| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073251 |
| E.1.2 | Term | Clear cell renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell 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 |
Part 1 of the study: To determine the safety, tolerability, maximum tolerated regimen (MTR), and recommended Phase II dose (RP2D) of pazopanib in combination with MK-3475 in treatment naïve patients with advanced RCC.
Part 2 of the study: To evaluate the clinical efficacy of pazopanib in
combination with MK-3475 as compared to single agent pazopanib and to single-agent MK-3475 in treatment naïve patients with advanced RCC as assessed by PFS. |
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| E.2.2 | Secondary objectives of the trial |
Part 1 of the study:
1. To evaluate the PK of pazopanib and MK-3475 administered in combination.
2.To evaluate the clinical activity of the combination treatment of pazopanib + MK-3475.
Part 2 of the study:
1. To evaluate the clinical efficacy of pazopanib in combination with MK-3475 and compare to single agent pazopanib and to single-agent MK-3475 as assessed by ORR, clinical benefit, time to response, duration of response, PFS assessed by Modified RECIST; PFSR18, and OS.
2. To evaluate the safety and tolerability of pazopanib in combination with MK-3475, and compare to singleagent pazopanib and to single-agent MK-3475. To determine the systemic exposure of pazopanib when administered alone and in combination with MK-3475 and to determine the population PK parameters of MK-3475 when administered alone and in combination with pazopanib.
See protocol for the Exploratory Objectives associated with both parts of the study. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent before performance of study-specific procedures or assessments and must be willing to comply with treatment and follow-up.
Informed consent may be obtained before the start of the specified screening
window. Procedures conducted as part of the patients routine clinical management (e.g blood count, imaging study such as bone scan) and obtained before signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
2. Diagnosis of locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to AJCC staging) that is predominantly clear cell histology. Cytology cannot be the only pathologic criteria to confirm clear cell RCC.
3. Must have measurable disease, i.e. presenting with at least one measurable lesion. A measurable lesion is defined for target lesions as equal to or greater than 10mm in one dimension by computerized tomography ([CT] or magnetic resonance imaging [MRI]) scan with scan thickness being no greater than 5mm. For lymph nodes to be considered pathologically enlarged and measurable by CT scan, the short-axis line-length must be equal to or greater than 15mm and scan thickness no greater than 5mm.
4. Patient has received no prior systemic therapy.
5. Male or female ≥18 years of age or legal age of consent if greater than 18 years.
6. A woman is eligible to participate in the study if she is of:
6a. Non-childbearing potential, including any female who; Has had a hysterectomy,Has had a bilateral oophorectomy (ovariectomy), Has had a bilateral tubal ligation, Is post-menopausal (total cessation of menses for ≥1 year).
6b. Childbearing potential, has a negative serum beta-human chorionic gonadotropin(beta-HCG) pregnancy test within 7 days of the first dose of study treatment, not lactating, and agrees to use adequate contraception during the study until at least 120
days after the last dose of investigational product. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows; An intrauterine device with a documented failure rate of less than 1% per year, Vasectomized partner who is sterile before the female patients entry and is the sole sexual partner for that female. Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the clinical trial, and for at least 120 days after the last dose of investigational product; Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).
Oral contraceptives are not reliable due to the potential for drug-drug interactions.
Lactating females who discontinue nursing before the first dose of study treatment and agree to refrain from nursing throughout the treatment period and for 120 days following the last dose of study treatment are eligible.
7. ECOG PS 0 or 1
8. Adequate organ:
Absolute neutrophil count (ANC) equal to greater than 1.5 X 109/L
Hemoglobina equal to greater than 9 g/dL
Platelets equal to greater than 100 X 109/L
International normalized ratio (INR) equal to less than 1.2 X ULN
Activated partial thromboplastin time (aPTT) equal to less than 1.2 X ULN
Total bilirubin equal to less than 1.5 X ULN
AST and ALT equal to less than 2.5 X ULN
Part 1 cohort C- AST and ALT equal or less that 1.5 X ULN
Calculated CLcrd equal to greater than 40 mL/min
Urine Protein to Creatinine Ratio (UPC) <1
Total serum calcium concentrationf <12.0 mg/dL
9. Left ventricular ejection fraction (LVEF) equal to or greater than lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan. The same modality used at baseline must be applied for subsequent evaluations.
10. French subjects: In France, a patient will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
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| E.4 | Principal exclusion criteria |
1. Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require use of bronchodilators or local steroid injections may not be excluded from the study if agreed by the investigator and GSK medical monitor. Patients with hypothyroidism stable on hormone replacement will not be
excluded from the study.
2. Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study treatment.
3. Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
4. Patient is on any systemic steroid therapy, within one week before the planned date for first dose of study treatment. Patient is on any other form of immunosuppressive medication.
5. Patient has a history of a malignancy (other than the disease under treatment in the study) within 5 years before first study treatment administration. Shorter intervals can be considered after discussion with sponsor.
6. Central nervous system metastasis.
Note: A baseline brain CT or MRI scan must be obtained in all subjects within 4 weeks of the first dose of study treatment.
7. Unable to swallow and retain orally administered medication. Malabsorption syndrome or disease that significantly affects GI function, or major resection of the stomach or small bowel that could affect the absorption of pazopanib.
8. Patient has interstitial lung disease or a history of pneumonitis.
9. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other GI conditions with increased risk of perforation; history of abdominal fistula, GI perforation, or intra-abdominal abscess within 4 weeks before beginning study treatment.
