Merrimack Pharmaceuticals, Inc., a fully integrated biopharmaceutical company, announced the initiation of a biomarker-selected, multi-arm phase 1 clinical study in metastatic colorectal, non-small cell lung (NSCL), and head and neck cancers.

Merrimack's first-of-its-kind basket study will use a combination of genetic and nongenetic biomarkers to match patients to appropriate novel combinations of investigational drug regimens based on their cancer's molecular signature. This approach is expected to enable more than 95 per cent of eligible patients to qualify for enrollment to one of the investigational arms of the study. Merrimack utilized its systems biology approach to identify the biomarkers and selection criteria of the study.

"This innovative trial design is a major step towards applying precision medicine in the earliest phases of clinical testing, while also ensuring that virtually every patient that enrolls in the study receives one of the investigational regimens," said Christopher Lieu, M.D., Investigator at the CU Cancer Center and Assistant Professor of Medical Oncology at the University of Colorado School of Medicine. "The difficulty with most basket studies is that they identify their patient population solely on genetic mutations, which often results in a very small percentage of patients qualifying for the investigational therapy. By targeting a combination of genetic markers and frequently activated resistance pathways, the vast majority of biopsied patients will be matched to a biomarker-selected study arm."

Merrimack's approach to biomarker profiling and subsequent patient assignment builds on the foundation of previous basket studies. This study design has broadened its scope by also identifying molecular features in the tumor and its surrounding environment that are believed to indicate which signaling mechanisms are responsible for tumor growth and drug resistance. By exploring the dynamics of multiple molecular features, and by including multiple combinations of investigational therapies from its oncology pipeline, Merrimack expects to investigate a personalized drug regimen in almost all of the basket trial's eligible patient population.

"We are committed to implementing precision medicine at every stage of clinical development," said Gavin MacBeath, Ph.D., Merrimack's senior vice president of translational medicine. "At Merrimack, our research has shown that most cancers have multiple mechanisms supporting tumor growth and we are developing a number of investigational agents that are designed to block key drivers of tumor growth and resistance. We know enough about the biology of these pathways to prospectively assign patients to the investigational regimen that we believe most closely matches their specific disease. We believe this is the first trial to rationally combine novel regimens based upon specific multi-dimensional characteristics of the patient's tumor. This unique approach is expected to provide a path forward in developing improved outcomes in difficult to treat patient populations."

All patients enrolling in the study will provide a core needle biopsy, which will be tested for KRAS and NRAS mutations and for expression of two resistance ligands - heregulin (HRG) and insulin-like growth factor 1 (IGF-1).

Patients will receive Merrimack's oligoclonal EGFR (epidermal growth factor receptor) inhibitor, MM-151, in combination with another agent that is intended to target their cancer's mechanism of resistance to EGFR inhibition. Assignment to one of the four trial arms will be based on the following criteria: Patients that test positive for HRG will be assigned to Group A and receive MM-151 in combination with seribantumab (MM-121), a fully human antibody designed to block heregulin-driven ErbB3 pro-survival signaling;  Patients that test negative for HRG and positive for activating mutations in either KRAS or NRAS will be assigned to Group B and receive MM-151 in combination with trametinib, a MEK inhibitor (Novartis). This regimen is designed to block signaling both upstream and downstream of RAS mutations;  Patients that test negative for HRG, wild-type for KRAS and NRAS, and positive for IGF-1 will be assigned to Group C and receive MM-151 in combination with istiratumab (MM-141), a bispecific antibody designed to block IGF-1R and ErbB3 pro-survival signaling; Patients that test negative for both HRG and IGF-1 and wild-type for KRAS and NRAS will be assigned to Group D and receive MM-151 in combination with trametinib. This regimen is designed to block signaling from alternative receptors and to delay potential acquisition of KRAS and NRAS mutations.

MM-151 is an oligoclonal therapeutic mixture consisting of three fully-human monoclonal antibodies designed to bind and inhibit signaling of the epidermal growth factor receptor (EGFR). EGFR-mediated signaling promotes the growth and survival of cancer cells and has long been recognized as an important drug target in several types of cancer, including colon, lung, breast, pancreatic, and head and neck cancers. MM-151 has previously been tested in a phase 1 dose-escalation clinical trial in patients with advanced solid tumors.

Istiratumab is a tetravalent bispecific antibody designed to block tumor survival signals by inhibiting IGF-1R and ErbB3 (HER3) signaling. IGF-1R and ErbB3 complexes activate major signaling pathways that allow tumor cells to grow and develop resistance to chemotherapy. Currently, istiratumab is in Phase 2 testing in patients with metastatic pancreatic cancer that have a pre-defined IGF-1 biomarker profile. The US Food and Drug Administration (FDA) has granted orphan drug designation for istiratumab for the treatment of pancreatic cancer.

Seribantumab is Merrimack's wholly owned, fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, seribantumab is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner. Seribantumab has been investigated in multiple phase 2 and phase 1 clinical trials covering a broad spectrum of patient populations and drug combinations.

Merrimack is a fully integrated biopharmaceutical company that views cancer as a complex engineering challenge. Through systems biology, which brings together the fields of biology, computing and engineering, Merrimack aims to decrease uncertainty in drug development and clinical validation, and move discovery efforts beyond trial and error.