Dose-Escalation Study of TH-302 in Combination With A) Gemcitabine or B) Docetaxel or C) Pemetrexed to Treat Advanced Solid Tumors

All Subjects:

1. Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens

2. Prior treatment with gemcitabine

3. Prior radiotherapy to more than 25% of the bone marrow

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

5. Seizure disorders requiring anticonvulsant therapy

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

7. Previously treated malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years

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

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

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

11. Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 4 weeks prior to study entry

12. Prior therapy with an hypoxic cytotoxin

13. Subjects who participated in an investigational drug or device study within 28 days prior to study entry

14. Known infection with HIV, hepatitis B or C

15. Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302

16. Females who are pregnant or breast-feeding

17. 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

18. Unwillingness or inability to comply with the study protocol for any reason Expanded cohort subjects ONLY: First-line advanced adenocarcinoma of the pancreas

1\. Prior chemotherapy therapy for advanced disease other than radiosensitizing doses of 5-fluorouracil

All Subjects:

1. Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens

2. Prior treatment with docetaxel

3. Prior radiotherapy to more than 25% of the bone marrow unless radiotherapy was completed \>5 years ago and there is not hematologic evidence of persistent bone marrow suppression

4. Uncontrolled pleural effusion or ascites

5. History of sensitivity to drugs formulated with polysorbate 80

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

7. Seizure disorders requiring anticonvulsant therapy

8. Symptomatic brain, leptomeningeal or epidural metastases (unless previously treated and well controlled for a period of ≥ 3 months)

9. Ongoing CTCAE grade 2 or greater peripheral neuropathy

10. Previously treated malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years

11. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation \<90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause systemic or regional hypoxemia

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

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

14. Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 4 weeks prior to study entry

15. Prior therapy with an hypoxic cytotoxin

16. Subjects who participated in an investigational drug or device study within 28 days prior to study entry

17. Known active infection with HIV, hepatitis B or C

18. Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302

19. Females who are pregnant or breast-feeding

20. 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

21. Unwillingness or inability to comply with the study protocol for any reason Expanded Cohort Subjects ONLY: Castrate-resistant prostate cancer

1\. Prior treatment with cytotoxic chemotherapy or radioisotope therapy Expanded Cohort Subjects ONLY: Second-line NSCLC

1. More than one prior cytotoxic chemotherapy regimen for advanced disease

2. Weight loss of \>10% body weight in the previous 6 weeks

All Subjects:

1. Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens

2. Prior treatment with pemetrexed

3. Prior radiotherapy to more than 25% of the bone marrow

4. Inability to discontinue non-steroidal anti-inflammatory drugs for 5 days (long half-life) or 2 days (short half-life, if subject has CrCl \<80 mL/min) before until 2 days following pemetrexed dosing

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

6. Seizure disorders requiring anticonvulsant therapy

7. Symptomatic brain, leptomeningeal or epidural metastases (unless previously treated and well controlled for a period of ≥ 3 months)

8. Previously treated malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years

9. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation \<90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause systemic or regional hypoxemia

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

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

12. Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 4 weeks prior to study entry

13. Prior therapy with an hypoxic cytotoxin

14. Subjects who participated in an investigational drug or device study within 28 days prior to study entry

15. Known active infection with HIV, hepatitis B, or hepatitis C

16. Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302

17. Females who are pregnant or breast-feeding

18. 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

19. Unwillingness or inability to comply with the study protocol for any reason Expanded Cohort Subjects ONLY: Second-line NSCLC

1\. More than one prior cytotoxic chemotherapy regimen for advanced disease 2. Weight loss of \>10% body weight in the previous 6 weeks

What this study is about