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

• safety and tolerability of TH-302 monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TH-302 monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• recommended Phase 2 dose for TH-302 monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

• preliminary efficacy of TH-302 monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• relationship between hypoxia within the bone marrow of subjects with relapsed/refractory multiple myeloma and response to TH-302 monotherapy and in combination with bortezomib using markers of hypoxia (e.g. pimonidazole) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• pharmacokinetics of TH-302 as a monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma including subjects with moderate or subclinical renal insufficiency [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• progression free survival of subjects with relapsed/refractory multiple myeloma [ Time Frame: 2 years ] [ Designated as safety issue: No ]

The primary objectives of this study are:

1. To evaluate the safety and tolerability of TH-302 and dexamethazone with or without bortezomib in subjects with relapsed/refractory multiple myeloma
2. To identify the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) of TH-302 and dexamethazone with or without bortezomib in subjects with relapsed/refractory multiple myeloma
3. To identify a recommended Phase 2 dose for TH-302 and dexamethasone with or without bortezomib in subjects with relapsed/refractory multiple myeloma

The secondary objectives are:

1. To assess the preliminary efficacy of TH-302 and dexamethasone with or without bortezomib in subjects with relapsed/refractory multiple myeloma
2. To study the relationship between hypoxia within the bone marrow of subjects with relapsed/refractory multiple myeloma and response to TH-302 and dexamethasone with or without bortezomib using markers of hypoxia (e.g. pimonidazole)
3. To study the pharmacokinetics of TH-302 and bortezomib in subjects with relapsed/refractory multiple myeloma including subjects with moderate or subclinical renal insufficiency
4. To assess progression free survival of subjects with relapsed/refractory multiple myeloma treated with TH-302 and dexamethasone with or without bortezomib

This is the initial study of TH-302 in subjects with relapsed/refractory multiple myeloma. It is an open-label dose-escalation study to determine the DLTs, MTD, safety and preliminary efficacy of TH-302 as a monotherapy with a Simon two-stage expansion at the MTD. The study will also investigate the DLTs, MTD, safety and preliminary efficacy of TH-302 in combination with Bortezomib. As such, the study is separated into three parts. Treatment will be administered on a 21-day cycle, until disease progression or unacceptable toxicity, or 12 cycles have been completed.

Part A: Monotherapy TH-302 Dose Escalation

The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. A Dose Level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue with approximately 40% increases from the previous dose level; however lower dose increases of 20-39% may be implemented after consultation between the Investigators, Medical Monitor and Sponsor with the percent increase dependent on the current dose level and the cumulative safety data.

Before applying the dose escalation rules, all three subjects in a given cohort dose level must complete 21 days (1 cycle) of therapy and safety evaluation. If the first 3 subjects within a cohort tolerate the first 21 days of therapy without dose limiting toxicity (DLT) as defined below, the next cohort may proceed.

If one of 3 subjects experiences a DLT during the first treatment cycle, 3 additional subjects will be enrolled at that dose level for a total of 6 subjects in that cohort. If no additional DLTs are observed, the next dose escalation will resume. However, if 2 or more of 6 subjects within a cohort experience a DLT, that dose will be considered to exceed the MTD. If at any time during a cohort, >2 subjects experience a drug-related DLT, the MTD will have been exceeded, additional enrollment will cease and dose escalation will stop.

The MTD will then be defined at the highest dose level whereby 6 subjects were treated and no more than 1 subject experienced a DLT and at least 2 subjects had a DLT at the next higher dose level. The maximum safe dose of TH-302 will be the single agent MTD or the highest dose tested in that study if the MTD was not reached.

Once the MTD has been reached an additional 3 subjects (for a total of 9) will be dosed at the MTD to access efficacy. If 2 DLTs do not occur in any dose level of the dose escalation of Part A and the highest dose tested is defined as the MTD, an additional 3 subjects (for a total of 9) will be dosed at the highest dose tested.

A Simon two-stage design will be implemented at the MTD. If there is sufficient activity (1 or more subjects of the first 9 subjects achieves partial response or better), then monotherapy enrollment will be expanded to Part B. If there is insufficient activity (no partial response or better in 9 subjects), then no further investigation of TH-302 as a monotherapy is warranted and investigation of TH-302 in combination with bortezomib begins in Part C.

