Trial Outcomes & Findings for A Proof of Concept Study of Maintenance Therapy With Tasquinimod in Patients With Metastatic Castrate-resistant Prostate Cancer Who Are Not Progressing After a First Line Docetaxel Based Chemotherapy (NCT NCT01732549)

Last Updated: 2019-11-22

Results Overview

The time from the date of randomisation to the date of radiological progression or death due to any cause. Radiological progression was defined \- Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue lesions (Eisenhauer, EJC 2009), as at least a 20% relative and a 5 mm absolute increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded on study (including Screening or the appearance of one or more new lesions) for target Lesions. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions \- Using Prostate Cancer Clinical Working Group in March 2008 (PCWG2) criteria for bone lesions (Scher, JCO 2008). Progression was defined as appearance of 2 or more bone lesions.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

144 participants

Primary outcome timeframe

Every 8 weeks until disease progression documentation (approximately up to 2.5 years)

Results posted on

2019-11-22

Participant Flow

The study was performed as a multicentre study at 51 investigational sites (of which 44 randomised patients) in Belgium, Czech Republic, Denmark, France, Germany, Hungary, Italy, Lithuania, Poland, Spain and United Kingdom (UK)

A total of 219 patients were screened and 144 patients were randomised.

Participant milestones

Participant milestones
Measure	Tasquinimod 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression. Tasquinimod: Patients received initially an oral dose of 0.25 mg/day of tasquinimod, starting on Day 1, for at least 2 weeks. Once tolerability of the 0.25 mg/day dose was established, patients received a dose increase to 0.5 mg/day for at least 2 weeks, and then increased to 1 mg/day of study treatment. Patients showing poor tolerability for the escalated doses of tasquinimod were allowed to continue study treatment at the highest individually tolerated dose	Placebo 1 capsule daily, taken orally with water and food until disease progression Placebo: Patients received Placebo capsules (identical to tasquinimod capsules) to be taken orally once a day with water and food
Overall Study STARTED	71	73
Overall Study Ongoing in Treatment Period:Data Cut-off	12	12
Overall Study Withdrawn During Treatment:Data Cut-off	59	61
Overall Study Ongoing Treatment Period:Final Analysis	0	0
Overall Study Withdrawn During Treatment:Final Analysi	71	73
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	71	73

Reasons for withdrawal

Reasons for withdrawal
Measure	Tasquinimod 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression. Tasquinimod: Patients received initially an oral dose of 0.25 mg/day of tasquinimod, starting on Day 1, for at least 2 weeks. Once tolerability of the 0.25 mg/day dose was established, patients received a dose increase to 0.5 mg/day for at least 2 weeks, and then increased to 1 mg/day of study treatment. Patients showing poor tolerability for the escalated doses of tasquinimod were allowed to continue study treatment at the highest individually tolerated dose	Placebo 1 capsule daily, taken orally with water and food until disease progression Placebo: Patients received Placebo capsules (identical to tasquinimod capsules) to be taken orally once a day with water and food
Overall Study Adverse Event	13	3
Overall Study Consent withdrawn	13	6
Overall Study Disease progression	37	50
Overall Study Other	8	14

