BRAF V600E Mutation PresentPhase 1NCT02097225
Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
A Phase 1 study testing Dabrafenib, Laboratory Biomarker Analysis and Onalespib in people with BRAF V600E Mutation Present and BRAF V600K Mutation Present, run by National Cancer Institute (NCI) at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- BRAF V600E Mutation Present, BRAF V600K Mutation Present, Metastatic Malignant Solid Neoplasm
- What is being tested?
- Dabrafenib, Laboratory Biomarker Analysis and Onalespib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 2 sitesUnited States
- Study dates
- 29 May 2014to 26 Oct 2022
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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%)
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- 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
Who cannot join
- 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)
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- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
About this study
Official title: Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in Patients With BRAF-Mutant Melanoma and Other Solid Tumors
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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.
- Conditions
- BRAF V600E Mutation Present, BRAF V600K Mutation Present, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7
- Being tested
- Dabrafenib, Laboratory Biomarker Analysis, Onalespib, Pharmacological Study, Trametinib
- Medical subject headings
- Neoplasm Metastasis, Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DabrafenibDrug
Also called BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436
Given PO
Laboratory Biomarker AnalysisOther
Correlative studies
OnalespibDrug
Also called AT 13387, AT-13387, AT13387
Given IV
Correlative studies
TrametinibDrug
Also called GSK 1120212, GSK-1120212, GSK1120212, JTP-74057
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Dose level -1 (dabrafenib, trametinib, onalespib) | Experimental | 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/m^2 Receives: Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Onalespib; Other: Pharmacological Study; Drug: Trametinib |
| Dose level 1 (dabrafenib, trametinib, onalespib) | Experimental | 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/m^2 Receives: Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Onalespib; Other: Pharmacological Study; Drug: Trametinib |
| Dose level 2 (dabrafenib, trametinib, onalespib) | Experimental | 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/m^2 Receives: Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Onalespib; Other: Pharmacological Study; Drug: Trametinib |
| Dose level 3 (dabrafenib, trametinib, onalespib) | Experimental | 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/m^2 Receives: Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Onalespib; Other: Pharmacological Study; Drug: Trametinib |
| Dose level 4 (dabrafenib, trametinib, onalespib) | Experimental | 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/m^2 Receives: Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Onalespib; Other: Pharmacological Study; Drug: Trametinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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
Measured: 28 days after start of treatment (1 cycle)
Secondary outcomes (4)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2014 (estimated)
- Study start29 May 2014
- Primary completion31 Mar 2019
- Study completion26 Oct 2022
Why it stopped: Drug supply issues
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for BRAF V600E Mutation PresentStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Ryan J Sullivan, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02097225
- Sponsor's protocol ID
- NCI-2014-00615
- Other IDs
- NCI-2014-00615, CTEP#9557, 14-186, 9557, 9557, P30CA006516, U01CA062490, UM1CA186709
- Status last verified
- Sep 2024
- First submitted
- 24 Mar 2014
- Last updated
- 16 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Mooradian MJ, Cleary JM, Giobbie-Hurder A, Darville LNF, Parikh A, Buchbinder EI, Cohen JV, Lawrence DP, Shapiro GI, Keer H, Chen HX, Ivy SP, Smalley KSM, Koomen JM, Sullivan RJ. Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors. Cancer. 2023 Jun 15;129(12):1904-1918. doi: 10.1002/cncr.34730. Epub 2023 Apr 11.
