Trial Outcomes & Findings for SAHA + CHOP in Untreated T-cell Non-Hodgkin's Lymphoma (NCT NCT00787527)

Last Updated: 2014-09-09

Results Overview

MTD of Vorinostat when administered in combination with Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). Continual reassessment during each 21-day cycle to assess dose limiting toxicity. Two schedules of Vorinostat were investigated: Phase I A) daily doses on days 5 to 14, or Phase II B) three times a day on days -2 to 3 of standard CHOP every 21 days. Vorinostat was administered orally on days 5 to 14 (Schedule A), first at 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), and next at 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle); and for Phase II Schedule B Vorinostat administered orally 300 mg orally three times daily from days -2 to 3 (4500 mg over 5 days per cycle).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

14 participants

Primary outcome timeframe

21 Days

Results posted on

2014-09-09

Participant Flow

Recruitment Period: 04/03/09 to 12/19/12. All participants were recruited at The University of Texas (UT) MD Anderson Cancer Center.

Participant milestones

Participant milestones
Measure	Zolinza + CHOP Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin: 50 mg/m\^2 by vein/intravenous (IV) over 15 minutes on Day 1 of 21 day cycle Prednisone: 100 mg tablets by mouth/orally (PO) once a day on Days 1-5 of 21 day cycle Zolinza (vorinostat): Phase I Starting dose of 300 mg by mouth each evening on Days 5-14 of 21 day cycle. Cyclophosphamide: 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle
Overall Study STARTED	14
Overall Study COMPLETED	11
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Zolinza + CHOP Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin: 50 mg/m\^2 by vein/intravenous (IV) over 15 minutes on Day 1 of 21 day cycle Prednisone: 100 mg tablets by mouth/orally (PO) once a day on Days 1-5 of 21 day cycle Zolinza (vorinostat): Phase I Starting dose of 300 mg by mouth each evening on Days 5-14 of 21 day cycle. Cyclophosphamide: 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle
Overall Study Toxicity	3

Baseline Characteristics

SAHA + CHOP in Untreated T-cell Non-Hodgkin's Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zolinza + CHOP n=14 Participants Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Zolinza (vorinostat) : Starting oral dose (Schedule A) of 300 mg once a day on Days 5-14 of 21 day cycle. Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle
Age, Continuous	55 years n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Region of Enrollment United States	14 participants n=5 Participants
Vorinostat Treatment (Schedule A/Schedule B) 300 mg once daily on Days 5 to14	6 participants n=5 Participants
Vorinostat Treatment (Schedule A/Schedule B) 200 mg twice daily on Days 5 to14	2 participants n=5 Participants
Vorinostat Treatment (Schedule A/Schedule B) 300 mg three times daily on Days -2 to 3	6 participants n=5 Participants

PRIMARY outcome

Timeframe: 21 Days

Outcome measures

Outcome measures
Measure	Schedule A - Vorinostat Once or Twice Daily n=8 Participants Vorinostat 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle or Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle	Schedule A - Vorinostat Twice Daily Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle
Phase I Maximum Tolerated Dose (MTD) of Vorinostat	300 mg/day	—

PRIMARY outcome

Timeframe: 21 Days

MTD of Vorinostat defined as highest dose level in which 6 patients have been treated with less than 2 instances of DLT. Continual reassessment during each 21-day cycle to assess DLT. Vorinostat was administered orally on days 5 to 14 (Schedule A), first at 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), and next at 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle. The dose of Vorinostat escalated in successive 3+3 cohorts of participants to determine the MTD.

Outcome measures

Outcome measures
Measure	Schedule A - Vorinostat Once or Twice Daily n=6 Participants Vorinostat 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle or Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle	Schedule A - Vorinostat Twice Daily n=2 Participants Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle
Number of Participants With Dose Limiting Toxicity for Determination Phase I (Schedule A) MTD of Vorinostat	1 participants	2 participants

PRIMARY outcome

Timeframe: 21 Days

MTD of Vorinostat when administered in combination with Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). Continual reassessment during each 21-day cycle to assess dose limiting toxicity. Two schedules of Vorinostat were investigated: Phase I A) daily doses on days 5 to 14, or Phase II B) three times a day on days -2 to 3 of standard CHOP every 21 days. Vorinostat was administered orally on days 5 to 14 (Schedule A), first at 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), and next at 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle); Schedule B Vorinostat administered orally 300 mg orally three times daily from days -2 to 3 (4500 mg over 5 days per cycle).

