Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

NCT02097225 | Terminated Phase 1 Results

• 7 other identifiers: NCI-2014-00615CTEP#955714-1869557P30CA006516U01CA062490UM1CA186709
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

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.

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; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Unresectable Solid Neoplasm

Outcome Measures

Primary Outcomes (4)

• 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

  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

  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

  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

  28 days after start of treatment (1 cycle)

Secondary Outcomes (4)

• Objective Response Rate

  up to 9 months

• Progression-free Survival

  up to 9 months

• Progression-free Survival at 6 Months

  6 months

• Overall Survival at 1 Year

  1 year

Other Outcomes (1)

• Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination

  1 hour immediately after Cycle 1, Day 1 infusion

Study Arms (5)

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

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

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

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

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

Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Onalespib; Other: Pharmacological Study; Drug: Trametinib

Interventions

Dabrafenib DRUG

Given PO

Also known as: BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436

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 Analysis OTHER

Correlative studies

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)

Onalespib DRUG

Given IV

Also known as: AT 13387, AT-13387, AT13387

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 Study OTHER

Correlative studies

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)

Trametinib DRUG

Given PO

Also known as: GSK 1120212, GSK-1120212, GSK1120212, JTP-74057, MEK Inhibitor GSK1120212

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)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• 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.

  PMID: 37042037 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis; Melanoma

Interventions

dabrafenib; (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone; trametinib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Ryan Sullivan, MD
• Organization: Massachusetts General Hospital

RSULLIVAN7@PARTNERS.ORG

617-643-3614

Study Officials

• Ryan J Sullivan

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2014
• First Posted: March 27, 2014
• Study Start: May 29, 2014
• Primary Completion: March 31, 2019
• Study Completion: October 26, 2022
• Last Updated: October 16, 2024
• Results First Posted: October 16, 2024

Record last verified: 2024-09

Locations

US (2)