| Study Summary: |
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This is a single-agent, open-label, Phase 1, dose-escalation study in adult patients with
advanced or recurrent solid tumors or lymphoma. Patients will receive orally administered
AR-12 once daily for 28 consecutive days. The first dosing cycle will be followed by at
least a 7 day off-treatment period; however, no off-treatment period will be scheduled
between subsequent treatment cycles. If daily dosing is not tolerated by the study
population, alternative dosing schedules may be pursued (eg, 21 consecutive days of dosing
followed by 7 days off treatment), as indicated by the safety, pharmacokinetic, and
pharmacodynamic data; all changes to the protocol-specified dosing schedule must be agreed
upon by the investigators and the medical monitor. If individual patients respond to AR-12
treatment with an objective response or stable disease according to RECIST criteria and meet
pre-specified retreatment criteria, they may continue to receive cycles of AR-12 in the
absence of untoward or serious toxicity; however, no patient is permitted to start a
subsequent cycle after each bi-monthly disease evaluation until it is confirmed that disease
progression has not occurred.
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| Criteria: |
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Inclusion Criteria:
1. Signed, written informed consent must be obtained and documented according to
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), the
local regulatory requirements, and the permission to use private health information
in accordance with the Health Insurance Portability and Accountability Act (HIPAA)
prior to study-specific Screening procedures.
2. Both men and women and members of all races and ethnic groups are eligible for this
trial.
3. Patients must be 18 years of age or greater.
4. Patients must have a histologically or cytologically confirmed advanced or recurrent
solid tumor or lymphoma for which standard curative or palliative measures do not
exist or are no longer effective. Patients who have recurrent disease after previous
surgery, radiation therapy, and/or chemotherapy are eligible. No restriction is
placed on the number of prior therapies. At least 4 weeks must have elapsed since
the completion of prior therapy, including major surgery, and patients must have
recovered from all associated toxicities no greater than grade 1 at the time of
Screening. Patients with prostate cancer must have discontinued anti-androgens (eg,
bicalutamide, nilutamide) for at least 6 weeks; chemical castration with LHRH
analogues can be continued.
5. Patients must have measurable or evaluable disease or disease that otherwise meets
criteria for treatment and can be followed by an acceptable biomarker (eg, PSA or
CA-125) documented within 28 days of starting treatment with AR-12. Pleural
effusions, ascites, bony metastasis, and laboratory parameters are not acceptable as
the only evidence of disease.
6. Patients must have acceptable organ and marrow function documented within 7 days of
registration, defined as follows:
- Leukocytes >3,000/mcL
- Absolute neutrophil count >1,500/mcL
- Platelets ≥150,000/mcL
- Fasting blood glucose Within normal institutional limits
- Total bilirubin Within normal institutional limits
- AST/ALT <2.5 X institutional ULN; <5 X ULN in presence of liver metastasis
- Creatinine Within normal institutional limits, OR
- Creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal
7. Patients must have an ECOG performance status of 0 or 1.
8. Patients must have adequate pulmonary function (no more than a grade 2 finding per
CTCAE version 3) and oxygen saturation ≥93% on room air, measured within 14 days
prior to initiation of treatment with AR-12.
9. All patients who are sexually active must use a medically acceptable, as judged by
the investigator, and highly effective method of birth control for the duration of
the study and to continue for 30 days after the last AR-12 dose. A highly effective
method of birth control is defined as any method that results in a low failure rate,
including implants, injectables, some intrauterine devices, sexual abstinence, and
surgical sterilization (eg, vasectomy, tubal ligation, hysterectomy). Women of
childbearing potential must have a negative serum pregnancy test documented within 7
days prior to Day 0. Furthermore, male study patients must also not donate sperm
from Study Day 1 until 90 days after the end of treatment.
10. Patients must have a life expectancy of greater than 12 weeks.
Exclusion Criteria:
1. Patients must not have had chemotherapy, radiotherapy, immunotherapy, or
investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior
to entering the study. Patients who have received prior chemotherapy must have
recovered to no greater than grade 1 from all AEs/toxicities (except alopecia) due to
prior agents.
2. Patients with a history of insulin- or non-insulin-dependent diabetes requiring
antidiabetic medication.
3. Patients requiring treatment with anticoagulants.
4. Patients requiring chronic corticosteroids (dose equivalent ≥20 mg prednisolone).
5. Patients requiring chronic Celebrex® (celecoxib) therapy.
6. History of allergic reactions attributed to compounds of similar chemical or biologic
composition (eg, celecoxib).
7. Patients who are unable or unwilling to swallow AR-12 capsules daily or who have any
concurrent medical condition that may impact drug absorption, including a history
suggestive of intermittent tumor-associated bowel obstruction, and partial small
bowel resection.
8. Patients with known or symptomatic brain metastases (including leptomeningeal
disease). Patients with asymptomatic, treated brain metastases are allowed.
Patients with primary brain tumors will be allowed in the MTD expansion cohort;
however, radiotherapy must have been completed ≥90 days prior to Screening.
9. Patients with any other prior malignancy are not allowed except for the following:
- Adequately treated basal cell or squamous cell skin cancer
- In situ cervical cancer
- Adequately treated Stage I or II cancer from which the patient is currently in
complete remission or other cancer from which the patient has been disease-free
for 2 years
10. Patients may have had prior palliative radiation therapy; however, radiation must not
have been to more than 15% of marrow-producing locations.
11. Pregnant women are excluded from this study because the potential for teratogenic or
abortifacient effects of AR-12 are not known. Because there is an unknown but
potential risk for AEs in nursing infants secondary to treatment of the mother with
AR-12, breastfeeding should be discontinued if the mother is treated with AR-12.
12. Patients with known human immunodeficiency virus (HIV) are not eligible for this
study.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
14. Patients with QTc > 470 msec on Screening ECG or a clinically relevant ECG
abnormality as determined by the investigator or his/her designee.
15. Patients with left bundle-branch block.
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