Baseline Characteristics

A Proof of Concept Study of Maintenance Therapy With Tasquinimod in Patients With Metastatic Castrate-resistant Prostate Cancer Who Are Not Progressing After a First Line Docetaxel Based Chemotherapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression. Tasquinimod: Patients received initially an oral dose of 0.25 mg/day of tasquinimod, starting on Day 1, for at least 2 weeks. Once tolerability of the 0.25 mg/day dose was established, patients received a dose increase to 0.5 mg/day for at least 2 weeks, and then increased to 1 mg/day of study treatment. Patients showing poor tolerability for the escalated doses of tasquinimod were allowed to continue study treatment at the highest individually tolerated dose	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression Placebo: Patients received Placebo capsules (identical to tasquinimod capsules) to be taken orally once a day with water and food	Total n=144 Participants Total of all reporting groups
Age, Continuous	69.6 years STANDARD_DEVIATION 7.18 • n=5 Participants	69.6 years STANDARD_DEVIATION 5.57 • n=7 Participants	69.6 years STANDARD_DEVIATION 6.39 • n=5 Participants
Age, Customized 18 to ≤ 65 years	18 participants n=5 Participants	17 participants n=7 Participants	35 participants n=5 Participants
Age, Customized 66 to ≤ 75 years	40 participants n=5 Participants	45 participants n=7 Participants	85 participants n=5 Participants
Age, Customized > 75 years	13 participants n=5 Participants	11 participants n=7 Participants	24 participants n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	71 Participants n=5 Participants	73 Participants n=7 Participants	144 Participants n=5 Participants
Race/Ethnicity, Customized Black/African American	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Caucasian/White	52 participants n=5 Participants	58 participants n=7 Participants	110 participants n=5 Participants
Race/Ethnicity, Customized Multiple Race	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Missing	18 participants n=5 Participants	14 participants n=7 Participants	32 participants n=5 Participants
Region of Enrollment Czech Republic	5 participants n=5 Participants	1 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Belgium	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Hungary	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Denmark	6 participants n=5 Participants	13 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment Poland	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Italy	9 participants n=5 Participants	5 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment United Kingdom	8 participants n=5 Participants	6 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment France	17 participants n=5 Participants	14 participants n=7 Participants	31 participants n=5 Participants
Region of Enrollment Lithuania	7 participants n=5 Participants	10 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Germany	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Spain	5 participants n=5 Participants	10 participants n=7 Participants	15 participants n=5 Participants
Weight	83.7 kg STANDARD_DEVIATION 12.57 • n=5 Participants	83.4 kg STANDARD_DEVIATION 15.09 • n=7 Participants	83.6 kg STANDARD_DEVIATION 13.86 • n=5 Participants
BMI	27.67 kg/m^2 STANDARD_DEVIATION 3.543 • n=5 Participants	28.01 kg/m^2 STANDARD_DEVIATION 4.399 • n=7 Participants	27.84 kg/m^2 STANDARD_DEVIATION 3.987 • n=5 Participants
Ethnicity Hispanic or Latino	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Ethnicity Not Hispanic or Latino	52 participants n=5 Participants	55 participants n=7 Participants	107 participants n=5 Participants
Ethnicity Missing	17 participants n=5 Participants	14 participants n=7 Participants	31 participants n=5 Participants
ECOG Performance Status Score 0 (Normal Activity)	39 participants n=5 Participants	31 participants n=7 Participants	70 participants n=5 Participants
ECOG Performance Status Score 1 (Restricted Activity)	32 participants n=5 Participants	38 participants n=7 Participants	70 participants n=5 Participants
ECOG Performance Status Score Missing	0 participants n=5 Participants	4 participants n=7 Participants	4 participants n=5 Participants
Region Eastern Europe	18 participants n=5 Participants	16 participants n=7 Participants	34 participants n=5 Participants
Region Western Europe	53 participants n=5 Participants	57 participants n=7 Participants	110 participants n=5 Participants

PRIMARY outcome

Timeframe: Every 8 weeks until disease progression documentation (approximately up to 2.5 years)

Population: Intention to treat (ITT) Population

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression
Time to Radiological Progression Free Survival [PFS]	31.7 weeks Interval 24.3 to 53.7	22.7 weeks Interval 16.1 to 25.9

SECONDARY outcome

Timeframe: Every 3 months after study treatment stop until death (approximately up to 2.5 years)

Population: ITT Population

Overall survival is defined as the time from randomisation to death due to any cause. The number of participants who died is presented since the Median was not reached for this assessment. Tasquinimod: Patients censored = 63, Patients at risk (t=0) = 71 Placebo: Patients censored = 67, Patients at risk (t=0) = 73

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression
Overall Survival Based on Number of Subjects Who Died	8 participants	6 participants

SECONDARY outcome

Timeframe: Every 3 months after study treatment stop (follow-up) until progression under the next line therapy (approximately up to 2.5 years)

Population: ITT Population

The time from the date of randomisation to the date of radiological progression free survival \[PFS\] on next-line therapy (PFS 2) or death due to any cause. Radiological progression was defined \- Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue lesions (Eisenhauer, EJC 2009), as at least a 20% relative and a 5 mm absolute increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded on study (including Screening or the appearance of one or more new lesions) for target Lesions. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions \- Using Prostate Cancer Clinical Working Group in March 2008 (PCWG2) criteria for bone lesions (Scher, JCO 2008). Progression was defined as appearance of 2 or more bone lesions.

