Dose Escalating Study of the Safety and Efficacy of Patupilone, q3w, in Patients With Non-small Cell Lung Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00171834
• Collaborator: (none)
• Enrollment: 89
• Locations: 4
• Duration (Months): 61
• Patients Per Site: 22.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The study objective is to evaluate the maximum tolerated dose, safety and efficacy of patupilone in patients with NSCLC who have progressed after prior chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Patupilone	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Phase I/II Dose Escalating Study Evaluating the Safety and Efficacy of EPO906, qw3, in Patients With Non-small Cell Lung Cancer.
• Study Start Date: Aug 1, 2003
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Outcome Measures

Primary Outcome Measures

1. Phase I: Number of Total Dose-limiting Toxicity (DLT) During Dose Escalation to Determine Maximum Tolerated Dose (MTD) [Cycle 1 (21 days)]

   The MTD was defined as the highest dose of patupilone administered every three weeks (q3w) where not more than one out of six patients experienced a DLT using a standard 3+3 design. Dose escalation started at 6.5 mg/m^2 until MTD in steps of 0.5 mg/m^2 until 12 mg/m^2, then in steps of 1 mg/m^2 till 13.0 mg/m^2. DLTs were assessed during cycle 1. During this time frame, no more than one DLT occurred in any of the explored dose levels up to 13 mg/m^2, thus, the MTD as defined by the protocol was not reached in this study.

2. Phase II: Number of Participants With Best Overall Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) [At baseline, then every second cycle (approximately every 6 weeks), until disease progression or discontinuation. Average 18 weeks.]

   Overall response is the number of participants who had a complete response (CR) or a partial response (PR) based on local investigator's assessment of RECIST criteria. Per RECIST: CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no worsening of non-TLs, and no new lesions; Progressive disease (PD), a >=20% increase in TLs, clearly worsening of non-TLs, or emergence of new lesions; Stable Disease (SD), small changes that do not meet previously given criteria.

Secondary Outcome Measures

1. Number of Participants With Best Overall Response-Phase I [Best achieved overall response according to RECIST from start of study until study discontinuation. Imaging was assessed every second cycle (ie. approximately every 6 weeks) until disease progression or discontinuation. Average 18 weeks]

   This was defined as the number of participants whose best overall response was CR or PR by RECIST. Per RECIST: CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no worsening of non-TLs, and no new lesions; Progressive disease (PD), a >=20% increase in TLs, clearly worsening of non-TLs, or emergence of new lesions; Stable Disease (SD), small changes that do not meet previously given criteria.

2. Overall Survival Time-Phase I and Phase II [From start of study drug to date of death due to any cause. Follow-up after treatment discontinuation approximately every 3 months until approximately 70% of participants have reached the survival endpoint. Average 9.75 months]

   Overall survival (OS) time was measured from the start of study drug to the date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Data was collected post treatment every 3 months until approximately 70% of patients have reached the survival endpoint (Phase I + Phase II).

3. Time to Progression (TTP)-Phase I and Phase II [From baseline, then every second cycle (i.e. approximately every 6 weeks), until disease progression or discontinuation from study. Average 18 weeks]

   Time to progression was measured from the start of study drug to the date of first documented disease progression by RECIST, discontinuation due to disease progression, or death from underlying cancer, whichever event occurred first. If a patient had not progressed by RECIST, discontinued due to disease progression, or died from underlying cancer, TTP was censored at the time of last adequate tumor assessment. However, if a patient took any new cancer therapy prior to PD or death, then TTP was censored at the date of last adequate tumor assessment prior to the start date of new cancer therapy.

4. Duration of Stable Disease-Phase I and Phase II [Imaging was assessed every second cycle (i.e. approximately every 6 weeks), until disease progression or discontinuation from treatment . Average 18 weeks]

   Duration of stable disease (CR, PR, or SD) by RECIST was defined as the time from start of study drug to the date of first documented disease progression or discontinuation due to disease progression, or death from underlying cancer, whichever event occured first.

