| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Mutations of BRAF V600E have been identified at a high frequency in melanoma, PTC, colorectal and ovarian cancers. Such mutations have also been reported in some rare cancers such as
anaplastic thyroid cancer, hairy cell leukemia, gastrointestinal stromal tumors, non-seminomatous/non-geminomatous germ cell tumors, biliary tract cancer, multiple myeloma, adenocarcinoma of the small intestine, World Health Organization Grade 1 and 2 gliomas and WHO Grade 3 and 4 gliomas. |
|
| E.1.1.1 | Medical condition in easily understood language |
Anaplastic Thyroid Cancer
Biliary Tract Cancer
Gastrointestinal Cancer
Germ Cell Tumors
Brain Tumors (Gliomas)
Cancer of the Small Intestine
Hairy Cell Leukemia
Multiple Myeloma
|
|
| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the ORR of dabrafenib and trametinib anti-cancer
combination therapy in subjects with rare BRAF V600E mutated
solid tumors or hematologic malignancies. |
|
| E.2.2 | Secondary objectives of the trial |
-To determine the duration of response of dabrafenib in
combination with trametinib in subjects with selected rare
BRAF-mutated cancers.
-To determine PFS of dabrafenib in combination with trametinib
in subjects with selected rare BRAF-mutated cancers.
-To determine OS of dabrafenib in combination with trametinib in
subjects with selected rare BRAF-mutated cancers
-To determine the safety of dabrafenib in combination with
trametinib in subjects with selected rare BRAF-mutated tumors. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
ALL subjects must meet
Please refer to section 8 of the Protocol 01 for cohort specific criteria.
all of the following inclusion criteria in order to be considered eligible for this study:
1. Signed, written informed consent
2. Sex: male or female
3. Age: > or = to 18 years of age at the time of providing informed consent
4. ECOG performance status: 0, 1 or 2
5. Subject must have histologically or cytologically confirmed advanced disease (as stated in the histology-specific inclusion/exclusion criteria [see Section 8]) and no available standard treatment options as determined by locally/regionally available standards of care.
6. BRAF V600E mutation-positive tumor:
a. Local testing: Local BRAF mutation test results obtained by an approved local laboratory may be used to permit enrollment of subjects with positive results. Local BRAF mutation test results will be subject to central verification.
b. Central testing: Local BRAF mutation test results will be confirmed by central testing in an approved, designated central reference laboratory by the THxID BRAF assay or an alternate GSK designated assay.
NOTE: For central testing, FFPE core bone marrow (BM) biopsies are not acceptable from subjects in the MM cohort.
7. Able to swallow and retain orally administered medication.
NOTE: Subject should not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. For example, subjects should have no more than 50% of the large intestine removed and no sign of malabsorption (i.e., diarrhea).
NOTE: If clarification is needed as to whether a condition will significantly affect the absorption of study treatments, contact the GSK Medical Monitor.
8. Female Subjects of Childbearing Potential: Subjects must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agrees to use effective contraception, as defined in Section 10.1, throughout the treatment period and for 4 months after the last dose of study treatment.
9. 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.
|
|
| E.4 | Principal exclusion criteria |
Please refer to section 8 of Protocol 01 for cohort specific criteria.
