Trial Outcomes & Findings for Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors (NCT NCT00605566)

Last Updated: 2019-02-19

Results Overview

Objective response (complete and partial) evaluated using RECIST criteria. Complete response (CR): disappearance of all clinical and radiological evidence of tumour (both target and non-target). Partial response (PR): at least a 30% decrease in the sum of longest diameter of target lesions.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

22 participants

Primary outcome timeframe

Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years

Results posted on

2019-02-19

Participant Flow

Patients were recruited from January 2008 to October 2010.

Participant milestones

Participant milestones
Measure	Sorafenib and Cyclophosphamide Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Overall Study STARTED	22
Overall Study COMPLETED	19
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Sorafenib and Cyclophosphamide Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Overall Study Adverse Event	1
Overall Study Clinical deterioration	1
Overall Study Poor compliance in run-in period	1

Baseline Characteristics

Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sorafenib Plus Cyclophosphamide n=22 Participants Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	17 Participants n=5 Participants
Age, Categorical >=65 years	5 Participants n=5 Participants
Age, Continuous	58 years n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years

Population: 19 out of 22 patients were evaluable for response.

Outcome measures

Outcome measures
Measure	Sorafenib and Cyclophosphamide n=19 Participants Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR).	1 Participants

PRIMARY outcome

Timeframe: Assessed from start of study treatment until death, assessed up to 7 years.

Population: 6 patients experienced a pharmacodynamic pShift change that was classified as positive, 16 experienced a negative pShift.

A phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells was used in order to predict clinical course and/or guide individual dose-titration. Positive pShift values denote stimulation of RAF signal transduction, whereas negative pShift values denote inhibition of RAF signal transduction as measured by flow-cytometry. Associations between pShift changes and treatment efficacy were measured using progression-free survival (PFS) and overall survival (OS).

Outcome measures

Outcome measures
Measure	Sorafenib and Cyclophosphamide n=22 Participants Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib PFS in patients with a negative pShift result	2.8 months Interval 1.8 to 6.7
Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib PFS in patients with a positive pShift result	14.9 months Interval 3.0 to Not reached
Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib OS for patients with a negative pShift	6.4 months Interval 2.8 to 6.4
Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib OS for patients with a positive pShift	21.3 months Interval 7.9 to Not reached

SECONDARY outcome

Timeframe: Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years

Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of measured lesions.

Outcome measures

Outcome measures
Measure	Sorafenib and Cyclophosphamide n=22 Participants Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Progression-free Survival (PFS)	3 months Interval 2.0 to 10.7

SECONDARY outcome

Timeframe: Assessed from start of study treatment until death, assessed up to 7 years.

Outcome measures

Outcome measures
Measure	Sorafenib and Cyclophosphamide n=22 Participants Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Overall Survival (OS)	11.7 months Interval 4.3 to Not reached

SECONDARY outcome

Timeframe: 1 year

Survival rate at 1 year.

Outcome measures

Outcome measures
Measure	Sorafenib and Cyclophosphamide n=22 Participants Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
1-year Survival Rate	45 percentage of participants

Adverse Events

Sorafenib Plus Cyclophosphamide

Serious events: 11 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Sorafenib Plus Cyclophosphamide n=22 participants at risk Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Gastrointestinal disorders Ileal perforation	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Abdominal Pain	9.1% 2/22 • Number of events 2 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Vascular disorders Flushing	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Renal and urinary disorders Protein Urine Positive	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Dyspepsia	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Weight Gain	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
General disorders Disease progression	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Bilirubin increased	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Lipase increased	9.1% 2/22 • Number of events 2 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Amylase increased	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
General disorders Fever	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Diarrhea	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Infections and infestations Infection	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Musculoskeletal and connective tissue disorders Neck pain	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Small intestinal obstruction	4.5% 1/22 • Number of events 1 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.

Other adverse events

Other adverse events
Measure	Sorafenib Plus Cyclophosphamide n=22 participants at risk Patients will receive sorafenib and cyclophosphamide. sorafenib and cyclophosphamide: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	45.5% 10/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Nervous system disorders Dysgeusia	22.7% 5/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Vascular disorders Hypertension	13.6% 3/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
General disorders Fatigue	40.9% 9/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Diarrhoea	54.5% 12/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Skin and subcutaneous tissue disorders Alopecia	18.2% 4/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Metabolism and nutrition disorders Hypophosphatemia	50.0% 11/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Skin and subcutaneous tissue disorders Rash	40.9% 9/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Lymphopenia	31.8% 7/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Weight loss	27.3% 6/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Aspartate aminotransferase elevation	27.3% 6/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Nausea	36.4% 8/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Thrombocytopenia	13.6% 3/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Lipase elevation	27.3% 6/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Nervous system disorders Peripheral sensory neuropathy	4.5% 1/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Amylase elevation	22.7% 5/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Gastrointestinal disorders Vomiting	22.7% 5/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Investigations Alanine aminotransferase elevation	13.6% 3/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
Metabolism and nutrition disorders Hypocalcemia	13.6% 3/22 • Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.

Additional Information

Dr. Lillian Siu

Princess Margaret Cancer Centre

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place