Hepatocellular CarcinomaPhase 1/2NCT00862082
Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
A Phase 1/2 study testing PR104 550 mg/m^2 + sorafenib and PR104 770 mg/m^2 + sorafenib in people with Hepatocellular Carcinoma, run by Proacta, Incorporated at 17 sites in 4 countries.
Trial summary
The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include: Hypoxia. Hepatocellular Carcinoma (HCC) is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatocellular Carcinoma
- What is being tested?
- PR104 550 mg/m^2 + sorafenib and PR104 770 mg/m^2 + sorafenib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 17 sitesin 4 countries
- Study dates
- Mar 2009to May 2010
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Advanced-stage hepatocellular carcinoma considered non-operable that is suitable for treatment with sorafenib. Subjects who have demonstrated progression following initial surgical or locoregional therapy are eligible
- Confirmed hepatocellular carcinoma by pathological analysis (tissue aspirate or biopsy)
- No previous systemic therapy for hepatocellular carcinoma
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Child-Pugh liver function class A
- Life expectancy of 12 weeks or more
Show all 11Show fewer
- Adequate hematologic function [Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥100×10^9 per liter; hemoglobin ≥8.5 g per deciliter maintained in the absence of red blood cell transfusions; and prothrombin time international normalized ratio ≤1.7; or prothrombin time ≤2 seconds above control]
- Adequate hepatic function (albumin ≥2.8 g per deciliter; total bilirubin ≤2 mg per deciliter [51.3 μmol per liter]; and alanine aminotransferase and aspartate aminotransferase ≤5 times the upper limit of the normal range)
- Adequate renal function (serum creatinine ≤1.5 times the upper limit of the normal range or creatinine clearance ≥60 mL/min).
- At least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST)
- Concomitant systemic antiviral therapy allowed
Who cannot join
- Previous molecularly targeted therapies or any other systemic treatment for hepatocellular carcinoma
- Active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study
- Women who are pregnant, breast-feeding or planning to become pregnant during the study
- Men or women of reproductive-potential who are unwilling to use an effective method of contraception during the study and for 30 days following the last dose of study medication
- Evidence of a significant medical disorder or laboratory finding that, in the opinion of the Investigator, compromises the subject's safety during study participation such as: uncontrolled infection or infection requiring a concomitant parenteral antibiotic; uncontrolled diabetes; congestive heart failure; myocardial infarction within 6 months of study; chronic renal disease; or coagulopathy (excluding prophylactic anticoagulation)
- Active central nervous system metastatic disease requiring intervention
- Less than four weeks since major surgery
- Known Human Immunodeficiency Virus (HIV) positivity
Trial locations and contacts
17 sites in 4 countries.
17 sites in 4 countries
United States9 sites
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
Baltimore, Maryland, 21231
Northwestern University
Chicago, Illinois, 60611
Indiana University Simon Cancer Center
Indianapolis, Indiana, 46202
Moores UCSD Cancer Center
La Jolla, California, 92093
Columbia University Medical Center
New York, New York, 10032
University of California, Irvine
Orange, California, 92868
Sharp Clinical Oncology Research
San Diego, California, 92123
Pacific Oncology/Hematology
San Francisco, California, 94115
University of Arizona
Tucson, Arizona, 85724
Taiwan6 sites
Chang Gung Memorial Hospital
Kaohsiung City
Kaohsiung Medical University Chung-Ho Memorial Hospital
Kaohsiung City
China Medical University Hospital
Taichung
Chi Mei Medical Center, Liouying
Tainan
Cathay General Hospital
Taipei, 10630
National Taiwan University Hospital
Taipei
About this study
Official title: A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
- Hypoxia. Hepatocellular Carcinoma (HCC) is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. In addition, in preclinical models, sorafenib has been demonstrated to increase the degree of hypoxia in tumors following treatment.
- Non-overlapping toxicity. PR104 and sorafenib do not share major toxicities. It is anticipated that both drugs can be administered at their full single agent dose when used in combination.
- Aldo-keto reductase 1C3 (AKR1C3). HCC has been shown to express high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic HCC cells.
- Preclinical data. The use of sorafenib and PR104 alone and in combination in a hepatocellular carcinoma model demonstrates activity of PR104 as a single agent and increased activity when PR104 and sorafenib are used in combination.
Read more
The current study will provide an estimate of the activity of PR104 in subjects with HCC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in HCC to warrant a larger phase III registration study in this indication.
Primary objectives
- Phase I: Determine the maximum tolerated dose (MTD) of PR104 when used in combination with standard dose sorafenib
- Phase II: Estimate the response rate (RR) of PR104/sorafenib [Note: Phase II was never initiated]
Secondary objectives
- Evaluate survival
- Evaluate Progression Free Survival (PFS)
- Evaluate time to progression (TTP)
- Evaluate safety
- Evaluate the pharmacokinetics (PK) of sorafenib, PR104 and PR104 metabolites
- Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
- Collect plasma samples for assessment of potential biomarkers of tumor hypoxia
Read the detailed description
A randomized phase I/II, multi-center, open-label, study with a single arm phase I portion to determine the appropriate dose of PR104 combined with sorafenib, followed by a phase II portion with randomization between sorafenib and sorafenib/PR104.
