BRAF V600E Mutation Present, BRAF V600K Mutation Present, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage III Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Unresectable Solid Neoplasm
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGDabrafenib
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGOnalespib
Given IV
OTHERPharmacological Study
Correlative studies
DRUGTrametinib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed, BRAF-mutant (V600E/K) solid tumor (molecularly confirmed using Cobas assay or a comparable Food and Drug Administration \[FDA\]-approved assay) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy, and for which standard curative measures do not exist or are no longer effective * If test at Clinical Laboratory Improvement Act (CLIA)-certified laboratory (lab) used a non-FDA approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam * Prior therapy is allowed; patients may have received any number of prior lines of therapy, including treatment with a BRAF and/or MEK inhibitor * All prior anti-cancer treatment-related toxicities must be less than or equal to grade 1 according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute \[NCI\], 2017) at the time of enrollment; a notable exception are endocrinopathies caused by immune checkpoint inhibitors that are appropriately treated with medical management (e.g. hormone replacement therapy, anti-diabetic agents) * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Life expectancy of greater than 3 months * Leukocytes \>= 3,000/mcL * Absolute neutrophil count \>= 1,200/mcL * Hemoglobin \>= 9 g/dl (patients may be transfused to this level) * Platelets \>= 100,000/mcL * Total bilirubin \< 1.5 x institutional upper limit of normal OR \> 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal * Prothrombin time (PT) \< 1.3 x upper limit of normal (ULN) * International normalized ratio (INR) \< 1.3 x ULN * Partial thromboplastin time (PTT) \< 1.3 x ULN * Serum creatinine =\< 1.5 mg/dL OR creatinine clearance \>= 50 mL/min/1.73 m\^2 * Potassium \> 3 and \< 5.5 mEq/L * Magnesium \> 1.2 and \< 2.5 mEq * Left ventricular \>= institutional lower limit of normal (LLN) by echocardiogram (ECHO) ejection fraction * Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately * Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency * Ability to understand and the willingness to sign a written informed consent document * Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
Exclusion criteria
* Patients who received prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing will change to protocol determined dose levels on day 1 of cycle 1 * Patients must not have received prior HSP90 inhibitor therapy * Patients who are receiving any other investigational agents; patients who have taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization * Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy * Patients must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for \>= 4 weeks (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids \> 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for \> 4 weeks * History of known immediate or delayed hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to AT13387, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO) * Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements * Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the mother being treated with the study drugs * Patients known to be human immunodeficiency virus (HIV)-positive patients and on combination antiretroviral therapy are ineligible * History of another malignancy other than the study indication under this trial within 5 years of study enrollment; does not apply to subjects who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, in situ breast cancer, or other in situ cancers * Exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility * History of interstitial lung disease or pneumonitis * History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): * History of RVO or RPED, or predisposing factors to RVO or RPED (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 RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure \> 21 mm mercury (Hg) * History or evidence of cardiovascular risk including any of the following: * An average of the three most recent QT intervals corrected for heart rate using the Bazett's formula QTcB \>= 460 msec * History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for \> 30 days prior to randomization are eligible) * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization * History or evidence of current \>= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system * Treatment-refractory hypertension defined as a blood pressure of systolic \> 140 mmHg and/or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy * Abnormal cardiac valve morphology (\>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study); subjects with moderate valvular thickening should not be entered on study * Prior placement of an implantable defibrillator * History of or identification on screening imaging of intracardiac metastases * No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV); patients with chronic or cleared HBV infection and HCV infection are eligible * Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: * Other anti-cancer therapy while on study treatment; (note: megestrol \[Megace\] if used as an appetite stimulant is allowed) * Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis * The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra \[ma huang\], ginkgo biloba, dehydroepiandrosterone \[DHEA\], yohimbe, saw palmetto, or ginseng) * Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | 28 days after start of treatment (1 cycle) | 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 |
| Maximum Tolerated Dose of Dabrafenib | 28 days after start of treatment | 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 |
| Maximum Tolerated Dose of Trametinib | 28 days after start of treatment | 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 |
| Maximum Tolerated Dose of Onalespib | 28 days after start of treatment | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at 1 Year | 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. |
| Objective Response Rate | up to 9 months | 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. |
| Progression-free Survival | up to 9 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. 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. |
| Progression-free Survival at 6 Months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination | 1 hour immediately after Cycle 1, Day 1 infusion | Pharmacokinetics (PKs) represents the absorption, distribution, metabolism, and elimination of study drugs from the body. PKs for this study are reported a Area Under the Curve (AUC), which is estimated using the trapezoidal rule based on the average drug concentrations in blood samples, specifically blood plasma, at 1 hour immediately after study drug infusion. AUC gives insight into the extent of exposure to a drug and its clearance rate from the body. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level -1: Dabrafenib = 75 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Fallback dose level -1 is initiated if more than 1 of 6 subjects in dose level 1 (starting dose) develop DLTs.
