A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma

Hypoxia is an independent marker of a poor prognosis for subjects with metastatic melanoma
(Simonetti 2012, Lartigau 1997). Hypoxic melanoma cells are more likely to exhibit a
stem-cell like phenotype with an associated increased propensity for invasion, angiogenesis,
and metastasis formation compared to normoxic cells. Moreover, this phenotype is also
associated with treatment resistance. TH-302, a hypoxia activated prodrug (HAP), was
designed to target the hypoxic nature of tumours while having a minimal effect on normoxic
tissue. TH-302 belongs to a class of alkylating agents that have significant experimental
and clinical activity (Brock 1989). Preclinical data support the hypothesis that TH-302
targets hypoxic regions of tumours and is also able to kill tumour cells in normoxic regions
as a result of cytotoxin diffusion, leading to significant effects on tumour growth (Meng
2011). TH-302 has been investigated in over 700 subjects with solid tumours or hematologic
malignancies, including subjects with metastatic melanoma. In this subset a disease control
rate of 63% (3 subjects with partial responses and 9 subjects with stable disease out of a
total of 19) was observed in an early phase clinical trial of TH-302 (Weber 2010).
Predictive biomarkers for response and toxicity have yet to be identified for subjects with
advanced melanoma treated with TH-302. Optimal patient selection may be critical to maximize
the clinical benefit. A predictive biomarker approach will be investigated to try to
identify subjects most likely to benefit from TH-302. Given the hypoxia-targeting mechanism
of TH- 302, it is believed that hypoxia biomarkers will be the most informative for
identifying subjects likely to benefit from TH- 302; however, additional biomarkers
including DNA repair biomarkers will also be investigated. In addition, this approach will
also have potential to synergise with future immunotherapeutic approaches as suppressive T
regulatory cells are thought to reside within hypoxic niches within the tumour
microenvironment that would be amenable to targeting by TH-302.

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 Regional Ethics
Board/Independent Ethics Committee (REB/IEC)

3. Histologically documented cutaneous or mucosal malignant melanoma, which is recurrent
or metastatic and is not curable by surgical or other means.

4. Adequate tumour tissue (greater than 0.5cm3 preferred, 3 X core biopsy acceptable)
available and agreement from subjects that this tissue from their primary and/or
metastatic tumour be made available for assessment of potential biomarkers.

5. Ability and availability to complete all prescribed biomarker studies (Screening and
after Cycle 2).

6. Recovered to Grade 1 from reversible toxicities of prior therapy

7. Presence of clinically and/or radiologically documented disease. At least one site of
disease (which will not be removed during the course of the study) must be
uni-dimensionally measurable as per RECIST 1.1 or clinically quantifiable (such as in
the case of skin disease)

8. ECOG performance status of 0 - 1.

9. Prior treatment with any number of immunotherapies (e.g., IL2, ipilimumab), targeted
therapies (e.g., vemurafenib) are permitted but no more than one 1 prior chemotherapy

10. Acceptable liver function

11. Acceptable renal function

12. Acceptable hematologic status (without growth factor support for neutropenia or
transfusion dependency):

13. Normal 12-lead ECG (clinically insignificant abnormalities permitted)

14. Female subjects of childbearing age must have a negative urine HCG test unless prior
hysterectomy or menopause (defined as age above 55 and twelve months without
menstrual activity). Female subjects should not become pregnant or breast-feed while
on this study. Sexually active male and female subjects should use effective birth
control.

Exclusion Criteria:

1. Anticancer treatment with radiation therapy, targeted therapies, chemotherapy,
immunotherapy, hormones or other antitumour therapies within 28 days prior to first
dose of TH-302.

2. Subjects who have received any other investigational drug or agent within 28 days of
first dose of TH-302

3. Current use of drugs with known cardiotoxicity

4. Significant cardiac dysfunction:

5. Seizure disorders requiring anticonvulsant therapy

6. Progressing brain metastases (unless previously treated and stable disease for a
period of greater than or equal to 3 months on repeat MRI following definitive
treatment).

7. History of other malignancies, except: adequately treated non-melanoma skin cancer,
curatively treated in-situ cancer of the cervix, or other solid tumours curatively
treated with no evidence of disease for greater than 2 years

8. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires
supplementary oxygen, symptoms due to hypoxemia or oxygen saturation less than 90% by
pulse oximetry after a 2 minute walk) or in the opinion of the investigator any
physiological state likely to cause hypoxia of normal tissue.

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

10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy

11. Prior therapy with an hypoxic cytotoxin

12. Known infection with HIV or active infection with hepatitis B or hepatitis C

13. History of allergic reaction to a structural compound or biological agent similar to
TH-302

14. Pregnancy or breast-feeding

15. Concomitant disease or 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.