Phase I/II Study of the Safety and Efficacy of the AKT Inhibitor GSK2141795 in Combination With Dabrafenib and Trametinib in Patients With BRAF Mutant Cancer
Overview
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 27
- Locations
- 16
- Primary Endpoint
- Maximum-tolerated Dose (MTD) of Akt Inhibitor GSK2141795 in Combination With Dabrafenib.
Overview
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.
Detailed Description
PRIMARY OBJECTIVES:
I. To assess the safety of dabrafenib mesylate (dabrafenib) in combination with uprosertib (GSK2141795) and select the optimal dose of GSK2141795 for the phase II portion in patients with BRAF mutant cancer. (Effective November 15, 2014, this trial will not proceed to the phase II study of dabrafenib and GSK2141795, but will move to an evaluation of triple therapy). (Phase I) II. To assess the safety of dabrafenib and trametinib dimethyl sulfoxide (trametinib) and GSK2141795 in combination and select the optimal dose of the combination for the phase II portion in patients with BRAF mutant cancer. (Phase I) III. To evaluate the objective response rate (confirmed and unconfirmed, complete and partial responses) in patients with BRAF^V600 mutant metastatic melanoma who have previously progressed on BRAF^V600 inhibitor-based therapy (BRAFi), or BRAFi + MEK inhibitor-based therapy (MEKi). (Phase II)
SECONDARY OBJECTIVES:
I. To estimate overall survival and progression-free survival. II. To assess the toxicity profile of the recommended phase II dose. III. To assess response (complete and partial, confirmed and unconfirmed) of patients enrolled on each phase I portion).
TRANSLATIONAL MEDICINE OBJECTIVES:
I. To explore the molecular mechanisms of acquired resistance to BRAF inhibitor therapy using available biopsies of lesions that progressed during prior BRAF inhibitor-based therapy.
II. To explore potential drug-drug interactions between dabrafenib and GSK2141795 leading to changes in the expected exposure with either agent compared to prior experience. (Phase I)
OUTLINE: This is a phase I, dose-escalation study of uprosertib followed by a phase II study. Dose escalation of dabrafenib mesylate, trametinib dimethyl sulfoxide, and uprosertib will be initiated after completion of the dabrafenib + uprosertib phase I dose escalation.
Dabrafenib mesylate and uprosertib (Phase I): Patients receive dabrafenib orally (PO) twice daily (BID) and uprosertib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) scan, magnetic resonance imaging (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, magnetic MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.
After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
Exclusion Criteria
- •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:
Arms & Interventions
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Biopsy (Procedure)
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Biospecimen Collection (Procedure)
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Computed Tomography (Procedure)
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Dabrafenib Mesylate (Drug)
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Trametinib Dimethyl Sulfoxide (Drug)
Treatment (uprosertib, dabrafenib, trametinib)
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.
Intervention: Uprosertib (Drug)
Outcomes
Primary Outcomes
Maximum-tolerated Dose (MTD) of Akt Inhibitor GSK2141795 in Combination With Dabrafenib.
Time Frame: Every 2 weeks during days 1-56 of treatment.
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.
Maximum-tolerated Dose (MTD) of Akt Inhibitor GSK2141795 in Combination With Dabrafenib and Trametinib.
Time Frame: Every 2 weeks during days 1-56 of treatment.
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.
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)
Time Frame: Disease assessments every 8 weeks for up to 3 years
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.
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)
Time Frame: Disease assessments every 8 weeks for up to 3 years
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.
Secondary Outcomes
- 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)
- Toxicity Rate of MTD Graded by the NCI CTCAE Version 4.0 (Phase II)(Up to 3 years)
- 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)
- 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)