Clinical Trials /

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

NCT02034110

Description:

This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is 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 will need 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 will be eligible for enrollment. Subjects will undergo 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.

Related Conditions:
  • Cholangiocarcinoma
  • Gastrointestinal Stromal Tumor
  • Germ Cell Tumor
  • Glioma
  • Hairy Cell Leukemia
  • Multiple Myeloma
  • Small Intestinal Adenocarcinoma
  • Thyroid Gland Undifferentiated (Anaplastic) Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers
  • Official Title: A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib

Clinical Trial IDs

  • ORG STUDY ID: 117019
  • NCT ID: NCT02034110

Conditions

  • Cancer

Interventions

DrugSynonymsArms
DabrafenibDabrafenib + Trametinib
TrametinibDabrafenib + Trametinib

Purpose

This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is 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 will need 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 will be eligible for enrollment. Subjects will undergo 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.

Trial Arms

NameTypeDescriptionInterventions
Dabrafenib + TrametinibExperimentalSubjects will receive Dabrafenib 150 mg twice daily orally plus Trametinib 2 mg once daily orally on a continuous basis. Dabrafenib will be administered under fasted conditions, either 1 hour (hr) before or 2 hours (hrs) after a meal with approximately 200 mL of water with an interval of 12 hours. Trametinib will be administered under fasted conditions, either 1 hr before or 2 hrs after a meal with approximately 200 mL of water. Subjects will take their dose of Trametinib concurrently with the morning dose of Dabrafenib. A treatment cycle is 28 days in duration. Subjects will continue treatment until an unacceptable toxicity, disease progression, or death occurs.
  • Dabrafenib
  • Trametinib

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Possibly up to Week 208
Safety Issue:
Description:To determine the ORR as measured radiographically via Response Evaluation Criteria in Solid tumors (RECIST) version 1.1 for solid tumor histologies or established response criteria for specific hematologic malignancies.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:From the time of first documented evidence of CR or PR until the first documented sign of disease progression or death (approximately up to Week 208)
Safety Issue:
Description:Duration of response is defined as the subset of subjects who show a confirmed clinical response (CR) or partial response (PR), the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.
Measure:Investigator-assessed Progression-free survival (PFS)
Time Frame:Possibly up to Week 208
Safety Issue:
Description:PFS is defined as the time from the date of enrollment to the earliest date of progression or death.
Measure:Overall Survival (OS)
Time Frame:Until death or lost to follow-up (approximately up to Week 208)
Safety Issue:
Description:OS is defined as the time from the date of enrollment to the date of death due to any cause.
Measure:Change from baseline in physical examination findings
Time Frame:Possibly up to Week 208
Safety Issue:
Description:Examination will include assessments of the head and neck, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, extremities and genitalia. Height (measured only at Screening) and weight will be measured and recorded. Complete physical examinations will also include thorough rectal and genitourinary (pelvic) examinations to assess secondary malignancies.
Measure:Change from baseline in vital signs
Time Frame:Possibly up to Week 208
Safety Issue:
Description:Vital sign measurements will include systolic and diastolic blood pressure, temperature, pulse rate and respiratory rate
Measure:Number of subjects with Adverse events (AEs)
Time Frame:Possibly up to Week 208
Safety Issue:
Description:AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Measure:Change from baseline in laboratory values
Time Frame:Possibly up to Week 208
Safety Issue:
Description:Laboratory assessments include haematology, clinical chemistry, urinalysis, coagulation and histology-specific tests
Measure:Change from baseline in cardiac assessments
Time Frame:Possibly up to Week 208
Safety Issue:
Description:Cardiac assessments include Electrocardiogram (ECG) and Echocardiograms (ECHOs)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • solid tumors
  • efficacy
  • BRAF V600E mutation
  • trametinib
  • safety
  • Dabrafenib

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