Trial Outcomes & Findings for Eurosarc Trial of Linsitinib in Advanced Ewing Sarcoma (NCT NCT02546544)

Last Updated: 2019-06-03

Results Overview

Metabolic response measured by PERCIST v1.0 using SULpeak. This methodology used SULpeak to measure change in glucose uptake in the tumour. Complete Metabolic Response - Complete resolution of 18F-FDG uptake within measurable target lesion so that it is less than mean liver activity and indistinguishable from surrounding background blood-pool levels. Partial Metabolic Response - Reduction of minimum of 30% in target measurable tumour 18F-FDG SULpeak. Absolute drop in SUL must be at least 0.8 SUL units, as well. No new lesions. Positive Metabolic Response - Participants having either "Complete Metabolic Response" or "Partial Metabolic Response". Stable Metabolic Disease - Not CMR, PMR or PMD. Progressive metabolic disease - Increase of more than 30% in 18F-FDG SUL peak. OR: Visible increase in extent of 18F-FDG tumour uptake (75% in TLG volume with no decline in SUL. OR: New 18F-FDG-avid lesions that are typical of cancer and not related to treatment effect or infection.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

16 participants

Primary outcome timeframe

Pre- and Post- dose responses following 1 cycle (21 days) of treatment

Results posted on

2019-06-03

Participant Flow

Patients were recruited from March 2014 until April 2016 at specialist cancer hospitals across Europe

Participant milestones

Participant milestones
Measure	Linsitinib Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Overall Study STARTED	16
Overall Study Received Allocated Intervention	16
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Linsitinib Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Overall Study Disease Progression	14
Overall Study Adverse Event	1
Overall Study Withdrawal by Subject	1

Baseline Characteristics

Eurosarc Trial of Linsitinib in Advanced Ewing Sarcoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Age, Continuous	26.3 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants
Region of Enrollment Netherlands	2 participants n=5 Participants
Region of Enrollment United Kingdom	8 participants n=5 Participants
Region of Enrollment Italy	4 participants n=5 Participants
Region of Enrollment Germany	2 participants n=5 Participants
WHO performance status 0	5 Participants n=5 Participants
WHO performance status 1	7 Participants n=5 Participants
WHO performance status 2	4 Participants n=5 Participants
Histology - Ewing Sarcoma	16 Participants n=5 Participants
Primary site Chest wall	4 Participants n=5 Participants
Primary site Extra-osseous site	2 Participants n=5 Participants
Primary site Lower extremity	3 Participants n=5 Participants
Primary site Pelvis	5 Participants n=5 Participants
Primary site Spine	1 Participants n=5 Participants
Primary site Upper extremity	1 Participants n=5 Participants
Disease stage at screening - Metastatic	16 Participants n=5 Participants
Sites of metastases Bone	3 participants n=5 Participants
Sites of metastases Lung	11 participants n=5 Participants
Sites of metastases Bone, Other	8 participants n=5 Participants
Number of lines of previous treatment Second line	1 Participants n=5 Participants
Number of lines of previous treatment Third line	1 Participants n=5 Participants
Number of lines of previous treatment > third line	14 Participants n=5 Participants
Time since most recent relapse/progression (days)	18 days n=5 Participants
Prior radiotherapy	13 Participants n=5 Participants
Prior chemotherapy	16 Participants n=5 Participants
Prior surgery	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre- and Post- dose responses following 1 cycle (21 days) of treatment

Outcome measures

Outcome measures
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0 Positive metabolic response	1 Participants
Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0 Stable metabolic disease	2 Participants
Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0 Progressive metabolic disease	4 Participants
Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0 Not measurable at Baseline	3 Participants
Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0 Not assessable - liver	4 Participants
Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0 No repeat scan available	2 Participants

PRIMARY outcome

Timeframe: Following 6 cycles of treatment (up to 6 months)

A patient is defined as having a toxic event if they experienced at least one grade 3 adverse event (CTCAE v4.0 grade)

Outcome measures

Outcome measures
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Number of Participants With a Toxic Event Experienced a toxic event	5 Participants
Number of Participants With a Toxic Event Did not experienced a toxic event	11 Participants

SECONDARY outcome

Timeframe: Duration of study (up to 18 months)

To determine the clinical outcome through assessment of * Progression free survival; where length of survival is defined in whole days as the time from entry into the study until Ewing sarcoma progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. * Disease specific survival; where length of survival is defined in whole days as the time from entry into the study until death from Ewing sarcoma.

Outcome measures

Outcome measures
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Clinical Outcome (PFS, DSS) Disease specific survival	7.1 months Interval 2.6 to Not enough participants achieved response to calculate upper 95% CI
Clinical Outcome (PFS, DSS) Progression free survival	1.3 months Interval 0.7 to Not enough participants achieved response to calculate upper 95% CI

SECONDARY outcome

Timeframe: Cycle 1 days 1,15,17, Cycle 2 day 3, Cycle 3 days 1 and 3, Cycle 4 day 1, Cycle 5 day 1, Cycle 6 day 1 and End of Treatment.0

Population: Data provided is as collected.

