A Study To Evaluate The Efficacy And Safety of The Investigational Drug PF-03446962 (A Monoclonal Antibody With Antiangiogenic Features) In Combination With Best Supportive Care Versus Placebo Plus Best Supportive Care In Patients Affected By Recurrent Liver Cancer

Study Overview
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Brief Summary
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The primary purpose of the study is to explore whether treatment with PF-03446962 and best supportive care is better than placebo plus best supportive care in prolonging survival of patients affected by recurrent liver cancer. In addition, the study will explore if adding PF-03446962 to best supportive care is safe, how PF-03446962 is metabolized, if there are patients' characteristics (biomarkers) that may predict response to PF-03446962, and if PF-03446962 has any effect on the patients' quality of life.

Detailed Description
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This study was terminated on June 24th, 2014 due to change in strategy of PF-03446962 clinical development. There were no safety or efficacy concerns regarding the study behind the decision to terminate the trial. The study was on temporary halt since March 10th and there are currently no patients on treatment or in the process of being randomized

Official Title
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A Phase 2, Randomized, Double Blind Study To Evaluate The Efficacy, Safety, Pharmacodynamics And Pharmacokinetics Of The Anti-alk-1 Monoclonal Antibody Pf-03446962 In Combination With Best Supportive Care Vs. Placebo Plus Best Supportive Care In Adult Patients With Advanced Hepatocellular Carcinoma Following Failure Of Sorafenib

