A phase IIa study of PEGylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-L-norleucine (DON) in patients with advanced refractory solid tumors

2533 Background: Our phase IIa study evaluated the safety and clinical activity of the glutamine depleting enzyme PEG-PGA in combination with DON. DON as a glutamine antagonist irreversibly inhibits key enzymes in the purine and pyrimidine synthesis. Based on the competitive mechanism, effectiveness of DON is greatly enhanced if plasma glutamine level is significantly depleted by PEG-PGA. Methods: In this multicenter study, patients (pts) with advanced solid tumors refractory to standard treatments were enrolled. Pts were treated with 120 I.U./m2 PEG-PGA (once weekly) and 140 mg/m2 DON (twice weekly) both as 15 min intravenous infusions. Three weeks were considered one cycle and tumor assessment (RECIST) was performed every two cycles. The primary endpoint was safety. Results: Fifty-five pts (20f/35m) were enrolled. Median age was 60 years (range 31–84). 30% had an ECOG PS <1. Pts were heavily pretreated and all had progressive disease at study entry. Treatment duration ranged from 1 to 379 days. Glutamine levels were depleted below 10% of baseline after the 2nd infusion of PEG-PGA and remained depleted in >90% of the patients. The treatment was very well tolerated. Most frequent (>2%) possibly related NCI-CTC grade 3 or 4 non-hematological toxicities were fatigue in 5 (9.1 %), nausea in 3 (5.5%), vomiting in 2 (3.6%) and diarrhea in 2 (3.6%) pts. Grade 3 or 4 hematological side effects were also rare, with neutropenia and thrombocytopenia being observed in 1 patient (pt), each. One pt with metastatic colorectal cancer (mCRC) experienced a confirmed partial response. One additional pt (mCRC) had a prolonged stable disease lasting > 12 months under treatment despite multiple lung metastases (>30). Among the pts with mCRC, 9/17 (53%) pts 5/17 (29%) pts were progression-free at 3 and 5 months, respectively. Signs of activity were also observed in pts with lung cancer. Five of six (83%) pts with lung cancer were progression-free 3 months after inclusion. Conclusions: PEG-PGA and DON were well tolerated and demonstrated activity in late stage colorectal and lung cancer. The therapeutic approach warrants further investigations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medical Enzymes AG