# Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors

> **NIH FDA R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $500,000

## Abstract

Project Summary/Abstract
This Orphan Drug Grant application is for a phase 2 clinical trial of combination therapy with a novel receptor
tyrosine kinase (RTK) inhibitor and mammalian target of rapamycin inhibitor against malignant peripheral nerve
sheath tumors (MPNSTs). No efficacious treatment options currently exist in this chemotherapy-resistant fatal
disease. This is an investigator-initiated, multicenter, first in man study with preclinical data spanning over
seven years which identified MPNST as a specific disease indication for PLX3397 (PLX), a potent and specific
RTK inhibitor that inhibits five kinases of the over 200 tested. PLX specifically inhibits CSF1R, c-KIT, and
PDGFRβ in vitro and in an MPNST xenograft model. We have shown that combination therapy with PLX and
sirolimus resulted in sustained tumor growth inhibition and a marked depletion of tumor-associated
macrophages and a shift from M2 (tumor promoting) to M1 (tumor inhibiting) macrophages. Therefore, this
drug combination, by potently blocking RTKs and by altering tumor macrophage infiltration, represents a novel
drug combination for MPNSTs.
The phase 1 portion of the phase 1/2 study has been approved by the FDA (IND #125719) and CUMC IRB
(#AAAO6059) and has to date enrolled four patients using an adaptive design to identify the recommended
phase 2 dose (RP2D). All three evaluable patients have experienced clinical benefit (1 response and 2 stable
disease by RECIST) which includes a patient with MPNST. Two patients have surpassed the dose limiting
toxicity (DLT) period and one DLT was observed at dose level 4, which is thought to be disease related in the
fourth patient who remains on study.
The phase 2 portion of the study, and the focus of this application, will require pre-treatment, on-treatment, and
on-progression biopsies in patients treated with the RP2D in hopes to demonstrate efficacy. The goal of the
study is to (1) demonstrate a performance free survival benefit, (2) determine the response rate and overall
survival, (3) correlate inhibition of target pathways and macrophage infiltration with efficacy, and (4) identify
pathways of resistance by determining RTK phosphorylation status and level of macrophage infiltration in
tumor samples from patients at time of progression compared to that on-treatment. Proof of efficacy of
combination therapy with PLX and sirolimus in MPNST would be invaluable in the treatment of patients with
MPNST and lead to improved medical management of this incurable and highly fatal disease.

## Key facts

- **NIH application ID:** 9444352
- **Project number:** 5R01FD005745-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gulam Abbas Manji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2020
- **Award amount:** $500,000
- **Award type:** 5
- **Project period:** 2017-03-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9444352

## Citation

> US National Institutes of Health, RePORTER application 9444352, Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors (5R01FD005745-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9444352. Licensed CC0.

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