| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced non-small cell lung cancer and BRAF mutations |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 assess the overall response rate (ORR) in subjects with stage IV BRAF V600E mutant non-small cell lung cancer administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C) |
|
| E.2.2 | Secondary objectives of the trial |
• To assess progression-free survival (PFS), duration of response and overall survival (OS) in subjects with stage IV BRAF V600E mutant nonsmall cell lung cancer administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C)
• To further characterize the safety and tolerability of dabrafenib
when administered as a single agent and in combination with
trametinib to subjects with stage IV BRAF V600E mutant nonsmall
cell lung cancer
• To characterize the population pharmacokinetics and identify
important determinants of variability of dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study and previously enrolled subjects crossing over from monotherapy to combination therapy must meet all of the following criteria:
1. Signed written informed consent;
2. Histologically- or cytologically-confirmed diagnosis of NSCLC stage IV (according to AJCC Staging 7th Edition);
3. For Cohorts A and B, documented tumor progression (based on radiological imaging) after receiving at least one prior approved platinum-based chemotherapy regimen for advanced stage/metastatic NSCLC. An alternate chemotherapeutic agent/regimen is an acceptable substitute in the event that the subject was intolerant to, or ineligible to receive platinum based chemotherapy. Subjects enrolled in Cohort B cannot have more than 3 prior systemic treatments for advanced stage/metastatic NSCLC (neoadjuvant and adjuvant therapies are not counted in number of prior regimens and maintenance therapy is not counted as a separate regimen). Subjects in Cohort C will be required to have not received prior systemic anti-cancer therapies for metastatic disease (i.e., dabrafenib/trametinib will be 1st line treatment for metastatic disease);
4. Measurable disease according to RECIST v1.1 [Eisenhauer, 2009]. Refer to Section 7.2.3.1 for the definition of a measurable lesion;
5. Male or female ≥18 years of age;
6. Anticipated life expectancy of at least 3 months;
7. Presence of a BRAF V600E mutation in lung cancer tissue. Mutation must be locally confirmed in a CLIA-certified laboratory (or equivalent). An adequate amount of umor tissue (archived tumor tissue, or fresh biopsy if archived tissue is not available) must be available at the time of enrolment for central validation of BRAF mutation see Section 7.1.1 for testing details and requirements regarding central confirmation);
8. Able to swallow and retain oral medication;
9. Women of childbearing potential must have a negative serum pregnancy test within 14 days before the first dose of study treatment and agree to use effective contraception, as defined in Section 7.4, during the study;
NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with dabrafenib
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 [Oken, 1982];
11. Must have adequate baseline organ function as definedin Table 1:
Hematologica
ANC ≥ 1.5 × 109/L
Hemoglobin ≥ 9 g/dL
Platelet count ≥ 100 x 109/L
PT/INRb and PTT ≤ 1.5 x ULN
Hepatic
Total bilirubin ≤ 1.5 x ULN
AST and ALT ≤ 2.5 x ULN
Renal (at least one of the following):
Serum creatininec ≤ 1.5 mg/dL
Creatinine clearancec ≥ 50 mL/min
Cardiac
Left Ventricular Ejection fraction (LVEF)d ≥ LLN by ECHO
12. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
13. Previously tested for presence of EGFR and ALK mutations in lung cancer tissue confirmed in a CLIA-certified laboratory (or equivalent). Subjects with EGFR or ALK mutation are eligible if they have previously received EGFR or ALK inhibitor(s) respectively. |
|
| E.4 | Principal exclusion criteria |
Subjects eligible for enrolment in the study and previously enrolled subjects crossing over from monotherapy to combination therapy must not meet any of the following criteria:
1. Previous treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119) prior to start of study treatment
(Note: Prior treatment with dabrafenib is allowed for crossover subjects in Cohort A);
2. Anti-Cancer therapy including chemotherapy, radiation-therapy, immunotherapy, biologic therapy or major surgery within 14 days prior to start of study treatment (Note: Dabrafenib monotherapy within 14 days prior to starting combination therapy
is allowed for crossover subjects in Cohort A);
3. Use of any investigational anti-cancer drug within 14 days or 5-half-lives (minimum 14 days), prior to start of study medication (Note: Dabrafenib monotherapy within 14 days prior to starting combination therapy is allowed for crossover subjects in Cohort
A);
4. Current use of a prohibited medication or expected to require any of thesemedications during treatment with study treatment (See Section 6.2);
5. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia;
6. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GlaxoSmithKlne
(GSK) medical monitor for guidance to enrol the subject;
7. Known Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled;
8. History of another malignancy < 3 years prior to starting study treatment or any malignancy with confirmed activating RAS-mutation;
Exceptions: subjects with any of the following malignancies within 3 years (does not include malignancies with confirmed activating RAS-mutation) are eligible: (a) a history of completely resected skin cancer, (b) successfully treated in situ carcinoma,
(c) chronic lymphocytic lymphoma (CLL) in stable remission, or (d) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score ≤6, and prostate specific
antigen [PSA] < 10 ng/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible
9. Subjects with brain metastases are excluded if their brain metastases are:
• Symptomatic OR
• Treated (surgery, radiation therapy) but not clinically and radiographically stable 3 weeks after local therapy(as assessed by contrast enhanced magnetic resonance imaging [MRI] or computed tomography [CT]), OR
• Asymptomatic and untreated but >1 cm in the longest dimension
10. A history or evidence of cardiovascular risk including any of the following:
• Corrected QT (QTc) interval ≥480 msecs
• History of acute coronary syndromes (including myocardial infarction or unstable angina) within 6 months prior to first dose of study treatment
• Coronary angioplasty, or stenting within the past 24 weeks;
• A history or evidence of current Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) guidelines;
• Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy;
• Abnormal cardiac valve morphology (≥Grade 2) documented by echocardiogram (subjects with Grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study;
• Patients with intra-cardiac defibrillators
• A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to randomization are eligible.
11. Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, etc.), psychological, familial, sociological, or geographical conditions that interfere with the subject’s safety or obtaining informed consent or do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol;
12. Pregnant, or actively breastfeeding females.
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
Additional Exclusion Criteria for combination therapy (Cohorts B and C as well as subjects that crossover from monotherapy to combination therapy) please refer to page 34 of the protocol for further information |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
ORR, which is defined as the percentage of subjects with a
confirmed complete response (CR) or partial response (PR) by
investigator assessment as per RECIST v1.1 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Scans are every 6 weeks from Week 1-36, then every 12 weeks after Week 36. |
|
| E.5.2 | Secondary end point(s) |
• PFS defined as the interval between first dose and the
earliest date of disease progression or death due to any cause
• Duration of response, defined for the subset of subjects with
confirmed CR or PR, as the time from first documented evidence
of CR or PR until time of first documented disease progression or death due to any cause
• OS defined as the time from first dose until death due to any cause
• Measurements used to evaluate safety will include physical and
dermatological examinations, ophthalmic examination, vital
signs, 12-lead ECGs, ECHO, clinical laboratory tests, and AEs
• Dabrafenib and trametinib population pharmacokinetic
parameters such as apparent clearance (CL/F) and volume of
distribution (V/F), and relevant covariates which may influence
exposure (e.g. age, weight, or disease related covariates) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Scans are every 6 weeks from Week 1-36, then every 12 weeks after Week 36. |
|
| 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 | 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) | 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 | 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 | Yes |
| 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.8.2.4 | 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 | 30 |
| 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 |
| Germany |
| Italy |
| Korea, Republic of |
| Netherlands |
| Norway |
| Spain |
| Taiwan |
|
| 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
|
| The study will be considered completed when progression of disease has occurred in all patients Cohorts B and C, a minimum of 70% of subjects have died in each cohort, or 5 years have passed since the last subject’s first dose, whichever comes first. Subjects who are still benefiting from study treatment at the time of study completion may continue to receive study treatment by an alternate mechanism (such as roll-over study, commercial product or a post-trial patient effort). |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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