Abstract B23: A phase 1 study in patients with mesothelioma or non small cell lung tumours requiring arginine to assess ADI-PEG 20 with pemetrexed and cisplatin (TRAP study)
Authors: Pacey Simon , Spicer James F. , Chan Pui Ying , Hategan Mirela , Repana Dimitra , Steele Jeremy Peter , Schmid Peter , Cook Gary J R , Diaz Monica , Johnston Amanda , Baird Richard , Barba Adelberto , Khadeir Ramsay , Sheaff Michael , Roca Jose , Szyszko Teresa , Bomalaski John , Szlosarek Peter Wojciech 
Published: May 2016

Abstract
Background: Loss of the metabolic tumor suppressor, argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine biosynthesis, sensitizes mesothelioma and lung carcinoma cells to apoptosis following arginine withdrawal. We have reported treatment with the arginine depletor pegylated arginine deiminase (ADI-PEG 20) in ASS1-negative tumor cells potentiates the cytotoxic effect of pemetrexed, accompanied by suppression of de novo pyrimidine synthesis and the pyrimidine salvage pathway (Allen et al, Cancer Res 2014. We have undertaken a phase I study (NCT02029690) of ADI-PEG 20 combined with first-line pemetrexed and cisplatin chemotherapy in patients (pt) with ASS1-deficient mesothelioma or non-squamous non-small cell lung cancer (NSCLC), primary objective was to recommend a dose for future study (RP2D).
Methods: Main inclusion criteria: ≥ 18 years, PS ≤ 1, tumour ASS1 loss (≤ 50% ASS expression by IHC) with adequate organ function and written, informed consent. Exclusion criteria: symptomatic CNS metastases, significant concurrent morbidity, therapeutic anticoagulation, history of seizures, or allergy to trial medication(s). A 3+3+3 phase 1 dose escalation design was used with increasing doses of weekly ADI-PEG 20 (18, 27 and 36 mg/m2 IM) in each of three cohorts plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 both given every 3 weeks (1 cycle), maximum 18 weeks. ADI-PEG 20 alone was allowed after 18 weeks if there was stable disease or better. Adverse events were graded using CTCAE v4.03 and dose limiting toxicities (DLT) were defined as: Grade 4 neutropenia (&gt; 7 days), febrile neutropenia, Grade 4 anaemia or thrombocytopenia, other clinically significant Grade 3/4 non haematological toxicity that occurred during cycle 1. Radiological disease response was assessed every 6 weeks (modified RECIST for mesothelioma and RECIST 1.1 for NSCLC) and peripheral blood samples were collected to measure plasma arginine and citrulline levels and antibodies to ADI-PEG 20.
Results: 42 pt were screened for tumor ASS1 expression and 15 (36%) were ASS1-deficient. Subsequently, 9 pt were eligible for DLT assessment. Demographics - 6 M:3 F, Age range 62 - 77, NSCLC (4): Mesothelioma (5), Prior therapy EGFRi (1 pt), External beam radiotherapy (2 pt) No DLT were observed at any dose level. Grade ≤ 3, AE related to pemetrexed and cisplatin were (5 pt): nausea (5), fatigue (2) and vomiting, peripheral neuropathy, dry mouth, mouth ulcers, dehydration and neutropenia (1 each). No AE were reported related to ADI PEG 20. Mean cycles of treatment: 9 (range 4 - 14) 1 pt was dose reduced after cisplatin toxicity. Arginine was depleted for ≥3 weeks (3-18 weeks in all treated patients. 7/9 pt had partial response (PR) and 2/9 had stable disease (SD) as best response.
Conclusions: The combination was well tolerated, the RP2D is 36mg/m2 ADI-PEG 20 weekly with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 every 3 weeks. Robust clinical activity has been observed with 78% pt having PR as best response on CT scan, as well as PR and SD in2 pt with sarcomatoid mesothelioma. The tolerability and response / disease control rate suggest that this combination may have clinical utility as first line treatment for these malignancies in ASS1-deficient pt. RP2D expansion cohorts are ongoing for pt with pleural mesothelioma or non-squamous NSCLC.
Citation Format: Simon Pacey, James F. Spicer, Pui Ying Chan, Mirela Hategan, Dimitra Repana, Jeremy Peter Steele, Peter Schmid, Gary J R Cook, Monica Diaz, Amanda Johnston, Richard Baird, Adelberto Barba, Ramsay Khadeir, Michael Sheaff, Jose Roca, Teresa Szyszko, John Bomalaski, Peter Wojciech Szlosarek. A phase 1 study in patients with mesothelioma or non small cell lung tumours requiring arginine to assess ADI-PEG 20 with pemetrexed and cisplatin (TRAP study). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B23.