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

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 and dexamethasone with a Simon two-stage expansion at the MTD. The study
will also investigate the DLTs, MTD, safety and preliminary efficacy of TH-302,
dexamethasone and bortezomib; and the DLTs, MTD, safety and preliminary efficacy of TH-302,
dexamethasone and pomalidomide. As such, the study is separated into four parts. Treatment
will be administered until disease progression or unacceptable toxicity, or 12 cycles (Arm
A, Arm B and Arm C) or 9 cycles (Arm D) have been completed.

Inclusion Criteria:

1. At least 18 years of age.

2. 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.

3. Relapsed/refractory multiple myeloma for which no standard therapy options are
anticipated to result in a durable remission.

4. Receipt of at least two prior therapies as indicated by protocol

5. Subjects with measurable disease

6. ECOG performance status of less than or equal to 2

7. Acceptable liver function

8. Acceptable renal function

9. Acceptable hematologic status

10. For Part A, B, C subjects: Women of childbearing potential must have a negative serum
pregnancy test and women and men subjects must agree to use effective means of
contraception with their partner as indicated by protocol For Part D subjects: a
negative serum pregnancy test is required within 10- 14 days prior to initiating with
pomalidomide, AND a negative serum pregnancy test within 24 hours of starting
pomalidomide and must either commit to continued abstinence from heterosexual
intercourse or begin two acceptable methods of birth control at least 28 days before
she starts taking pomalidomide.

Women of childbearing potential must enroll into and follow all requirements of the
POMALYST REMS program, which includes adhering to the scheduled pregnancy testing.

Men must agree to use a latex or synthetic condom during sexual contact with women of
child bearing potential even if they have had a vasectomy.

All subjects must be counseled at a minimum of every 28 days about pregnancy
precautions and risks of fetal exposure, or when a female patient misses her period
or if there is any abnormality in her menstrual bleeding.

11. 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 who meet any of the following exclusion criteria are not eligible to be enrolled
in this study:

1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy
and skin changes.)

2. Waldenstrom's macroglobulinemia

3. Localized radiation therapy to only measurable disease site(s) within 2 weeks of
treatment

4. New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial
infarction within 6 months prior to Day 1, or unstable arrhythmia

5. Significant neuropathy (Grade 3 or 4, or Grade 2 with pain) at the time of enrollment
or within 14 days before enrollment

6. Symptomatic brain metastases (unless previously treated and well controlled for a
period of ≥ 3 months)

7. Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the
investigator any physiological state leading to hypoxemia

8. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without
complete recovery

9. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy within 14 days prior to the first dose

10. 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

11. Subjects who participated in an investigational drug or device study within 2 weeks
prior to study entry

12. Known or suspected active infection with HIV, hepatitis A, hepatitis B, or hepatitis
C

13. Subjects who have exhibited allergic reactions to a similar structural compound,
biological agent, or formulation similar to TH-302, bortezomib (for subjects enrolled
in Part C only), pomalidomide (Part D), dexamethasone or pimonidazole

14. Females who are pregnant or breast-feeding

15. 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

16. Unwillingness or inability to comply with the study protocol for any reason

17. Previous cytotoxic therapies for multiple myeloma within 3 weeks prior to study entry
(2 weeks for biologic, novel therapy or corticosteroids)

18. 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).

19. Prior peripheral stem cell transplant within 12 weeks of the start of study

20. Epilepsy or other convulsive disorder requiring active management

21. Prior therapy with a pomalidomide-containing regimen

22. Subjects on strong inducers or strong inhibitors of cytochrome P450 CYP3A4 or CYP1A2

23. Any other medical condition that in opinion of investigator would place patient at
increased risk for toxicity during pomalidomide treatment (i.e. history of recurrent
or serious thromboembolic events)