Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer

NCT01902173 | Completed Phase 1 Results

• 6 other identifiers: NCI-2013-01320SWOG-S1221S1221U10CA180830U10CA180888U10CA032102
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 16

Brief Summary

This phase I/II trial studies the side effects and the best dose of uprosertib when given together with dabrafenib and trametinib and to see how well they work in treating patients with stage IIIC-IV cancer. Uprosertib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving uprosertib with dabrafenib and trametinib may be a better treatment for cancer.

Conditions

Hematopoietic and Lymphoid Cell Neoplasm; Locally Advanced Malignant Solid Neoplasm; Locally Advanced Melanoma; Metastatic Malignant Solid Neoplasm; Metastatic Melanoma; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Unresectable Malignant Solid Neoplasm; Unresectable Melanoma

Outcome Measures

Primary Outcomes (4)

• Maximum-tolerated Dose (MTD) of Akt Inhibitor GSK2141795 in Combination With Dabrafenib.

  MTD was evaluated by testing increasing doses up to 75 mg once a day, given in combination with dabrafenib dosed at 150 mg twice daily. MTD reflects the highest dose that did not cause a DLT. DLTs were defined as treatment regimen related: febrile neutropenia; Grade 4 neutropenia lasting more than 7 days; Grade 4 platelet count decrease; Grade 3-4 rash, fever, or hyperglycemia \> 14 days, e) Grade 3-4 non-hematologic adverse events lasting greater than 7 days. Adverse events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  Every 2 weeks during days 1-56 of treatment.

• Maximum-tolerated Dose (MTD) of Akt Inhibitor GSK2141795 in Combination With Dabrafenib and Trametinib.

  MTD was evaluated by testing increasing doses up to 75 mg once a day, given in combination with dabrafenib dosed at 150 mg twice daily and trametinib at either 1.5 mg or 2 mg once a day. MTD reflects the highest dose that did not cause a dose-limiting toxicity (DLT). DLTs were defined as treatment regimen related: febrile neutropenia; Grade 4 neutropenia lasting more than 7 days; Grade 4 platelet count decrease; Grade 3-4 rash, fever, or hyperglycemia \> 14 days, e) Grade 3-4 non-hematologic adverse events lasting greater than 7 days. Adverse events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Note: MTD for the triplet regimen could not be determined due to the end of supply of the study drug. Number reported is the maximum dose of GSK2141795 that was assessed in combination with 150 mg Dabrafenib and 2 mg trametinib.

  Every 2 weeks during days 1-56 of treatment.

• Objective Response Rate (Confirmed and Unconfirmed, Complete and Partial Responses) as Assessed by RECIST Version 1.1 of the Doublet Regimen GSK2141795 + Dabrafenib at the Phase I Determined MTD. (Phase II)

  All measurable lesions up to a maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, were identified as target lesions at baseline. All other lesions (or sites of disease) were identified as non-target lesions. Complete Response (CR): Complete disappearance of all target and nontarget lesions. No new lesions. No disease related symptoms. Any lymph nodes (whether target or non-target) must have reduction in short axis to \< 1.0 cm. Partial Response (PR): \<= 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Unconfirmed CR: One objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR: One objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

  Disease assessments every 8 weeks for up to 3 years

• Objective Response Rate (Confirmed and Unconfirmed, Complete and Partial Responses) as Assessed by RECIST Version 1.1 of the Triplet Regimen GSK2141795 + Dabrafenib + Trametinib at the Phase I Determined MTD. (Phase II)

  All measurable lesions up to a maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, were identified as target lesions at baseline. All other lesions (or sites of disease) were identified as non-target lesions. Complete Response (CR): Complete disappearance of all target and nontarget lesions. No new lesions. No disease related symptoms. Any lymph nodes (whether target or non-target) must have reduction in short axis to \< 1.0 cm. Partial Response (PR): \<= 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Unconfirmed CR: One objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR: One objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

  Disease assessments every 8 weeks for up to 3 years

Secondary Outcomes (5)

• Overall Survival (Phase II) of Patients Treated at the Phase I Determined MTD of Doublet Regimen

  From date of registration to date of death due to any cause, assessed up to 3 years

• Overall Survival (Phase II) of Patients Treated at the Phase I Determined MTD of Triplet Regimen

  From date of registration to date of death due to any cause, assessed up to 3 years

• Progression-free Survival as Assessed by RECIST Version 1.1 of the Doublet Regimen at the Phase I Determined MTD (Phase II)