5. Time to Overall Response -Phase I and Phase II [From baseline, then every second cycle (i.e. approximately every 6 weeks), until disease progression or discontinuation from study. Average 18 weeks]

   Time to overall response (CR or PR) measured by RECIST was the time between study start until date of first documented response (CR or PR).

6. Duration of Overall Response -Phase I and Phase II [Duration of response according to RECIST from start of study until study discontinuation. Duration of response was assessed every second cycle ( i.e. approximately every 6 weeks) until disease progression or discontinuation from study. Average 18 weeks]

   Duration of overall response (CR or PR) measured by RECIST was measured from the first documented CR or PR to the date of first documented disease progression or discontinuation due to disease progression, or death from underlying cancer, whichever event occured first.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients with histologic or cytologic confirmation of unresectable locally advanced or metastatic NSCLC (stage IIIB with pleural effusion only / stage IV) documented before first line therapy.

• Prior treatment with a platinum-containing regimen

• Age ≥18 years.

• Performance status of 0-1 on the WHO scale.

• Life expectancy of ≥3 months.

• NSCLC patients should have at least one measurable lesion as defined by modified RECIST criteria. If the patient has had previous radiation to the marker lesion(s), the lesion must have demonstrated progression since the radiation.

• NSCLC patients with controlled brain metastases are eligible to be enrolled in the brain metastases cohort at the MTD. "Controlled brain metastases" patients are defined as patients who are neurologically stable, i.e. have not experienced an increase in dose of steroidal or anticonvulsive therapy for at least 14 days prior to study entry.

• Patients with brain metastases must be verified to have metastases secondary to NSCLC based on histology of primary and by temporal sequence of events (note: these patients are eligible even if lung disease is quiescent).

• Patients with brain metastases must show evidence of residual disease or progression of disease since prior radiological or surgical therapy.

• Patients with brain metastases should have at least one bidimensionally measurable intracranial lesion of minimum diameter 2 cm. Multifocal disease is permitted, but the eligibility of BM patients presenting with more than 6 intracranial lesions should be discussed with Novartis prior to enrolling the patient.

• Patients with adequate hematologic parameters:

• ANC ≥1.5 x 10^9/L;

• Hb ≥9.0 g/dL,

• Platelet count ≥100 x 10^9/L (untransfused).

• Demonstrate the following blood chemistry laboratory values:

• total bilirubin ≤ 1.5 x ULN;

• AST/ALT ≤ 2.5 X ULN; (≤ 5 x ULN if hepatic metastasis is present)

• alkaline phosphatase ≤ 2.5 x ULN; (≤ 5 x ULN if hepatic and/or bone metastasis are present)

• serum creatinine < 2 x ULN.

• Female patients must have a negative serum pregnancy test at screening. (Not applicable to patients with bilateral oophorectomy and/or hysterectomy or to those patients who are postmenopausal).

• All patients of reproductive potential must agree to use an effective method of contraception during the study and three months following termination of treatment.

• All patients must use a barrier method for contraception for sexual intercourse or avoid this for the first 5 days after patupilone infusion.

• Written informed consent must be obtained.

Exclusion Criteria:

• Patients who have received more than one prior chemotherapy regimen or any other systemic antineoplastic treatment including immunotherapy.

• Patients who have received any investigational compound within the past 28 days or who are planning to receive other investigational drugs while participating in the study.

• Patients with brain metastases who have received any prior chemotherapy regimen or any other systemic antineoplastic treatment for brain metastases.

• Patients with brain metastases who have experienced a dose increase of 25% or more above previous dose, in concomitant steroidal or anticonvulsive therapy within 14 days prior to study entry.

• Patients with brain metastases receiving steroidal or anticonvulsive therapy for whom a dose increase has been required within 14 days prior to start of study drug.

• Patients with brain metastases who have leptomeningeal disease.

• Patients with brain metastases who have extracranial metastases in more than two organs.

• Patients with any peripheral polyneuropathy > Grade 1.

