Date: 2016-08-04
Type of information: Resumption of patient enrollment
phase: 1-2
Announcement: resumption of patient enrollment
Company: Momenta Pharmaceuticals (USA - MA)
Product: necuparanib (M402) in combination with Abraxane® (paclitaxel) and gemcitabine
Action
mechanism: heparan sulfate mimetic. Necuparanib is a heparan sulfate mimetic, is a novel oncology drug candidate engineered to have a broad range of effects on tumor cells. The use of heparins to treat venous thrombosis in cancer patients has generated numerous reports of antitumor activity; however, the dose of these products has been limited by their anticoagulant activity. Necuparanib, which is derived from unfractionated heparin, has been engineered to have significantly reduced anticoagulant activity while preserving the relevant antitumor properties of heparin. In the next several months,
Disease: metastatic pancreatic cancer
Therapeutic area: Cancer - Oncology
Country: Canada, USA
Trial
details: This phase I/II, two-Part, multicenter study is evaluating the safety and eficacy of M402 in combination with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer. People with primary metastatic pancreatic cancer will be treated with nab-paclitaxel and gemcitabine in combination with necuparanib (M402). It is made from heparin, which is a well known blood thinner. Blood thinners have been shown in prior animal and human studies to have anti-cancer effects. Necuparanib has been re-engineered from heparin to have much lower blood thinning activity while keeping the anti-tumor activity. The investigators are testing whether necuparanib administered in combination with nab-paclitaxel and gemcitabine may be more effective than nab-paclitaxel and gemcitabine. (NCT01621243)
Latest
news: * On August 4, 2016, Momenta Pharmaceuticals announced that the company has discontinued further accrual in its Phase 2 trial evaluating necuparanib in combination with Abraxane® and gemcitabine in patients with advanced metastatic pancreatic cancer. The decision to discontinue enrollment into the study was based on the recommendation from the independent Data Safety Monitoring Board (DSMB) following a planned interim futility analysis conducted once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Data were assessed from 120 randomized patients as of July 20, 2016 . While no new safety signals were observed and the toxicity profile was considered manageable, the DSMB determined that necuparanib in combination with Abraxane® and gemcitabine did not show a sufficient level of efficacy to warrant continued enrollment. Additionally, no new toxicities were observed that necessitate immediate discontinuation of study drug in patients currently active on protocol. The DSMB also recommended that the company consider unblinding the data to provide more information to determine how best to address ongoing patients. * On June 4, 2016, Momenta Pharmaceuticals has presented final results from the phase 1 study of its drug candidate, necuparanib, in patients with metastatic pancreatic cancer at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting (Abstract #4117 / Poster #109: Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Updated Phase 1 Results. Eileen Mary O'Reilly, MD of David M. Rubenstein Center for Pancreatic Cancer Research , Memorial Sloan Kettering Cancer Center). * On December 21, 2015, Momenta Pharmaceuticals announced that it has resumed patient enrollment in its ongoing Phase 2 portion of its multicenter study to evaluate M402 in combination with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer. Study enrollment was paused last month following Momenta's acceptance of recommendations from its Data Safety Monitoring Board (DSMB) to develop guidelines for diagnosing and managing thrombocytopenia, based on a limited number of specific toxicities observed in the study. * On November 13, 2015, Momenta Pharmaceuticals announced that it has put a temporary hold on patient enrollment in its ongoing Phase 2 portion of its multicenter study to evaluate M402 in combination with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer, pending the institution of a protocol amendment following receipt of recommendations from its independent Data Safety Monitoring Board (DSMB). The DSMB met to discuss a limited number of specific toxicities, including thrombocytopenia, risk of bleeding, and thromboembolic events. After thorough review, the DSMB found no safety signals to suggest the need to unblind results, close the study, or discontinue dosing in patients already enrolled in the trial. The DSMB did recommend that the company amend its protocol to standardize the approach to diagnosing and managing thrombocytopenia and consider holding new patient accrual until the amendment is instituted. The DSMB also noted that the causes of thrombocytopenia and subsequent bleeding in these patients can be multifactorial. The Company is assessing whether its protocol amendment and enrollment pause will delay release of top-line data beyond the first half of 2017.
The Phase 1/2 necuparanib trial is a two-part study in patients with advanced metastatic pancreatic cancer. Part A was a Phase 1, open-label, multiple ascending dose study of necuparanib given first as a single dose and then daily in combination with Abraxane® and gemcitabine; final data from Part A was reported at the 2016 ASCO Annual Meeting (see below).
Necuparanib was administered daily in combination with 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, and 15 of each 28-day cycle). The necuparanib starting dose was 0.5 mg/kg, which was increased until the maximum tolerated dose of 5 mg/kg was determined. nabP was added to the treatment regimen starting with the third cohort. Thirty-nine patients (12 patients in the first two cohorts and 27 patients in the five subsequent cohorts) received necuparanib and were included in the analyses. Top-line results included:
Necuparanib was well tolerated when added to standard of care; no increases in incidence, severity, or duration for known adverse events of gem or nabP + gem were observed when combined with necuparanib.
Measurable levels of necuparanib were seen starting at the 2 mg/kg dose group. Release of heparin-binding protein (a pharmacodynamic marker) increased with increasing doses and plateaued at 4-5 mg/kg.
Encouraging signals of activity were observed:
16 patients treated with necuparanib + nabP + gem completed Cycle 1 and had ?1 scan on treatment; 9 (56%) achieved RECIST partial response (PR) and 5 (31%) achieved stable disease, for a disease control rate (DCR) of 14/16 (88%); median OS in this subset was 15.6 months. Median OS of patients treated with ?1 dose of necuparanib + nabP + gem (n=24) was 13.1 months.
24-month survival rates for patients treated with ?1 cycle and ?1 dose of necuparanib + nabP + gem were 25% and 21%, respectively.
Of 15 CA19.9 evaluable patients, 15 (100%) had ?20%, 14 (93%) had ?50%, and 7 (47%) had ?90% decreases from baseline. Momenta Pharmaceuticals expects to report results from the Phase 2 study in the second half of 2017.
