LY3022855 With BRAF/MEK Inhibition in Patients With Melanoma
A Phase I/II Study of LY3022855 With BRAF/MEK Inhibition in Patients With Melanoma
1 other identifier
interventional
5
1 country
1
Brief Summary
This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation The interventions involved in this study are:
- LY3022855
- Vemurafenib
- Cobimetinib
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Jun 2017
Typical duration for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 30, 2017
CompletedFirst Posted
Study publicly available on registry
April 5, 2017
CompletedStudy Start
First participant enrolled
June 6, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 21, 2020
CompletedStudy Completion
Last participant's last visit for all outcomes
November 11, 2020
CompletedResults Posted
Study results publicly available
July 17, 2024
CompletedJuly 17, 2024
July 1, 2024
3.4 years
March 30, 2017
November 1, 2023
July 12, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Dose Limiting Toxicity (DLT) [Phase I]
DLT is based on CTCAE v4.03. DLT refers to toxicities experienced during the first cycle of treatment that are possibly, probably, or definitely related to the study medication regimen, and grade or category outlined in protocol section 5.4.
Participants were assessed cycle 1 on day 1, 8, 15 and 22. The observation period for DLT evaluation was the first cycle (28 days).
LY3022855 Maximum Tolerated Dose (MTD) With Vemurafenib and Cobimetinib Combination [Phase I]
See previous primary outcome measure for the DLT defination. A conventional algorithm (3+3 design) will be used to identify the MTD, escalating on 0/3 or 1/6 DLTs, and de-escalating if two DLTs are encountered. The MTD will be the highest dose level at which ≤ 1/6 subjects experience a DLT. If dose level 1 is discovered to be intolerable (with 2/3 or ≥ 2/6 subjects experiencing a DLT), the trial will be discontinued.
Participants were assessed cycle 1 on day 1, 8, 15 and 22. The observation period is the first cycle (28 days).
Secondary Outcomes (3)
Median Progression-Free Survival (PFS) [Phase I]
Disease was assessed radiologically at baseline and after treatment every 3-4 months. Median follow-up for survival was 202 days with maximum of 480 days.
Overall Response Rate (ORR) [Phase I]
Radiologic measurements is performed at Cycle 2 Day 28 and at the day 28 of every 2 cycles of treatment thereafter. Median treatment duration is 112 days (range 56 - 1008 days ).
Grade 3-5 Treatment-related Toxicity Rate [Phase II]
AE evaluated on treatment on each cycle at day 1, 8, 15 and 22. Median treatment duration for this study cohort was 112 days (range 56 - 1008 days).
Study Arms (4)
Phase I: Dose Level 1: LY3022855 (50mg) + Vemurafenib + Cobimetinib
EXPERIMENTAL* Starting dose level of LY3022855 50mg IV administered intravenously every week * Vemurafenib 960 mg BID administered by mouth twice daily * Cobimetinib 60 mg administered by mouth once daily on days 1-21of each cycle
Phase I: Dose Level 2: LY3022855 (75mg) + Vemurafenib + Cobimetinib
EXPERIMENTAL* LY3022855 50mg IV administered intravenously every week * Vemurafenib 960 mg BID administered by mouth twice daily * Cobimetinib 60 mg administered by mouth once daily on days 1-21of each cycle
Phase I: Dose Level 3: LY3022855 (100mg) + Vemurafenib + Cobimetinib
EXPERIMENTAL* LY3022855 100mg IV administered intravenously every week * Vemurafenib 960 mg BID administered by mouth twice daily * Cobimetinib 60 mg administered by mouth once daily on days 1-21of each cycle
Phase II: LY3022855 (MTD) + Vemurafenib + Cobimetinib
EXPERIMENTAL* MTD of LY3022855 was not established * Vemurafenib planned 960 mg BID administered by mouth twice daily * Cobimetinib planned 60 mg administered by mouth once daily on days 1-21of each cycle
Interventions
LY3022855 is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor
Vemurafenib is a BRAF inhibitor that works by blocking altered BRAF proteins from stimulating the growth of melanoma cancer cells
Cobimetinib works by blocking a protein called MEK that has been known to promote melanoma growth
Eligibility Criteria
You may qualify if:
- For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective.
- For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and cannot have received prior BRAF or MEK inhibitor therapy.
- Participants enrolling to the phase I portion of the trial must have evaluable or measurable disease (see Section 11 for definitions).
- Participants enrolling to the phase II portion of the trial 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 ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
- Age ≥ 18 years. As no dosing or adverse event data are currently available in participants \< 18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
- ECOG performance status 0 - 1 (see APPENDIX A).
- Participants must have normal organ and marrow function as defined below:
- Absolute neutrophil count ≥ 1.5 K/uL
- Platelets ≥ 100 K/uL
- Hemoglobin ≥ 9 g/dL
- Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
- AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN
- Serum creatinine ≤ 1.5 × institutional ULN
- PT-INR ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)
- aPTT ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)
- +5 more criteria
You may not qualify if:
- Participants who have had chemotherapy, radiotherapy, biologic therapy, major surgery, or another investigational agent within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
- Participants who have not recovered to ≤ CTCAE grade 1 or baseline from toxicity as a result of previous cancer treatment prior to entering the study (with the exception of alopecia and peripheral neuropathy which can be ≤ grade 2).
- For enrollment to the phase II portion: participants who have received prior BRAF or MEK inhibitor therapy.
- Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for ≥ 4 weeks following the last date of treatment are permitted.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to LY3022855, vemurafenib, or cobimetinib.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Pregnant women are excluded from this study because LY3022855 is an anti-cancer agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY3022855, breastfeeding should be discontinued if the mother is treated with LY3022855. These potential risks may also apply to the other agents used in this study.
- Participants with a known history of HIV are ineligible because of the potential for pharmacokinetic interactions with LY3022855, vemurafenib, and cobimetinib with antiretroviral agents. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
- Participants with a personal or family history of long QT syndrome.
- Participants with a history of a second primary malignancy. Exceptions include: patients with a history of malignancies that were treated curatively and have not recurred within 3 years prior to study entry; resected basal and squamous cell carcinomas of the skin, and completely resected carcinoma in situ of any type.
- Participants with impairment of GI function or GI disease that may significantly alter the absorption of vemurafenib and cobimetinib in the opinion of the treating investigator (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
- Participants who are unable to swallow or retain oral medication.
- Participants that require co-administration of strong or moderate CYP3A inhibitors, as these medications may alter vemurafenib and cobimetinib concentrations.
- Participants who require treatment with medications that are strong or moderate CYP3A inducers, as these medications may alter the concentration of cobimetinib.
- Participants with evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Dana-Farber Cancer Institutelead
- Eli Lilly and Companycollaborator
Study Sites (1)
Dana Farber Cancer Institute
Boston, Massachusetts, 02215, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr. Elizabeth Buchbinder
- Organization
- Dana-Farber Cancer Institute
Study Officials
- PRINCIPAL INVESTIGATOR
Elizabeth Buchbinder, MD
Dana-Farber Cancer Institute
Publication Agreements
- PI is Sponsor Employee
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Elizabeth Buchbinder MD
Study Record Dates
First Submitted
March 30, 2017
First Posted
April 5, 2017
Study Start
June 6, 2017
Primary Completion
October 21, 2020
Study Completion
November 11, 2020
Last Updated
July 17, 2024
Results First Posted
July 17, 2024
Record last verified: 2024-07
Data Sharing
- IPD Sharing
- Will not share