Following informed consent, subjects will undergo baseline evaluation with history, physical exams, blood work and disease assessment. Selected subjects will undergo PK assessment of sorafenib, PR104 and PR104 metabolites.
In the phase I portion of the study, the starting dose of PR104 will be 770 mg/mg2 in combination with standard dose sorafenib. PR104 will be administered on an every 4 week schedule with the dose of PR104 escalated in a standard phase I fashion (3 subjects per cohort, dose escalation between cohorts) in order to determine the MTD of PR104. Cohorts may be expanded up to 12 subjects to better define toxicity at a particular dose level. Following determination of the MTD of PR104, new subjects will be entered into the phase II portion of the study. [Note: the Phase II portion was never initiated]
In the phase II portion of the study, subjects will be randomized between sorafenib, 400 mg, by mouth (PO), twice a day (the approved dose and schedule) versus sorafenib with PR104 at the dose determined in the phase I portion of the study. PR104 will be administered every 4 weeks (one cycle). Subjects will be evaluated each week during cycle 1 and every two weeks thereafter. A disease assessment will be performed after every two cycles. Subjects with progression will be removed from study. Subjects with a response or stable disease may continue on study if this is considered beneficial by their physician.
- Conditions
- Hepatocellular Carcinoma
- Being tested
- PR104 550 mg/m^2 + sorafenib, PR104 770 mg/m^2 + sorafenib
- Medical subject headings
- Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PR104 550 mg/m^2 + sorafenibDrug
Also called PR-104, Nexavar
550 mg/m^2 PR104 IV on day 1 of each 28 day cycle + 400 mg sorafenib PO twice daily. Number of Cycles: until progression or unacceptable toxicity develops.
PR104 770 mg/m^2 + sorafenibDrug
Also called PR-104, Nexavar
770 mg/m^2 PR104 IV on day 1 of each 28 day cycle + 400 mg sorafenib PO twice daily. Number of Cycles: until progression or unacceptable toxicity develops.
| Study group | Role | What they receive |
|---|---|---|
| PR104 + Sorafenib | Experimental | PR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily Receives: Drug: PR104 550 mg/m^2 + sorafenib; Drug: PR104 770 mg/m^2 + sorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population
Measured: 4 weeks (1 cycle)
Secondary outcomes (7)
Safety and Tolerability: Serious Adverse Events
The number of participants with at least one Serious Adverse Event was measured.
Measured: 30 days following the last administration of study treatment
Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Measured: Day 1 of Cycles 1 and 2
Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Measured: Day 1 of Cycles 1 and 2
Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Measured: Day 1 of Cycles 1 and 2
Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Measured: Day 1 of Cycles 1 and 2
Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Measured: Day 1 of Cycles 1 and 2
Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Measured: Day 1 of Cycles 1 and 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Mar 2009 (estimated)
- Study startMar 2009
- Primary completionJan 2010
- Study completionMay 2010
Why it stopped: PR104 plus sorafenib was poorly tolerated in patients with advanced HCC
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Proacta, Incorporated
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00862082
- Sponsor's protocol ID
- PR104-2002
- Status last verified
- Jul 2013
- First submitted
- 12 Mar 2009
- Last updated
- 23 Aug 2013
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
- ClinicalTrials.gov ID
- NCT00862082
- Acronym / sponsor ID
- PR104-2002
- Conditions
- Hepatocellular Carcinoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: PR104 plus sorafenib was poorly tolerated in patients with advanced HCC
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Proacta, IncorporatedIndustry (pharma, biotech, devices)
- Study start
- Mar 2009
- Primary completion
- Jan 2010 (actual)
- Study completion
- May 2010 (actual)
- First posted
- 16 Mar 2009 (estimated)
- Results
- Posted 23 Aug 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
- Hypoxia. Hepatocellular Carcinoma (HCC) is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. In addition, in preclinical models, sorafenib has been demonstrated to increase the degree of hypoxia in tumors following treatment.
- Non-overlapping toxicity. PR104 and sorafenib do not share major toxicities. It is anticipated that both drugs can be administered at their full single agent dose when used in combination.
- Aldo-keto reductase 1C3 (AKR1C3). HCC has been shown to express high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic HCC cells.
- Preclinical data. The use of sorafenib and PR104 alone and in combination in a hepatocellular carcinoma model demonstrates activity of PR104 as a single agent and increased activity when PR104 and sorafenib are used in combination.