Outcome measures

Outcome measures
Measure	Schedule A - Vorinostat Once or Twice Daily n=6 Participants Vorinostat 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle or Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle	Schedule A - Vorinostat Twice Daily Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle
Phase II MTD of Vorinostat	300 mg/three times daily	—

Adverse Events

Schedule A: Vorinostat Once or Twice Daily

Serious events: 8 serious events

Other events: 8 other events

Deaths: 0 deaths

Schedule B: Vorinostat Three Times Daily

Serious events: 5 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Schedule A: Vorinostat Once or Twice Daily n=8 participants at risk Phase I: Vorinostat administered Days 5 to 14 at starting dose 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), next administered dose 200 mg orally twice daily (4000 mg over 10 days per cycle). Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 21 day cycle: Doxorubicin 50 mg/m\^2 IV Day 1; Prednisone 100 mg tablets orally/day Days 1-5; Cyclophosphamide 750 mg/m\^2 IV Day 1; Vincristine 1.4 mg/m\^2 IV Day 1.	Schedule B: Vorinostat Three Times Daily n=6 participants at risk Phase II: Vorinostat administered at starting dose 300 mg orally three times daily from Days -2 to 3 (4500 mg over 5 days per cycle). Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 21 day cycle: Doxorubicin 50 mg/m\^2 IV Day 1; Prednisone 100 mg tablets orally/day Days 1-5; Cyclophosphamide 750 mg/m\^2 IV Day 1; Vincristine 1.4 mg/m\^2 IV Day 1.
General disorders Oral Mucositis	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Dehydration	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Pain	25.0% 2/8 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Vomiting	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Constipation	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Respiratory, thoracic and mediastinal disorders Cough	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Metabolism and nutrition disorders Hyponatraemia	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Infections and infestations Neutropenic fever	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Thrombocytopenia	25.0% 2/8 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Neutropenia	62.5% 5/8 • Number of events 5 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	50.0% 3/6 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Diarrhoea	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	16.7% 1/6 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Thrombosis	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Anaemia	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	16.7% 1/6 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).

Other adverse events

Additional Information

Yasuhiro Oki, MD/ Associate Professor

University of Texas MD Anderson Cancer Center

Phone: 713-792-2860

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Schedule A: Vorinostat Once or Twice Daily n=8 participants at risk Phase I: Vorinostat administered Days 5 to 14 at starting dose 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), next administered dose 200 mg orally twice daily (4000 mg over 10 days per cycle). Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 21 day cycle: Doxorubicin 50 mg/m\^2 IV Day 1; Prednisone 100 mg tablets orally/day Days 1-5; Cyclophosphamide 750 mg/m\^2 IV Day 1; Vincristine 1.4 mg/m\^2 IV Day 1.	Schedule B: Vorinostat Three Times Daily n=6 participants at risk Phase II: Vorinostat administered at starting dose 300 mg orally three times daily from Days -2 to 3 (4500 mg over 5 days per cycle). Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 21 day cycle: Doxorubicin 50 mg/m\^2 IV Day 1; Prednisone 100 mg tablets orally/day Days 1-5; Cyclophosphamide 750 mg/m\^2 IV Day 1; Vincristine 1.4 mg/m\^2 IV Day 1.
General disorders Fatigue	75.0% 6/8 • Number of events 6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	83.3% 5/6 • Number of events 5 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Oral Mucositis	25.0% 2/8 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Insomnia	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Dizziness	50.0% 4/8 • Number of events 4 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Anorexia	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
General disorders Pain	37.5% 3/8 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Diarrhoea	62.5% 5/8 • Number of events 5 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Nausea	62.5% 5/8 • Number of events 5 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Vomiting	37.5% 3/8 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	50.0% 3/6 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Gastrointestinal disorders Constipation	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	50.0% 3/6 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Respiratory, thoracic and mediastinal disorders Dyspnea	37.5% 3/8 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Cardiac disorders Oedema	37.5% 3/8 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Skin and subcutaneous tissue disorders Rash	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	16.7% 1/6 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Skin and subcutaneous tissue disorders Pruritus	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	16.7% 1/6 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Nervous system disorders Memory impairment	25.0% 2/8 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Nervous system disorders Sensory neuropathy	37.5% 3/8 • Number of events 3 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	0.00% 0/6 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Psychiatric disorders Depression	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	16.7% 1/6 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Metabolism and nutrition disorders Hyperuricaemia	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	16.7% 1/6 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Infections and infestations Other infection	25.0% 2/8 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Thrombocytopenia	12.5% 1/8 • Number of events 1 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Neutropenia	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Thrombosis	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	33.3% 2/6 • Number of events 2 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).
Blood and lymphatic system disorders Anaemia	0.00% 0/8 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).	66.7% 4/6 • Number of events 4 • Adverse event reporting period begins once study drug treatment is initiated through 30 days after the last study treatment (21 day cycle). Overall study participation July 2009 to August 2012 for Phase I (Schedule A) and Phase II (Schedule B).