A Phase I Study of AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) Given on Days 1, 4 8, 12 & 15 of an Every 21-day Cycle in Adult Patients With Refractory or Metastatic Solid Malignancies

Inclusion criteria

• Patients must be 18 years of age or greater and have a histologically or cytologically proven solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. Patients who have recurred after previous surgery and/or radiation may participate in this trial, although no restriction is placed on the number of prior therapies. Patients must be willing and able to have two core-needle biopsies of their tumor to participate in this trial.
• Patients with known brain metastases are eligible for this clinical trial if their disease has been treated and they are clinically stable (based on the assessment of their treating physician) and documented by a stable or improved pretreatment CT or MRI scan of the brain to evaluate for CNS disease within 28 days prior to registration.
• Patients may have measurable OR non-measurable disease documented by CT, MRI, X-ray or nuclear exam (FDG-PET). All disease must be assessed within 28 days prior to registration. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of measurable disease.
• Patients must have progressed after at least one prior chemotherapy and not be candidates for salvage surgery. Prior biologic therapy or prior radiation is permitted; however, at least two weeks must have elapsed since the completion of prior therapy and patients must have recovered from all associated toxicities (due to prior therapy) at the time of registration.
• At least three weeks must have elapsed since surgery (thoracic or other major surgeries) and patients must have recovered from all associated toxicities at the time of registration.
• Patients must have acceptable organ and marrow function documented within seven days of registration and as defined below:

• Leukocytes >3,000/mcL
• Absolute neutrophil count >1,500/mcL
• Platelets >100,000/mcL
• Total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) <2.5 X institutional ULN
• Creatinine within normal institutional limits, OR
• Creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of <2.
• No other prior malignancy is 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 3 years.
• Pregnant or nursing women may not participate in this trial because of the increased risk of fetal harm including fetal death from the chemotherapeutic agents. In order to participate in this trial, women / men of reproductive potential must agree to use an effective contraceptive method (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of childbearing potential must have a negative serum pregnancy test documented within seven days of registration.
• Patients must be informed of the investigational nature of this study and must sign and provide a written informed consent in accordance with institutional and federal guidelines.
• Patients must have a life expectancy of greater than 12 weeks.
• Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of AR-67 will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients taking drugs that are strong inducers of the enzyme CYP3A4 including anticonvulsants (i.e., phenytoin, phenobarbital, carbamazepine, or primidone) and rifampin OR strong inhibitors of CYP3A4 (clarithromycin, itraconazole, and ketoconazole) to other appropriate medications

Exclusion criteria

• Patients must not have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
• Patients may not be receiving any other investigational agents.
• 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.
• History of ≥ Grade 3 allergic reactions attributed to compounds of similar chemical or biologic composition to AR-67 (i.e. camptothecins such as irinotecan, topotecan or others of this class of pharmaceuticals).
• Patients with prior anaphylactic injection reaction of > Grade 3 to paclitaxel or any other product formulated with Cremophor.
• Pregnant women are excluded from this study because AR-67 is a camptothecin with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AR-67, breastfeeding should be discontinued if the mother is treated with AR-67.
• HIV-associated symptoms may preclude accurate assessment of toxicity or response to the treatment and because the primary endpoint of this Phase I trial is toxicity, patients with HIV disease will be ineligible for participation. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AR-67. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy and are ineligible for enrollment on this study.
• Subjects with leukemia or primary brain tumors are excluded from this study.
• Subjects may not receive any of the following medications two weeks prior to, during or two weeks after initiation of AR-67: aprepitant, atazanavir, bacillus of Calmette and Guerin vaccine, carbamazepine, citalopram, ketoconazole, intraconazole, measles virus vaccine, mumps virus vaccine, phenobarbital, phenytoin, poliovirus vaccine, rifabutin, rifampin, rotavirus vaccine, rubella virus vaccine, smallpox vaccine, St John's wort, typhoid vaccine, varicella virus vaccine or yellow fever vaccine.