LAM Pilot Study with Nilotinib LAMP-2

The primary pulmonary manifestation of tuberous sclerosis (TS) is lymphangioleiomyomatosis (LAM), a rare cystic lung disease occurring primarily in women of childbearing age. The disease causes progressive loss of lung function due to the production of enzymes by LAM cells that cause cysts to form in the lungs. Patients present with shortness of breath, cough, chest discomfort, and even lung collapse. Outside of the lung, patients can also develop kidney tumors, known as angiomyolipomas (AML), which can grow and bleed at larger sizes.

Patients with LAM exhibit increased activity in LAM lung cells of a protein complex called mammalian target of rapamycin (mTOR) complex 1. This causes cells to proliferate and with more LAM cells present, more cysts can form. At present, the only approved therapy for LAM is sirolimus (also known as rapamycin), which slows the rate of replication of the LAM cell by blocking the mTOR pathway, but does not cause death of the LAM tumor cell. Therefore, sirolimus is only a temporary treatment for LAM, and the LAM cells still grow on therapy and AML size can increase when the drug is stopped. Identification of alternate pathways to inhibit LAM cell growth, or even to cause the death of the LAM cell would have tremendous potential to treat patients with both sporadic and TS-associated LAM.

Our laboratory has identified a different pathway, platelet derived growth factor, that is also responsible for the proliferation of LAM cells. We identified in cell culture studies that Imantinib mesylate (imantinib), a tyrosine kinase inhibitor, which is an FDA-approved drug for chronic myelogenous leukemia (CML), initiates LAM cell death. Based on these findings, a first-in-LAM-patients trial was funded by the DOD in 2016 (LAMP-1) to investigate the safety and tolerability of imantinib in patients with LAM. We found that short course of imantinib was well tolerated and that it was safe to be administered concurrent with sirolimus. Concurrent cell-based research studies during that time showed the related drug nilotinib had equal efficacy in causing LAM cell death as imantinib. Due to the side effect profile favoring nilotinib over imatinib for long-term use, we propose further longer-term clinical studies evaluating the safety and tolerability of nilotinib in patients with LAM. The hypothesis is that nilotinib can be safely co-administered with sirolimus and will result in change in serum biomarkers of LAM.

We aim to determine the safety and tolerability of nilotinib use in LAM over a 6-month time frame and to determine if it is well tolerated to be administered concurrent with the only FDA-approved drug for LAM, sirolimus. Finally, we will evaluate if nilotinib changes blood biomarkers of LAM. We have opted to allow patients to continue sirolimus and to not offer a placebo-controlled trial design in this pilot study because patients with this rare lung disease are reticent to come off of the only FDA-approved drug for LAM. Furthermore, we have already demonstrated that the tyrosine kinase inhibitor imantinib and sirolimus were safely co-administered. Once enrolled in this 6-month trial, participants will receive the drug and will undergo regular laboratory screening and pulmonary function testing. We will also evaluate weekly home breathing tests, the first trial of this technology in the LAM community. Finally, we will evaluate blood biomarkers of LAM and how nilotinib changes the biomarkers of interest.

If the above study is successful, we will establish the tolerability of nilotinib in patients with LAM both on and off sirolimus therapy. We will obtain data about optimal biomarkers to follow as a response to nilotinib therapy and gather preliminary data to inform sample size requirements for larger clinical studies to establish the efficacy of nilotinib as an mTOR independent therapy in LAM. Bringing forward an alternate therapy that causes the death of LAM cells would be a major advancement in the field.