| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| METASTATIC RENAL CELL CARCINOMA |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038407 |
| E.1.2 | Term | Renal cell cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Part I: To confirm that the combination of PF-04856884 and AG-013736 is safe and tolerable at the doses to be used in Part II of the study.
Part II: To document clinical activity of the combination of PF-04856884 and AG-013736 or AG-013736 alone as measured by PFS in adult patients with previously treated mRCC.
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of the combination of PF-04856884 and AG-013736 and of AG-013736 alone.
• To document clinical activity as measured by overall response rate (ORR) and duration of response of the combination of PF-04856884 and AG-013736 and of AG-013736 alone in patients with mRCC.
• To assess the pharmacokinetics (PK) of PF-04856884 and of AG-013736.
• To evaluate immunogenicity in patients treated with PF-04856884.
• To assess pharmacodynamic (PD) effects of the combination of PF-04856884 and AG-013736 and of AG-013736 alone as measured by Ang 1, Ang 2 and VEGF A levels.
• Part II: To document clinical activity of the combination of PF-04856884 and AG-013736 or AG-013736 alone as measured by PFS based on an independent radiological assessment.
• Part II: To determine overall survival (OS) at two years in patients receiving PF-04856884 in combination with AG-013736 and AG-013736 alone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
• Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
• Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Histologically or cytologically confirmed renal cell cancer (RCC) with a component of clear cell subtype and evidence of metastasis.
2. Evidence of unidimensionally measurable disease (ie, ≥ malignant tumor mass that can be accurately measured in at least 1 dimension ≥20 mm with conventional computerized tomography [CT] scan or magnetic resonance imaging [MRI], or ≥10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm).
3. Prior therapy:
• Part I: Having received 1-3 prior systemic regimens for treatment of mRCC.
• Part II: Evidence of disease progression following 1 prior regimen administered as 1st line therapy for mRCC. The prior regimen must have contained one of the following:
• VEGFR2 tyrosine kinase inhibitor (TKI) such as (but not limited to) pazopanib, sunitinib, tivozanib, or sorafenib.
• Other anti VEGF compounds, such as bevacizumab.
4. Adequate bone marrow as defined by the following criteria:
• Platelets ≥75,000 cells/mm3.
• Absolute neutrophil count (ANC) ≥1500 cells/mm3.
• Hemoglobin (Hb) ≥9.0 g/dL.
5. Adequate liver function as defined by the following criteria:
• Bilirubin ≤1.5 mg/dL.
• AST/ALT ≤2.5x upper limit of normal (ULN) or ≤5.0x ULN with documented liver metastases.
• Partial thromboplastin time (PTT) and Prothrombin time (PT) or International Normalized Ration (INR) ≤1.5x ULN.
6. Adequate renal function as defined by:
• Serum creatinine ≤1.5 mg/dL or calculated or measured creatinine clearance (CrCl) ≥50 cc/min using the following formula: Calculated Creatinine Clearance = (140 - age) x wt (kg) x 0.85 (if female) / 72 x serum creatinine (mg/dl).
7. Urinary dipstick <2+ protein. If ≥2+ protein on urine dipstick, then urine protein to creatinine ratio (UPCR) ratio ≤0.5 as characterized by spot urine sample.
8. ECOG performance status 0 or 1.
9. At least two weeks (prior to Day 1) since end of prior systemic treatment (four weeks for bevacizumab), radiotherapy, or surgical procedure for RCC with resolution of all treatment-related toxicity (except alopecia or hypothyroidism) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V. 4.0, Grade ≤1 or back to baseline.
10. Male or female, age ≥18 years.
11. Life expectancy ≥12 weeks.
12. Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to treatment.
13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures, including in Part II the completion of the patient-reported outcome (PRO) measures
|
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.
2. Prior therapy:
• Part I
• Intolerant to prior AG-013736 therapy.
• Prior treatment with compounds which contain the core platform antibody as PF-04856884. These include CVX-045, CVX-096, and CVX-241.
• Part II
• Prior AG-013736 therapy.
