Inclusion Criteria:

• Pathologically confirmed diagnosis of solid tumors, CRC, TNBC, ER/PR Breast Cancer, NSCLC, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer, GEJ adenocarcinoma, Head and Neck Cancer
• Metastatic disease
• ECOG Performance Status 0 to 2
• Adequate bone marrow, hepatic and renal function
• Normal ECG
• 18 years of age or above
• Able to understand and sign informed consent

Expansion Phase Additional Criteria:

The following invasive breast cancer tumor sub-types are required:

• Cohorts 1 and 2 must be documented to be HER2 negative as outlined in the ASCO/CAP 2013 guidelines for HER2 testing, defined by at least one of the following:
  • HER2 immunohistochemistry (IHC) staining of 0 or 1+,OR if HER2 IHC 2+
  • Negative by In-Situ Hybridization (ISH) based on defined as a Single probe average HER2 copy number <4.0 signals/cell
  • OR Negative by Dual-probe ISH defined as a HER2/CEP17 ratio <2.0 with an average HER2 copy number <4.0 signals/cell
• Cohort 1: hormone receptor positive breast cancer patients with ER-positive and/or PR-positive tumors defined as ≥1% of tumor nuclei that are immunoreactive for ER and/or PR and HER2 negative
• Cohort 2: triple negative breast cancer (TNBC) patients with ER-negative, PR-negative tumors defined as < 1% of tumor nuclei that are immunoreactive for ER and PR and HER2 negative
• Cohort 3: Any sub-type of metastatic breast cancer and active brain metastases
• Documented locally advanced or metastatic disease with at least two radiologically measurable lesions as defined by RECIST v1.1 (except Expansion Cohort 3)
• ECOG performance status 0 or 1
• Bone marrow reserves as evidenced by: ANC > 1,500 cells/μl without the use of hematopoietic growth factors; Platelet count > 100,000 cells/μl; Hemoglobin > 9 g/dL
• Adequate hepatic function as evidenced by: Normal serum total bilirubin; AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are present)
• Adequate renal function as evidenced by serum creatinine ≤ 1.5 x ULN
• Normal ECG or ECG without any clinically significant findings
• Recovered from the effects of any prior surgery, radiotherapy or other anti-neoplastic therapy
• At least 18 years of age
• Able to understand and sign an informed consent (or have a legal representative who is able to do so)
• Received at least one cytotoxic therapy in the locally advanced and metastatic setting, with exception of TNBC patients who progressed within 12 months of adjuvant therapy
• Received 5 prior lines of chemotherapy in the metastatic setting (no limit to prior lines of hormonal therapy in Cohort 1)
• At least one lesion amenable to multiple pass core biopsy (exception: Cohort 3 patients)
• Candidate for chemotherapy

Expansion Phase Cohort 3 additional inclusion criteria:

• Radiographic evidence of new or progressive brain metastases after prior radiation therapy with at least one brain metastasis measuring ≥ 1 cm in longest diameter on gadolinium-enhanced MRI (note: progressive brain lesions are not required to meet RECIST criteria in order to be eligible; extra-cranial metastatic disease is also allowed)
• Neurologically stable
• No evidence of diffuse leptomeningeal disease on brain MRI or by previously documented cerebrospinal fluid (CSF) cytology. NOTE: discrete dural metastases are permitted.

Exclusion Criteria:

• Active CNS metastasis (applies to pilot phase and expansion phase cohort 1 and 2 only)
• Clinically significant GI disorders
• Prior irinotecan or bevacizumab therapy within last 6 months and for Expansion Phase patients, have received any prior treatment with Topol inhibitor
• Known hypersensitivity to MM-398 or ferumoxytol
• Inability to undergo MRI
• Active infection
• Pregnant or breast feeding
• Prior chemotherapy administered within 3 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to the first scheduled day of dosing in this study
• Received radiation therapy in the last 14 days
• Treated with parenteral iron in the previous 4 weeks