Plasma concentrations of linsitinib (ng/ml). Samples were taken 3 hours post-dose at Cycle 1 days 1,15,17, Cycle 2 day 3, Cycle 3 days 1 and 3, Cycle 4 day 1, Cycle 5 day 1, Cycle 6 day 1, and End of Treatment (this could occur at anytime during the 6 cycles).

Outcome measures

Outcome measures
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Screening	1 ng/ml Interval 1.0 to 1.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 1 Day 1	4790 ng/ml Interval 286.0 to 7538.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 1 Day 15	2163 ng/ml Interval 1090.0 to 3206.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 1 Day 17	4977 ng/ml Interval 144.0 to 9628.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 2 Day 3	3409 ng/ml Interval 1534.0 to 5284.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 3 Day 1	6791 ng/ml Interval 849.0 to 8478.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 3 Day 3	1964 ng/ml Interval 417.0 to 14080.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) Cycle 4 Day 1	3591 ng/ml Interval 3591.0 to 3591.0
Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib) End of treatment visit	1 ng/ml Interval 1.0 to 1432.0

SECONDARY outcome

Timeframe: Measured cycle 1 day 15, cycle 3 and cycle 6

Radiological response measured using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) Per RECIST for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), \>20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable disease (SD), Not CR, PR or PD.

Outcome measures

Outcome measures
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 1 · Stable disease	7 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 1 · Progressive disease	7 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 1 · No repeat scan available	2 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 3 · Stable disease	2 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 3 · Progressive disease	4 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 3 · No repeat scan available	10 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 6 · Stable disease	0 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 6 · Progressive disease	0 Participants
Number of Participants With a Radiological Response as Evaluated by RECIST v1.1 Cycle 6 · No repeat scan available	16 Participants

SECONDARY outcome

Timeframe: Measured cycle 1 day 15

Outcome measures

Outcome measures
Measure	Linsitinib n=16 Participants Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Number of Participants With a Metabolic Response as Evaluated by EORTC 1.0 Positive metabolic response	2 Participants
Number of Participants With a Metabolic Response as Evaluated by EORTC 1.0 Stable metabolic disease	5 Participants
Number of Participants With a Metabolic Response as Evaluated by EORTC 1.0 Progressive metabolic disease	7 Participants
Number of Participants With a Metabolic Response as Evaluated by EORTC 1.0 No repeat scan available	2 Participants

Adverse Events

Linsitinib

Serious events: 3 serious events

Other events: 15 other events

Deaths: 13 deaths

Serious adverse events

Serious adverse events
Measure	Linsitinib n=16 participants at risk Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Gastrointestinal disorders Diarrhoea	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Respiratory, thoracic and mediastinal disorders Pneumothorax	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Respiratory, thoracic and mediastinal disorders Pneumonia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.

Other adverse events

Other adverse events
Measure	Linsitinib n=16 participants at risk Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg
Blood and lymphatic system disorders Anaemia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Blood and lymphatic system disorders Thrombocytopenia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Gastrointestinal disorders Abdominal discomfort	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Gastrointestinal disorders Constipation	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
Gastrointestinal disorders Diarrhoea	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Gastrointestinal disorders Nausea	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
Gastrointestinal disorders Vomiting	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
General disorders Chest discomfort	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
General disorders Chest pain	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
General disorders Fatigue	25.0% 4/16 • Adverse events were collected from baseline until 28 days post treatment.
General disorders Pain	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Infections and infestations Pharyngitis streptococcal	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Infections and infestations Respiratory tract infection	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Injury, poisoning and procedural complications Spinal cord injury	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Investigations Blood creatine phosphokinase increased	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Investigations Electrocardiogram QT prolonged	37.5% 6/16 • Adverse events were collected from baseline until 28 days post treatment.
Investigations Haemoglobin decreased	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Investigations Lymphocyte count decreased	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Investigations Platelet count decreased	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Metabolism and nutrition disorders Decreased appetite	18.8% 3/16 • Adverse events were collected from baseline until 28 days post treatment.
Metabolism and nutrition disorders Hyperglycaemia	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
Metabolism and nutrition disorders Hypokalaemia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Metabolism and nutrition disorders Hypomagnesaemia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Musculoskeletal and connective tissue disorders Arthralgia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Musculoskeletal and connective tissue disorders Back pain	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Musculoskeletal and connective tissue disorders Flank pain	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
Nervous system disorders Headache	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
Nervous system disorders Somnolence	12.5% 2/16 • Adverse events were collected from baseline until 28 days post treatment.
Psychiatric disorders Insomnia	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Renal and urinary disorders Pollakiuria	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.2% 1/16 • Adverse events were collected from baseline until 28 days post treatment.

Additional Information

Joint Research Office

University of Oxford

Phone: +441865572245

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place