• Patients with unresolved diarrhea > Grade 1.

• Patients receiving hematopoietic growth factors except erythropoietin (refer Section 3.4.4).

• Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease.

• Patients taking warfarin or other agents containing warfarin, with the exception of low dose warfarin (1 mg or less daily) administered prophylactically for maintenance of in-dwelling lines or ports.

• Patients who have not recovered fully from surgery for any cause, including brain metastases patients who have had a biopsy or surgical resection of the brain tumor within 2 weeks prior to starting study drug or who are not fully recovered from any prior biopsy or surgical resection.

• Patients who have received radiation therapy or chemotherapy within the last four weeks. Palliative radiotherapy of metastasis in extremities is allowed but such lesions cannot be used as tumor markers.

• Patients with the presence of active or suspected acute or chronic uncontrolled infection, including abscess or fistulae.

• Patients known to be HIV positive.

• History of another malignancy within 3 years prior to study entry, except curatively treated non-melanotic skin cancer or cervical cancer in situ.

• For patients enrolling in the brain metastases cohort, any of the following exclusions to MRI imaging:

Cardiac pacemaker Ferromagnetic metal implants other than those approved as safe for use in MRI scanners Claustrophobia Obesity (exceeding the limits of scanning equipment)

• Pregnant or lactating females.

• A history of noncompliance to medical regimens or inability or unwillingness to return for all scheduled visits.

Other protocol-dependent inclusion / exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Norton Healthcare/Hospital Inc	Louisville	Kentucky	United States	40232-5070
2	Ellis Fisher Cancer Center	Columbia	Missouri	United States	65203
3	Hillman Cancer Center	Pittsburg	Pennsylvania	United States	15232
4	MD Anderson Cancer Center	Houston	Texas	United States	77030-4009

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00171834
• Other Study ID Numbers: CEPO906A2209; NCT00088127
• First Posted: Sep 15, 2005
• Last Update Posted: Feb 5, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by Novartis Pharmaceuticals: EPO; EPO906; Brain metastasis; Lung cancer; Lung metastasis; NSCLC
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Epothilones; Epothilone B

Study Results

Participant Flow

Arm/Group Title	Patupilone ≤7.0 mg/m^2 (Phase I)	Patupilone 7.5-8.0 mg/m^2 (Phase I)	Patupilone 8.5-9.5 mg/m^2 (Phase I)	Patupilone 10.0-11.5 mg/m^2 (Phase I)	Patupilone 12.0-13.0 mg/m^2 (Phase I)	Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort	Patupilone 10 mg/m^2 (Phase II) NSCLC w.BM Cohort
Arm/Group Description	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.	Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.
Period Title: Overall Study
STARTED	6	12	12	12	8	35	4
Completed 6 Cycles of Treatment	0	0	1	0	2	1	0
COMPLETED	0	0	0	0	0	0	0
NOT COMPLETED	6	12	12	12	8	35	4

Baseline Characteristics

Arm/Group Title	Patupilone ≤7.0 mg/m^2 (Phase I)	Patupilone 7.5-8.0 mg/m^2 (Phase I)	Patupilone 8.5-9.5 mg/m^2 (Phase I)	Patupilone 10.0-11.5 mg/m^2 (Phase I)	Patupilone 12.0-13.0 mg/m^2 (Phase I)	Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort	Patupilone 10 mg/m^2 (Phase II) NSCLC w.BM Cohort	Total
Arm/Group Description	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.	Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.	Total of all reporting groups
Overall Participants	6	12	12	12	8	35	4	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (12.01)	59.4 (8.98)	57.8 (9.31)	57.6 (9.07)	56.3 (13.31)	63.3 (8.04)	60.5 (9.71)	57.9 (9.85)
Sex: Female, Male (Count of Participants)
Female	3 50%	5 41.7%	4 33.3%	4 33.3%	2 25%	10 28.6%	2 50%	30 33.7%
Male	3 50%	7 58.3%	8 66.7%	8 66.7%	6 75%	25 71.4%	2 50%	59 66.3%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	6 100%	12 100%	11 91.7%	12 100%	8 100%	35 100%	4 100%	88 98.9%
Black or African American	0 0%	0 0%	1 8.3%	0 0%	0 0%	0 0%	0 0%	1 1.1%

