Amanda Johnston

A Phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma.

Inoperable hepatocellular carcinoma is an incurable malignancy with no accepted standard therapy. Chemotherapy has demonstrated occasional responses and the need is great for a new and effective agent. Therefore the authors conducted this Phase II trial of a novel thymidylate synthase inhibitor, nolatrexed dihydrochloride (designed using structure‐based computer modeling), in patients with advanced hepatocellular carcinoma.

A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma

Purpose: A multi-centre randomized phase II study of single agent nolatrexed dihydrochloride versus doxorubicin was undertaken in Chinese patients with advanced hepatocellular carcinoma (HCC) to study and compare the clinical efficacy of the two drugs. Methods: Fifty-four patients with clinical or histological diagnosis of HCC were randomized in a 2:1 ratio to receive nolatrexed or doxorubicin. Nolatrexed 725 mg/m2/day was given by continuous infusion via a central venous device for 5 days and doxorubicin 60 mg/m2 was given as a rapid intravenous infusion every 3 weeks. Results: No objective responses were observed in either treatment arm. Two patients in the nolatrexed arm and none in the doxorubicin arm had >50% decline in serum α-fetoprotein. The median survival for the patients in the nolatrexed and doxorubicin arms was 139 days and 104 days, respectively. Moderate toxicities including leukopenia, thrombocytopenia, mucositis and skin rash were observed in both treatment arms. Conclusion: Nolatrexed and doxorubicin are minimally active in the treatment of advanced HCC. Given the small sample size, no difference is observed between the two drugs.

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial

Importance Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. Objective To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. Design, Setting, and Participants A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. Interventions Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. Results Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. Conclusions and Relevance In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. Trial Registration clinicaltrials.gov Identifier: NCT01279967

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1–Deficient Thoracic Cancers

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) –negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non–small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.

Initial clinical trial and pharmacokinetics of ThymitaqTM (AG337) by 10-day continuous infusion in patients with advanced solid tumors

Purpose: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate ThymitaqTM. Methods: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. Results: The dose of 716 mg/m2 per day × 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m2 per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added. Conclusion: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done.

A phase 1/1B trial of ADI‐PEG 20 plus nab‐paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma

ADI‐PEG 20 is a pegylated form of the arginine‐depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI‐PEG 20 selectively targets malignant cells, which lack ASS1.

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)

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 (> 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.