\* Dose Level -1 (fallback dose):
* Dabrafenib = 75 mg
* Trametinib = 1 mg
* Onalespib = 180 mg/m2
Dabrafenib: Given PO
Laboratory Biomarker Analysis: Correlative studies
Onalespib: Given IV
Pharmacological Study: Correlative studies
Trametinib: Given PO | 0 |
| Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose).
\* Dose Level 1 (starting dose):
* Dabrafenib = 150 mg
* Trametinib = 1 mg
* Onalespib = 180 mg/m2
Dabrafenib: Given PO
Laboratory Biomarker Analysis: Correlative studies
Onalespib: Given IV
Pharmacological Study: Correlative studies
Trametinib: Given PO | 3 |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose).
\* Dose Level 2:
* Dabrafenib = 150 mg
* Trametinib = 2 mg
* Onalespib = 180 mg/m2
Dabrafenib: Given PO
Laboratory Biomarker Analysis: Correlative studies
Onalespib: Given IV
Pharmacological Study: Correlative studies
Trametinib: Given PO | 4 |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose).
\* Dose Level 3:
* Dabrafenib = 150 mg
* Trametinib = 2 mg
* Onalespib = 220 mg/m2
Dabrafenib: Given PO
Laboratory Biomarker Analysis: Correlative studies
Onalespib: Given IV
Pharmacological Study: Correlative studies
Trametinib: Given PO | 6 |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose).
\* Dose Level 4:
* Dabrafenib = 150 mg
* Trametinib = 2 mg
* Onalespib = 260 mg/m2
Dabrafenib: Given PO
Laboratory Biomarker Analysis: Correlative studies
Onalespib: Given IV
Pharmacological Study: Correlative studies
Trametinib: Given PO | 9 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Dose Level 4 | Adverse Event | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1: 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 | Total | Dose Level -1: Dabrafenib = 75 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 |
|---|---|---|---|---|---|---|
| Age, Continuous | 51.0 years | 66.5 years | 54.0 years | 58.0 years | 57.5 years | — |
| Disease Histology Adenocarcinoma, Not otherwise specified | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | — |
| Disease Histology Adenocarcinoma of colon | 2 Participants | 4 Participants | 2 Participants | 4 Participants | 12 Participants | — |
| Disease Histology Adenocarcinoma of lung | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | — |
| Disease Histology Anaplastic thyroid carcinoma | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | — |
| Disease Histology Epithelioid sarcoma | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | — |
| Disease Histology Metastatic melanoma | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 6 Participants | — |
| Months since diagnosis at time of study enrollment | 7.8 months | 19.2 months | 68.8 months | 18.9 months | 19.7 months | — |
| Performance Status Score 0 | 0 Participants | 0 Participants | 3 Participants | 4 Participants | 7 Participants | 0 Participants |
| Performance Status Score 1 | 3 Participants | 4 Participants | 3 Participants | 5 Participants | 15 Participants | 0 Participants |
| Prior Therapy Received Chemotherapy, multiple agents systemic | 3 Participants | 4 Participants | 4 Participants | 8 Participants | 19 Participants | — |
| Prior Therapy Received Chemotherapy, non-cytotoxic | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | — |
| Prior Therapy Received Chemotherapy, not otherwise specified | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | — |
| Prior Therapy Received Chemotherapy, single agent systemic | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 7 Participants | — |
| Prior Therapy Received Immunotherapy | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 8 Participants | — |
| Prior Therapy Received Limited Radiation Therapy | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 5 Participants | — |
| Prior Therapy Received Prior therapy, not otherwise specified | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | — |
| Prior Therapy Received Radiation Therapy, not otherwise specified | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | — |
| Prior Therapy Received Surgery | 3 Participants | 4 Participants | 6 Participants | 9 Participants | 22 Participants | — |
| Prior Therapy Received Vaccine therapy | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 6 Participants | 8 Participants | 21 Participants | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 13 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 9 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 4 / 4 | 6 / 6 | 7 / 8 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 6 / 6 | 8 / 8 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 | 0 / 6 | 2 / 8 |
Outcome results
