| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Part I: Subjects with histologically or cytologically confirmed diagnosis of advanced solid tumours for which there is no standard therapy or for whom paclitaxel is standard therapy.
Part II: Stage IIIB wet (with histologically- or cytologically-confirmed malignant pleural effusion) or Stage IV NSCLC |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
|
| 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 |
Phase I: To assess the safety and tolerability and to determine the maximum tolerated regimen of pazopanib in combiantion with paclitaxel in subjects with previously untreated advanced solid tumours, including Stage IIIB wet (with histologically- or cytologically-confirmed malignant pleural effusion) or Stage IV NSCLC.
Phase II: To evaluate the efficacy of pazopanib in combination with paclitaxel in subjects with previously untreated Stage IIIB wet (with histologically- or cytologically-confirmed malignant pleural effusion) or Stage IV NSCLC, by assessment of PFS. A standard of care doublet (carboplatin and paclitaxel) will be used to provide reference data for comparison. |
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| E.2.2 | Secondary objectives of the trial |
Phase I: To determine the effect of pazopanib administered once daily on the PK of paclitaxel administered as a 3-hour intravenous (IV) infusion once every 3 weeks; To estimate the PK of pazopanib in the presence of paclitaxel administered as a 3-hour infusion; To assess the clinical activity of pazopanib in combination with paclitaxel.
Phase II: To estimate the effect of pazopanib in combination with paclitaxel on OS and best overall response rate; To evaluate the safety and tolerability of pazopanib in combiantin with paclitaxel in the treatment of subjects with advanced NSCLC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the IP that may impact subject eligibility is provided in the IB for pazopanib. For paclitaxel and carboplatin, please refer to the approved product labels.
Subjects eligible for enrollment in the study must meet all of the following criteria:
Must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up assessments. Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be used for screening or baseline purposes provided these procedures were conducted as specified in the protocol.
Age 18 years old or greater (or legal age of consent if greater than 18 years)
Histologically- or cytologically-confirmed diagnosis of Stage IIIBwet (with confirmed malignant pleural effusion) or Stage IV NSCLC. Phase I only: Additionally, subjects with histologically- or cytologically-confirmed diagnosis of advanced solid tumor for which there is no standard therapy or for whom paclitaxel is standard therapy may also be entered.
ECOG performance status of 0 or 1 (Appendix 3).
Life expectancy of at least 12 weeks.
Measurable disease as defined by RECIST criteria (Section 6.2.3) [Therasse, 2000]
No prior systemic first-line therapy for Stage IIIBwet/IV NSCLC either by chemotherapy or any other systemic treatment. Prior surgery and/or localised irradiation for NSCLC are permitted as long as it was a minimum of 4 weeks before entering the study. Subjects with recurrence after previous NSCLC that has been treated with surgery and adjuvant chemotherapy or a radio-chemotherapy regimen with curative intent are eligible, provided 1 year has passed since this treatment ended. Phase I only: No prior systemic first-line therapy for treatment of the advanced solid tumor.
Able to swallow and retain oral medication.
Adequate organ system function as defined in Table 3.
A female is eligible to enter and participate in this study if she is of:
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
A hysterectomy
A bilateral oophorectomy (ovariectomy)
A bilateral tubal ligation
Or who is post-menopausal
Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L). For most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be post-menopausal, she must use adequate contraception, as defined immediately below.
Childbearing potential, including any female who has had a negative serum pregnancy test within one week prior to the first dose of study treatment, preferably as close to the first dose as possible and agrees to use adequate contraception. GSK-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.
Vasectomised partner who is sterile prior to the female subject’s entry and is the sole sexual partner for that female.
Complete abstinence from sexual intercourse for 14 days before exposure to IP or reference product, through the dosing period and for at least 21 days after the last dose of IP or reference product.
Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).
Oral contraceptives.
Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
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|
| E.4 | Principal exclusion criteria |
Active malignancy or any malignancy in the 3 years prior to first dose of study drug other than NSCLC. Subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. Phase I only: subjects with advanced solid tumors are eligible for the study; only one active malignancy is permitted.
History or clinical evidence of CNS metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 1 week prior to first dose of study drug. Screening with CNS imaging (computerised tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.
Clinically significant gastrointestinal abnormalities including, but not limited to:
Malabsorption syndrome .
Major resection of the stomach or small bowel that could affect the absorption of study drug.
Active peptic ulcer disease.
Known intraluminal metastatic lesion/s with risk of bleeding.
Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation.
History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
Presence of uncontrolled infection.
Prolongation of heart-rate corrected QT interval (QTc) >480 msecs (using Bazett’s formula).
History of at least one of the following cardiovascular conditions within the past 6 months:
Cardiac angioplasty or stenting.
Myocardial infarction.
Unstable angina.
Symptomatic peripheral vascular disease.
Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA; Appendix 4).
Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥90 mmHg].
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study (See Section 6.3.3 for details on BP control and re-assessment prior to study enrollment).
8. History of cerebrovascular accident, including transient ischemic attack (TIA), PE, or untreated DVT within the past 6 months.
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
9. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer.
10. Evidence of active bleeding or bleeding diathesis.
11. Recent haemoptysis (½ teaspoon of red blood within 8 weeks before first dose of study drug).
12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels (Note: tumour abutting the vessels is acceptable, but contiguous tumour and vessels is not; CT with contrast is strongly recommended to evaluate such lesions).
13. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that would make the subject inappropriate for study participation including any serious condition that could interfere with subject’s safety, provision of informed consent, or compliance with study procedures.
14. Use of any prohibited medication within the timeframes listed in Section 5.11.
15. Prior use of an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
16. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity except alopecia.
17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib, paclitaxel, and/or carboplatin.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: Safety and tolerability endpoints will consist of the evaluation of AEs, exposure, withdrawals due to AEs, dose reductions or interruptions, and changes from baseline in vital signs, ECG, and clinical laboratory parameters. A regimen where no more than 1 out of 6 subjects experience DLT will define the MTR along with safety and tolerability, and PK results from the 6 additional subjects.
Phase II: The primary efficacy endpoint is PFS defined as the time between randomization and the first occurence of PD or death from any cause. Subjects who have neither progressed nor died will be censored for the primary analysis at the date of last adequate tumour assessment at the time of the cut-off for the final analysis. If a subject receives a different anti-cancer therapy without prior documentation of disease progression, the subject will be censored at the date of last adequate tumour assessment before starting the new anti-cancer therapy. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| dose-finding combination treatment |
|
| 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 | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | No |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
|
| 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 |
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