Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers

This was a Phase II, open-label, non-randomized, multi-center study of oral dabrafenib in combination with oral trametinib in subjects with rare cancers harboring the BRAF V600E mutation including anaplastic thyroid cancer (ATC), biliary tract cancer (BTC), gastrointestinal stromal tumor (GIST), low grade (WHO G1/G2) glioma (LGG), high grade (WHO G3/G4) glioma (HGG), non-seminomatous germ cell tumors (NSGCT) / non-germinomatous germ cell tumors (NGGCT), adenocarcinoma of the small intestine (ASI), hairy cell leukemia (HCL) and multiple myeloma (MM).

This study was designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects needed to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. Only subjects with histologically confirmed advanced disease and no available standard treatment options were eligible for enrollment. Subjects underwent screening assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease assessments) prior to the start of treatment to determine their eligibility for enrollment in the study. All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, withdrawal of consent or death. Once a subject discontinued treatment, a post-treatment follow-up visit was conducted within 28 days (+ 7 days) after the last dose of study treatment(s). Extended follow-up visits were conducted every 4 weeks (+/- 7 days) for the first 6 months and then every 3 months (+/- 14 days) thereafter. A subject was considered to have discontinued the study if the subject was lost to follow-up or withdrew consent or another reason existed that prevented additional data from being collected on the subject. A subject was considered to have completed the study at the time of death.

For each histology, up to 25 patients were planned to be enrolled in each of the 9 primary analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy. All planned histology cohorts enrolled at least one subject, with the exception of the germ cell tumor cohort. Enrolment in the study was closed in July 2018.

Eligibility Criteria:
Inclusion Criteria:

* Signed, written informed consent.
* Sex: male or female.
* Age: \>=18 years of age at the time of providing informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2.
* Must have advanced disease and no standard treatment options as determined by locally/regionally available standards of care and treating physician's discretion
* Must have a a BRAF V600E mutation-positive tumor as confirmed by an approved local laboratory or a sponsor designated central reference laboratory. 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
* 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.
* 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 4 months after the last dose of study treatment.
* 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

Exclusion Criteria:

* 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 prior nitrosourea or mitomycin C containing therapy within 42 days prior to enrollment and/or prior daily or weekly chemotherapy or biologic therapy without the potential for delayed toxicity within 14 days prior to enrolment or prior nvestigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to enrollment
* History of malignancy with confirmed activating RAS mutation at any time. Prospective RAS testing is not required. However, if the results of previous RAS testing are known, then those results must be used in assessing eligibility.
* Prior radiotherapy less than 14 days prior to enrollment, except for WHO Grade 1 4 glioma (radiotherapy is not permitted within 3 months prior to enrollment) and ATC (radiotherapy is not permitted within 7 days prior to enrollment). Treatment-related AEs must have resolved prior to enrollment.
* Prior major surgery less than 14 days prior to enrollment. Any surgery-related AE(s) must have resolved prior to enrollment
* Prior solid organ transplantation or allogenic stem cell transplantation (ASCT). However, previous autologous BM transplant (ABMT) or autologous peripheral blood stem cell transplant (PBSCT) is permitted.
* History of another malignancy. Subjects with another malignancy are eligible if: (a) disease-free for 3 years, or (b) have a history of completely resected non-melanoma skin cancer, and/or (c) have an indolent second malignancy(ies).
* Presence of brain metastases (except for subjects in the WHO Grade 1 or 2 or 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
* Presence of symptomatic or untreated leptomeningeal or spinal cord compression. Subjects who have been previously treated for these conditions and have stable CNS disease (documented by consecutive imaging studies) for \>60 days, are asymptomatic and currently not taking corticosteroids, or have been on a stable dose of corticosteroids for at least 30 days prior to enrollment, are permitted
* Presence of interstitial lung disease or pneumonitis
* Presence of 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. Subjects with MM who have ≤Grade 2 peripheral neuropathy (per CTCAE v4.0) are permitted.
* Presence of 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
* History of retinal vein occlusion
* 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)
* 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 enrolment; clinically significant uncontrolled arrhythmias; however, subjects with controlled atrial fibrillation for \>30 days prior to enrollment are eligible; class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) criteria; left ventricular ejection fraction (LVEF) below the institutional LLN. If a LLN does not exist at an institution, then use LVEF \<50%; abnormal cardiac valve morphology (≥Grade 2) documented by ECHO; however, subjects with Grade 1 abnormalities (i.e., mild regurgitation/stenosis) may be entered on study but subjects with moderate valvular thickening should NOT be enrolled; 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
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result within 3 months prior to first dose of study treatment. Subjects with positive Hepatitis C antibody due to prior exposure can be enrolled, only if a confirmatory negative Hepatitis C RNA polymerase chain reaction (PCR) test is obtained.
* Current use of prohibited medication(s) or requirement for prohibited medications during study as per the study protocol. Use of anticoagulants such as warfarin is permitted; however, international normalization ratio (INR) must be monitored according to local institutional practice.
* 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).
* Pregnant, lactating or actively breastfeeding female subjects