Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Ph II Trial of Intermittent Versus Continuous Dosing of Dabrafenib/Trametinib Mutant Melanoma

Protocol: SWOG-S1320

Full Title

A Randomized, Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAFV600E/K Mutant Melanoma

Study Objective

PRIMARY OBJECTIVES:

I. To compare progression-free survival with intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma.

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the two dosing schedules.

II. To compare the frequency and severity of fever >= grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) 4.0 of the two dosing schedules.

III. To compare the response rate (complete and partial response, confirmed and unconfirmed), overall survival, and survival after progression between the two dosing schedules on step 2.

TERTIARY OBJECTIVES:

I. To evaluate whether acquired molecular events leading to reactivation of the MAPK pathway are more common among patients on the continuous dosing arm than on the intermittent dosing arm using circulating tumor DNA (ctDNA).

II. To assess the prognostic association between baseline biomarkers and early molecular events with progression free survival (PFS).

III. To explore the potential interaction between treatment arm and baseline biomarkers/early molecular events with PFS.

IV. To bank tissue and whole blood in anticipation of future studies to evaluate molecular events associated with clinical benefit and disease progression in patients treated with continuous versus intermittent dabrafenib and trametinib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CONTINUOUS DOSING): Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.

ARM II (INTERMITTENT DOSING): Patients receive dabrafenib PO BID and trametinib PO QD on days 1-7 and 29-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years and then yearly for 2 years.

Are you eligible?

Inclusion Criteria:

Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma

Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to deoxyribonucleic acid (DNA) sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry

Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1)

Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor

Patients must not have brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration

Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration

Patients must not have received any major surgery or immunotherapy within 28 days prior to registration

Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration

Absolute neutrophil count (ANC) >= 1,200/ul

Platelets >= 100,000/ul

Hemoglobin >= 9 g/dL

Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert’s syndrome)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases)

Serum albumin >= 2.5 g/dL

Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration

Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information

Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration

Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett’s formula) within 28 days prior to registration

Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible:

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, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)

Visible retinal pathology as assessed by ophthalmic exam 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

NOTE: ophthalmic exam is required for all patients; exam must be obtained within 28 days prior to registration

Patients must be able to take oral medications; patients must not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of protocol treatment (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range

Patients must not have a history of pneumonitis or interstitial lung disease

Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration

Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load

Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria:

Cluster of differentiation (CD)4 cells >= 500/uL

Serum HIV viral load of < 25,000 IU/ml

No current antiretroviral therapy

  • Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection)

Prestudy history and physical must be obtained with 28 days prior to registration

Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist

Patients must have Zubrod performance status of 0 or 1

No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS) mutation are ineligible regardless of stage or time since diagnosis

Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed

Patients must be offered the opportunity to participate in specimen banking

Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine

Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

STEP 2: RANDOMIZATION

After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria

Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1)

Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment

Skin Cancers Melanoma