Part B: Monotherapy TH-302 MTD Dose Expansion

If there is sufficient activity in Part A at the MTD (at least 1 of 9 subjects achieves partial response or better), an additional 15 subjects will be enrolled for a total of 24 subjects treated at the MTD. After the last patient in the Part B expansion has completed Cycle 1 and review of the cumulative safety data confirms that the monotherapy is well-tolerated, patients may be enrolled into Part C of the trial (TH-302 in combination with bortezomib).

Part C: TH-302 Dose Escalation in combination with bortezomib

The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. Follow same DLTs as above. A Dose Level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue with 40% increases from the previous dose level; however lower dose increases of 20-39% may be implemented after consultation between the Investigators, Medical Monitor and Sponsor with the percent increase dependent on the current dose level and the cumulative safety data.

The dose of bortezomib will remain fixed at 1.3 mg/m2. If a subject experiences a DLT, 3 additional subjects will be enrolled at that dose level for a total of 6 subjects in that cohort. If no additional DLTs are observed, dose escalation will resume. However, if 2 or more of 6 subjects within a cohort experience a DLT, that dose will be considered to exceed the MTD. The MTD will then be defined at the next lower dose level whereby 6 subjects were treated and no more than one subject experienced a DLT. The maximum safe dose of TH-302 and 1.3 mg/m2 of bortezomib will be the combination MTD or the highest dose tested if the MTD was not reached.

The MTD will be based on toxicities occurring during the first cycle.

An additional 6 subjects (for a total of 12) will be enrolled at the MTD for the dose expansion portion of the study. If 2 DLTs do not occur in the dose escalation of Part C and the highest dose tested is defined as the MTD, an additional 6 subjects (for a total of 12) will be dosed at the highest dose tested.

TH-302 will be administered by IV infusion over 30-60 minutes on Days 1, 4, 8 and 11 of a 21 day cycle.

Bortezomib will be administered by IV push over 3-5 seconds on Days 1, 4, 8 and 11 of a 21 day cycle. On days where bortezomib and TH-302 are given on the same day, administer bortezomib at least 2 hours after TH-302 infusion.

There will be no dose escalation in individual subjects. Missed doses will not be made up. Doses of TH 302 or bortezomib may be rescheduled for +2 days, if the scheduled dose falls on a holiday. Anticipated delays of >2 days should be discussed with the medical monitor.

Subjects who successfully complete a 3-week treatment cycle without evidence of significant treatment-related toxicity or progressive disease will continue to receive treatment for up to 12 cycles.

Up to six subjects may be enrolled in any of the other cohorts below the MTD. Subjects receiving less than 4 days of dosing and not experiencing a DLT during Cycle 1 will be replaced. In addition, subjects not completing the first 21 days of Cycle 1 and not experiencing a DLT may be replaced at the discretion of the Principal Investigator.

• Drug: TH-302
  The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. A Dose Level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue with approximately 40% increases from the previous dose level; however lower dose increases of 20-39% may be implemented after consultation between the Investigators, Medical Monitor and Sponsor with the percent increase dependent on the current dose level and the cumulative safety data.
• Drug: TH-302
  If there is sufficient activity in Part A at the MTD (at least 1 of 9 subjects achieves partial response or better), an additional 15 subjects will be enrolled for a total of 24 subjects treated at the MTD. After the last patient in the Part B expansion has completed Cycle 1 and review of the cumulative safety data confirms that the monotherapy is well-tolerated, patients may be enrolled into Part C of the trial (TH-302 in combination with bortezomib).
• Drug: TH-302 and bortezomib

  The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. Follow same DLTs as above. A Dose Level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue with 40% increases from the previous dose level; however lower dose increases of 20-39% may be implemented after consultation between the Investigators, Medical Monitor and Sponsor with the percent increase dependent on the current dose level and the cumulative safety data.

  The dose of bortezomib will remain fixed at 1.3 mg/m2.

• Experimental: Monotherapy TH-302 Dose Escalation
  Intervention: Drug: TH-302
• Experimental: Monotherapy TH-302 MTD Dose Expansion
  Intervention: Drug: TH-302
• Experimental: TH-302 Dose Escalation in combination with bortezomib
  Intervention: Drug: TH-302 and bortezomib

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