ANY subject who meets any of the following criteria is excluded from enrollment in this study:
1. Prior treatment with:
•BRAF and/or MEK inhibitor(s)
•Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, immunotherapy, biologic therapy or chemoradiation) within 21 days (or within 42 days if prior nitrosourea or mitomycin C containing therapy) prior to enrolment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment
•Investigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to enrolment
2. Previous major surgery within 21 days prior to enrollment
3. Prior extensive radiotherapy treatment within 21 days prior to enrollment
4. Prior solid organ transplantation or allogenic stem cell transplantation (ASCT)
5. History of:
•Interstitial lung disease or pneumonitis
•Another malignancy
6. Presence of:
•cerebral metastases (except for subjects in the WHO Grade 1 or 2 Glioma or WHO Grade 3 or 4 Glioma histology cohorts; see histology-specific eligibility criteria)
•symptomatic or untreated leptomeningeal or spinal cord compression
•pre-existing >or= to Grade 2 peripheral neuropathy
•unresolved treatment-related toxicity of >or= to Grade 2 (except alopecia) or toxicities listed in the general and histology-specific adequate organ function tables at the time of enrolment
•Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures
7. History or current evidence/risk of RVO or CSR:
•History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension or diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
•Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as:
•Evidence of new optic disc cupping
•Evidence of new visual field defects
•Intraocular pressure >21 mmHg
8. History or evidence of cardiovascular risk including any of the following:
•Acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment
•Clinically significant uncontrolled arrhythmias
•Class II or higher congestive heart failure as defined by the NYHA criteria (Appendix 2)
•Left ventricular ejection fraction (LVEF) below the institutional LLN
•Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) >or+ to 480 msec
•Intracardiac defibrillator and/or permanent pacemaker
•Treatment-refractory hypertension defined as a blood pressure (BP) >140/90 mmHg which may not be controlled by anti-hypertensive medication(s) and/or lifestyle modifications
•Known cardiac metastases
9. Current use of prohibited medication(s) or requirement of prohibited medications during study (see Section 11.2).
10. Positive for:
•Hepatitis B surface antigen or Hepatitis C antibody
•Human immunodeficiency virus (HIV); testing not required
11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients, or to dimethyl sulfoxide and/or sulfonamides (structural component of dabrafenib)
12. Female subjects: Pregnant, lactating or actively breastfeeding
13. Subjects enrolled in France: The French subject has participated in any study using an investigational product (IP) within 30 days prior to enrolment in this study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Tumor response as defined by: RECIST, version 1.1 for solid tumor histologies, Modified RANO and RANO for glioma or established response criteria for specific hematologic malignancies |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Solid tumors – every 8 weeks until week 48 , then every 12 weeks until week 104, then institutional standard of care.
Hematologic – HCL once blood counts are consistent with a complete response after 4 weeks, both a bone marrow biopsy and aspirate will be performed. If these tests are negative, a bone marrow biopsy and bone marrow aspirate will be performed every 6 months for 1 year, once a year for 2 years and then once every 2 years and at the time of relapse.
MM - at Week 8, at the time of achieving a complete response or best response, and at the time of disease progression. |
|
| E.5.2 | Secondary end point(s) |
-Duration of response
-Investigator-assessed PFS
-OS
-Change from baseline in physical examination findings, vital signs, AEs, laboratory values and cardiac assessments |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Duration of response - Solid– q 8 wks - wk 48, q 12 wks - wk 104, then institutional SoC.
Hematologic–HCL once counts are consistent with CR after 4 wks, both a BM biopsy and aspirate. If negative, a BM biopsy and aspirate q 6 mths for 1 yr, q yr for 2 yrs, q 2 yrs and relapse
MM-at Wk 8, at time of CR or best response, at PD
•Investigator-assessed PFS - Solid tumors - q 8 wks - wk 48, q 12 wks - wk 104, then institutional SoC
Hematologic – HCL once counts are consistent with CR after 4 wks, both a BM biopsy and aspirate. If negative a BM biopsy and aspirate q 6 mths for 1 yr, q yr for 2 yrs, q 2 yrs and relapse.
MM - at Wk 8, time of CR or best response, at PD
•OS q 3 mths after withdrawal of drug
Change from baseline in PE, vital signs, AEs, labs and cardiac tests q 4 wks
|
|
| 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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 9 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Italy |
| Austria |
| Netherlands |
| Norway |
| Sweden |
| Germany |
| Korea, Democratic People's Republic of |
| United States |
|
| 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
|
The study will be considered complete when 70% of enrolled subjects across all histology-specific cohorts have died. Subjects who are still benefiting from study treatment at the time of study completion or closure of the study may have the option to
enter a rollover study if available at the time of study completion. If subjects are transitioned to a rollover study, only safety will be followed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| 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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