Trial Outcomes & Findings for Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC) (NCT NCT00862082)

NCT ID: NCT00862082

Last Updated: 2013-08-23

Results Overview

• Recruitment status: TERMINATED
• Study phase: PHASE1/PHASE2
• Target enrollment: 14 participants
• Primary outcome timeframe: 4 weeks (1 cycle)
• Results posted on: 2013-08-23

Participant Flow

Participant milestones

Measure	PR104 550 mg/m^2 + Sorafenib 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104 770 mg/m^2 + Sorafenib 770 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)
Overall Study STARTED	8	6
Overall Study COMPLETED	3	5
Overall Study NOT COMPLETED	5	1

Reasons for withdrawal

Measure	PR104 550 mg/m^2 + Sorafenib 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104 770 mg/m^2 + Sorafenib 770 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)
Overall Study Sponsor decision to terminate the study	5	0
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)

Baseline characteristics by cohort

Measure	PR104 550 mg/m^2 + Sorafenib n=8 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104 770 mg/m^2 + Sorafenib n=6 Participants 770 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Total n=14 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	7 Participants n=5 Participants	5 Participants n=7 Participants	12 Participants n=5 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Age Continuous	57 years STANDARD_DEVIATION 13 • n=5 Participants	59 years STANDARD_DEVIATION 13 • n=7 Participants	58 years STANDARD_DEVIATION 13 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Region of Enrollment United States	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Taiwan	5 participants n=5 Participants	2 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Hong Kong	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants

PRIMARY outcome

Timeframe: 4 weeks (1 cycle)

Outcome measures

Measure	Cohorts 1 and 2 n=14 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G major plasma metabolite	PR104S1 semi-mustard metabolite	PR104H activated reduced metabolites	PR104M activated reduced metabolites
Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population	NA mg/m2 There were no DLTs, however myelosuppression in several patients led to the decision to discontinue the study; therefore, a MTD was not determined.	—	—	—	—	—

SECONDARY outcome

Timeframe: 30 days following the last administration of study treatment

The number of participants with at least one Serious Adverse Event was measured.

Outcome measures

Measure	Cohorts 1 and 2 n=6 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=8 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G major plasma metabolite	PR104S1 semi-mustard metabolite	PR104H activated reduced metabolites	PR104M activated reduced metabolites
Safety and Tolerability: Serious Adverse Events	2 participants	5 participants	—	—	—	—

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 2

Population: Participation in pharmacokinetic (PK) sampling was optional to subjects, therefore not all subjects in the study were analyzed.

Outcome measures

Measure	Cohorts 1 and 2 n=2 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=2 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G n=2 Participants major plasma metabolite	PR104S1 n=2 Participants semi-mustard metabolite	PR104H n=2 Participants activated reduced metabolites	PR104M n=2 Participants activated reduced metabolites
Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) Cmax Cycle 1	7.1 ng/ml Standard Deviation 3.2	7.6 ng/ml Standard Deviation 1.9	9.6 ng/ml Standard Deviation 2.3	0.17 ng/ml Standard Deviation 0.15	0.21 ng/ml Standard Deviation 0.11	0.04 ng/ml Standard Deviation 0.02
Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) Cmax Cycle 2	6.0 ng/ml Standard Deviation 3.3	7.6 ng/ml Standard Deviation 1.0	10.4 ng/ml Standard Deviation 2.2	0.18 ng/ml Standard Deviation 0.07	0.20 ng/ml Standard Deviation 0.05	0.04 ng/ml Standard Deviation 0.02

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 2

Population: Participation in PK sampling was optional to subjects, therefore not all subjects in the study were analyzed.

Outcome measures

Measure	Cohorts 1 and 2 n=2 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=2 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G n=2 Participants major plasma metabolite	PR104S1 n=2 Participants semi-mustard metabolite	PR104H n=2 Participants activated reduced metabolites	PR104M n=2 Participants activated reduced metabolites
Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) T1/2 Cycle 1	0.15 hr Standard Deviation 0.10	0.75 hr Standard Deviation 0.35	0.62 hr Standard Deviation 0.08	0.87 hr Standard Deviation 0.11	1.37 hr Standard Deviation 0.18	3.57 hr Standard Deviation 0.82
Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) T1/2 Cycle 2	0.17 hr Standard Deviation 0.11	0.85 hr Standard Deviation 0.20	0.67 hr Standard Deviation 0.17	0.79 hr Standard Deviation 0.14	1.05 hr Standard Deviation 0.35	02.93 hr Standard Deviation 2.48

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 2

Population: Participation in PK sampling was optional to subjects, therefore not all subjects in the study were analyzed.