Outcome Measures

1. Secondary Outcome

Title	Number of Participants With Best Overall Response-Phase I
Description	This was defined as the number of participants whose best overall response was CR or PR by RECIST. Per RECIST: CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no worsening of non-TLs, and no new lesions; Progressive disease (PD), a >=20% increase in TLs, clearly worsening of non-TLs, or emergence of new lesions; Stable Disease (SD), small changes that do not meet previously given criteria.
Time Frame	Best achieved overall response according to RECIST from start of study until study discontinuation. Imaging was assessed every second cycle (ie. approximately every 6 weeks) until disease progression or discontinuation. Average 18 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone ≤7.0 mg/m^2 (Phase I)	Patupilone 7.5-8.0 mg/m^2 (Phase I)	Patupilone 8.5-9.5 mg/m^2 (Phase I)	Patupilone 10.0-11.5 mg/m^2 (Phase I)	Patupilone 12.0-13.0 mg/m^2 (Phase I)
Arm/Group Description	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.
Measure Participants	6	12	12	12	8
Complete Response (CR)	0 (0) 0%	0 (0) 0%	0 (0) 0%	0 (0) 0%	0 (0) 0%
Partial Response (PR)	0 (0) 0%	3 (25) 25%	1 (8.3) 8.3%	1 (8.3) 8.3%	0 (0) 0%
Stable Disease (SD)	1 (16.7) 16.7%	2 (16.7) 16.7%	5 (41.7) 41.7%	4 (33.3) 33.3%	5 (62.5) 62.5%
Progressive Disease (PD)	5 (83.3) 83.3%	4 (33.3) 33.3%	5 (41.7) 41.7%	6 (50.0) 50%	1 (12.5) 12.5%
Unknown	0 (0) 0%	3 (25.0) 25%	1 (8.3) 8.3%	1 (8.3) 8.3%	2 (25.0) 25%
Best overall response (CR,PR) & the response rate	0 (0) 0%	3 (25.0) 25%	1 (8.3) 8.3%	1 (8.3) 8.3%	0 (0) 0%

2. Secondary Outcome

Title	Overall Survival Time-Phase I and Phase II
Description	Overall survival (OS) time was measured from the start of study drug to the date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Data was collected post treatment every 3 months until approximately 70% of patients have reached the survival endpoint (Phase I + Phase II).
Time Frame	From start of study drug to date of death due to any cause. Follow-up after treatment discontinuation approximately every 3 months until approximately 70% of participants have reached the survival endpoint. Average 9.75 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone (EPO906) Phase I	Patupilone (EPO906) Phase II
Arm/Group Description
Measure Participants	50	35
Median (95% Confidence Interval) [Months]	9.2	10.3

3. Secondary Outcome

Title	Time to Progression (TTP)-Phase I and Phase II
Description	Time to progression was measured from the start of study drug to the date of first documented disease progression by RECIST, discontinuation due to disease progression, or death from underlying cancer, whichever event occurred first. If a patient had not progressed by RECIST, discontinued due to disease progression, or died from underlying cancer, TTP was censored at the time of last adequate tumor assessment. However, if a patient took any new cancer therapy prior to PD or death, then TTP was censored at the date of last adequate tumor assessment prior to the start date of new cancer therapy.
Time Frame	From baseline, then every second cycle (i.e. approximately every 6 weeks), until disease progression or discontinuation from study. Average 18 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone (EPO906) Phase I	Patupilone (EPO906) Phase II
Arm/Group Description
Measure Participants	50	35
Median (95% Confidence Interval) [Months]	2.1	2.1