PubMed 37042037
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in Patients With BRAF-Mutant Melanoma and Other Solid Tumors
- ClinicalTrials.gov ID
- NCT02097225
- Acronym / sponsor ID
- NCI-2014-00615
- Conditions
- BRAF V600E Mutation Present, BRAF V600K Mutation Present, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Drug supply issues
- Enrolment
- 22 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 29 May 2014 (actual)
- Primary completion
- 31 Mar 2019 (actual)
- Study completion
- 26 Oct 2022 (actual)
- First posted
- 27 Mar 2014 (estimated)
- Results
- Posted 16 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- 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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Dose level -1 (dabrafenib, trametinib, onalespib) | Experimental | Drug: Dabrafenib, Other: Laboratory Biomarker Analysis, Drug: Onalespib, Other: Pharmacological Study, Drug: TrametinibPatients 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/m^2 |
| Dose level 1 (dabrafenib, trametinib, onalespib) | Experimental | Drug: Dabrafenib, Other: Laboratory Biomarker Analysis, Drug: Onalespib, Other: Pharmacological Study, Drug: TrametinibPatients 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/m^2 |
| Dose level 2 (dabrafenib, trametinib, onalespib) | Experimental | Drug: Dabrafenib, Other: Laboratory Biomarker Analysis, Drug: Onalespib, Other: Pharmacological Study, Drug: TrametinibPatients 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/m^2 |
| Dose level 3 (dabrafenib, trametinib, onalespib) | Experimental | Drug: Dabrafenib, Other: Laboratory Biomarker Analysis, Drug: Onalespib, Other: Pharmacological Study, Drug: TrametinibPatients 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/m^2 |
| Dose level 4 (dabrafenib, trametinib, onalespib) | Experimental | Drug: Dabrafenib, Other: Laboratory Biomarker Analysis, Drug: Onalespib, Other: Pharmacological Study, Drug: TrametinibPatients 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/m^2 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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
- 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%)
Key exclusion criteria (30 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DabrafenibAlso: BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436Given PO | Drug | Dose level -1 (dabrafenib, trametinib, onalespib), Dose level 1 (dabrafenib, trametinib, onalespib), Dose level 2 (dabrafenib, trametinib, onalespib), Dose level 3 (dabrafenib, trametinib, onalespib), Dose level 4 (dabrafenib, trametinib, onalespib) |
| Laboratory Biomarker AnalysisCorrelative studies | Other | Dose level -1 (dabrafenib, trametinib, onalespib), Dose level 1 (dabrafenib, trametinib, onalespib), Dose level 2 (dabrafenib, trametinib, onalespib), Dose level 3 (dabrafenib, trametinib, onalespib), Dose level 4 (dabrafenib, trametinib, onalespib) |
| OnalespibAlso: AT 13387, AT-13387, AT13387Given IV | Drug | Dose level -1 (dabrafenib, trametinib, onalespib), Dose level 1 (dabrafenib, trametinib, onalespib), Dose level 2 (dabrafenib, trametinib, onalespib), Dose level 3 (dabrafenib, trametinib, onalespib), Dose level 4 (dabrafenib, trametinib, onalespib) |
| Pharmacological StudyCorrelative studies | Other | Dose level -1 (dabrafenib, trametinib, onalespib), Dose level 1 (dabrafenib, trametinib, onalespib), Dose level 2 (dabrafenib, trametinib, onalespib), Dose level 3 (dabrafenib, trametinib, onalespib), Dose level 4 (dabrafenib, trametinib, onalespib) |
| TrametinibAlso: GSK 1120212, GSK-1120212, GSK1120212, JTP-74057Given PO | Drug | Dose level -1 (dabrafenib, trametinib, onalespib), Dose level 1 (dabrafenib, trametinib, onalespib), Dose level 2 (dabrafenib, trametinib, onalespib), Dose level 3 (dabrafenib, trametinib, onalespib), Dose level 4 (dabrafenib, trametinib, onalespib) |
Primary outcome
Maximum Tolerated Dose of Dabrafenib
Time frame: 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
Time frame: 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
Time frame: 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
Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose
Time frame: 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
4 secondary outcomes
Objective Response Rate
Time frame: up to 9 months
Progression-free Survival
Time frame: up to 9 months
Progression-free Survival at 6 Months
Time frame: 6 months
Overall Survival at 1 Year
Time frame: 1 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37042037Mooradian MJ, Cleary JM, Giobbie-Hurder A, Darville LNF, Parikh A, Buchbinder EI, Cohen JV, Lawrence DP, Shapiro GI, Keer H, Chen HX, Ivy SP, Smalley KSM, Koomen JM, Sullivan RJ. Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors. Cancer. 2023 Jun 15;129(12):1904-1918. doi: 10.1002/cncr.34730. Epub 2023 Apr 11.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ryan J Sullivan principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dabrafenib, Laboratory Biomarker Analysis and Onalespib in people with BRAF V600E Mutation Present and BRAF V600K Mutation Present, run by National Cancer Institute (NCI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose of Dabrafenib (time frame: 28 days after start of treatment). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02097225, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2024.