A Phase I Study of Oral Carboxyamidotriazole Orotate (CTO) Titrated as a Single Agent in Patients With Advanced or Metastatic Solid Tumors and Titrated in Combination Therapy With Temodar® in Patients With Glioblastoma Multiforme or Other Recurrent Malignant Gliomas

Inclusion Criteria

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 multiforme 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 hepatic enzyme-inducing anti-epileptic drugs (e.g.
Dilantin, Tegretol, valproic acid, trileptal) 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 with the
exception of anti-seizure medications given at stable and effective doses prior to
study drug treatment