Open-label Study of TH-302 and Dexamethasone With or Without Bortezomib in Subjects With Relapsed/Refractory Multiple Myeloma

Inclusion Criteria:

• At least 18 years of age.
• Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee.
• Relapsed/refractory multiple myeloma for which no standard therapy options are anticipated to result in a durable remission.
• Subjects with refractory disease are allowed to participate on study. (Refractory disease is defined as progressive disease within 60 days of last therapy or progression while on therapy).
• Receipt of at least two prior therapies (induction therapy with stem cell transplant with or without maintenance is considered a prior therapy) including prior therapy with a bortezomib-containing regimen (and did not discontinue due to toxicity) and a lenalidomide- or thalidomide-containing regimen

• Subjects with measurable disease defined as at least one of the following:

  • Serum M-protein ≥ 0.5 mg/dl
  • Urine M-protein ≥ 200 mg/24 h
  • Serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l)
  • Measurable plasmacytoma (should be measured by CT or PET/CT within 28 days of initial investigational agent dosing).
• ECOG performance status of less than or equal to 2 (see Appendix B)
• Acceptable liver function:
• Total bilirubin ≤ 1.5 times upper limit of normal (x ULN). If total bilirubin is elevated, check direct and if normal then the subject is eligible
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3.0 x ULN (≤ 5.0 x ULN if due to myeloma involvement).
• Alkaline phosphatase ≤ 3.0 x ULN (≤ 5.0 x ULN if due to leukemic involvement)
• Acceptable renal function:
• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance above 40 mL/min using the formula of Cockcroft and Gault, or a 24 hr creatinine clearance if borderline
• Acceptable hematologic status (without hematologic support):
• ANC ≥ 1000 cells/μL (growth factors may not be used within 7 days prior to evaluation)
• Platelet count ≥ 75,000/μL (for subjects in whom < 50% of bone marrow nucleated cells are plasma cells); platelet count > 50,000/μL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells (without transfusion during the previous 14 days prior to evaluation)
• Hemoglobin ≥ 8.0 g/dL (without transfusion during the previous 14 days prior to evaluation).
• All women of childbearing potential must have a negative serum pregnancy test and women and men subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose
• Subjects must adhere to the study visit schedule and other protocol requirements and receive outpatient therapy and laboratory monitoring at the institute that administers the study drug.

Exclusion Criteria:

• Subjects with non secretory or hyposecretory MM
• POEMS syndrome (polyneuropathy, organomegaly, endrocintopathy, monoclonal gammothy and skin changes.
• Plasma cell leukemia
• Waldnestrom's macroglobinemia
• Subject with known or suspected amyloidosis
• Corticosteroid therapy in a dose equivalent to dexamethasone > 1.5 mg/day or prednisone > 10 mg/day within 2 weeks prior to first dose, Subjects may be receiving chronic corticosteroids if they are being given for disorders other than multiple myeloma if they meet the above
• Planned radiation therapy that occurs after the start of therapy
• Localized radiation therapy to only measurable disease site(s) within 4 weeks of treatment
• New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within 6 months prior to Day 1, or unstable arrhythmia
• Significant neuropathy (Grade 3 or 4, or Grade 2 with pain) at the time of enrollment or within 14 days before enrollment
• Symptomatic brain metastases (unless previously treated and well controlled for a period of ≥ 3 months)
• Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
• Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy within 14 days prior to the first dose
• Previously treated malignancies, except for adequately treated non-melanoma skin cancer (basal cell or squamous cell), in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years
• Subjects who participated in an investigational drug or device study within 2 weeks prior to study entry
• Known or suspected active infection with HIV, hepatitis A, hepatitis B, or hepatitis C
• Subjects who have exhibited allergic reactions to a similar structural compound, biological agent, or formulation similar to TH-302, bortezomib or pimonidazole
• Females who are pregnant or breast-feeding
• Concomitant psychiatric disease or medical condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
• Unwillingness or inability to comply with the study protocol for any reason
• All previous cytotoxic therapies for multiple myeloma must have been completed at least 3 weeks prior to start of study. Biologic, novel therapy or corticosteroids must have been completed at least 2 weeks prior to start of study.
• Subjects who have been on hormone replacement less than 2 months (subjects on hormone replacement for at least 2 months will not be excluded provided the HRT regimen remains unchanged during the conduct of the study).
• Prior peripheral stem cell transplant within 12 weeks of the start of study
• Epilepsy or other convulsive disorder requiring active management