Inclusion Criteria:

Gemcitabine + 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 IRB/Ethics Committee

3. Dose escalation subjects:

   1. Histologically or cytologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective OR solid malignancy for which monotherapy with gemcitabine is considered standard therapy
   2. Tumor progression after most recent therapy

   Dose expansion subjects:

   a. Locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma proven either by histology (surgical biopsy) or cytology (CT- or endoscopic-guided) previously untreated with chemotherapy other than radiosensitizing doses of 5-fluorouracil

4. Recovered from toxicities of prior therapy to grade 0 or 1
5. Evaluable disease by RECIST criteria (at least one target or non-target lesion)
6. ECOG performance status of 0 or 1
7. Life expectancy of at least 3 months

8. Acceptable liver function:

   1. Bilirubin ≤ 1.5 times upper limit of normal
   2. AST (SGOT) and ALT (SGPT) ≤ 2.5 times upper limit of normal (ULN); if liver metastases are present, then ≤ 5 x ULN is allowed

9. Acceptable renal function:

   a. Serum creatinine within normal limits, AND calculated creatinine clearance ≥ 60 mL/min/1.73m2

10. Acceptable hematologic status (without hematologic support):

    1. ANC ≥ 1500 cells/μL
    2. Platelet count ≥ 100,000/μL
    3. Hemoglobin ≥ 9.0 g/dL
11. 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

Docetaxel + TH-302 Inclusion Criteria:

All Subjects:

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. Dose escalation subjects ONLY:

   1. Histologically or cytologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective OR solid malignancy for which monotherapy with docetaxel would be appropriate
   2. Tumor progression after most recent therapy
4. Recovered from toxicities of prior therapy to grade 0 or 1
5. Evaluable disease by RECIST criteria (at least one target or non-target lesion) or evidence of disease progression for subjects with metastatic castrate-resistant prostate cancer
6. ECOG performance status of 0 or 1
7. Life expectancy of at least 3 months

8. Acceptable liver function:

   1. Bilirubin ≤ upper limit of normal
   2. AST (SGOT) and ALT (SGPT) ≤ 1.5 times upper limit of normal (ULN) with alkaline phosphatase ≤ 2.5 times upper limit of normal

9. Acceptable renal function:

   a. Serum creatinine within normal limits, AND calculated creatinine clearance ≥ 60 mL/min/1.73m2

10. Acceptable hematologic status (without hematologic support):

    1. ANC ≥ 1500 cells/μL
    2. Platelet count ≥ 100,000/μL
    3. Hemoglobin ≥ 9.0 g/dL
11. 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

Expanded Cohort Subjects or dose-escalation subjects with metastatic castrate-resistant prostate cancer previously untreated with chemotherapy

1. Histologically or cytologically confirmed adenocarcinoma of the prostate with clinical or radiologic evidence of metastatic disease
2. Disease progression during hormone therapy and received primary androgenablation therapy as maintenance
3. For subjects who have not had orchiectomy: serum testosterone concentration <50 ng/mL (<1.7 nmol/L); GnRH analog therapy must be continued during this study
4. If there has been antiandrogen withdrawal, it must have occurred at least 4 weeks before study enrollment (6 weeks for bicalutamide) OR in subjects who have had an antiandrogen added as second-line therapy and there was no response to the most recent antiandrogen therapy or if the PSA decline lasted ≤3 months, antiandrogen therapy must be discontinued for at least 2 weeks

5. Evidence of disease progression, manifested by at least one of the following:

   1. Rising PSA on at least 3 measurements at least 1 week apart
   2. Disease progression on physical examination or imaging studies (if progression is based on bone scan alone, there must be at least 2 new bone lesions)
6. Previously untreated with systemic chemotherapy
7. PSA at least 2 ng/mL

Pemetrexed + TH-302 Inclusion Criteria:

All Subjects:

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. Dose escalation subjects:

   1. Histologically or cytologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective OR solid malignancy for which monotherapy with pemetrexed is considered standard therapy
   2. Tumor progression after most recent therapy
4. Recovered from toxicities of prior therapy
5. Evaluable disease by RECIST criteria (at least one target or non-target lesion)
6. ECOG performance status of 0 or 1
7. Life expectancy of at least 3 months

8. Acceptable liver function:

   1. Bilirubin ≤ 1.5 times upper limit of normal
   2. AST (SGOT) and ALT (SGPT) ≤ 2.5 times upper limit of normal (ULN); if liver metastases are present, then ≤ 5 x ULN is allowed

9. Acceptable renal function:

   a. Serum creatinine within normal limits, AND calculated creatinine clearance ≥ 60 mL/min/1.73m2

10. Acceptable hematologic status (without hematologic support):

    1. ANC ≥ 1500 cells/μL
    2. Platelet count ≥ 100,000/μL
    3. Hemoglobin ≥ 9.0 g/dL
11. 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

Expanded cohort subjects ONLY: Second-line NSCLC

1. Histological or cytological confirmation of NSCLC with stage IIIB or IV disease not amenable to curative therapy
2. Prior treatment with only one systemic chemotherapy regimen for advanced disease
3. Tumor progression after most recent therapy

Exclusion Criteria:

Gemcitabine + TH-302 Exclusion Criteria:

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. 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
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
10. Treatment with radiation therapy, surgery, chemotherapy, targeted therapies (erlotinib, lapatinib, etc.) or hormones within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)
11. Prior therapy with an hypoxic cytotoxin
12. Subjects who participated in an investigational drug or device study within 28 days prior to study entry
13. Known infection with HIV, hepatitis B, or hepatitis C
14. Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302
15. Females who are pregnant or breast-feeding
16. 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
17. 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

Docetaxel + Prednisone + TH-302 Exclusion Criteria:

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. 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
11. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
12. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
13. Treatment with radiation therapy, surgery, chemotherapy, targeted therapies (erlotinib, lapatinib, etc.) or hormones within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)
14. Prior therapy with an hypoxic cytotoxin
15. Subjects who participated in an investigational drug or device study within 28 days prior to study entry
16. Known infection with HIV, hepatitis B, or hepatitis C
17. Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302
18. Females who are pregnant or breast-feeding
19. 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
20. 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

Pemetrexed + TH-302 Exclusion Criteria:

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/1.73 m2) 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. 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 (erlotinib, lapatinib, etc.) or hormones within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)
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 hepatitis 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: 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