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
This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an
investigational intervention and also tries to define the appropriate dose of the
investigational intervention to use for further studies. "Investigational" means that the
intervention is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved LY3022855 as a treatment for
any disease.
The FDA has approved vemurafenib and cobimetinib as treatment options for this disease.
LY3022855 is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor. It is a human
monoclonal antibody. A monoclonal antibody is a type of protein made in the laboratory that
can locate and bind to substances in the body, including tumor cells. By binding to the tumor
cells, the antibody might prevent the tumor cell from growing and spreading. LY3022855 is
being developed as a treatment for patients with advanced cancer.
Vemurafenib and cobimetinib attack different proteins that promote the growth of cancerous
cells. 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. In order to participate in the
study, participant's disease needs to be tested positive for a mutation (a permanent change
in the DNA sequence of a gene) of the BRAF gene that belongs to a class of genes known as
oncogenes. When mutated, oncogenes have the potential to cause normal cells to become
cancerous. Once the BRAF gene is mutated, the normal functioning of the BRAF protein may be
changed.
In this research study, the investigators are combining LY3022855 with vemurafenib and
cobimetinib in the hopes that the LY3022855 will enhance how your cancer responds to
vemurafenib and cobimetinib.
Inclusion Criteria:
- 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)
- Participants must have a left ventricular ejection fraction (LVEF) ≥ 50%.
- Participants must have a QTc of ≤ 470 msec on the screening EKG.
- The effects of LY3022855 on the developing human fetus are unknown. For this reason
and because anti-cancer agents are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of LY3022855 administration.
- Ability to understand and the willingness to sign a written informed consent document.
- Participants must have archival tumor tissue available. Participants without archival
tissue may be enrolled at the discretion of the principal investigator.
Exclusion Criteria:
- 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.