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Maximum Tolerated Dose of Dabrafenib | 150 mg |
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Maximum Tolerated Dose of Onalespib | 260 mg/m2 |
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Maximum Tolerated Dose of Trametinib | 2 mg |
Primary
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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 3 toxicity | 0 dose limiting toxicities |
| Treatment (Dabrafenib, Trametinib, Onalespib) | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 4 toxicity | 0 dose limiting toxicities |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 4 toxicity | 0 dose limiting toxicities |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 3 toxicity | 0 dose limiting toxicities |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 3 toxicity | 5 dose limiting toxicities |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 4 toxicity | 0 dose limiting toxicities |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 3 toxicity | 1 dose limiting toxicities |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose | Grade 4 toxicity | 0 dose limiting toxicities |
Secondary
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Objective Response Rate | Complete response (CR) | 0 Participants |
| Treatment (Dabrafenib, Trametinib, Onalespib) | Objective Response Rate | Partial response (PR) | 0 Participants |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Objective Response Rate | Partial response (PR) | 0 Participants |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Objective Response Rate | Complete response (CR) | 0 Participants |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Objective Response Rate | Complete response (CR) | 0 Participants |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Objective Response Rate | Partial response (PR) | 2 Participants |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Objective Response Rate | Complete response (CR) | 0 Participants |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Objective Response Rate | Partial response (PR) | 0 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Overall Survival at 1 Year | 0 Participants |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Overall Survival at 1 Year | 0 Participants |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Overall Survival at 1 Year | 1 Participants |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Overall Survival at 1 Year | 3 Participants |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Progression-free Survival | 1.6 months |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Progression-free Survival | 1.5 months |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Progression-free Survival | 3.9 months |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Progression-free Survival | 2.7 months |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Progression-free Survival at 6 Months | 0 Participants |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Progression-free Survival at 6 Months | 0 Participants |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Progression-free Survival at 6 Months | 2 Participants |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Progression-free Survival at 6 Months | 2 Participants |
Other Pre-specified
Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination
Pharmacokinetics (PKs) represents the absorption, distribution, metabolism, and elimination of study drugs from the body. PKs for this study are reported a Area Under the Curve (AUC), which is estimated using the trapezoidal rule based on the average drug concentrations in blood samples, specifically blood plasma, at 1 hour immediately after study drug infusion. AUC gives insight into the extent of exposure to a drug and its clearance rate from the body.
Time frame: 1 hour immediately after Cycle 1, Day 1 infusion
Population: There were 18 out of 21 total evaluable patients had blood samples analyzed on Cycle 1 Day 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Dabrafenib, Trametinib, Onalespib) | Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination | 357 ng*hr/mL |
| Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 | Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination | 344 ng*hr/mL |
| Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 | Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination | 395 ng*hr/mL |
| Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 | Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination | 448 ng*hr/mL |