  From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years

• Progression-free Survival as Assessed by RECIST Version 1.1 of the Triplet Regimen at the Phase I Determined MTD (Phase II)

  From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years

• Toxicity Rate of MTD Graded by the NCI CTCAE Version 4.0 (Phase II)

  Up to 3 years

Other Outcomes (2)

• Pharmacokinetic Parameters

  Baseline, pre-dose and 1, 2, 4, and 8 hours on day 15, and pre-dose day 29

• Prevalence of Markers

  Up to 3 years

Study Arms (1)

Treatment (uprosertib, dabrafenib, trametinib)

EXPERIMENTAL

Dabrafenib mesylate and uprosertib (Phase I): Patients receive dabrafenib PO BID and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial. Dabrafenib mesylate, trametinib dimethyl sulfoxide, and uprosertib (Phase I and Phase II): Patients receive dabrafenib PO BID, trametinib PO QD, and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.

Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Dabrafenib Mesylate; Procedure: Magnetic Resonance Imaging; Drug: Trametinib Dimethyl Sulfoxide; Drug: Uprosertib

Interventions

Biopsy PROCEDURE

Undergo a biopsy

Also known as: BIOPSY_TYPE, Bx

Treatment (uprosertib, dabrafenib, trametinib)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (uprosertib, dabrafenib, trametinib)

Computed Tomography PROCEDURE

Undergo a CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (uprosertib, dabrafenib, trametinib)

Dabrafenib Mesylate DRUG

Given PO

Also known as: Dabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, Tafinlar

Treatment (uprosertib, dabrafenib, trametinib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (uprosertib, dabrafenib, trametinib)

Trametinib Dimethyl Sulfoxide DRUG

Given PO

Also known as: Mekinist, Meqsel, Spexotras

Treatment (uprosertib, dabrafenib, trametinib)

Uprosertib DRUG

Given PO

Also known as: GSK2141795, Oral Akt Inhibitor GSK2141795

Treatment (uprosertib, dabrafenib, trametinib)

Eligibility Criteria

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

You may qualify if:

• PHASE I PORTION ELIGIBILITY CRITERIA:
• Patients must have BRAF\^V600 mutant metastatic cancer irrespective of the histology or prior therapy; BRAF\^V600 mutant status must be documented by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; use of an Food and Drug Administration (FDA)-approved test is preferred although other BRAF tests at a CLIA-certified laboratory may also be accepted
• Patients must have locally advanced unresectable stage IIIC or metastatic stage IV cancer with either progression to prior therapy or a newly diagnosed cancer that does not have an available treatment with curative intent
• Patients must have a complete physical examination and medical history within 28 days prior to registration
• Patients must have measurable or non-measurable disease; all measurable lesions must be assessed (by physical examination, computed tomography \[CT\], or magnetic resonance imaging \[MRI\] scan) within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the baseline tumor assessment form (Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1)
• All patients must undergo a CT or MRI of the brain within 42 days prior to registration; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of registration will be eligible
• Patients may have received prior systemic therapy (chemotherapy, immunotherapy, biologic therapy, or combination regimens); all adverse events associated with prior treatment must have resolved to \< grade 1 prior to registration
• Patients progressing on a prior BRAF inhibitor-based therapy will be eligible, as are patients naive to BRAF inhibitor therapy; resistance to BRAF inhibitor-based therapy will be defined as progressive disease by RECIST 1.1 criteria while receiving therapy with a BRAF inhibitor (vemurafenib or dabrafenib, alone or in combination with a mitogen-activated protein kinase \[MEK\] inhibitor); this may be innate resistance (patients who never achieved a tumor response while on BRAF inhibitor therapy) or acquired resistance (progression after having a tumor response to BRAF inhibitor therapy); there will not be a period of break between progression on the prior BRAF inhibitor-based therapy and the start of dabrafenib, trametinib and GSK2141795
• Patients may have received prior surgery (for both the primary and stage IV disease); all adverse events associated with prior surgery must have resolved to =\< grade 1 prior to registration
• Patients may have received prior radiation therapy; all adverse events associated with prior radiation therapy must have resolved to =\< grade 1 prior to registration
• Patients must be willing to submit blood for pharmacokinetics; sites must order S1221 pharmacokinetic (PK) kit immediately after registration; the Southwest Oncology Group (SWOG) patient identification (ID) number must be provided on the S1221 PK Kit request form
• Patients must have available and be willing to submit baseline tissue taken at the time of disease progression to prior BRAF inhibitor-based therapy (either fresh frozen \[preferred\], or paraffin-embedded tumor blocks) OR must have a site of disease that can be biopsied within this study for translational medicine studies; tissue may be from an archival biopsy or a new biopsy after the patient has been registered to the protocol; since patients are referred to this protocol after progression on prior BRAF inhibitor-based therapy, the biopsy taken at the time of progression will be used as the baseline biopsy for this study; patients must be willing to submit plasma and whole blood for translational medicine studies
• Patients must have Zubrod performance status =\< 1
• Absolute neutrophil count (ANC) \>= 1,200/ul (obtained within 28 days prior to registration)
• Platelets \>= 100,000/ul (obtained within 28 days prior to registration)

