E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced hepatocellular carcinoma (HCC) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether overall survival (OS) of PF-03446962 plus best
supportive care (BSC) is superior to OS of BSC in patients with advanced HCC following sorafenib failure. |
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E.2.2 | Secondary objectives of the trial |
- To compare measures of tumor control between treatment arms.
- To evaluate the safety and tolerability of PF-03446962 administered in combination with BSC.
- To assess the potential influence on PF-03446962 efficacy of gene alterations, transcripts and proteomic profiles related to ALK-1 signaling and HCC biology in patients’ tumor (pre-randomization biopsy in all patients) and blood samples.
- To assess biomarkers associated with tumor resistance mechanisms and/or tumor progression in HCC patients treated with PF-03446962 who have experienced objective response or SD for at least 16 weeks from randomization and have then experienced disease progression on or after study treatment (in Arm A only).
Please refer to protocol to review the rest of secondary objectives. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of locally advanced or metastatic HCC, obtained by histology/cytology (on a prior tumor biopsy) or by imaging (acceptable imaging modalities include triphasic contrast-enhanced helical CT, triphasic dynamic contrast-enhanced MRI and contrast-enhanced ultrasonography); all patients must provide one archival tumor specimen (if collected at the time of primary diagnosis and still available).
2. HCC not amenable to local therapy.
3. Documented progression on or after treatment with sorafenib. Patients who withdrew from sorafenib due to intolerance are eligible provided that they had disease progression and did not receive any anti-cancer therapy after the last sorafenib dose. Sorafenib failure must be confirmed by the Investigator upon review of appropriate imaging documentation. Imaging documentation of sorafenib failure must be retained at the site by the Investigator for potential retrospective independent central review; before randomization, all patients must provide a de novo tumor block obtained after disease progression on sorafenib (pre-randomization de novo biopsy). Inability to obtain this biopsy will make the patient ineligible for the study
4. Measurable or non-measurable disease according to RECIST v. 1.1.
5. Child-Pugh Class A disease (see Appendix 1). Score for hepatic encephalopathy must be 1; ascites score must be ≤ 2.
6. At least 2 weeks since completion of prior radiotherapy, or surgical procedure (4 weeks for major surgery).
7. All prior treatment-related toxicities must have resolved to baseline severity or CTCAE Grade ≤1 except for alopecia or other AEs not constituting a safety risk for the patients by investigator’s judgement.
8. Age ≥18 years (or ≥20 years for Japanese patients).
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0 or 1.
10. Adequate bone marrow function (including ANC ≥1,500/mm3; Platelets ≥ 75,000/mm3; Hemoglobin ≥9 g/dL).
11. Adequate renal function (including serum creatinine ≤1.5 x ULN, or creatinine clearance ≥60 ml/min as per institution standard).
12. INR <1.7 or prothrombin time (PT) prolongation < 4 seconds* above ULN.
13. Adequate liver function (including AST/ALT ≤5.0 x ULN; total serum bilirubin ≤2 mg/dL*; and serum albumin ≥ 2.8 g/d**) [See Appendix 1: Child-Pugh Score ≤1* or ≤2**].
14. Prior liver transplantation is permitted; immunosuppressive agents in transplanted patients are also allowed.
15. Male and female patients of childbearing potential, must agree to use a highly effective method of contraception throughout the study and for 6 months after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
16. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
17. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures. |
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E.4 | Principal exclusion criteria |
1. Prior systemic treatment for advanced HCC other than 1st-line sorafenib (single agent or in combination).
2. Prior local therapy (such as hepatic arterial embolization, TACE, hepatic arterial infusion, radiofrequency ablation, percutaneous ethanol injection or cryoablation) within 2 weeks of starting the study treatment.
3. Presence of main portal vein invasion by HCC (invasion to 1st or 2nd branch of portal vein is acceptable).
4. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are radiographically and neurologically stable.
5. Clinically significant bleeding disorders, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis or melena in the past 3 months; or untreated high risk esophageal varices in patients with known portal hypertension.
6. History of Osler-Weber-Rendu syndrome or Hereditary Hemorrhagic Telangiectasia.
7. Known active and clinically significant bacterial, fungal or viral infection (other than hepatitis B (HBV), hepatitis C (HCV)), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
8. Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsades de points, clinically significant ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF NY Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms. Ongoing cardiac dysrrhythmias of CTCAE Grade ≥2, atrial fibrillation of any grade, or QTc interval >480 msec (unless considered not clinically significant) at screening are exclusionary.
9. Pregnant females; breastfeeding females; males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for 6 month after last dose of investigational product.
10. Participation in other studies involving investigational drugs (Phases 1-4) within 1 month before the current study begins and/or during study participation.
11. Other severe acute or chronic medical or psychiatric condition (including recent [within the past year] or active suicidal ideation or behavior) or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
12. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
13. History of any other malignancy in the previous 3 years (except for local cancers resected with curative intent without evidence of recurrence over the past 12 months). |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time Frame: From 1st randomization to about 30 months
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E.5.2 | Secondary end point(s) |
- Time to Progression (TTP), Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DR) and Disease Control Rate (DCR) at 16 weeks [by Response Evaluation Criteria in Solid Tumor (RECIST 1.1)].
- Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.0), timing, seriousness and relationship to study therapy.
- Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
- Tumor molecular characteristics including but not limited to transcriptomic (RNA) signatures of efficacy. Gene alterations studied may include but are not limited to TGF-β. Somatic DNA mutations, and expression of proteins associating with sensitivity and resistance may also be assessed.
- Levels of circulating proteins including but not limited to angiogenesis and HCC biology.
- Observed maximum serum concentration (Cmax) and serum trough concentrations (Ctrough).
- Human Anti-Human Antibodies (HAHA).
- Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire (FACT-Hep). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From 1st randomization to about 18 months:
- TTP
- ORR
- DR
- DCR at 12 weeks
- Change From Baseline in Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire (FACT-Hep)
From 1st randomization to about 30 months:
- PFS
- Cmax
- Ctrough of PF-03446962
- Ratio to baseline of serum circulating protein concentration Protein involved would be TGFB1, VEGF-A, VEGF-C, PIGF, Endoglin, BMP-9, VEGFR1, VEGFR2, VEGFr3, Ang-2, VEGF-D, CD54, CD106, CCL2.
- Ratio to baseline of tumor mRNA transcript
Baseline: Observed serum concentration of circulating protein
Adverse Events: From Screening to End of Treatment/Withdrawal
For SAEs, from the time that the patient provides informed consent to 28 calendar days after the last administration of the investigational product |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Italy |
Japan |
Germany |
Hong Kong |
Korea, Republic of |
Spain |
Taiwan |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of Trial is defined as:
- (in a Member State of the EU), the time at which it is deemed that sufficient patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
- (in all other participating countries), at least 2 years after the randomization of the last patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |