Adding ADI-PEG 20 to Abraxane (nab-paclitaxel) and gemcitabine showed promising activity with little additional toxicities in the treatment of patients with advanced pancreatic adenocarcinoma, according to data presented at the 2017 Gastrointestinal Cancers Symposium in San Francisco.
Seven of 18 patients (39 percent) in the trial treated with various doses of ADI-PEG 20 plus Abraxane and gemcitabine experienced partial response (PR) per RECIST v1.1 criteria. Ten patients (56 percent) demonstrated stable disease (SD), and seven patients experienced higher than a grade 3 toxicity—including neutropenia in four patients—which was considered to potentially be caused by ADI-PEG 20.
Maeve A. Lowery, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and her colleagues presented the data from the open-label, single-arm phase 1b dose-escalation study.
In the trial, nine patients with metastatic pancreatic cancer who received up to one line of prior treatment were enrolled. The dose of ADI-PEG 20 was escalated using a 3+3 design, in which cohorts of three to six patients were enrolled to one of three dose levels of ADI-PEG 20 (nine, 18 or 36 mg/m2
) with gemcitabine and Abraxane. After the recommended phase 2 dose was established, an additional nine patients with untreated disease were treated at this dose level. Four patients (44 percent) in the dose escalation phase received prior 5-fluorouracil-based chemotherapy for metastatic disease.
Of the six patients who received 36 mg/m2
of ADI-PEG 20 in the dose-escalation phase, one experienced a dose-limiting grade 3 liver toxicity, which was considered to be potentially related to the study drug. The recommended phase 2 dose of ADI-PEG 20 was set at 36 mg/m2
Fifteen patients were treated at the recommended phase 2 dose. Best response among these 15, per RECIST v1.1 criteria, was PR in six patients (40 percent) and SD in eight (53 percent). One patient came off the study due to disease progression. Four patients (26.7 percent) had SD of at least eight weeks, and the disease control rate at 24 weeks was 47 percent. The median progression-free survival was 6.5 months and three of the 15 patients (20 percent) were progression-free at 12 months. Two patients remained on study. The median overall survival was 11.3 months (4.9 months to not reached).
Pancreatic cancers are often deficient in argininosuccinate synthetase (ASS), the rate-limiting enzyme involved in arginine synthesis. Arginine has multiple intracellular roles, including nitric oxide formation and protein biosynthesis. In a preclinical study, arginine depletion with ADI-PEG 20 has been shown to be synthetically lethal with ASS deficiency. Synergy between ADA-PEG 20 and docetaxel has also been demonstrated in both preclinical studies and in a phase 1 study of patients with various solid tumors.
The authors of the current study measured ASS expression and found that median levels were 20 percent to 95 percent among the four patients with a confirmed PR, and ranged from 5 percent to 95 percent in those with SD. Arginine depletion was also confirmed in responders; the median duration of depletion up to 10µm was 16 weeks for patients with PR and 13 weeks for patients with SD.
Overall, seven patients (39 percent) had grade 3 or higher toxicity that was considered potentially related to ADI-PEG 20, including four (22 percent) with neutropenia, three (17 percent) with lymphopenia, and one (5 percent) with thrombocytopenia. Six patients (33 percent) reported a rash, predominantly at the injection site, all of which were grade 1 or 2. There were no systemic allergic reactions or seizures attributed to ADI-PEG 20.
“Preliminary assessment of efficacy among patients treated at the maximally tolerated dose [36 mg/m2
] is encouraging, with responses observed in ASS1-deficient and -proficient tumors,” the authors indicated.
A phase 2 trial comparing this regimen to chemotherapy alone in patients with advanced pancreas adenocarcinoma is planned.