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Gastrointestinal Agents

Clofarabine

Cimetidine

Antimetabolites

Intravenous Clofarabine (10mg/m2) Oral clofarabine (30mg/m2) Cimetidine (800mg)

Matthew Foster, MD

This is a non-blinded, non-randomized pharmacokinetic study to determine the oral bioavailability of clofarabine, and the effect of cimetidine on clofarabine pharmacokinetics in patients with poor-risk acute leukemias and myelodysplastic syndrome (MDS).

Clofarabine is a second-generation adenosine nucleoside analog with activity in hematologic malignancies. It has gained FDA-approval for use in children with relapsed-refractory ALL, and early phase studies have shown activity in patients with AML and MDS. Clofarabine's activity in acute leukemias and MDS has been established in multiple phase I and II studies, both alone and in combination with cytosine arabinoside (araC), and in both relapsed-refractory patients, and untreated older adults.

Pharmacokinetic investigations comparing I.V. and P.O. dosing within the same patient have not been performed. Furthermore, the effect of OCT2 inhibition on clofarabine pharmacokinetics in humans has not been investigated. The potential for enhanced drug exposure and toxicity in the setting of OCT2 inhibition is of clinical importance as clofarabine gains broader indications in hematologic oncology. In particular, bioavailability and the OCT2 mechanism are important with prolonged drug exposure and oral administration in older adults, who are likely to have impaired renal function and take other drugs that interact with OCT2 such as metformin (a substrate) and trimethoprim (one of several inhibitors). OCT2 is expressed on several solid tumor cell lines, and is thought to play a role in tumor uptake of cationic cytotoxins. Whether OCT2 or other transporters are expressed on leukemic blasts, or influence drug uptake has not been investigated. However, variation in the expression of drug transporters could be one of several mechanistic explanations for the fact that clofarabine-responsive patients accumulate intracellular clofarabine triphosphate, whereas non-responders do not.

Single nucleotide polymorphisms have been identified in the gene encoding OCT2, which may influence substrate uptake or inhibitor potency. Such polymorphisms may explain variation in clofarabine pharmacokinetics and pharmacodynamics between individuals, but the potential for this phenomenon has not previously been investigated.

Patients will receive clofarabine as induction therapy in five doses. Initially, and unless dose escalation or de-escalation criteria are met, patients will be assigned to dose level 0 (IV Clofarabine 15mg/m2; Oral clofarabine 30mg/m2). The first three doses (on days 1, 3 and 5) will be administered followed by washout periods that extend until the next clofarabine dose is administered. During the washout periods, frequent phlebotomy for PK sampling will be performed in an outpatient setting at the UNC Clinical Translational Research Center (CTRC). The duration of the induction period will be determined by time to recovery of hematologic toxicity (platelets \>50 x 109/liter, ANC \>1.0x109/liter).

AML patients achieving CR, and MDS patients achieving CR, PR or hematologic improvement will receive additional consolidation cycles of oral clofarabine daily on days 1 through 5 of each subsequent cycle, with clofarabine dose according to assigned dose level (0: 30 mg/m2, -1: 20 mg/m2, +1: 40 mg/m2). Consolidation cycles will begin no sooner than 28 days after the first day of the previous clofarabine cycle. Patients will be evaluated for response after each cycle, and will be continued on trial for up to 6 total cycles of therapy as long as a response or lack of progression is maintained and no Grade 3-4 non-hematologic toxicities have been observed in that patient.

PK Study of Oral and IV Clofarabine in High Risk Myelodysplasia+Acute Leukemias

A Pharmacokinetic Study of Oral and Intravenous Clofarabine in Patients With High Risk Myelodysplasia and Acute Leukemias - Determination of Oral Bioavailability and the Effect of Cimetidine on Clofarabine Clearance

Regarding primary endpoints, each patient will generate pharmacokinetic data sufficient to compute area under the concentration versus time curve (AUC) and clearance (Cl) for each of the initial three clofarabine doses (IV, PO and IV administered after cimetidine) for each patient.

These values will be used to compute the human oral bioavailability of clofarabine and compare AUC and Cl of clofarabine when given after cimetidine with AUC and Cl of clofarabine when administered alone

Regarding secondary objectives, safety will be evaluated by grading and reporting all adverse experiences during protocol therapy.

The DLT rate of ≤ 20% is considered to be acceptable.