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression
Time to Progression Free Survival [PFS] on Next-line Therapy (PFS 2)	19.3 weeks Interval 7.1 to 30.7	24.1 weeks Interval 12.6 to The data for this maximum confidence interval (CI) is not evaluable (NE), listed as Not Available (NA). Patients censored = 44 Patients at risk (t=0) = 47

SECONDARY outcome

Timeframe: Every 8 weeks until symptomatic or radiological progression documentation (approximately up to 2.5 years)

Population: ITT Population

Symptomatic PFS is defined as the time from the date of randomisation to the date of symptomatic progression or death due to prostate cancer, whichever occurs first \[symptomatic progression as assessed by Brief Pain Inventory (BPI) and analgesic use\]. Symptomatic progression was defined by the occurrence of pain with documented disease, skeleton related adverse events. The median symptomatic PFS for placebo and tasquinimod groups was not reached. Tasquinimod: Patients censored = 48, Patients at risk (t=0) = 71 Placebo: Patients censored = 54, Patients at risk (t=0) = 73

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression
Symptomatic PFS Based on Number of Subjects Who Had Symptomatic Progression or Death	23 participants	19 participants

SECONDARY outcome

Timeframe: Every 3 months after study treatment stop until further anticancer therapy for prostate cancer (approximately up to 2.5 years)

Population: ITT population

Time from randomisation to further treatment for prostate cancer

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression
Time to Further Anticancer Treatment for Prostate Cancer	42.3 weeks Interval 32.0 to 58.0	29.0 weeks Interval 23.1 to 39.1

SECONDARY outcome

Timeframe: Up to End of Study visit (approximately up to 2.5 years)

Population: ITT population

End of Study visit (within 14 days of last dose of study treatment) Impact of tasquinimod on health related quality of life (QoL) - Analysis of time to deterioration in FACT-P The FACT-P measurement system is a validated collection of health related quality of life (HRQOL) questionnaires used to assess HRQOL in men with prostate cancer. It is appropriate for use with patients with any form of cancer and extensions of it have been used and validated in other chronic illness condition. The FACT-P is a self-administered 39-item scale comprising five domains: physical well-being, social/family well-being, functional well-being, emotional well-being and additional concerns. The individual subscale scores range from 0 to a high between 24 and 48 and the total score ranges between 0 and 156, with higher scores representing better Quality of Life (QoL)

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=73 Participants 1 capsule daily, taken orally with water and food until disease progression
Time to Deterioration in Functional Assessment of Cancer Therapy - Prostate (FACT-P)	8.1 weeks Interval 8.1 to 13.1	15.7 weeks Interval 10.6 to 16.3

SECONDARY outcome

Timeframe: Baseline and End-of-study Visit (approximately up to 2.5 years)

Population: ITT population

Baseline is defined as last measurement collected prior to the first dose of study drug. End of Study visit (within 14 days of last dose of study treatment) The EQ-5D, a 5-item scale useful in health resource utilisation and cost comparisons between treatment groups designed for self-completion by patients consists of two pages \[EQ-5 descriptive system and EQ Visual Analogue Scale(VAS)\]. The EQ-5 descriptive system comprises five dimensions: mobility, self care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, severe problems. The EQ-VAS records the respondent's self-rated health on a vertical VAS. The respondents are asked to mark health status on the day of the interview on a 10cm vertical scale with end points of 0 to100. There are notes at the both ends of the scale that the bottom rate(0) corresponds to "the worst health you can imagine", and the highest rate(100) corresponds to "the best health you can imagine"

Outcome measures

Outcome measures
Measure	Tasquinimod n=39 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=50 Participants 1 capsule daily, taken orally with water and food until disease progression
Change From Baseline of EuroQol-5 Dimension QoL Instrument (EQ-5D) VAS Score	-9.0 Score on scale Interval -74.0 to 63.0	-3.5 Score on scale Interval -55.0 to 30.0

SECONDARY outcome

Timeframe: At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years)

Population: Safety Population: All patients who received at least one dose of study treatment. Patients were allocated to the treatment they actually received

Number of subjects reporting adverse events

Outcome measures

Outcome measures
Measure	Tasquinimod n=71 Participants 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression.	Placebo n=70 Participants 1 capsule daily, taken orally with water and food until disease progression
Safety Profile of Tasquinimod Any Treatment Emergent Adverse Event (TEAEs)	69 participants	66 participants
Safety Profile of Tasquinimod Intensity of TEAEs [Grade 3-5 (severe)]	36 participants	19 participants
Safety Profile of Tasquinimod Intensity of TEAEs [Grade 5]	1 participants	3 participants
Safety Profile of Tasquinimod Intensity of TEAEs [Grade 4]	3 participants	2 participants
Safety Profile of Tasquinimod Intensity of TEAEs [Grade 3]	32 participants	14 participants
Safety Profile of Tasquinimod Intensity of TEAEs [Grade 2 (moderate)]	28 participants	28 participants
Safety Profile of Tasquinimod Intensity of TEAEs [Grade 1 (mild)]	5 participants	19 participants
Safety Profile of Tasquinimod Causality of TEAEs [Drug Related]	54 participants	38 participants
Safety Profile of Tasquinimod Causality of TEAEs [Not Drug Related]	15 participants	28 participants
Safety Profile of Tasquinimod TEAEs Leading to Drug Withdrawal	12 participants	3 participants
Safety Profile of Tasquinimod TEAEs leading to Dose Reduction	16 participants	2 participants
Safety Profile of Tasquinimod TEAEs leading to Drug Interruption	33 participants	12 participants
Safety Profile of Tasquinimod TEAEs Leading to Death	1 participants	0 participants
Safety Profile of Tasquinimod Serious Adverse Event (SAEs)	24 participants	16 participants
Safety Profile of Tasquinimod Drug Related SAEs	6 participants	2 participants

