7%	12 32.4%	0 0%
Early PD	0 0%	0 0%	0 0%	0 0%	1 2.7%	0 0%
TF	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.1%

5. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS) was defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death had not occurred at the time of the analysis, the PFS was censored.
Time Frame	Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
Measure Participants	3	3	6	6	33	10
Median (95% Confidence Interval) [months]	3.5	3.1	3.1	5.4	3.9	6.7

6. Secondary Outcome

Title	Duration of Response (DR)
Description	Duration of response (DR) was defined as the time from the date when the response criteria (PR or CR, whichever was reached first) were fulfilled, to the first date when PD, recurrence or death was documented
Time Frame	Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

In cohort II, no patients with PR or CR.

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
Measure Participants	1	0	2	4	13	5
Median (95% Confidence Interval) [months]	1.6	NA	2.2	4.1	4.6

7. Secondary Outcome

Title	Quality of Life (QoL)
Description	Change from baseline to last cycle. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL scale scores. The EORTC QLQ-C15-PAL is an abbreviated 15-item version of the EORTC QLQ-C30 (version 3.0) developed for palliative care. Wilcoxon signed ranks test repeat-measure analyses of variance were used to measure the change value from baseline value. Data has to be analysed following the corresponding EORTC manual http://www.eortc.be/qol/files/SCManualQLQ-C15-PAL.pdf and the overall quality of life assessment is contained in 0 to 100 where a higher value represents a better state.
Time Frame	Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]	Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD	Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]	Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.	All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
Measure Participants	3	3	6	6	26	8
Pain	5.6 (9.6)	8.3 (11.8)	-13.3 (21.7)	13.3 (13.9)	-4.2 (21.0)	12.5 (30.5)
Dyspnea	0.0 (0.0)	0.0 (47.1)	-6.7 (27.9)	6.7 (14.9)	11.1 (25.4)	12.5 (24.8)
Insomnia	0.0 (33.3)	16.7 (23.6)	0.0 (0.0)	-6.7 (14.9)	4.2 (34.5)	-12.5 (30.5)
Appetite loss	-22.2 (38.5)	0.0 (0.0)	-6.7 (14.9)	0.0 (0.0)	1.4 (30.3)	16.7 (25.2)
Constipation	11.1 (19.2)	0.0 (0.0)	6.7 (14.9)	13.3 (29.8)	-2.8 (23.9)	8.3 (23.6)
Overall QoL	5.6 (9.6)	-16.7 (0.0)	-8.3 (21.5)	-6.7 (19.0)	-6.3 (22.4)	-10.4 (17.7)
Physical functioning	-11.1 (19.2)	-6.7 (9.4)	-2.7 (6.0)	-13.3 (8.2)	-2.8 (19.8)	-8.3 (17.0)
Fatigue	3.7 (33.9)	0.0 (0.0)	-2.2 (24.1)	11.1 (13.6)	6.5 (23.4)	2.8 (22.0)
Nausea / vomiting	-5.6 (9.6)	8.3 (11.8)	0.0 (11.8)	3.3 (7.5)	3.5 (9.8)	2.4 (6.3)
Emotional functioning	16.7 (28.9)	-8.3 (35.4)	0.0 (11.8)	5.0 (33.1)	6.3 (18.4)	5.2 (16.0)

