IDO Inhibitor/Chemo Combo Shows Early Promise in Advanced Pancreatic Cancer

Nathan Bahary, MD

Early findings of a phase Ib study investigating the combination of the indoleamine 2,3-dioxygenase (IDO) pathway inhibitor indoximod plus gemcitabine and nab-paclitaxel showed that the regimen elicited durable responses in patients with metastatic pancreatic adenocarcinoma. The objective response rate was 42%.

IDO an Immune Regulator

“The investigators are finding very interesting, prolonged responses in some patients,” said Nathan Bahary, MD, of the University of Pittsburgh Medical Center, who presented the study's findings during the 2016 Gastrointestinal Cancers Symposium. “While we know to be cautious—as plenty of phase I data has been upended on phase II—there appears to be a signal.”IDO is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression. In cancer, IDO mediates an acquired immune tolerance towards tumors.

In other words, IDO allows tumors “to thwart the host immune response,” the investigators explained in their study.

Indoximod is an orally available, small-molecule, broad IDO pathway inhibitor that potentially interferes with multiple targets within the IDO pathway. Preclinical models have demonstrated synergy between indoximod and chemotherapy.

High Response Rate

This phase Ib/II study is evaluating the efficacy of the addition of indoximob to the standard-of-care regimen of gemcitabine and nab-paclitaxel. Indoximod was escalated (600 mg/1000 mg/1200 mg PO twice daily continuous dosing) in combination with gemcitabine (1000 mg/m²) and nab-paclitaxel (125mg/m²) weekly in the first-line metastatic setting until disease progression. The primary endpoints were safety, toxicity, and determination of a phase II dose.Fifteen patients were required to successfully dose escalate the phase I study to 1200 mg twice daily. Two patients were replaced in the lowest dose cohort after rapid deterioration due to underlying disease during the regimen limiting toxicity (RLT) window, the authors noted.

The objective response rate was 42%, including 1 complete response (CR). This is higher than observed in the MPACT trial of patients treated with gemcitabine/nab-paclitaxel (23%), the researchers noted. The 1 patient who achieved a CR did so in cycle 8. A delayed response pattern was seen in a number of patients, which is suggestive of an immune-mediated mechanism of action, Bahary said.

“We are seeing reductions in tumor size of 50% to 70%, and we have some phase II patients with ongoing responses now out to 6 months,” he said. “This is in something that has otherwise been difficult to see with immune therapies.”

Indoximob Well Tolerated

“The overall response rate, observance of a complete response, and delayed and durable response patterns are promising for this combination regimen in metastatic pancreatic cancer,” the researchers noted in the study.The triplet was found to be well tolerated, with 1 dose-limiting toxicity observed during the study (grade 3 ascites) at the highest dose cohort. The most common adverse events (all grade 1 or 2), regardless of attribution, included nausea, fatigue, peripheral edema, peripheral neuropathy, and alopecia.

The phase II dose was set at 1200 mg twice daily; enrollment of the phase II study is ongoing with a target 80 patients.

“We hope to have phase II interim data in time for the 2016 ASCO Annual Meeting, to see if we can confirm those delayed responses,” Bahary added.