Status and phase
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About
The purpose of this study is to determine if TH-302, in combination with A) Gemcitabine, or B) Docetaxel or C) Pemetrexed methotrexate, are safe and effective in the treatment of Pancreatic Cancer, Castrate-resistant Prostate Cancer, and Non-small Cell Lung Cancer, respectively.
Full description
A broad range of tumors have been shown to contain significant numbers of hypoxic cells and hypoxia has been shown to be associated with a poor prognosis and an increase in resistance to chemotherapy and radiotherapy (Brizel 1997, Vaupel 2007, Shannon 2003).
It is likely that an agent that could effectively target hypoxic regions in tumors would improve efficacy when combined with standard chemotherapy or radiotherapy. TH-302 is activated at lower oxygen concentrations than other bioreductive prodrugs (Duan 2008) and tirapazamine, a hypoxic cytotoxin that has been extensively studied in both preclinical and clinical studies. This should result in an improved therapeutic ratio (tumor vs normal tissue toxicity) as compared with other bioreductive agents. Because TH-302 is expected to be minimally toxic to aerobic cancer cells, optimal efficacy would be expected when TH-302 is combined with treatments that are most effective under aerobic conditions such as radiotherapy and cytotoxic chemotherapy. Preclinical data have shown at least additive efficacy when TH-302 is combined with either docetaxel or gemcitabine. In order to minimize the risk of additive toxicity, TH-302 is not being evaluated in combination with alkylating agents.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Gemcitabine + TH-302 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
Dose escalation subjects:
a. 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 b. 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
Recovered from toxicities of prior therapy to grade 0 or 1
Evaluable disease by RECIST criteria (at least one target or non-target lesion)
ECOG 0 or 1
Life expectancy of at least 3 months
Acceptable liver function:
a. Bilirubin ≤ 1.5 times upper limit of normal b. AST (SGOT) and ALT (SGPT) ≤ 2.5xULN; if liver metastases are present, then ≤ 5xULN is allowed
Acceptable renal function:
a. Serum creatinine ≤ ULN
Acceptable hematologic status:
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 with their partner from entry into the study through 6 months after the last dose
Docetaxel + TH-302 Inclusion Criteria:
All Subjects:
At least 18 years of age
Ability to understand the purposes and risks of the study and has signed a written informed consent form
Dose escalation subjects ONLY:
a. 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 b. Tumor progression after most recent therapy
Recovered from toxicities of prior therapy to grade 0 or 1
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
ECOG 0 or 1
Life expectancy of at least 3 months
Acceptable liver function:
a. Bilirubin ≤ upper limit of normal b. AST (SGOT) and ALT (SGPT) ≤ 1.5x ULN with alkaline phosphatase ≤ 2.5x ULN
Acceptable renal function:
a. Serum creatinine ≤ ULN
Acceptable hematologic status:
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 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:
Histologically or cytologically confirmed adenocarcinoma of the prostate with clinical or radiologic evidence of metastatic disease
Disease progression during hormone therapy and received primary androgenablation therapy as maintenance
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
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
Evidence of disease progression, manifested by at least one of the following:
Previously untreated with systemic chemotherapy
PSA at least 2 ng/mL
Expanded Cohort Subjects or dose-escalation subjects with second-line NSCLC:
Pemetrexed + TH-302 Inclusion Criteria:
All Subjects:
At least 18 years of age
Ability to understand the purposes and risks of the study and has signed a written informed consent form
Dose escalation subjects:
a. 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 b. Tumor progression after most recent therapy
Recovered from toxicities of prior therapy
Evaluable disease by RECIST criteria (at least one target or non-target lesion)
ECOG performance status of 0 or 1
Life expectancy of at least 3 months
Acceptable liver function:
Acceptable renal function:
a. Serum creatinine ≤ ULN and calculated CrCl ≥ 45 mL/min
Acceptable hematologic status:
a. ANC ≥ 1500 cells/μL b. Platelet count ≥ 100,000/μL c. Hemoglobin ≥ 9.0 g/dL
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 with their partner from entry into the study through 6 months after the last dose Expanded cohort subjects ONLY: Second-line NSCLC
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
Gemcitabine + TH-302 Exclusion Criteria:
All Subjects:
Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
Prior treatment with gemcitabine
Prior radiotherapy to more than 25% of the bone marrow
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
Seizure disorders requiring anticonvulsant therapy
Symptomatic brain, leptomeningeal or epidural metastases, (unless previously treated and well controlled for a period of ≥ 3 months)
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
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
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
Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 4 weeks prior to study entry
Prior therapy with an hypoxic cytotoxin
Subjects who participated in an investigational drug or device study within 28 days prior to study entry
Known infection with HIV, hepatitis B or C
Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302
Females who are pregnant or breast-feeding
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
Unwillingness or inability to comply with the study protocol for any reason Expanded cohort subjects ONLY: First-line advanced adenocarcinoma of the pancreas
Prior chemotherapy therapy for advanced disease other than radiosensitizing doses of 5-fluorouracil
Docetaxel + Prednisone + TH-302 Exclusion Criteria:
All Subjects:
Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
Prior treatment with docetaxel
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
Uncontrolled pleural effusion or ascites
History of sensitivity to drugs formulated with polysorbate 80
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
Seizure disorders requiring anticonvulsant therapy
Symptomatic brain, leptomeningeal or epidural metastases (unless previously treated and well controlled for a period of ≥ 3 months)
Ongoing CTCAE grade 2 or greater peripheral neuropathy
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
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
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
Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 4 weeks prior to study entry
Prior therapy with an hypoxic cytotoxin
Subjects who participated in an investigational drug or device study within 28 days prior to study entry
Known active infection with HIV, hepatitis B or C
Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302
Females who are pregnant or breast-feeding
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
Unwillingness or inability to comply with the study protocol for any reason Expanded Cohort Subjects ONLY: Castrate-resistant prostate cancer
Prior treatment with cytotoxic chemotherapy or radioisotope therapy Expanded Cohort Subjects ONLY: Second-line NSCLC
More than one prior cytotoxic chemotherapy regimen for advanced disease
Weight loss of >10% body weight in the previous 6 weeks
Pemetrexed + TH-302 Exclusion Criteria:
All Subjects:
Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
Prior treatment with pemetrexed
Prior radiotherapy to more than 25% of the bone marrow
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
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
Seizure disorders requiring anticonvulsant therapy
Symptomatic brain, leptomeningeal or epidural metastases (unless previously treated and well controlled for a period of ≥ 3 months)
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
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
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
Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 4 weeks prior to study entry
Prior therapy with an hypoxic cytotoxin
Subjects who participated in an investigational drug or device study within 28 days prior to study entry
Known active infection with HIV, hepatitis B, or hepatitis C
Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302
Females who are pregnant or breast-feeding
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
Unwillingness or inability to comply with the study protocol for any reason Expanded Cohort Subjects ONLY: Second-line NSCLC
More than one prior cytotoxic chemotherapy regimen for advanced disease 2. Weight loss of >10% body weight in the previous 6 weeks
Primary purpose
Allocation
Interventional model
Masking
71 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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