Adverse Events

Time Frame	Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks)
Adverse Event Reporting Description	In Group B: 14 patients were included, although only 12 were treated.
Arm/Group Title	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]		Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD		Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
Arm/Group Description	Cohort I Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 3.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.		Cohort II Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.		Cohort III Paclitaxel 60.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.		Cohort IV Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 5.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.		Cohort V Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour via a central or peripheral venous catheter through a pump device with an appropriate infusion line and filter. PM01183 4.0 mg FD as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour via a central catheter (or over a minimum dilution of 250 mL if a peripheral venous catheter was used) through a pump device. Patients in this group were to receive paclitaxel and PM01183 for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, PM01183 could be continued alone until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.		All three study medications were administered via a central or a peripheral venous catheter through a pump device, as follows: Paclitaxel 80.0 mg/m2 as an i.v. infusion on Days 1, 8 and 15 q3wk, over one hour. PM01183 as an i.v. infusion on Day 1 q3wk, after paclitaxel infusion, over one hour. Bevacizumab (BEV) 15 mg/kg as an i.v. infusion on Day 1 q3wk, immediately after paclitaxel and PM01183 infusions, Minimum duration of infusion was 90 minutes for the first dose and, if well tolerated, 60 minutes for the second dose and 30 minutes for all subsequent doses. nous catheter was used) through a pump device. Patients in this group were to receive paclitaxel, PM01183 and BEV for up to six cycles, in the absence of disease progression or unacceptable toxicity; then, both PM01183 and BEV could be continued until progression, unacceptable toxicity, patient's decision, or Investigator's decision upon the Sponsors' agreement.
All Cause Mortality
	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]		Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD		Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/6 (0%)		3/37 (8.1%)		2/14 (14.3%)
Serious Adverse Events
	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]		Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD		Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		3/6 (50%)		2/6 (33.3%)		15/37 (40.5%)		7/14 (50%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	2	0/14 (0%)	0
Febrile neutropenia	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	1/6 (16.7%)	1	1/37 (2.7%)	1	2/14 (14.3%)	2
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Eye disorders
Retinal detachment	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	2	0/14 (0%)	0
Intestinal obstruction	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Nausea	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Vomiting	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Large intestine perforation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
General disorders
Pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Pyrexia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/37 (2.7%)	1	0/14 (0%)	0
Chest pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Hepatobiliary disorders
Hepatic failure	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Gallbladder obstruction	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Infections and infestations
Catheter site cellulitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Pneumonia pneumococcal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Sepsis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Abdominal abscess	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Investigations
Alanine aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Aspartate aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Neutrophil count decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Metabolism and nutrition disorders
Hypocalcaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor associated fever	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	2	0/14 (0%)	0
Nervous system disorders
Dizziness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Psychiatric disorders
Confusional state	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Renal and urinary disorders
Urinary retention	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Respiratory failure	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Pulmonary embolism	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	2/14 (14.3%)	5
Vascular disorders
Venous thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	4	0/14 (0%)	0
Other (Not Including Serious) Adverse Events
	Paclitaxel [60.0 mg/m2] / PM01183 [3.0 mg FD]		Paclitaxel [60.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel 60.0 mg/m2 / PM01183 5.0 mg FD		Paclitaxel [80.0 mg/m2] / PM01183 [5.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD]		Paclitaxel [80.0 mg/m2] / PM01183 [4.0 mg FD] / BEV 15 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		6/6 (100%)		6/6 (100%)		36/37 (97.3%)		12/14 (85.7%)
Blood and lymphatic system disorders
Anaemia	1/3 (33.3%)	2	0/3 (0%)	0	3/6 (50%)	9	1/6 (16.7%)	1	7/37 (18.9%)	16	3/14 (21.4%)	4
Neutropenia	0/3 (0%)	0	1/3 (33.3%)	9	4/6 (66.7%)	17	5/6 (83.3%)	30	10/37 (27%)	22	3/14 (21.4%)	5
Lymphopenia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Cardiac disorders
