Heparan Sulfate-Like Drug Active in Pancreatic Cancer

Article

Half of patients with metastatic pancreatic cancer had objective responses when treated with a novel inhibitor of heparin-binding growth factors in addition to conventional chemotherapy, a small preliminary clinical trial showed.

Eileen M. O'Reilly, MD

Half of patients with metastatic pancreatic cancer had objective responses when treated with a novel inhibitor of heparin-binding growth factors in addition to conventional chemotherapy, a small preliminary clinical trial showed.

Eight of 16 evaluable patients had partial responses to necuparanib plus nab-paclitaxel and gemcitabine. Six others had stable disease, resulting in a disease control rate of 88%.

The addition of necuparanib did not increase the frequency or severity of adverse events known to be associated with the other two drugs, as reported at the 2016 ASCO Annual Meeting in Chicago.

“We observed encouraging signals of activity in this preliminary clinical study,” reported Eileen M O’Reilly, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. “Noting differences in sample sizes and study populations, these results compared favorably with published data for the combination of nab-paclitaxel and gemcitabine.”

The results supported further evaluation in an ongoing randomized, double-blind phase 2 clinical trial, she and her colleagues concluded in a poster presentation.

Several studies of heparins to treat cancer-associated venous thromboembolism have produced evidence of anticancer activity. However, the anticoagulant activity of heparins, and associated dosing limitations, has been an obstacle to assessment of the anticancer potential the drug class.

Necuparanib is a low-anticoagulant heparan sulfate mimetic that has retained activity against molecules involved in tumor angiogenesis (such as VEGF, kFGF-2, and heparanase), progression (such as SDF-1 alpha), and metastasis (P-selection and heparanase).

O’Reilly and colleagues reported findings from a phase I trial to assess the safety, tolerability, and recommended phase II dose of necuparanib for use in combination with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer.

Investigators administered open-label necuparanib in escalating doses to seven cohorts totaling 39 patients. All patients received nab-paclitaxel at a dose of 125 mg/m2and gemcitabine 1000 mg/m2on days 1, 8, and 15 of each 28-day cycle.

The study population had a mean age of 63 and was predominantly female (27 of 39) and white (35 of 39). They received necuparanib at doses ranging from 0.5 mg/kg to 6 mg/kg. A dose of 5 mg/kg was selected for phase II evaluation.

The most common adverse events (any grade) at the highest doses evaluated (1-6 mg/kg, N=27) were anemia and fatigue (52% each); neutropenia (48%); leukopenia and thrombocytopenia (44% each); elevated ALT and nausea (41% each); abdominal pain (37%); diarrhea (33%); and elevated AST, hyperglycemia, hypoalbuminemia, and peripheral neuropathy (30% each).

Grade 3/4 adverse events occurred infrequently, the most common being elevated ALT (four patients, 15%). No other grade 3/4 adverse event affected more than one patient.

Of the 39 patients enrolled, 16 were evaluable for response. Eight patients had partial responses and six others achieved stable disease. The 16 patients had a median overall survival of 16 months. In the subset of 24 patients who received at least one dose of therapy, median overall survival was 12.4 months.

Data on the cancer associated antigen CA19-9 were available for 15 patients. All 15 had at least a 20% decrease in CA19-9 from baseline, 14 (93%) had >50% decrease, and seven had >90% decrease.

The manufacturer of necuparanib, Momenta Pharmaceuticals, reports in a statement that a phase II, randomized, double-blind, controlled study in pancreatic cancer is ongoing, which will evaluate the antitumor activity of necuparanib in combination with nab-paclitaxel plus gemcitabine, versus nab-paclitaxel plus gemcitabine alone. Necuparanib has received orphan drug and fast track designations from the FDA for the treatment of pancreatic cancer.

O’Reilly EM, Mahalingam D, Roach JM, et al. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of necuparanib combined with nab-Paclitaxel and gemcitabine in patients with metastatic pancreatic cancer: Updated phase 1 results.J Clin Oncol34, 2016 (suppl; abstr 4117).

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