4. Primary Outcome

Title	Phase I: Number of Total Dose-limiting Toxicity (DLT) During Dose Escalation to Determine Maximum Tolerated Dose (MTD)
Description	The MTD was defined as the highest dose of patupilone administered every three weeks (q3w) where not more than one out of six patients experienced a DLT using a standard 3+3 design. Dose escalation started at 6.5 mg/m^2 until MTD in steps of 0.5 mg/m^2 until 12 mg/m^2, then in steps of 1 mg/m^2 till 13.0 mg/m^2. DLTs were assessed during cycle 1. During this time frame, no more than one DLT occurred in any of the explored dose levels up to 13 mg/m^2, thus, the MTD as defined by the protocol was not reached in this study.
Time Frame	Cycle 1 (21 days)

Outcome Measure Data

Analysis Population Description

Maximum tolerated dose (MTD) determining population.included all patients who completed the first treatment cycle (Cycle 1) according to protocol or discontinued due to a DLT. The first cycle data from this patient population were used to determine the MTD in the Phase I part of the study.

Arm/Group Title	Patupilone 6.5 mg/m^2 (Phase I)	Patupilone 7.0 mg/m^2 (Phase I)	Patupilone 7.5 mg/m^2 (Phase I)	Patupilone 8.0 mg/m^2 (Phase I)	Patupilone 8.5 mg/m^2 (Phase I)	Patupilone 9.0 mg/m^2 (Phase I)	Patupilone 9.5 mg/m^2 (Phase I)	Patupilone 10.0 mg/m^2 (Phase I)	Patupilone 10.5 mg/m^2 (Phase I)	Patupilone 11.0 mg/m^2 (Phase I)	Patupilone 11.5 mg/m^2 (Phase I)	Patupilone 12.0 mg/m^2 (Phase I)	Patupilone 13.0 mg/m^2 (Phase I)
Arm/Group Description	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.
Measure Participants	3	3	6	6	6	3	3	3	3	3	3	3	5
Asthenia	0	0	1	0	0	0	0	0	0	0	0	0	0
Diarrhea	0	0	0	1	1	0	0	0	0	0	0	0	1
Any DLT	0	0	1	1	1	0	0	0	0	0	0	0	1

5. Primary Outcome

Title	Phase II: Number of Participants With Best Overall Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Overall response is the number of participants who had a complete response (CR) or a partial response (PR) based on local investigator's assessment of RECIST criteria. Per RECIST: CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no worsening of non-TLs, and no new lesions; Progressive disease (PD), a >=20% increase in TLs, clearly worsening of non-TLs, or emergence of new lesions; Stable Disease (SD), small changes that do not meet previously given criteria.
Time Frame	At baseline, then every second cycle (approximately every 6 weeks), until disease progression or discontinuation. Average 18 weeks.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort
Arm/Group Description	Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.
Measure Participants	35
Complete Response	0 0%
Partial Response (PR)	6 100%
Stable Disease (SD)	9 150%
Progressive Disease (PD)	13 216.7%
Unknown	7 116.7%
Best overall response (CR, PR) & the response rate	6 100%

6. Secondary Outcome

Title	Duration of Stable Disease-Phase I and Phase II
Description	Duration of stable disease (CR, PR, or SD) by RECIST was defined as the time from start of study drug to the date of first documented disease progression or discontinuation due to disease progression, or death from underlying cancer, whichever event occured first.
Time Frame	Imaging was assessed every second cycle (i.e. approximately every 6 weeks), until disease progression or discontinuation from treatment . Average 18 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone (EPO906) Phase I	Patupilone (EPO906) Phase II
Arm/Group Description
Measure Participants	50	35
Median (95% Confidence Interval) [Months]	3.7	5.6

7. Secondary Outcome

Title	Time to Overall Response -Phase I and Phase II
Description	Time to overall response (CR or PR) measured by RECIST was the time between study start until date of first documented response (CR or PR).
Time Frame	From baseline, then every second cycle (i.e. approximately every 6 weeks), until disease progression or discontinuation from study. Average 18 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone (EPO906) Phase I	Patupilone (EPO906) Phase II
Arm/Group Description
Measure Participants	50	35
Median (95% Confidence Interval) [Months]	2.6	3.4