Sinus tachycardia	0/3 (0%)	0	1/3 (33.3%)	4	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Palpitations	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	3	0/14 (0%)	0
Ear and labyrinth disorders
Tinnitus	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	28	1/14 (7.1%)	5
Hypoacusis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Eye disorders
Dry eye	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	2	2/14 (14.3%)	23
Vision blurred	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	9
Photophobia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	1/3 (33.3%)	4	0/6 (0%)	0	3/6 (50%)	13	2/37 (5.4%)	6	1/14 (7.1%)	3
Aphthous stomatitis	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	1/6 (16.7%)	2	0/37 (0%)	0	0/14 (0%)	0
Ascites	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/37 (2.7%)	3	1/14 (7.1%)	1
Constipation	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	2/6 (33.3%)	9	11/37 (29.7%)	33	6/14 (42.9%)	19
Diarrhoea	2/3 (66.7%)	3	2/3 (66.7%)	2	2/6 (33.3%)	6	2/6 (33.3%)	6	13/37 (35.1%)	29	5/14 (35.7%)	13
Dry mouth	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	1/14 (7.1%)	1
Dyspepsia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	2/6 (33.3%)	2	4/37 (10.8%)	13	2/14 (14.3%)	16
Dysphagia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	3
Gastrooesophageal reflux disease	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	4/37 (10.8%)	7	1/14 (7.1%)	8
Nausea	2/3 (66.7%)	4	2/3 (66.7%)	5	2/6 (33.3%)	9	4/6 (66.7%)	16	24/37 (64.9%)	57	6/14 (42.9%)	29
Stomatitis	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	10	0/6 (0%)	0	1/37 (2.7%)	1	1/14 (7.1%)	6
Vomiting	1/3 (33.3%)	1	1/3 (33.3%)	2	2/6 (33.3%)	5	3/6 (50%)	14	19/37 (51.4%)	29	3/14 (21.4%)	3
Colonic fistula	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Gastrointestinal fistula	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Inguinal hernia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	4
Rectal haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	4
Abdominal discomfort	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Gastrointestinal obstruction	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Subileus	0/3 (0%)	0	1/3 (33.3%)	3	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Enteritis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Abdominal pain upper	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/37 (2.7%)	1	0/14 (0%)	0
General disorders
Chest pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	1/14 (7.1%)	6
Extravasation	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	14
Fatigue	2/3 (66.7%)	11	3/3 (100%)	23	6/6 (100%)	42	6/6 (100%)	40	27/37 (73%)	153	10/14 (71.4%)	110
Influenza like illness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	3/37 (8.1%)	7	0/14 (0%)	0
Oedema peripheral	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/6 (50%)	18	4/37 (10.8%)	22	1/14 (7.1%)	5
Pain	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	5	0/6 (0%)	0	4/37 (10.8%)	16	2/14 (14.3%)	19
Pyrexia	0/3 (0%)	0	2/3 (66.7%)	5	1/6 (16.7%)	1	2/6 (33.3%)	3	7/37 (18.9%)	17	0/14 (0%)	0
Injection site erythema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Oedema	1/3 (33.3%)	4	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Catheter site inflammation	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Chills	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Face oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	5	1/37 (2.7%)	5	0/14 (0%)	0
Infusion site thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	3	0/37 (0%)	0	0/14 (0%)	0
Thrombosis in device	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	3	0/37 (0%)	0	0/14 (0%)	0
Infusion site phlebitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	5	1/14 (7.1%)	1
Malaise	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	6	0/14 (0%)	0
Immune system disorders
Hypersensitivity	0/3 (0%)	0	1/3 (33.3%)	3	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Infections and infestations
Respiratory tract infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	2	2/14 (14.3%)	2
Abdominal abscess	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Abdominal infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	2
Nasopharyngitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	3
Septic shock	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Tooth abscess	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Urinary tract infection	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	4	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Lung infection	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Pneumonia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Enterococcal infection	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Herpes zoster	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	1/37 (2.7%)	1	0/14 (0%)	0
Influenza	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/37 (2.7%)	2	0/14 (0%)	0
Nail infection	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Pharyngitis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Oral herpes	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Cellulitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	3	0/14 (0%)	0
Oral candidiasis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	3	0/14 (0%)	0
Upper respiratory tract infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	3	0/14 (0%)	0
Injury, poisoning and procedural complications
Infusion related reaction	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	1	1/14 (7.1%)	7
Thermal burn	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Investigations
Alanine aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/37 (8.1%)	4	0/14 (0%)	0
Neutrophil count decreased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	5	1/6 (16.7%)	2	6/37 (16.2%)	13	1/14 (7.1%)	3
Weight decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	3/37 (8.1%)	5	1/14 (7.1%)	1
Weight increased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	8	0/6 (0%)	0	2/37 (5.4%)	12	0/14 (0%)	0
Blood cholesterol increased	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Gamma-glutamyltransferase increased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/3 (33.3%)	2	0/3 (0%)	0	2/6 (33.3%)	6	2/6 (33.3%)	6	10/37 (27%)	38	4/14 (28.6%)	20
Dehydration	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	1/37 (2.7%)	2	1/14 (7.1%)	1
Hypocalcaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	2/37 (5.4%)	18	0/14 (0%)	0
Hypokalaemia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	3/37 (8.1%)	7	0/14 (0%)	0
Hypomagnesaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	23	2/37 (5.4%)	5	0/14 (0%)	0
Hyponatraemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Hypertriglyceridaemia	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	6	1/37 (2.7%)	3	2/14 (14.3%)	38
Back pain	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	2/37 (5.4%)	4	3/14 (21.4%)	17
Muscular weakness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	5	2/37 (5.4%)	14	0/14 (0%)	0
Fistula	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	12
Hypertrophic osteoarthropathy	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	5
Myalgia	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	0/37 (0%)	0	0/14 (0%)	0
Groin pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	0/37 (0%)	0	0/14 (0%)	0
Muscle spasms	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Musculoskeletal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Neck pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	3	0/37 (0%)	0	0/14 (0%)	0
Pain in extremity	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	3	0/14 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	3	5/37 (13.5%)	14	0/14 (0%)	0
Nervous system disorders
Dizziness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	1/14 (7.1%)	2
Dysgeusia	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	4/37 (10.8%)	19	0/14 (0%)	0
Headache	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	3/37 (8.1%)	26	1/14 (7.1%)	1
Neuropathy peripheral	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	12	1/6 (16.7%)	3	0/37 (0%)	0	1/14 (7.1%)	3
Paraesthesia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	4/37 (10.8%)	22	0/14 (0%)	0
Peripheral sensory neuropathy	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	2/6 (33.3%)	10	12/37 (32.4%)	59	2/14 (14.3%)	16
Peripheral motor neuropathy	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	6
Disturbance in attention	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Memory impairment	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Presyncope	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Somnolence	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/37 (2.7%)	2	0/14 (0%)	0
Agitation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Dysaesthesia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	0/14 (0%)	0
Psychiatric disorders
Anxiety	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	3/37 (8.1%)	19	1/14 (7.1%)	1
Depression	1/3 (33.3%)	7	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/37 (8.1%)	8	1/14 (7.1%)	20
Insomnia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	5/37 (13.5%)	34	2/14 (14.3%)	13
Libido decreased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	8	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Renal and urinary disorders
Renal failure acute	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Urinary tract pain	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)	2	1/3 (33.3%)	1	4/6 (66.7%)	20	2/6 (33.3%)	8	11/37 (29.7%)	40	3/14 (21.4%)	13
Dysphonia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	3/37 (8.1%)	5	2/14 (14.3%)	7
Dyspnoea	1/3 (33.3%)	1	0/3 (0%)	0	2/6 (33.3%)	4	1/6 (16.7%)	4	8/37 (21.6%)	45	3/14 (21.4%)	21
Epistaxis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	1/37 (2.7%)	4	3/14 (21.4%)	7
Nasal congestion	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	2/37 (5.4%)	6	2/14 (14.3%)	11
Pneumonitis	0/3 (0%)	0	1/3 (33.3%)	2	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Pleural effusion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Aspiration	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Rhonchi	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	6	0/6 (0%)	0	0/37 (0%)	0	0/14 (0%)	0
Oropharyngeal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	0/37 (0%)	0	0/14 (0%)	0
Dermatitis acneiform	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	6	0/37 (0%)	0	0/14 (0%)	0
Hiccups	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/37 (5.4%)	2	0/14 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)	3	1/3 (33.3%)	2	1/6 (16.7%)	6	5/6 (83.3%)	36	9/37 (24.3%)	47	5/14 (35.7%)	24
Dry skin	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/37 (2.7%)	3	1/14 (7.1%)	11
Erythema	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1	0/37 (0%)	0	1/14 (7.1%)	18
Pruritus	0/3 (0%)	0	1/3 (33.3%)	2	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	2
Rash maculo-papular	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	2/37 (5.4%)	7	2/14 (14.3%)	7
Vascular disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	8	1/6 (16.7%)	1	2/37 (5.4%)	6	3/14 (21.4%)	13
Deep vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/37 (0%)	0	1/14 (7.1%)	1
Jugular vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	3	0/37 (0%)	0	0/14 (0%)	0
Thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	0/37 (0%)	0	0/14 (0%)	0

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.