This phase I trial studies the side effects and best dose of onalespib when given together with dabrafenib and trametinib in treating patients with BRAF-mutant melanoma or solid tumors that have spread to another place in the body (metastatic) or cannot be removed by surgery. Onalespib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of onalespib (AT13387) given weekly in combination with dabrafenib and trametinib in patients with BRAF-mutant metastatic or unresectable solid tumors. SECONDARY OBJECTIVES: I. To obtain preliminary estimates of the objective response rate (ORR) and progression-free survival (PFS) and document the 6-month PFS and 1-year overall survival (OS) of patients with BRAF-mutant metastatic or unresectable melanoma treated with AT13387 given weekly in combination with dabrafenib and trametinib. II. To describe the pharmacokinetics of treatment with dabrafenib, trametinib, and AT13387. OUTLINE: This is a dose-escalation study of onalespib. Four dose levels, plus a fallback dose, are specified in the protocol and are summarized below. The trial is based on a standard 3+3 design with dose escalation beginning in dose level 1 (DL1). In a 3+3 design," three patients are initially enrolled into a given dose cohort. If there is no dose limiting toxicity (DLT) observed in any of these subjects, the trial proceeds to enroll additional subjects into the next higher dose cohort. If one subject develops a DLT at a specific dose, an additional three subjects are enrolled into that same dose cohort. Development of DLTs in more than 1 of 6 subjects in a specific dose cohort suggests that the maximum total dose (MTD) has been exceeded, and further dose escalation is not pursued. Fallback dose level -1 is initiated if more than 1 of 6 subjects in dose level 1 (starting dose) develop DLTs. Patients receive dabrafenib orally (PO) twice daily (BID), trametinib PO once daily (QD) on days 1-28, and onalespib intravenously (IV) over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dose Level -1 (fallback dose): * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m\^2 Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m\^2 Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m\^2 Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m\^2 Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m\^2 After completion of study treatment, patients are followed up at 28 days and every 6 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Given PO
Correlative studies
Given IV
Correlative studies
Given PO
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Maximum Tolerated Dose of Dabrafenib
Maximum tolerated dose is defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity (DLT) within 28 days after start of treatment. Toxicities will be graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. Participant enrollment occurred from July 2015 to June 2018, spanning Dose Levels 1-4. * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2
Time frame: 28 days after start of treatment
Maximum Tolerated Dose of Trametinib
Maximum tolerated dose is defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity (DLT) within 28 days after start of treatment. Toxicities will be graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. Participant enrollment occurred from July 2015 to June 2018, spanning Dose Levels 1-4. * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2
Time frame: 28 days after start of treatment
Maximum Tolerated Dose of Onalespib
Maximum tolerated dose is defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity (DLT) within 28 days after start of treatment. Toxicities will be graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. Participant enrollment occurred from July 2015 to June 2018, spanning Dose Levels 1-4. * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2
Time frame: 28 days after start of treatment
Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose
Dose limiting toxicities (DLTs) are at least possibly related to study treatment and graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0: * any grade 4 toxicity * grade 3 (or grade 2 intolerable) non-hematologic toxicity (including fatigue lasting \>1 week or that requires hospitalization) * grade 3 or higher hematologic toxicity with complications (e.g., thrombocytopenia with bleeding, neutropenia with fever) * toxicity that lead to missing a dose of onalespib or \>25% of dabrafenib/trametinib in the first cycle The following grade 3 toxicities are not considered DLTs: * cutaneous squamous cell carcinoma or keratoacanthoma * nausea, vomiting, or diarrhea persisting \</= 72 hours with maximum supportive care * electrolyte events that resolve with replacement within 24 hours * any grade lymphopenia * lab abnormalities that return to baseline within 7 days: elevated bilirubin, AST, ALT, cholesterol, amylase, lipase, creatinine, hypertriglyceridemia
Time frame: 28 days after start of treatment (1 cycle)
Objective Response Rate
Objective response rate is defined as the number of participants with complete response or partial response as their best response to therapy assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. * Complete response (CR) = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial response (PR) = At least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: up to 9 months
Progression-free Survival
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, or death, whichever occurs first. Progressive disease (PD) = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum of diameters. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.
Time frame: up to 9 months
Progression-free Survival at 6 Months
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, or death, whichever occurs first. PFS at 6 months will report the number of participants without progression at 6 months after starting treatment. Progressive disease (PD) = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum of diameters. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.
Time frame: 6 months
Overall Survival at 1 Year
Overall survival (OS) is defined as the time from start of treatment to death from any cause. OS at 1 year will report the number of participants alive at 1 year after starting treatment.
Time frame: 1 year
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