8. Secondary Outcome

Title	Duration of Overall Response -Phase I and Phase II
Description	Duration of overall response (CR or PR) measured by RECIST was measured from the first documented CR or PR to the date of first documented disease progression or discontinuation due to disease progression, or death from underlying cancer, whichever event occured first.
Time Frame	Duration of response according to RECIST from start of study until study discontinuation. Duration of response was assessed every second cycle ( i.e. approximately every 6 weeks) until disease progression or discontinuation from study. Average 18 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all patients who received at least one dose of patupilone. Analysis of the primary and all secondary efficacy endpoints was performed based on this population. According to the Intention to Treat (ITT) principle, patients were analyzed based on the treatment to which they were assigned at study entry.

Arm/Group Title	Patupilone (EPO906) Phase I	Patupilone (EPO906) Phase II
Arm/Group Description
Measure Participants	50	35
Median (95% Confidence Interval) [Months]	2.6	NA

Adverse Events

Arm/Group Title	Patupilone ≤7.0 mg/m^2 (Phase I)		Patupilone 7.5-8.0 mg/m^2 (Phase I)		Patupilone 8.5-9.5 mg/m^2 (Phase I)		Patupilone 10.0-11.5 mg/m^2 (Phase I)		Patupilone 12.0-13.0 mg/m^2 (Phase I)		Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort		Patupilone 10 mg/m^2 (Phase II) NSCLC w. Brain Metastases (BM)
Arm/Group Description	Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.		Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.		Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.		Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.		Patupilone was administered as a single i.v. infusion over 5 to 10 minutes (Amendment 1) until (Amendment 2) and over 10 to 20 minutes (Amendment 2) until the completion of Phase I part of the study.		Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.		Patupilone was administered as a single i.v. infusion over 20 minutes (Amendment 4), once every 3 weeks.
All Cause Mortality
	Patupilone ≤7.0 mg/m^2 (Phase I)		Patupilone 7.5-8.0 mg/m^2 (Phase I)		Patupilone 8.5-9.5 mg/m^2 (Phase I)		Patupilone 10.0-11.5 mg/m^2 (Phase I)		Patupilone 12.0-13.0 mg/m^2 (Phase I)		Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort		Patupilone 10 mg/m^2 (Phase II) NSCLC w. Brain Metastases (BM)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Patupilone ≤7.0 mg/m^2 (Phase I)		Patupilone 7.5-8.0 mg/m^2 (Phase I)		Patupilone 8.5-9.5 mg/m^2 (Phase I)		Patupilone 10.0-11.5 mg/m^2 (Phase I)		Patupilone 12.0-13.0 mg/m^2 (Phase I)		Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort		Patupilone 10 mg/m^2 (Phase II) NSCLC w. Brain Metastases (BM)
	Affected / at Risk (%)	# Events	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	3/6 (50%)		3/12 (25%)		2/12 (16.7%)		3/12 (25%)		4/8 (50%)		14/35 (40%)		2/4 (50%)
Cardiac disorders
Pericardial effusion	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Gastrointestinal disorders
Abdominal pain	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Colitis	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Diarrhoea	1/6 (16.7%)		1/12 (8.3%)		1/12 (8.3%)		1/12 (8.3%)		1/8 (12.5%)		8/35 (22.9%)		0/4 (0%)
Enteritis	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Intestinal obstruction	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Nausea	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Vomiting	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
General disorders
Asthenia	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		1/35 (2.9%)		0/4 (0%)
Fatigue	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Oedema peripheral	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Infections and infestations
Escherichia infection	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Pneumonia	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Pseudomonas infection	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Respiratory tract infection	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Urinary tract infection	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Metabolism and nutrition disorders
Dehydration	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Nervous system disorders
