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Trial Tests Combo of Pexidartinib and Pembrolizumab in Ovarian and Other Solid Tumors

Published: Monday, Mar 21, 2016

Jasgit Sachdev, MD

Jasgit Sachdev, MD

An ongoing clinical trial has begun the process of evaluating whether the addition of a booster agent can take the anticancer activity of PD-1 directed immunotherapy to another level.

Investigators in a multicenter trial are evaluating the impact of pexidartinib (PLX3397)—an inhibitor of colony stimulating factor 1 (CSF1)—on the activity of the PD-1 signaling inhibitor pembrolizumab (Keytruda) in various types of solid tumors.

The two-part phase 1/2 trial will establish a recommended dose for pexidartinib to use in combination with standard pembrolizumab dosing and then evaluate the combination in 500 patients representing 12 types of cancer.

Enrollment in the first part of the investigation has just begun, according to a presentation at the 2016 Society of Gynecologic Oncology (SGO) Annual Meeting. During the second part of the trial, “overall response rate and progression-free survival will be evaluated,” Jasgit Sachdev, MD, a medical oncologist at HonorHealth Research Institute in Scottsdale, Arizona, and colleagues reported during a poster session.

“Secondary objectives will be to define the adverse event profile of the combination of pexidartinib and pembrolizumab, evaluate objective response rate relative to the assumed historical control rate for pembrolizumab in subjects treated with the recommended phase II dose combination of pexidartinib and pembrolizumab…[determine] progression-free survival [by tumor type], and determine drug target activity using pre- and posttreatment biopsies for exploratory pharmacology studies.”

Investigators also will conduct exploratory analyses aimed at identifying novel biomarkers of clinical activity and mechanisms of action.

The biological underpinnings of pexidartinib development came from recognition that tumor-associated macrophages (TAMs) support tumor growth and facilitate resistance to chemotherapy and radiation therapy. Additionally, myeloid-derived suppressor cells (MDSCs) inhibit antitumor immunity to promote resistance to PD-1 inhibition. Regulation of TAMs and MSDCs involves CSF1 signaling.

Preclinical studies demonstrated enhanced tumor response to pembrolizumab when PLX3397 was given in combination with the PD1 inhibitor (Cancer Res. 2014;74:5057-5069).

During the first part of the ongoing trial, pembrolizumab will be evaluated in combination with escalating doses of pexidartinib determine the optimal combination for phase II evaluation. During the second part of the trial, investigators will evaluate the phase II dose combination in patients with recurrent, metastatic, persistent, relapsed, or refractory malignancies that have no recognized standard of care.

The phase II dose combination will be administered to cohorts that have accrual targets of 23 to 48 patients each. The tumor types included in the phase II component of the trial consist of 3 categories of melanoma (based on exposure and response to anti¬–PD-1/PD-L1 therapy), ovarian cancer, non–small cell lung cancer, triple-negative breast cancer, head and neck squamous cell carcinoma, bladder cancer, pancreatic ductal adenocarcinoma, gastric cancer, gastrointestinal stromal tumor, leiomyosacoma, cholangiosarcoma, and colorectal cancer.

“For part two, a sequential evaluation procedure establishes continuous evaluation to stop enrollment for either success or futility at any time up to the total sample size,” the investigators stated in their presentation. “This sequential monitoring procedure sets up criteria for the number of responders required to indicate either efficacy or futility continuously.”

Pexidartinib received an FDA breakthrough therapy designation in October 2015 for the treatment of patients with tenosynovial giant cell tumor (TGCT) for which surgical removal is contraindicated.

The designation was based on findings from a phase I study, which were published in The New England Journal of Medicine. In an expansion cohort of the study, the objective response rate with pexidartinib was 52.2% (95% CI, 32-73).

The pexidartinib study presented at the SGO meeting was jointly sponsored by Plexxikon, the developer of pexidartinib, and Merck, which develops pembrolizumab.


Sachdeva JC, Hu-Lieskovanb S, Patnaikc A, et al. Phase 1/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti–PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors. Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Abstract 353.

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