Response to therapy will be determined at the time of hematologic reconstitution (platelets \>50 x 109/liter, ANC \>1.0x109/liter for MDS patients or platelets \>100 x 109/liter, ANC \>1.0x109/liter for leukemia patients) or day 28, whichever is sooner by complete blood count with differential and bone marrow aspirate, biopsy and cytogenetics.

The effect of previously-described OCT2 polymorphisms on clofarabine pharmacokinetics will be investigated in an exploratory study. If specific OCT2-encoding single nucleotide polymorphisms are detected in study subjects, the geometric mean AUC and Cl of clofarabine in such patients will be compared with the geometric mean AUC and Cl in patients with wild-type OCT2.

Genzyme, a Sanofi Company

UNC Lineberger Comprehensive Cancer Center

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Recurrence

Carcinoma

Adenocarcinoma

Endometrial Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Endothelial Growth Factors

Mitogens

Arsenic Trioxide

Arsenic trioxide - 0.25 mg/kg/day for 5 consecutive days, every 4 weeks.

Arsenic trioxide

Paola Gehrig, MD

The primary purpose of this study is to see whether women who have already received chemotherapy for their endometrial cancer, or who have disease that has spread outside of the uterus, will respond to the drug arsenic trioxide (Trisenox®) as judged by shrinkage of their tumor.

This is an open-label, single arm, single institution, phase II trial designed to assess the response rate and safety of Trisenox® in women with recurrent endometrial carcinoma. Trisenox® will be administered at a dose of 0.25 mg/kg/day for 5 consecutive days (D1-5) every 4 weeks. A 4-week period will be defined as a cycle of treatment. Marker and non-marker lesions will be assessed every 2 cycles (every 8 weeks) and the response assigned according to Gynecologic Oncology Group (GOG) RECIST guidelines. Safety will be assessed by routine physical, laboratory and ECG evaluations. Up to 10 patients will be enrolled into the study. Patients are expected (excluding any unforeseen toxicities) to receive a minimum of 2 and a maximum of 6 cycles of Trisenox®. (Patients with at least documented stable disease may be eligible for \>6 cycles). Patients will be followed for 6 months after their last dose of Trisenox®.

For this trial we would allow one prior cytotoxic regimen since the time of recurrence and patients may have had one prior regimen as part of their induction chemotherapy. Patients will be treated with 0.25 mg/kg/day for days 1-5 every 28 days and patients may remain on trial until progression of disease.

Trisenox® in Women With Metastatic Endometrial Cancer

A Phase II Trial of Trisenox in Women With Recurrent or Metastatic Endometrial Adenocarcinoma

To estimate the objective response (CR+PR) rate (as defined by the Gynecologic Oncology Group \[GOG\] RECIST Criteria)of Trisenox® in women with recurrent or metastatic endometrial cancer when administered at 0.25 mg/kg/day for 5 consecutive days (D1-5) every 4 weeks.

Progression-Free survival is the period from start of treatment until disease progression, death, or date of last contact.

We will request a blood sample to measure vascular endothelial growth factor (VEGF) as well as other angiogenic factors and correlate levels to response to arsenic trioxide. Such effects have been observed in cultured cell lines and animal models, as well as clinical studies.

Cephalon

Arsenic trioxide: Arsenic trioxide - 0.25 mg/kg/day for 5 consecutive days, every 4 weeks.

Trisenox Treatment

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

The study accrued few patients secondary to the strict entry criteria regarding labs, EKG, etc in a sick endometrial cancer population.

Robin V. Johnson

Objective Response (CR+PR) Rate of Subjects Given Trisenox

Progression Free Survival in Patients Treated With Trisenox®

Arsenic trioxide - 0.25 mg/kg/day for 5 consecutive days, every 4 weeks.

Arsenic trioxide: Arsenic trioxide - 0.25 mg/kg/day for 5 consecutive days, every 4 weeks.

Overall Survival

No patients achieved a CR or PR response, no angiogenesis was performed.

Associations Between Markers of Angiogenesis (e.g. VEGF) With Response

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PK Study of Oral and IV Clofarabine in High Risk Myelodysplasia+Acute Leukemias	NCT01169012	Myelodysplastic... Acute Myeloid L... Acute Lymphobla... Chronic Myelomo...	Clofarabine	18 Years -	UNC Lineberger Comprehensive Cancer Center
Trisenox® in Women With Metastatic Endometrial Cancer	NCT01184053	Endometrial Car...	Arsenic trioxid...	18 Years -	UNC Lineberger Comprehensive Cancer Center

Spots Global Cancer Trial Database for university of north carolina at chapel hill