Paraparesis	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Peripheral sensorimotor neuropathy	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Psychiatric disorders
Confusional state	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Dyspnoea	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Pleural effusion	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Pulmonary embolism	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		1/35 (2.9%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Patupilone ≤7.0 mg/m^2 (Phase I)		Patupilone 7.5-8.0 mg/m^2 (Phase I)		Patupilone 8.5-9.5 mg/m^2 (Phase I)		Patupilone 10.0-11.5 mg/m^2 (Phase I)		Patupilone 12.0-13.0 mg/m^2 (Phase I)		Patupilone 10 mg/m^2 (Phase II) NSCLC Cohort		Patupilone 10 mg/m^2 (Phase II) NSCLC w. Brain Metastases (BM)
	Affected / at Risk (%)	# Events	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	6/6 (100%)		11/12 (91.7%)		12/12 (100%)		10/12 (83.3%)		8/8 (100%)		33/35 (94.3%)		4/4 (100%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		2/12 (16.7%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		4/35 (11.4%)		0/4 (0%)
Neutropenia	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		2/35 (5.7%)		0/4 (0%)
Cardiac disorders
Supraventricular tachycardia	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Ear and labyrinth disorders
Vertigo	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		1/4 (25%)
Eye disorders
Eyelid oedema	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Scotoma	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Vision blurred	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Gastrointestinal disorders
Abdominal distension	4/6 (66.7%)		2/12 (16.7%)		2/12 (16.7%)		3/12 (25%)		0/8 (0%)		4/35 (11.4%)		1/4 (25%)
Abdominal pain	3/6 (50%)		5/12 (41.7%)		3/12 (25%)		4/12 (33.3%)		0/8 (0%)		10/35 (28.6%)		1/4 (25%)
Abdominal pain upper	0/6 (0%)		1/12 (8.3%)		1/12 (8.3%)		2/12 (16.7%)		1/8 (12.5%)		1/35 (2.9%)		0/4 (0%)
Abnormal faeces	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Constipation	1/6 (16.7%)		2/12 (16.7%)		1/12 (8.3%)		2/12 (16.7%)		3/8 (37.5%)		1/35 (2.9%)		1/4 (25%)
Diarrhoea	3/6 (50%)		6/12 (50%)		9/12 (75%)		7/12 (58.3%)		7/8 (87.5%)		29/35 (82.9%)		4/4 (100%)
Dyspepsia	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Dysphagia	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		2/8 (25%)		0/35 (0%)		0/4 (0%)
Faecal incontinence	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Flatulence	0/6 (0%)		0/12 (0%)		0/12 (0%)		3/12 (25%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Ileus	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Nausea	3/6 (50%)		3/12 (25%)		4/12 (33.3%)		5/12 (41.7%)		3/8 (37.5%)		6/35 (17.1%)		1/4 (25%)
Stomatitis	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Tooth loss	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Toothache	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		0/4 (0%)
Vomiting	1/6 (16.7%)		4/12 (33.3%)		5/12 (41.7%)		3/12 (25%)		3/8 (37.5%)		12/35 (34.3%)		1/4 (25%)
General disorders
Asthenia	1/6 (16.7%)		2/12 (16.7%)		3/12 (25%)		0/12 (0%)		1/8 (12.5%)		11/35 (31.4%)		0/4 (0%)
Axillary pain	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Chest pain	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Chills	0/6 (0%)		1/12 (8.3%)		2/12 (16.7%)		3/12 (25%)		3/8 (37.5%)		3/35 (8.6%)		0/4 (0%)
Face oedema	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Fatigue	3/6 (50%)		2/12 (16.7%)		4/12 (33.3%)		3/12 (25%)		3/8 (37.5%)		5/35 (14.3%)		1/4 (25%)
Feeling hot	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Localised oedema	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Oedema peripheral	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		1/35 (2.9%)		1/4 (25%)
Pyrexia	0/6 (0%)		3/12 (25%)		3/12 (25%)		1/12 (8.3%)		2/8 (25%)		4/35 (11.4%)		0/4 (0%)
Temperature intolerance	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Immune system disorders
Hypersensitivity	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Infections and infestations
Bronchitis	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Gastroenteritis	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		2/35 (5.7%)		0/4 (0%)
Influenza	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Nasopharyngitis	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Pneumonia	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		1/35 (2.9%)		0/4 (0%)
Urinary tract infection	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Investigations