Adverse Events

Tasquinimod

Serious events: 24 serious events

Other events: 69 other events

Deaths: 0 deaths

Placebo

Serious events: 16 serious events

Other events: 66 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director, Oncology

Ipsen

Phone: [email protected]

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Tasquinimod n=71 participants at risk 1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg and then to 1 mg per day) until disease progression. Tasquinimod: Patients received initially an oral dose of 0.25 mg/day of tasquinimod, starting on Day 1, for at least 2 weeks. Once tolerability of the 0.25 mg/day dose was established, patients received a dose increase to 0.5 mg/day for at least 2 weeks, and then increased to 1 mg/day of study treatment. Patients showing poor tolerability for the escalated doses of tasquinimod were allowed to continue study treatment at the highest individually tolerated dose	Placebo n=70 participants at risk 1 capsule daily, taken orally with water and food until disease progression Placebo: Patients received Placebo capsules (identical to tasquinimod capsules) to be taken orally once a day with water and food
Musculoskeletal and connective tissue disorders Arthralgia	25.4% 18/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	21.4% 15/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Back pain	21.1% 15/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	20.0% 14/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Pain in extremity	15.5% 11/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	15.7% 11/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Myalgia	7.0% 5/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	14.3% 10/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Bone pain	8.5% 6/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	7.1% 5/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	8.5% 6/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	7.1% 5/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.9% 7/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	5.7% 4/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Spinal pain	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	7.1% 5/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Musculoskeletal and connective tissue disorders Neck pain	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	2.9% 2/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
General disorders Fatigue	29.6% 21/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	21.4% 15/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
General disorders Asthenia	23.9% 17/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	14.3% 10/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
General disorders Oedema peripheral	18.3% 13/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	11.4% 8/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
General disorders Pain	7.0% 5/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	5.7% 4/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
General disorders Pyrexia	8.5% 6/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	4.3% 3/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
General disorders Influenza like illness	7.0% 5/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	0.00% 0/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Nausea	26.8% 19/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	21.4% 15/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Constipation	32.4% 23/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	11.4% 8/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Vomiting	12.7% 9/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	12.9% 9/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Diarrhoea	12.7% 9/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	8.6% 6/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Abdominal pain	12.7% 9/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	5.7% 4/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Flatulence	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	4.3% 3/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Gastrointestinal disorders Abdominal pain upper	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	1.4% 1/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Nervous system disorders Headache	11.3% 8/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	10.0% 7/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Nervous system disorders Paraesthesia	8.5% 6/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	2.9% 2/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Nervous system disorders Peripheral sensory neuropathy	11.3% 8/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	0.00% 0/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Nervous system disorders Dizziness	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	4.3% 3/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Infections and infestations Cystitis	7.0% 5/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	2.9% 2/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Metabolism and nutrition disorders Decreased appetite	36.6% 26/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	11.4% 8/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Vascular disorders Hypertension	12.7% 9/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	8.6% 6/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Skin and subcutaneous tissue disorders Onycholysis	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	0.00% 0/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Investigations Weight decreased	8.5% 6/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	1.4% 1/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Psychiatric disorders Insomnia	14.1% 10/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	8.6% 6/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Psychiatric disorders Depression	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	0.00% 0/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Respiratory, thoracic and mediastinal disorders Cough	11.3% 8/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	4.3% 3/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	0.00% 0/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	5.6% 4/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	0.00% 0/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Renal and urinary disorders Urinary retention	1.4% 1/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	7.1% 5/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Blood and lymphatic system disorders Anaemia	12.7% 9/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	2.9% 2/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented
Injury, poisoning and procedural complications Fall	1.4% 1/71 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented	7.1% 5/70 • At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) Non-SAE details: A summary of common (incidence \>5%) TEAEs is presented