You may not qualify if:

• Patients must not have a corrected QT (QTc) interval \>= 480 msecs within 28 days prior to registration
• Patients must not have a history of acute coronary syndromes (including unstable angina), myocardial infarction within 6 months, coronary angioplasty, or stenting within the past 24 weeks; class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; or history of known cardiac arrhythmias (such as atrial fibrillation) unless it has been stably controlled for \> 30 days prior to registration; 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 are not eligible
• At the time of registration, patients must not be receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8); patients must not be planning to use herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1)
• Patients must not be pregnant or nursing due to unknown teratogenic side effects; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• Patient must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, previously diagnosed type 1 diabetes mellitus/type 2 diabetes, psychiatric illness/social situations, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance with study requirements; patients must not have any evidence of mucosal or internal bleeding; patients must not have a history of pneumonitis or interstitial lung disease; patients must not have received any major surgery within four weeks prior to registration
• Patients must not have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib or other agents used in this study including dimethyl sulfoxide (DMSO)
• Patients with known history or current evidence of retinal vein occlusion (RVO) are not eligible:
• History of RVO, or predisposing factors to RVO (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 such as:
• Evidence of new optic disc cupping
• Evidence of new visual field defects
• Intraocular pressure \> 21 mmHg
• NOTE: Ophthalmic exam is required for all patients; exam must be obtained within 28 days prior to registration
• Patients must not have uncontrolled hypertension (defined as systolic blood pressure \> 140 mm Hg and/or diastolic blood pressure \> 90 mm Hg which cannot be controlled by anti-hypertensive therapy)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• GlaxoSmithKline: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (16)

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

California Pacific Medical Center-Pacific Campus

San Francisco, California, 94115, United States

Location

UCSF Medical Center-Mount Zion

San Francisco, California, 94115, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Clackamas Radiation Oncology Center

Clackamas, Oregon, 97015, United States

Location

Providence Milwaukie Hospital

Milwaukie, Oregon, 97222, United States

Location

Providence Newberg Medical Center

Newberg, Oregon, 97132, United States

Location

Providence Willamette Falls Medical Center

Oregon City, Oregon, 97045, United States

Location

Providence Portland Medical Center

Portland, Oregon, 97213, United States

Location

Providence Saint Vincent Medical Center

Portland, Oregon, 97225, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

PeaceHealth Southwest Medical Center

Vancouver, Washington, 98664, United States

Location

Related Publications (1)

• Algazi AP, Moon J, Lao CD, Chmielowski B, Kendra KL, Lewis KD, Gonzalez R, Kim K, Godwin JE, Curti BD, Latkovic-Taber M, Lomeli SH, Gufford BT, Scumpia PO, Lo RS, Othus M, Ribas A. A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers. Cancer. 2024 May 15;130(10):1784-1796. doi: 10.1002/cncr.35200. Epub 2024 Jan 23.

  PMID: 38261444 DERIVED

MeSH Terms

Conditions

Hematologic Neoplasms; Neoplasm Metastasis; Melanoma

Interventions

Biopsy; Specimen Handling; dabrafenib; Magnetic Resonance Spectroscopy; trametinib; GSK2141795

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; 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; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Results Point of Contact

• Title: Melanoma Statistician
• Organization: SWOG

jmoon@fredhutch.org

2066674623

Study Officials

• Antoni Ribas

  SWOG Cancer Research Network

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2013
• First Posted: July 18, 2013
• Study Start: October 8, 2013
• Primary Completion: May 16, 2018
• Study Completion: December 23, 2023
• Last Updated: January 14, 2025
• Results First Posted: October 14, 2020

Record last verified: 2024-12

Locations

US (16)