The current study will provide an estimate of the activity of PR104 in subjects with HCC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in HCC to warrant a larger phase III registration study in this indication.
Primary objectives
- Phase I: Determine the maximum tolerated dose (MTD) of PR104 when used in combination with standard dose sorafenib
- Phase II: Estimate the response rate (RR) of PR104/sorafenib [Note: Phase II was never initiated]
Secondary objectives
- Evaluate survival
- Evaluate Progression Free Survival (PFS)
- Evaluate time to progression (TTP)
- Evaluate safety
- Evaluate the pharmacokinetics (PK) of sorafenib, PR104 and PR104 metabolites
- Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
- Collect plasma samples for assessment of potential biomarkers of tumor hypoxia
Detailed description
A randomized phase I/II, multi-center, open-label, study with a single arm phase I portion to determine the appropriate dose of PR104 combined with sorafenib, followed by a phase II portion with randomization between sorafenib and sorafenib/PR104.
Following informed consent, subjects will undergo baseline evaluation with history, physical exams, blood work and disease assessment. Selected subjects will undergo PK assessment of sorafenib, PR104 and PR104 metabolites.
In the phase I portion of the study, the starting dose of PR104 will be 770 mg/mg2 in combination with standard dose sorafenib. PR104 will be administered on an every 4 week schedule with the dose of PR104 escalated in a standard phase I fashion (3 subjects per cohort, dose escalation between cohorts) in order to determine the MTD of PR104. Cohorts may be expanded up to 12 subjects to better define toxicity at a particular dose level. Following determination of the MTD of PR104, new subjects will be entered into the phase II portion of the study. [Note: the Phase II portion was never initiated]
In the phase II portion of the study, subjects will be randomized between sorafenib, 400 mg, by mouth (PO), twice a day (the approved dose and schedule) versus sorafenib with PR104 at the dose determined in the phase I portion of the study. PR104 will be administered every 4 weeks (one cycle). Subjects will be evaluated each week during cycle 1 and every two weeks thereafter. A disease assessment will be performed after every two cycles. Subjects with progression will be removed from study. Subjects with a response or stable disease may continue on study if this is considered beneficial by their physician.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| PR104 + Sorafenib | Experimental | Drug: PR104 550 mg/m^2 + sorafenib, Drug: PR104 770 mg/m^2 + sorafenibPR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Advanced-stage hepatocellular carcinoma considered non-operable that is suitable for treatment with sorafenib. Subjects who have demonstrated progression following initial surgical or locoregional therapy are eligible
- Confirmed hepatocellular carcinoma by pathological analysis (tissue aspirate or biopsy)
- No previous systemic therapy for hepatocellular carcinoma
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Child-Pugh liver function class A
Key exclusion criteria (8 listed)
- Previous molecularly targeted therapies or any other systemic treatment for hepatocellular carcinoma
- Active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study
- Women who are pregnant, breast-feeding or planning to become pregnant during the study
- Men or women of reproductive-potential who are unwilling to use an effective method of contraception during the study and for 30 days following the last dose of study medication
- Evidence of a significant medical disorder or laboratory finding that, in the opinion of the Investigator, compromises the subject's safety during study participation such as: uncontrolled infection or infection requiring a concomitant parenteral antibiotic; uncontrolled diabetes; congestive heart failure; myocardial infarction within 6 months of study; chronic renal disease; or coagulopathy (excluding prophylactic anticoagulation)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PR104 550 mg/m^2 + sorafenibAlso: PR-104, Nexavar550 mg/m^2 PR104 IV on day 1 of each 28 day cycle + 400 mg sorafenib PO twice daily. Number of Cycles: until progression or unacceptable toxicity develops. | Drug | PR104 + Sorafenib |
| PR104 770 mg/m^2 + sorafenibAlso: PR-104, Nexavar770 mg/m^2 PR104 IV on day 1 of each 28 day cycle + 400 mg sorafenib PO twice daily. Number of Cycles: until progression or unacceptable toxicity develops. | Drug | PR104 + Sorafenib |
Primary outcome
Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population
Time frame: 4 weeks (1 cycle)
7 secondary outcomes
Safety and Tolerability: Serious Adverse Events
Time frame: 30 days following the last administration of study treatment
Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Time frame: Day 1 of Cycles 1 and 2
Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Time frame: Day 1 of Cycles 1 and 2
Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Time frame: Day 1 of Cycles 1 and 2
Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Time frame: Day 1 of Cycles 1 and 2
Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Time frame: Day 1 of Cycles 1 and 2
Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Time frame: Day 1 of Cycles 1 and 2
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
17 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PR104 550 mg/m^2 + sorafenib and PR104 770 mg/m^2 + sorafenib in people with Hepatocellular Carcinoma, run by Proacta, Incorporated at 17 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 23 Aug 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in United States, Taiwan, Hong Kong, Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Aug 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population (time frame: 4 weeks (1 cycle)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2013.