Merrimack Pharmaceuticals, Inc. today announced Phase 1 results from a clinical pilot study demonstrating that ferumoxytol*, an iron oxide nanoparticle, was well tolerated when used as a tumor contrast agent prior to MM-398 treatment. Data from the first cohort of patients in this study were presented at the American Association of Cancer Research Annual Meeting, April 5-9, 2014, in San Diego, California.
"This application of ferumoxytol magnetic resonance imaging has the potential to become a minimally invasive predictive biomarker for liposomal therapies. We hope that the continuation and expansion of this approach will allow us to identify patients most likely to benefit from MM-398 treatment," said Jonathan Fitzgerald, Ph.D., Senior Director of Discovery at Merrimack. "Though our initial data are from a small sample of a diverse patient population, we are encouraged to see that almost all of the tumor lesions that shrank after MM-398 treatment were associated with higher levels of ferumoxytol, as seen on the MRI."
Ferumoxytol's propensity for uptake by tumor associated macrophages and similar distribution patterns to MM-398 in preclinical models led to the clinical feasibility study. The ability to image and analyze the levels of ferumoxytol in tumors may be correlated to estimating the MM-398 tumor concentration.
These data are also supported by Merrimack's proprietary Systems Biology approach, as computational modeling of ferumoxytol MRI was used to calculate parameters describing its behavior in tumor tissue. This modeling platform, coupled with the imaging approach with ferumoxytol MRI, may be useful as a predictive biomarker of nanotherapeutics such as MM-398. Primary objectives of this study are to evaluate the feasibility of ferumoxytol to identify tumor-associated macrophages, which may positively correlate with MM-398 activity, and to measure tumor levels of irinotecan and SN-38. The ongoing study has shown that there were no safety-related interactions between ferumoxytol and MM-398 in this preliminary patient population.
Methodology and Results
Pilot study in patients with advanced solid tumors to evaluate feasibility of ferumoxytol (FMX) as tumor imaging agent prior to MM-398, a nanoliposomal irinotecan (nal-IRI) (Poster #CT224)
- To evaluate the feasibility and safety of ferumoxytol prior to MM-398 treatment, 12 eligible patients were enrolled with refractory solid tumors in multiple indications, including ER/PR-positive breast cancer, pancreatic cancer and ovarian cancer.
- Scans were performed prior to and following ferumoxytol infusion at 1h, 24h, and 72h. Patients were biopsied at 72h to ferumoxytol high or low regions, and continued on MM-398 treatment at 80 mg/m2 biweekly until progression.
- Ferumoxytol levels were quantified from Fe-MRI scans and biopsy images. Measurements of tumor tissue analyses and drug metabolites in this study confirmed previous analytics by pharmacokinetic modeling of tumor tissue permeability and binding to ferumoxytol, based on prior preclinical and clinical observations.
- Overall, ferumoxytol was well tolerated, with no safety-related interactions with MM-398. Adverse events of MM-398 therapy were consistent with previous studies, and no adverse events were directly attributable to ferumoxytol.
MM-398 is a nanoliposomal formulation of irinotecan (nal-IRI). MM-398 is being evaluated in several clinical trials including a Phase 3 study in metastatic pancreatic cancer, a Phase 2 study in patients with metastatic colorectal cancer and a Phase 1 clinical pilot study. MM-398 is not approved for any indication by the U.S. Food and Drug Administration or any other regulatory agency. Under a 2011 agreement with PharmaEngine, Inc. (Taipei, Taiwan), Merrimack consolidated the worldwide development and commercialization rights to MM-398, with the exception of commercialization rights in Taiwan, which are held by PharmaEngine, Inc.
Merrimack is a biopharmaceutical company discovering, developing and preparing to commercialize innovative medicines paired with companion diagnostics for the treatment of cancer. Merrimack applies its systems biology-based approach to biomedical research throughout the research and development process. Merrimack currently has six oncology therapeutics in clinical development. For more information, please visit Merrimack's website at www.merrimackpharma.com.
*Ferumoxytol, commercially available as Feraheme® (AMAG Pharmaceuticals),is an iron-oxide, super-paramagnetic nanoparticle, known to be taken up by macrophages and for exhibiting magnetic resonance imaging properties. The U.S. Food and Drug Administration has approved ferumoxytol for intravenous use as an iron replacement product for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). The use of ferumoxytol in the pilot study mentioned above is for clinical investigational studies only.