Aspartate aminotransferase increased	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		2/35 (5.7%)		0/4 (0%)
Blood magnesium decreased	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Gamma-glutamyltransferase increased	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		5/35 (14.3%)		0/4 (0%)
Weight decreased	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		1/8 (12.5%)		8/35 (22.9%)		1/4 (25%)
Metabolism and nutrition disorders
Decreased appetite	0/6 (0%)		3/12 (25%)		1/12 (8.3%)		0/12 (0%)		4/8 (50%)		12/35 (34.3%)		0/4 (0%)
Dehydration	0/6 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		5/35 (14.3%)		0/4 (0%)
Hypoalbuminaemia	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		2/35 (5.7%)		0/4 (0%)
Hypokalaemia	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		2/35 (5.7%)		0/4 (0%)
Hypomagnesaemia	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		0/12 (0%)		2/12 (16.7%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Back pain	0/6 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		3/35 (8.6%)		0/4 (0%)
Flank pain	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Groin pain	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Muscular weakness	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Musculoskeletal pain	0/6 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/12 (0%)		1/8 (12.5%)		3/35 (8.6%)		0/4 (0%)
Myalgia	0/6 (0%)		0/12 (0%)		2/12 (16.7%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Pain in extremity	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Pain in jaw	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Pathological fracture	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Malignant pleural effusion	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Tumour pain	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Nervous system disorders
Dizziness	0/6 (0%)		0/12 (0%)		2/12 (16.7%)		1/12 (8.3%)		0/8 (0%)		3/35 (8.6%)		0/4 (0%)
Dysaesthesia	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Headache	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/8 (0%)		2/35 (5.7%)		1/4 (25%)
Neuropathy peripheral	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Neurotoxicity	0/6 (0%)		0/12 (0%)		2/12 (16.7%)		0/12 (0%)		0/8 (0%)		6/35 (17.1%)		0/4 (0%)
Paraesthesia	2/6 (33.3%)		1/12 (8.3%)		3/12 (25%)		3/12 (25%)		2/8 (25%)		8/35 (22.9%)		1/4 (25%)
Peripheral motor neuropathy	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		1/4 (25%)
Polyneuropathy	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Presyncope	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Speech disorder	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Psychiatric disorders
Anxiety	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		3/35 (8.6%)		1/4 (25%)
Depression	1/6 (16.7%)		0/12 (0%)		2/12 (16.7%)		1/12 (8.3%)		0/8 (0%)		2/35 (5.7%)		0/4 (0%)
Insomnia	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		2/12 (16.7%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Restlessness	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Sleep disorder	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Renal and urinary disorders
Haematuria	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)		0/12 (0%)		2/12 (16.7%)		1/12 (8.3%)		0/8 (0%)		2/35 (5.7%)		0/4 (0%)
Dyspnoea	0/6 (0%)		2/12 (16.7%)		1/12 (8.3%)		1/12 (8.3%)		1/8 (12.5%)		8/35 (22.9%)		0/4 (0%)
Epistaxis	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Haemoptysis	0/6 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		5/35 (14.3%)		0/4 (0%)
Hiccups	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Pneumonitis	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Productive cough	0/6 (0%)		0/12 (0%)		2/12 (16.7%)		0/12 (0%)		1/8 (12.5%)		1/35 (2.9%)		0/4 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/6 (16.7%)		0/12 (0%)		1/12 (8.3%)		2/12 (16.7%)		2/8 (25%)		0/35 (0%)		0/4 (0%)
Rash	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Skin lesion	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		1/8 (12.5%)		0/35 (0%)		0/4 (0%)
Vascular disorders
Hypertension	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Hypotension	0/6 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)
Peripheral coldness	0/6 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/8 (0%)		0/35 (0%)		0/4 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.