• More than one systemic first-line regimen for the treatment of mRCC.
• Prior treatment with compounds which contain the core platform antibody as PF-04856884. These include CVX-045, CVX-096, and CVX-241.
3. Major surgery <4 weeks or radiation therapy <2 weeks prior to start of therapy.
4. Clinically significant gastrointestinal abnormalities including any of the following:
• Inability to take oral medications.
• Requiring intravenous alimentation.
• Malabsorption syndromes.
• Requiring treatment of active ulcer disease in prior six months.
• Prior gastric resection.
• Active gastrointestinal bleeding, related or unrelated to cancer, as evidenced by either hematemesis, hematochezia, or melena in prior 3 months.
5. Current use or anticipated need for drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, ergot derivatives, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine) during the course of the study.
6. Current use or anticipated need for drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazapine, dexamethasone, felbamate, omeprazole, Phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John’s wort) during the course of the study.
7. Requirement for therapeutic anticoagulant therapy including daily aspirin (>325 mg/day) or non steroidal anti inflammatory agents known to inhibit platelet function. Low dose anti coagulants such as low dose heparin or 1-2 mg/day of warfarin for prevention of deep vein thrombosis or maintenance of patency of central venous devices is permitted.
8. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
• Patients with clinical evidence suggestive of new brain metastases are excluded if brain metastases have not been ruled out using CT or MRI imaging.
• Patients with previously diagnosed brain metastases are eligible if they have completed their radiation therapy to the central nervous system (CNS) and have recovered from the acute effects of that treatment prior to enrollment, have discontinued corticosteroid treatment for these metastases for at least 2 weeks, and are neurologically stable.
9. History of bleeding diathesis or coagulopathy.
10. NCI CTCAE Grade 3 or greater hemorrhage from any cause <4 weeks prior to screening.
11. Hemoptysis >½ teaspoon of blood per day within 2 weeks prior to screening.
12. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody or IgG fusion protein.
13. Any of the following in the preceding 12 months to receiving study drug: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack. Deep vein thrombosis or pulmonary embolism in the preceding six months to receiving study drug.
14. Evidence of pre-existing uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure must be ≤140 mm Hg, and baseline diastolic blood pressure must be ≤90 mm Hg. Patients whose hypertension is controlled by medications are eligible.
15. Known human immunodeficiency virus (HIV) seropositivity.
16. Female patients who are pregnant or lactating, or men or women of reproductive potential not willing or not able to employ effective method of birth control/contraception to prevent pregnancy during treatment and for six months after discontinuing study therapy.
17. Participation in other studies within 14 days prior to screening and/or during study participation.
18. Other severe acute or chronic medical or psychiatric condition 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 subject inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part I:The highest dose level at which first cycle dose limiting toxicities (DLTs) occur in <33% of patients.
Part II: Median progression free survival (PFS) based on investigator assessments.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I (Establish dose for Part II): February 2012
Part II (PFS): March 2014 |
|
| E.5.2 | Secondary end point(s) |
1. Incidence of adverse events (AE) and serious AE (SAE).
2. Objective response rate (ORR) and duration of response based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
3. Pharmacokinetics of PF-04856884 and AG-013736.
4. Immunogenicity based on the presence of anti drug antibody (ADA).
5. Levels of circulating Ang 1, Ang 2 and VEGF A.
6. Part II: Median progression free survival (PFS) based on an independent radiological assessment.
7. Part II: Two year overall survival rate (OS).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Safety and Tolerability: March 2014
2. Overall Response Rate: March 2014
3. Pharmacokinetics: March 2014
4. Immunogenicity: March 2014
5. Pharmacodynamics: March 2014
6. Part II/Progression Free Survival by independent review: March 2014
7. Part II/Overall Survival: March 2015 |
|
| 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 | No |
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Brazil |
| Canada |
| Croatia |
| Czech Republic |
| Germany |
| India |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Taiwan |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| End of Trial is defined as as the date that all patients have completed the follow-up period for overall survival. (As specified in the protocol.) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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 |
Print
