Novel therapy with indoximod, an indoleamine 2,3-dioxygenase (IDO) pathway inhibitor, in combination with standard chemotherapy, yielded a response rate of 42% as first-line therapy for metastatic pancreatic adenocarcinoma
“The investigators are finding very interesting, prolonged responses in some patients,” said Nathan Bahary, MD, of the University of Pittsburgh Medical Center, in Pennsylvania, who presented the findings. “While we know to be cautiousas plenty of phase 1 data has been upended on phase 2—there appears to be a signal.”
IDO an Immune Regulator
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 poster.
Indoximod is an orally available, small molecule, broad IDO pathway inhibitor that potentially interferes with multiple targets within the IDO pathway. Pre-clinical models have demonstrated synergy between indoximod and chemotherapy.
This phase 1b/2 study is evaluating the effect of adding indoximob to the standard-of-care regimen of gemcitabine and nab-paclitaxel (gem/nab). Researchers presented the phase 1b portion of the study at the Symposium.
Indoximod was escalated (600mg/1000mg/1200mg 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 2 dose.
High Response Rate
Fifteen patients were required to successfully dose escalate the Phase 1 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 objective response rate was 42% (including one complete response), which is higher than observed in the MPACT trial of patients treated with gemcitabine/nab-paclitaxel (23%), the researchers noted.
The one patient with a complete response achieved this in Cycle 8. A delayed response pattern was seen in a number of patients, which is suggestive of an immune-mediated mechanism of action, Dr. Bahary said.
“We are seeing reductions in tumor size of 50% to 70%, and we have some phase 2 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.”
“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 on their poster.
Indoximob Well Tolerated
The triplet was well tolerated, investigators noted. Only one dose-limiting toxicity was observed during the study (ascites Grade 3) at the highest dose cohort. The most common adverse events (all Grade 1 or 2), regardless of attribution, were nausea, fatigue, peripheral edema, peripheral neuropathy, alopecia.
The Phase 2 dose was set at 1200 mg twice daily and Phase 2 enrollment (target 80 patients) is ongoing.