Alternative Drug Names:
PLX-3397 is also called Pexidartinib. MK-3475 is now Pembrolizumab (Keytruda brand in the US).
Purpose of Trial:
The purpose of this phase 1/2 study is to establish the safety of the combination of these 2 agents in any solid tumor, and in the phase 2 component to establish whether there is a preliminary signal of activity/efficacy in selected solid tumors including metastatic TNBC. MK-3475 has been FDA approved in other tumor types such as melanoma and non small cell lung cancer. MK-3475 is an antibody that is an immunotherapy drug belonging to the PD-1 class. Inhibiting PD-1 removes the brakes on T cells, so that they may kill tumor cells. PLX-3397 is a multi-target small molecule inhibitor that works via inhibiting various signaling pathways. The target that is thought to be most relevant across cancers is CSF1R (colony-stimulating factor 1 receptor) that induces proliferation of immune cells known as tumor-associated macrophages (TAMs). TAMs are thought to be important in breast cancer and IBC because they secrete factors that increase the aggressiveness of the IBC cells, including increasing invasion/further metastasis. TAMs can suppress natural anti-tumor immunity. For this reason, the combination of CSF-1 inhibition and PD-1 inhibitors are thought to better activate the immune system than either drug alone.
Why this study is relevant for IBC patients:
While this is not an IBC-specific trial, it does make sense as a novel strategy in patients who have not responded to standard chemotherapies. Currently there are no FDA-approved immunotherapies in IBC (1 other IBC specific trial), however there is increasing preclinical research on the roles of cells in the tumor microenvironment that contribute to bad outcomes. In terms of the value of MK-3475 in IBC, it is known that IBC tumors frequently express PD-L1 (~38% are positive), a protein that binds to PD-1 and actively turns off T cells so the tumor cells can hide from the immune system. MK-3475 can disrupt this loop so that the immune system can recognize and kill tumor cells around the body.
There are a number of other studies in adult populations with both drugs (individually) that have demonstrated the safety profile. A larger body of data exists regarding MK-3475. These results suggest that this drug appears tolerable without major serious side effects. An example of the frequency of side effects may be found in this abstract presented at ASCO in 2014. Since this drug is now FDA approved in several disease settings, the drug information website is www.keytruda.com. PLX-3997 is a multi-target tyrosine kinase inhibitor that works via several signaling pathways that are important for tumor cell survival. There is less clinical information about PLX-3397 however multiple phase 1-3 studies are underway, including more than one in breast cancer. There is a recent publication (2015) about a phase 1/2 trial in adults with different solid tumors which demonstrated the side effects to be relatively minor. According to this study, the most common side effects were fatigue, changes in hair color, nausea, unpleasant taste and swelling around the eye – however these problems were rarely severe enough to cause drug discontinuation.
This trial is a broad phase 1/2 study open to patients with various solid tumors. In the phase 1 (safety and dose-escalation) part, IBC patients with any subtype are eligible. If the combination proceeds into phase 2, then only IBC patients who have triple negative disease are eligible. Importantly for both parts, metastatic or refractory disease is required. For IBC patients who are diagnosed already metastatic, this trial cannot be the first line of treatment. Prior treatment with immunotherapy drugs is only permitted in the dose-escalation phase (phase 1), but not in the dose-expansion TNBC-only phase (phase 2). Also in the phase 2 portion, you must have biopsy-accessible tumors for correlative science.
There are several washout periods that apply to prior treatment – 28 days since other antibodies, or 14 days for chemotherapy, radiation or targeted therapies.
MK-3475 is an infusion. PLX-3397 is a pill you will take daily. The scheduling of these will be explained to you if you enroll. However, the cycle will be 42 days long, and you will have appointments frequently with the trial team to monitor the side effects of the combination.
Location of Trial:
The trial is open at 5 sites in Arizona, California, Michigan and Texas. The information for each site is in the section below.
For more information:
Contact the trial coordinators listed below for the site nearest you.
Honor Health in Scottsdale. The principal investigator is Jasgit Sachdev, and the study coordinator (who you would contact) is Michael Graham. His email is email@example.com and the telephone number is 480-323-1970.
University of California at Los Angeles in Los Angeles. The principal investigator is Siwen Hu-Lieskovan, and the study coordinator (who you would contact) is Jill Paroly. Her email is firstname.lastname@example.org and the telephone number is 310-794-3879.
Marin Cancer Care in Greenbrae. The principal investigator is Peter Eisenberg, and the study coordinator (who you would contact) is Jaime Chang. Jaime’s email address is email@example.com and the telephone number is 415-925-5040.
Karmanos Cancer Institute at Wayne State University in Detroit. The principal investigator is Amy Weise, and the study coordinator (who you would contact) is Delaney Erickson. Her email address is firstname.lastname@example.org and the telephone number is 313-576-9806.
START (South Texas Accelerated Research Therapeutics) in San Antonio. The principal investigator is Amita Patnaik, and the study coordinator (who you would contact) is Amy Guthrie. Her email address is email@example.com and the telephone number is 210-593-5286.
Is this study NCI Compliant?:
NCT trial number & link:
NCT# 02452424 – click for more info
Poster from scientific meeting: