Safety and Tolerability of Carboxyamidotriazole Orotate (CTO) in Solid Tumors or With Temodar® in Glioblastoma or Other Recurrent Malignant Gliomas or in Combination With Temodar® and Radiation Therapy for Patients With Newly Diagnosed Glioblastoma and Malignant Gliomas
Safety and Tolerability of Carboxyamidotriazole Orotate (CTO) in Solid Tumors or With Temodar® in Glioblastoma or Other Recurrent Malignant Gliomas or in Combination With Temodar® and Radiation Therapy for Patients With Newly Diagnosed Glioblastoma and Malignant Gliomas
The purpose of this study is to determine the safety, tolerability, and the maximum tolerated
 dose/recommended phase II dose of carboxyamidotriazole orotate (CTO) as a single agent in
 patients with advanced or metastatic solid tumors; in combination with oral Temodar® in
 patients with glioblastoma or other recurrent malignant gliomas; or in combination with oral
 Temodar® and radiation therapy in patients with newly diagnosed glioblastoma or other
 malignant gliomas.
Inclusion Criteria (Treatment Arm A)

 1. Patients must have histologically-confirmed solid tumors that are advanced or
 metastatic, and refractory after standard therapy, or for which there is no standard
 therapy.

 2. Patients must have measurable disease as defined by RECIST version 1.1.

 3. Patients must have received prior anticancer therapy or not be eligible for any
 established conventional therapy whether surgical or pharmacologic.

 4. Patients must have recovered from all acute adverse effects (excluding alopecia) of
 prior therapies to baseline or <=grade 1 prior to study entry.

 5. Patients must have a performance status of 0, 1, or 2.

 6. Patients must be men and women >=18 years of age.

 7. Patients must have adequate bone marrow function, defined as an absolute neutrophil
 count >=1.5 x 10^9/L and a platelet count >= 100 x 10^9/L.

 8. Patients must have adequate renal function, defined as serum creatinine <= 1.2 mg/dL
 (if > 1.2 mg/dL, a calculated creatinine clearance [by the Cockcroft-Gault method]
 must be >=60 mL/min/1.73 m^2).

 9. Patients must have adequate hepatic function, defined as plasma total bilirubin <=1.5
 mg, alanine transaminase (ALT) and aspartate transaminase (AST) <=2.5 X ULN. Patients
 with Gilbert's disease outside these limits are judged to be ineligible.

 10. Female patients of childbearing potential must have a negative serum or urine
 pregnancy test result at time of pre-treatment screening.

 11. Patients with reproductive potential must agree to use at least one form of barrier
 contraception prior to study entry and for up to 30 days beyond the last
 administration of study drug.

 12. Patients must be judged to be capable by the Investigator of providing informed
 consent and must be willing to provide written informed consent prior to the start of
 any study specific procedures.

 13. Patients should have a life expectancy of at least 12 weeks.

 Exclusion Criteria (Treatment Arm A)

 1. Patients may not have had prior chemotherapy, hormonal therapy, radiation therapy, or
 biologic therapy in the 4 weeks prior to study entry with the exception of mitomycin C
 or nitrosoureas, for which patients must be 6 weeks from prior treatment. For patients
 who have been treated with targeted therapy, 5 half-lives of that therapy (or 28 days,
 whichever is shorter) must have passed prior to enrollment in the study.

 2. Patients may not have any concomitant condition that could compromise the objectives
 of this study and the patients' compliance and ability to tolerate this therapy and
 complete at least 2 cycles of therapy, including, but not limited to the following:

 -  Congestive heart failure or uncontrolled angina pectoris, previous history of
 myocardial infarction within 1 year from study entry, uncontrolled hypertension,
 or dysrhythmias.

 -  Active infection.

 -  Unstable diabetes mellitus

 -  Psychiatric disorder that may interfere with consent and/or protocol compliance.

 3. Pregnant or breastfeeding women.

 4. Patients with another malignancy in the past 3 years except: curatively treated
 non-melanoma skin cancer; or carcinoma in situ, of either cervix or breast, that does
 not require further treatment.

 5. Patients with known HIV, HBV, or HCV infection.

 6. Patients with an underlying diagnosis or disease state associated with an increased
 risk of bleeding.

 7. Patients with central nervous system metastases. Baseline CT or MRI scan of brain is
 required only in the case of clinical suspicion of central nervous system metastases.
 Patients with evidence of brain involvement, leptomeningeal disease, or seizure
 disorder are also excluded.

 8. Patients may not be treated with known CYP3A4 inhibitors or inducers.

 Inclusion and Exclusion Criteria for Combination CTO Plus Temodar® (Treatment Arm B):
 Inclusion Criteria (Treatment Arm B)

 In addition to the inclusion criteria for adequate organ function as defined for the
 patients with advanced or metastatic solid tumors, patients enrolled in Arm B (Combination
 Therapy CTO Plus Temodar-R) must meet the following inclusion criteria:

 1. Patients must have histologically proven malignant glioblastoma or other recurrent
 malignant gliomas.

 2. Measurable tumor must be present on gadolinium-enhanced MRI.

 3. Patients must have a life expectancy of at least 8 weeks.

 4. Patients must have a Performance Status of 0, 1, or 2 (ECOG scale).

 5. Patients must be men and women >=18 years of age.

 6. Patients must have recovered from all acute adverse effects (excluding alopecia) of
 prior therapies to baseline or <=grade 1 prior to study entry.

 7. Patients must have shown unequivocal radiographic evidence for tumor progression by
 MRI scan to be performed within 14 days prior to registration and must be on a steroid
 dose that has been stable for at least 5 days. If the steroid dose is increased
 between the date of imaging and registration, a new baseline MRI scan is required.

 8. Patients who have undergone recent resection for recurrent or progressive malignant
 tumor will be eligible as long as all of the following conditions apply:

 1. They have recovered from the effects of surgery

 2. The extent of residual disease is assessed post-operatively, with an MRI scan
 done no later than 96 hours in the immediate post-operative period or at least 4
 weeks post-operatively, within 14 days prior to registration. If the 96-hour scan
 is more than 14 days before registration, the scan needs to be repeated.

 9. Patients must have had prior radiation therapy with or without chemotherapy and must
 have progressed following radiation therapy and must have an interval of >=12 weeks
 from the completion of radiation therapy to registration date to minimize the
 possibility of pseudo-progression.

 10. Patients under treatment with anti-epileptic drugs which are not known CYP3A4
 inhibitors or inducers must have been receiving a stable dose for at least 2 weeks
 with no evidence of seizures at the time of registration.

 Exclusion Criteria (Treatment Arm B)

 1. Patients may not have had prior chemotherapy, hormonal therapy, or biologic therapy in
 the 4 weeks prior to study entry with the exception of mitomycin C or nitrosoureas,
 for which patients must be 6 weeks from prior treatment. For patients who have been
 treated with targeted therapy, 5 half-lives of that therapy (or 28 days, whichever is
 shorter) must have passed prior to enrollment in the study. Additional exceptions: The
 following specific drugs are permitted shorter recovery times: 14 days for
 vincristine, 21 days for procarbazine, and 7 days for non-cytotoxic agents such as
 interferon, tamoxifen, thalidomide, and cis-retinoic acid.

 2. Patients may not have any concomitant condition that could compromise the objectives
 of this study and the patients' compliance and ability to tolerate this therapy and
 complete at least 2 cycles of therapy, including, but not limited to the following:

 -  Congestive heart failure or uncontrolled angina pectoris, previous history of
 myocardial infarction within 1 year from study entry, uncontrolled hypertension,
 or dysrhythmias.

 -  Active infection.

 -  Unstable diabetes mellitus.

 -  Psychiatric disorder that may interfere with consent and/or protocol compliance.

 3. Pregnant or breastfeeding women.

 4. Patients with another malignancy in the past 3 years except: curatively treated
 non-melanoma skin cancer; or carcinoma in situ, of either cervix or breast, that does
 not require further treatment.

 5. Patients with known HIV, HBV, or HCV infection.

 6. Patients with an underlying diagnosis or disease state associated with an increased
 risk of bleeding.

 7. Uncontrolled seizure activity.

 8. Patients may not be treated with known CYP3A4 inhibitors or inducers.

 Inclusion and Exclusion Criteria for Combination CTO and Temodar® in combination with
 radiation therapy (Treatment Arm C):

 Inclusion Criteria (Treatment Arm C)

 In addition to the inclusion criteria for adequate organ function as defined for the
 patients with advanced or metastatic solid tumors, patients enrolled in Arm C (Combination
 Therapy CTO and Temodar® in combination with radiation therapy) must meet the following
 inclusion criteria:

 1. Patients must have histologically proven newly diagnosed glioblastoma or other
 malignant gliomas. Note: Patients with anaplastic oligodendroglioma with 1p/19q
 deletion or unknown 1p/19q status are not eligible

 2. Patients must have a life expectancy of at least 8 weeks

 3. Patients must have a Performance Status of 0, 1, or 2 (ECOG scale).

 4. Patients must be men and women >=18 years of age.

 5. Patients must have undergone an MRI scan performed within 14 days prior to
 registration and must be on a steroid dose that has been stable for at least 5 days.
 If the steroid dose is increased between the date of imaging and registration, a new
 baseline MRI is required.

 6. Patients under treatment with anti-epileptic drugs which are not known CYP3A4
 inhibitors or inducers must have been receiving a stable dose for at least 2 weeks
 with no evidence of seizures at the time of registration.

 Exclusion Criteria (Treatment Arm C)

 1. Patients may not have had any prior chemotherapy, hormonal therapy, or biologic
 therapy for gliomas.

 2. Patients may not have any concomitant condition that could compromise the objectives
 of this study and the patients' compliance and ability to tolerate this therapy and
 complete at least 2 cycles of therapy, including, but not limited to the following:

 -  Congestive heart failure or uncontrolled angina pectoris, previous history of
 myocardial infarction within 1 year from study entry, uncontrolled hypertension,
 or dysrhythmias.

 -  Active infection.

 -  Unstable diabetes mellitus.

 -  Psychiatric disorder that may interfere with consent and/or protocol compliance.

 3. Pregnant or breastfeeding women.

 4. Patients with another malignancy in the past 3 years except: curatively treated
 non-melanoma skin cancer; or carcinoma in situ, of either cervix or breast, that does
 not require further treatment.

 5. Patients with known HIV, HBV, or HCV infection.

 6. Patients with an underlying diagnosis or disease state associated with an increased
 risk of bleeding.

 7. Uncontrolled seizure activity.

 8. Patients may not be treated with known CYP3A4 inhibitors or inducers.

 9. Patients with anaplastic oligodendroglioma with 1p/19q deletion or unknown 1p/19q
 status are excluded.