| 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 | 20.0 |
| 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 selected 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 |
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. Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2
(Appendix 1).
5. Must have advanced disease and no standard treatment options as determined by locally/regionally available standards of care and treating physician’s discretion.
6. Must have a BRAF V600E mutation-positive tumor as confirmed by an approved local laboratory or a sponsor designated central reference laboratory.
NOTE: All subjects must provide an archived or fresh tumor sample (for solid tumors) or a fresh BM aspirate and peripheral blood sample (for HCL and MM) for confirmation testing of the BRAF V600E mutation by a sponsor designated central reference laboratory using a sponsor designated assay
7. ATC, BTC, GIST, NSGCT/NGGCT, and ASI ONLY: Must have at least one
measurable lesion per RECIST 1.1 outside of a prior radiation field or within the field with evidence of progression.
8. Able to swallow and retain orally administered medication.
9. 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, throughout the treatment period and for 16 weeks following discontinuation of
trametinib when taken in combination with dabrafenib, or for 2 weeks
following discontinuation of dabrafenib monotherapy.
10. Has adequate baseline organ function as outlined in Table 3: (Protocol P 47)
11. 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 reference to Section 5.2.2.1 for Histology Specific Exclusion Criteria.
1. Prior treatment with:
•BRAF and/or MEK inhibitor(s)
• Chemotherapy, immunotherapy, biologic therapy or chemoradiation with delayed toxicity within 21 days (or within 42 days if prior therapy contains nitrosourea or mitomycin C) prior to enrolment
• Chemotherapy or biologic therapy without evidence of delayed toxicity
•Investigational product(s) IP within 30 days or 5 half-lives, whichever is longer, prior to enrolment
- Subjects enrolled in France: Subject has participated in any study using an investigational product (IP) within 30 days prior to enrollment in this study.
2. History of malignancy with confirmed activating RAS mutation at any time.
3. Prior radiotherapy less than 14 days prior to enrolment, except for WHO Grade 1-4 glioma and ATC. Treatment-related
AE´s must have resolved prior to enrollment
For WHO Grades 1, 2, 3, or 4 Glioma ONLY: Radiotherapy is not permitted
within 3 months prior to enrollment (extended period of time of >3 months
needed to prevent subjects with pseudo-progression from radiotherapy from being enrolled in the study). Subjects may be ≥2 weeks from radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the primary radiation field. Treatment-related AEs must have resolved prior to enrolment.
For ATC Only: Radiotherapy is not permitted within 7 days prior to enrollment.
Treatment-related toxicity must have resolved prior to enrollment.
4.Prior major surgery less than 14 days prior to enrolment. Any surgery-related AE(s) must have resolved prior to enrolment.
5. Prior solid organ transplantation or allogenic stem cell transplantation (ASCT)
6. History of another malignancy
7. Presence of:
•Brain metastases (except for subjects in the WHO Grade 1 or 2 Glioma or
WHO Grade 3 or 4 Glioma histology cohorts) that are symptomatic or
untreated or not stable for ≥3 months (must be documented by imaging) or
requiring corticosteroids. Subjects on a stable dose of corticosteroids >14 days and have not required treatment with enzyme-inducing anticonvulsants for >30 days prior to enrollment can be enrolled with
approval of the Medical Monitor.
•symptomatic or untreated leptomeningeal or spinal cord compression
•Interstitial lung disease or pneumonitis
•Any unresolved ≥Grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) toxicity from previous anti-cancer therapy at the time of enrollment, except alopecia or Grade 2 anemia
NOTE: Subjects with MM who have ≤Grade 2 peripheral neuropathy (per CTCAE v4.0) are permitted.
•Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject’s safety. obtaining informed consent or compliance to the study procedures
8. History of retinal vein occlusion (RVO)
9. Clinically significant 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).
10. 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
•Abnormal cardiac valve morphology (≥Grade 2) documented by ECHO
•Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) ≥480 msec
•Intracardiac defibrillator
•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
Subjects enrolled in Germany: Subjects with a left bundle branch block (LBBB) are NOT eligible for inclusion in this study.
11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result within 3 months prior to first dose of study treatment.
12.Current use of prohibited medication(s) or requirement of prohibited medications during study (see Section 10.2).
13. Clinically significant known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients, or to dimethyl sulfoxide (structural component of dabrafenib)
14. Female subjects: Pregnant, lactating or actively breastfeeding
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Tumor response as defined by: RECIST, V 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 thereafter.
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. 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. 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 | 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Korea, Democratic People's Republic of |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Sweden |
|
| 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 at a date that would represent a minimum follow up of approximately 2 years for all subjects enrolled. |
|
| 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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