Outcome measures

Measure	Cohorts 1 and 2 n=2 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=2 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G n=2 Participants major plasma metabolite	PR104S1 n=2 Participants semi-mustard metabolite	PR104H n=2 Participants activated reduced metabolites	PR104M n=2 Participants activated reduced metabolites
Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) AUC Cycle 1	5.1 ng.h/ml Standard Deviation 3.2	11.0 ng.h/ml Standard Deviation 4.4	12.3 ng.h/ml Standard Deviation 1.3	0.26 ng.h/ml Standard Deviation 0.23	0.47 ng.h/ml Standard Deviation 0.27	0.22 ng.h/ml Standard Deviation 0.09
Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) AUC Cycle 2	4.3 ng.h/ml Standard Deviation 2.9	10.6 ng.h/ml Standard Deviation 0.1	15.8 ng.h/ml Standard Deviation 2.9	0.28 ng.h/ml Standard Deviation 0.10	0.42 ng.h/ml Standard Deviation 0.04	0.19 ng.h/ml Standard Deviation 0.17

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 2

Population: Participation in PK sampling was optional to subjects, therefore not all subjects in the study were analyzed.

Outcome measures

Measure	Cohorts 1 and 2 n=5 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=5 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G n=1 Participants major plasma metabolite	PR104S1 n=5 Participants semi-mustard metabolite	PR104H n=5 Participants activated reduced metabolites	PR104M n=5 Participants activated reduced metabolites
Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) Cmax Cycle 1	3.2 ng/ml Standard Deviation 1.1	15.8 ng/ml Standard Deviation 8.9	4.9 ng/ml Standard Deviation NA Not determined for PR-104G due to the availability of only one subject's dataset from each cycle	0.21 ng/ml Standard Deviation 0.18	0.72 ng/ml Standard Deviation 0.80	0.12 ng/ml Standard Deviation 0.12
Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) Cmax Cycle 2	4.3 ng/ml Standard Deviation 0.7	14.6 ng/ml Standard Deviation 10.4	5.8 ng/ml Standard Deviation NA Not determined for PR-104G due to the availability of only one subject's dataset from each cycle.	0.17 ng/ml Standard Deviation 0.17	0.69 ng/ml Standard Deviation 0.78	0.16 ng/ml Standard Deviation 0.13

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 2

Population: Participation in PK sampling was optional to subjects, therefore not all subjects in the study were analyzed.

Outcome measures

Measure	Cohorts 1 and 2 n=5 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=5 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G n=1 Participants major plasma metabolite	PR104S1 n=5 Participants semi-mustard metabolite	PR104H n=5 Participants activated reduced metabolites	PR104M n=5 Participants activated reduced metabolites
Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) T1/2 Cycle 2	0.09 hr Standard Deviation 0.01	0.79 hr Standard Deviation 0.23	0.50 hr Standard Deviation NA Not determined for PR-104G due to the availability of only one subject's dataset from each cycle.	0.90 hr Standard Deviation 0.44	0.91 hr Standard Deviation 0.25	0.99 hr Standard Deviation 0.52
Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) T1/2 Cycle 1	0.10 hr Standard Deviation 0.01	0.68 hr Standard Deviation 0.04	0.53 hr Standard Deviation NA Not determined for PR-104G due to the availability of only one subject's dataset from each cycle.	0.69 hr Standard Deviation 0.20	0.84 hr Standard Deviation 0.34	1.02 hr Standard Deviation 0.42

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 2

Population: Participation in PK sampling was optional to subjects, therefore not all subjects in the study were analyzed.

Outcome measures

Measure	Cohorts 1 and 2 n=5 Participants 770 and 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	Cohort 2 n=5 Participants 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104G n=1 Participants major plasma metabolite	PR104S1 n=5 Participants semi-mustard metabolite	PR104H n=5 Participants activated reduced metabolites	PR104M n=5 Participants activated reduced metabolites
Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) AUC Cycle 1	2.4 ng.h/ml Standard Deviation 0.8	19.7 ng.h/ml Standard Deviation 9.7	6.4 ng.h/ml Standard Deviation NA Not determined for PR-104G due to the availability of only one subject's dataset from each cycle.	0.30 ng.h/ml Standard Deviation 0.23	0.81 ng.h/ml Standard Deviation 0.71	0.18 ng.h/ml Standard Deviation 0.13
Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) AUC Cycle 2	3.3 ng.h/ml Standard Deviation 0.6	22.7 ng.h/ml Standard Deviation 18.2	7.6 ng.h/ml Standard Deviation NA Not determined for PR-104G due to the availability of only one subject's dataset from each cycle.	0.31 ng.h/ml Standard Deviation 0.21	1.07 ng.h/ml Standard Deviation 1.02	0.25 ng.h/ml Standard Deviation 0.18

Adverse Events

PR104 550 mg/m^2 + Sorafenib

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

PR104 770 mg/m^2 + Sorafenib

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	PR104 550 mg/m^2 + Sorafenib n=8 participants at risk 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104 770 mg/m^2 + Sorafenib n=6 participants at risk 770 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)
Gastrointestinal disorders Abdominal Pain	25.0% 2/8 • Number of events 3	0.00% 0/6
Infections and infestations Cellulitis	12.5% 1/8 • Number of events 1	0.00% 0/6
General disorders Decrease in general condition	12.5% 1/8 • Number of events 1	0.00% 0/6
General disorders Fatigue	0.00% 0/8	16.7% 1/6 • Number of events 1
Blood and lymphatic system disorders Febrile neutropenia	12.5% 1/8 • Number of events 1	0.00% 0/6
General disorders Fever in absence of neutropenia	25.0% 2/8 • Number of events 2	0.00% 0/6
Infections and infestations Sepsis	0.00% 0/8	16.7% 1/6 • Number of events 1
Investigations Thrombocytopenia	12.5% 1/8 • Number of events 1	0.00% 0/6