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: PF-03446962
* Other: Best Supportive Care
* Other: Placebo
* Other: Best Supportive Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of locally advanced or metastatic liver cancer obtained by histology/cytology or by imaging Documented progression on or after treatment with sorafenib, confirmed by the Investigator upon review of appropriate imaging documentation Child Pugh Class A disease ECOG [Eastern Cooperative Oncology Group] Performance Status (PS) 0 or 1 Mandatory tumor biopsy at study entry (pre-randomization, unless already collected after sorafenib progression but within 3 months of enrollment and no systemic anticancer therapies received) Exclusion Criteria: Prior systemic treatment for advanced liver cancer other than sorafenib-including therapy Prior local therapy within 2 weeks of starting the study treatment Presence of main portal vein invasion by liver cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF 03446962 plus best supportive care (BSC)<br> | Drug: PF-03446962<br>* PF 03446962 7 mg/kg, IV, every 2 weeks, until disease progression, patient refusal or unacceptable toxicity, whichever occurs first<br>Other: Best Supportive Care<br>* BSC may include medications and supportive measures deemed necessary to palliate disease related symptoms and improve quality of life<br>|
| Placebo Comparator: Placebo plus best supportive care (BSC)<br>Placebo, IV, every 2 weeks, until disease progression, patient refusal or unacceptable toxicity, whichever occurs first | Other: Placebo<br>* Placebo will consist of Saline (0.9% w/v Sodium Chloride Injection, USP or NS)<br>Other: Best Supportive Care<br>* BSC may include medications and supportive measures deemed necessary to palliate disease related symptoms and improve quality of life.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was the duration from date of randomization to date of death due to any cause. For participants who are alive, overall survival was censored at the last contact. Death was determined from adverse event (AE) data where outcome was death or from follow-up contact data where the participant current status was death. | From first randomization to date of death from any cause, whichever came first, assessed up to 24 months after last participant randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Progression (TTP) | TTP was defined as the time from first randomization to date of first documentation of objective tumor progression. If tumor progression data included more than (>) 1 date, the first date was to be used. TTP (in months) was calculated as first event date or last known progression-free date minus the first randomization date plus 1 divided by 30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). | Screening and every 8 weeks by calendar thereafter, up to 24 months after last participant randomization. | 
| Progression-Free Survival (PFS) | PFS was defined as the time from randomization to first documentation of objective tumor progression or to death due to any cause, whichever occured first. If tumor progression data included >1 date, the first date was to be used. PFS (in months) was calculated as first event date minus first randomization date plus 1 divided by 30.4. | Screening and every 8 weeks by calendar thereafter, up to 24 months after last participant randomization. | 
| Objective Response Rate (ORR) - Percentage of Participants With Objective Response | ORR was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1, relative to all randomized participants. CR were those that persisted on repeat imaging study more than or equal to (>=) 4 weeks after initial documentation of response. PR was defined as >=30% decrease in the sum of diameters of target lesions and non CR/non PD to non-target lesions. Participants who did not have on study radiographic tumor re-evaluation or who died, progressed or dropped out for any reason prior to reaching a CR or PR were to be counted as non-responders in the assessment of ORR. A participant who initially met the criteria for a PR and then subsequently became a confirmed CR, was to be assigned a best response of CR. | Screening and every 8 weeks by calendar thereafter, up to 24 months after last participant randomization. | 
| Duration of Response (DR) | DR was defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. If tumor progression data included >1 date, the first date was to be used. DR (in months) was calculated as the end date for DR minus date of first CR or PR that was subsequently confirmed plus 1 divided by 30.4. CR was defined as disappearance of all target lesions and non-target, if any. PR was defined as >=30% decrease in the sum of diameters of target lesions and non CR/non PD to non-target lesions. | From first randomization to date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after last participant randomization | 
| Percentage of Participants With Disease Control Rate (DCR) at 16 Weeks | DCR was defined as the proportion of participants with confirmed CR or confirmed PR or a best response of stable disease (SD) >=16 weeks according to RECIST, relative to all randomized participants. CR was defined as disappearance of all target lesions. PR was defined as >=30% decrease in the sum of diameters of target lesions and non CR/non PD to non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. | From first randomization to date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after last participant randomization | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep) | Patient reported outcomes (PROs) were assessed using the FACT-Hep. The FACT-Hep included the FACT-general (FACT-G) and a hepatobiliary module, it consisted of the 27-item FACT-G, which assessed generic health-related quality of life (HRQoL) concerns, and the 18-item hepatobiliary subscale (HS), which assessed disease-specific issues. The questionnaire used a 5 point Likert scale from '0' not at all to '4' very much regarding how much each item was present in the last 7 days; lower score indicated severer symptom. Eight of the items (lack of energy, pain, weight loss, back pain, fatigue, stomach pain/discomfort, nausea, and jaundice) made up the Fact Hepatobiliary Symptom Index (FHSI 8) were considered to be symptoms specific to hepatobiliary cancer. | Screening, Cycle 1 Day1,8; Cycle >=2 Day1; End of treatment, survival follow-up up to 24 months after last participant randomization. | 
| Maximum Serum Concentration (Cmax) |  | 1 hour (after start of infusion) on Day1 of Cycles 1, 2, 4, 6, and 8 | 
| Trough Serum Concentration of PF-03446962 (Ctrough) |  | 0 hour (predose) on Day 1 of Cycles 1, 2, 4, 6, and 8 | 
| Number of Participants With Human Anti-Human Antibodies (HAHA) |  | Cycle 1, 2, 4, 6, 8 Day 1 at 0 hour (pre-dose) | 
| Presence of Sensitivity Signature | Tumor molecular characteristics including but not limited to transcriptomic (RNA) signatures of sensitivity | Cycle 1 Day 1 (before infusion), Cycle 4 Day 1 (before infusion), at disease progression/participant withdrawal. | 
| Ratio to Baseline of Serum Circulating Protein Concentration | Protein involved TGFB1, VEGF-A, VEGF-C, PIGF, Endoglin, BMP-9, VEGFR1, VEGFR2, VEGFr3, Ang-2, VEGF-D, CD54, CD106, and CCL2. Tumor molecular characteristics including but not limited to transcriptomic (ribonucleic acid) signatures of efficacy. | Cycle 1 Day 1 (before infusion), Cycle 4 Day 1 (before infusion), at disease progression/participant withdrawal. | 
| Observed Serum Concentration of Circulating Protein |  | Cycle 1 Day 1 (before infusion), Cycle 4 Day 1 (before infusion), at disease progression/participant withdrawal. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular carcinoma, monoclonal antibody, ALK-1, best supportive care