A Drug Interaction Study of Tasisulam in Patients With Advanced Cancer or Lymphoma

Study Overview
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Brief Summary
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The purpose of this study was to assess the effect of tasisulam as an inhibitor of CYP2C9, using tolbutamide as a probe substrate. This study was to have 3 treatment periods, and continued access in an extension period. Period 1 is 4 days in length. Periods 2 and 3 are each approximately 28 days in length. Due to the early termination of the trial, only 1 Period 3 participant enrolled in the extension period before study termination.

Official Title
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The Effect of Tasisulam on the CYP2C9-Mediated Metabolism of Tolbutamide: A Pharmacokinetic Interaction Study in Cancer Patients With Advanced and/or Metastatic Solid Tumors or Lymphoma

Conditions
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Lymphoma, Advanced Cancer

Intervention / Treatment
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* Drug: Tolbutamide
* Drug: Tasisulam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically or cytologically confirmed solid malignancy or lymphoma that is advanced and/or metastatic disease which has not responded to standard therapy or for which no standard therapy exists. Have given written informed consent prior to any study-specific procedures. Have a performance status of less than or equal to 1 on the Eastern Cooperative Oncology Group (ECOG) scale and an estimated life expectancy of greater than 12 weeks. Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 30 days (45 days for mitomycin-C or nitrosoureas) prior to study enrollment and recovered from the acute effects of therapy. Limited field radiotherapy is permitted (in consultation with the investigator). Have adequate organ function. Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures. Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drug. Females with child-bearing potential must have had a negative serum pregnancy test less than 7 days prior to the first dose of study drug. Exclusion Criteria: Have received treatment within 30 days of the initial dose of study drug with an experimental agent for noncancer indications that has not received regulatory approval for any indication. Have known allergies to tasisulam or related compounds. Have serious preexisting medical conditions. Show evidence of significant active neuropsychiatric disease or central nervous system (CNS) disease (for example, Alzheimer's disease or Parkinson's disease). Patients with active brain metastasis are excluded. Have current acute or chronic leukemia. Females who are pregnant or lactating. Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb). History of severe allergies or multiple adverse drug reactions. Are persons who have previously completed or withdrawn from this study or any other study investigating tasisulam. Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study. Serious concomitant systemic disorder, including diabetes or active infection, incompatible with the study. Clinically significant cardiac symptomology. Patients being treated with warfarin. Patients being treated with sulfonylureas Regularly use drugs of abuse and/or show positive findings on urinary drug screening that is not in accordance with known/acceptable concomitant medication. Patients who have received medications that are known inducers or inhibitors of CYP2C9 within 30 days prior to enrollment. Have donated or lost blood of more than 500 milliliter (mL) within the last month. Have an average weekly alcohol intake that exceeds 21 units per week (males up to age 65) and 14 units per week (males over 65 and females) (1 unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits). Failure for any reason to satisfy the investigator for adequate fitness to participate in the study. Screening albumin levels less than 30 grams/Liter (g/L).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tasisulam and Tolbutamide<br>Three study periods and continued access to tasisulam every 28 days (except Period 1 which was tolbutamide only and lasted 4 days) until disease progression: Period 1: 500 milligram (mg) tolbutamide administered on Day 1. Period 2: 500 mg of tolbutamide and individualized tasisulam dose [based on area under the curve albumin-corrected threshold (AUCalb)]. The AUCalb is a surrogate marker for unbound tasisulam, and this dosing approach represents the maximum level of unbound tasisulam which may be achieved clinically, administered on Day 1. Period 3: Individualized tasisulam dose (based on AUCalb) administered on Day 1 and 500 mg tolbutamide administered on Day 4. | Drug: Tolbutamide<br>* Administered orally<br>Drug: Tasisulam<br>* Administered intravenously<br>* Other names: LY573636;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Tolbutamide, Concurrent Dosing, Area Under the Curve (AUC 0-∞) | AUC0-∞ is defined as the area under the concentration time curve from time 0 to infinity. | Period 2 Predose; and 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 6, 8, 24, 48, 72, 120, 168, 336 hours post tolbutamide dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Tolbutamide, Staggered Dosing in Period 3, Area Under the Curve (AUC 0-∞) | AUC0-∞ is defined as the area under the concentration time curve from time 0 to infinity. | Period 3 Predose; and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 96, and 264 hours post tolbutamide dose | 
| Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax) |  | Period 1, 2, and 3 Predose; and 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 6, 8, 24, 48, 72, 96, 120, 168, 264, 336 hours post tolbutamide dose | 
| Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax) |  | Period 1, 2, and 3 Predose; and 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 6, 8, 24, 48, 72, 96, 120, 168, 264, 336 hours post tolbutamide dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced or Metastatic Solid Tumors or Lymphoma