Other adverse events

Measure	PR104 550 mg/m^2 + Sorafenib n=8 participants at risk 550 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)	PR104 770 mg/m^2 + Sorafenib n=6 participants at risk 770 mg/m\^2 PR104 administered IV every 4 weeks + Standard dose sorafenib (400 mg PO twice daily)
Blood and lymphatic system disorders Leukopenia	87.5% 7/8	66.7% 4/6
Blood and lymphatic system disorders Anemia	50.0% 4/8	83.3% 5/6
Blood and lymphatic system disorders Neutropenia	75.0% 6/8	50.0% 3/6
Blood and lymphatic system disorders Thrombocytopenia	37.5% 3/8	83.3% 5/6
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/8	16.7% 1/6
Metabolism and nutrition disorders Hypoalbuminemia	50.0% 4/8	50.0% 3/6
Metabolism and nutrition disorders Anorexia	37.5% 3/8	33.3% 2/6
Metabolism and nutrition disorders Hyperglycemia	12.5% 1/8	50.0% 3/6
Metabolism and nutrition disorders Hyponatremia	12.5% 1/8	50.0% 3/6
Metabolism and nutrition disorders Hypocalcemia	12.5% 1/8	16.7% 1/6
Metabolism and nutrition disorders Hypokalemia	12.5% 1/8	16.7% 1/6
General disorders Fatigue	37.5% 3/8	50.0% 3/6
General disorders Induration	12.5% 1/8	0.00% 0/6
General disorders Mucosal inflammation	0.00% 0/8	16.7% 1/6
General disorders Oedema peripheral	12.5% 1/8	0.00% 0/6
General disorders Pyrexia	0.00% 0/8	16.7% 1/6
Investigations Aspartate aminotransferase increased	75.0% 6/8	50.0% 3/6
Investigations Alanine aminotransferase increased	50.0% 4/8	33.3% 2/6
Investigations Blood alkaline phosphatase increased	37.5% 3/8	16.7% 1/6
Investigations International normalised ratio increased	12.5% 1/8	0.00% 0/6
Investigations Weight decreased	12.5% 1/8	0.00% 0/6
Gastrointestinal disorders Abdominal pain	37.5% 3/8	33.3% 2/6
Gastrointestinal disorders Diarrhea	37.5% 3/8	16.7% 1/6
Gastrointestinal disorders Abdominal distension	12.5% 1/8	16.7% 1/6
Gastrointestinal disorders Ascites	12.5% 1/8	16.7% 1/6
Gastrointestinal disorders Constipation	12.5% 1/8	16.7% 1/6
Gastrointestinal disorders Gingival bleeding	0.00% 0/8	16.7% 1/6
Gastrointestinal disorders Vomiting	12.5% 1/8	0.00% 0/6
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	12.5% 1/8	33.3% 2/6
Skin and subcutaneous tissue disorders Leukocytoclastic vasulitis	12.5% 1/8	0.00% 0/6
Skin and subcutaneous tissue disorders Pruritis	12.5% 1/8	0.00% 0/6
Skin and subcutaneous tissue disorders Rash	12.5% 1/8	0.00% 0/6
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/8	16.7% 1/6
Hepatobiliary disorders Hyperbilirubinemia	37.5% 3/8	16.7% 1/6
Hepatobiliary disorders Jaundice	12.5% 1/8	0.00% 0/6
Infections and infestations Upper respiratory tract infection	12.5% 1/8	16.7% 1/6
Infections and infestations Cellulitis	0.00% 0/8	16.7% 1/6
Infections and infestations Urinary tract infection	12.5% 1/8	0.00% 0/6
Psychiatric disorders Insomnia	12.5% 1/8	16.7% 1/6
Respiratory, thoracic and mediastinal disorders Cough	12.5% 1/8	0.00% 0/6
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/8	16.7% 1/6
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/8	16.7% 1/6
Nervous system disorders Coordination abnormal	12.5% 1/8	0.00% 0/6
Vascular disorders Hypertension	12.5% 1/8	0.00% 0/6

Additional Information

Director of Clinical Development

Proacta, Inc.

Phone: 858-642-0386

Email: clinicalops@proacta.com

Results disclosure agreements

• Principal investigator is a sponsor employee Single site data may be published/presented prior to the publication of multi-center data from overall study if agreed to by the sponsor in writing, or 12 months have elapsed following termination or completion of the study, whichever comes first.
• Publication restrictions are in place

Restriction type: OTHER