Abstract
2569 Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3+3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were >18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ≥ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.