10. Known history of human immunodeficiency virus (HIV) infection or a known history of or is positive for Hepatitis B (Hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (HCV RNA [qualitative] is detected).
11. Presence of active infection requiring systemic therapy.
12. QTc prolongation defined as QTc interval > 480 msecs.
13. History of any one or more of the following cardiac conditions within the past 6 months:
a. Cardiac angioplasty or stenting b. Myocardial infarction c. Unstable angina d. History of Class III or IV congestive heart failure according to New York Heart Association (NYHA) classification (see Appendix 4).
14. History of cerebrovascular accident within the past 6 months.
15. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of equal to or greater than 140 mmHg, or diastolic blood pressure (DBP) of equal to or greater than 90 mmHg].
16. History of untreated deep venous thrombosis (DVT) (e.g. a calf vein thrombosis that is not treated or pulmonary embolism within the past 6 months).
17. Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease.
18. Evidence of bleeding diathesis or coagulopathy.
19. Recent hemoptysis (½ teaspoon of red blood within 8 weeks before first dose of study treatment).
20. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage, for example:
Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions i the segmented bronchi are allowed.
Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of the bronchi are allowed.
Lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, tumor touching but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions).
21. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions
that could interfere with patient’s safety, obtaining informed consent or compliance
to the study procedures.
22. Previous severe hypersensitivity reaction to another mAb. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the excipients in pazopanib tablets (see pazopanib IB).
23. Has taken any prohibited medications that are listed in Section 5.8.2 within 14 days of the first dose of study treatment. Patient has received or will receive a live vaccine within 30 days before the first administration of study treatment.
Note: Seasonal flu vaccines that do not contain live virus are permitted. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For Part 1 of the Study:
1. Incidence and severity of AEs and SAEs
2. DLT; MTR defined where no more than 1 out of 6 subjects
experiences a DLT.
3. Investigational product exposure, including permanent
discontinuation of treatment, dose reductions, interruptions, or
delays.
4. Changes from baseline in safety assessments (e.g., laboratory
parameters, vital signs, and cardiac parameters).
5. Immunogenicity: incidence and titer of anti-MK-3475 antibodies.
For Part 2 of the study:
1. PFS assessed by RECIST v1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Part 1 of the study: Safety, Tolerability, MTR and RP2D
1. AEs/SAEs are evaluated at each clinic visit
2. DLTs are drug-related AEs within the first 8 wks of study treatment
3. IP exposure / discontinuation, reductions, interuptions are evaluated at each clinic visit.
4. Changes from baseline in safety assessments are evaluated at each clinic visit.
5. Immunogenicity—the Anti-MK-3475 Antibody test—is evaluated at MK dose # 1, 4, 7, 13, 19, 25, 31, 37, 43, 49, then 30, 90 and 180 days post-last dose MK.
For Part 2 of the Study:
To evaluate the clinical efficacy: Every 12 weeks, however- If a subject has achieved a CR or PR in the previous radiologic assessment, a repeat scan should be performed as a part of the confirmation of response, within 4-6 weeks to confirm the response. |
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| E.5.2 | Secondary end point(s) |
For Part 1 of the study:
To evaluate the PK of pazopanib and MK-3475 administered in combination:
1. Dose-escalation cohorts: pazopanib plasma concentrations and
serum MK-3475 concentrations.
2. Expansion cohort: Pazopanib AUC(0-24), Cmax, tmax, and
concentration at 24 hours (C24); MK-3475 Cmax, Ct, and CL.
To evaluate the clinical activity of the combination:
1. ORR ; Clinical benefit (CR+PR+ stable disease [SD] equal to greater than 6 months)
2. Time to response (RECIST v1.1); Duration of response; PFS
rate at 18 months (PFSR18).
Note: unless otherwise specified all response endpoints
assessed by RECIST v1.1 and by Modified RECIST.
For Part 2 of the study:
To evaluate the clinical efficacy:
1. ORR; Clinical benefit (CR+PR+SD equal to greater than 6 months).
2. Time to response (RECIST v1.1); Duration of response.
3. PFS by Modified RECIST; PFSR18; OS at 18months; OS.
Note: unless otherwise specified all response endpoints assessed by RECIST v1.1 and Modified RECIST.
To evaluate the safety and tolerability of pazopanib in combination with MK-3475, and compare to single agent pazopanib and to single-agent MK-3475:
1. Incidence and severity of AEs and SAEs
2.Investigational product exposure, including permanent discontinuation of treatment, dose reductions, interruptions, or delays
3. Changes from baseline in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters).
4. Immunogenicity: incidence and titer of anti-MK-3475 antibodies for pazopanib + MK-3475 and single-agent MK-3475.
To determine the systemic exposure:
1. Pazopanib AUC(0-24), Cmax, tmax, and C24 and MK-3475 Cmax, Ct, CL and V.
See the protocol for the endpoints associated with the exploratory objectives concerning both parts of the study. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For Part 1 of the study:
To evaluate the PK of pazopanib and MK-3475 administered in combination: Please refer to Tables 43, 44, and 45 in the protocol.
To evaluate clincial activity: See E.5.1.1 of the CTA form
For Part 2 of the study:
To evaluate clincial efficacy: See E.5.1.1 of the CTA form
To evaluate safety and tolerability: See E.5.1.1 of the CTA form
To determine the systemic exposure: Please refer to Tables 43, 44, and 45 in the protocol. |
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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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First adminstration of the pazopanib & MK-3475 combination in humans |
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| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| An open-label, 2-part multi-center study of pazopanib and/or MK-3475. |
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| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 10 |
| 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 |
| Canada |
| France |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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