Lymphoma, Advanced Cancer
Conditions
Keywords
Advanced or Metastatic Solid Tumors or Lymphoma
Brief summary
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.
Interventions
DRUGTolbutamide
Administered orally
DRUGTasisulam
Administered intravenously
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Have given written informed consent prior to any study-specific procedures. 3. 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. 4. 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). 5. Have adequate organ function. 6. Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures. 7. 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. 8. 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
1. 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. 2. Have known allergies to tasisulam or related compounds. 3. Have serious preexisting medical conditions. 4. 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. 5. Have current acute or chronic leukemia. 6. Females who are pregnant or lactating. 7. Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb). 8. History of severe allergies or multiple adverse drug reactions. 9. Are persons who have previously completed or withdrawn from this study or any other study investigating tasisulam. 10. 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. 11. Serious concomitant systemic disorder, including diabetes or active infection, incompatible with the study. 12. Clinically significant cardiac symptomology. 13. Patients being treated with warfarin. 14. Patients being treated with sulfonylureas 15. Regularly use drugs of abuse and/or show positive findings on urinary drug screening that is not in accordance with known/acceptable concomitant medication. 16. Patients who have received medications that are known inducers or inhibitors of CYP2C9 within 30 days prior to enrollment. 17. Have donated or lost blood of more than 500 milliliter (mL) within the last month. 18. 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). 19. Failure for any reason to satisfy the investigator for adequate fitness to participate in the study. 20. Screening albumin levels less than 30 grams/Liter (g/L).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Tolbutamide, Concurrent Dosing, Area Under the Curve (AUC 0-∞) | 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 | AUC0-∞ is defined as the area under the concentration time curve from time 0 to infinity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Tolbutamide, Staggered Dosing in Period 3, Area Under the Curve (AUC 0-∞) | 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 | AUC0-∞ is defined as the area under the concentration time curve from time 0 to infinity. |
| 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 | — |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Three study periods: Period 1 which was tolbutamide only and lasted 4 days and Periods 2 and 3 which had continued access to tasisulam every 28 days until disease progression:
Period 1: 500 mg tolbutamide administered once on Day 1.
Period 2: 500 mg of tolbutamide and individualized tasisulam dose administered once on Day 1.
Period 3: individualized tasisulam dose administered once on Day 1 and 500 mg tolbutamide administered once on Day 4. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2: Tasisulam and Tolbutamide | Sponsor Decision | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United Kingdom | 4 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 4 | 4 / 4 | 1 / 2 |
| serious Total, serious adverse events | 0 / 4 | 1 / 4 | 0 / 2 |
Outcome results
Primary
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.
Time frame: 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
Population: All enrolled participants who started Period 2 (tasisulam and tolbutamide).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 2: Tasisulam and Tolbutamide | Pharmacokinetics of Tolbutamide, Concurrent Dosing, Area Under the Curve (AUC 0-∞) | 2670000 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 20 |
Secondary
Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax)
Time frame: 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
Population: All enrolled participants who started Periods 1, 2, or 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 2: Tasisulam and Tolbutamide | Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax) | 39600 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26 |
| Tasisulam and Tolbutamide: Period 2 | Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax) | 39800 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 18 |
| Tasisulam and Tolbutamide: Period 3 | Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax) | 48000 nanogram per milliliter (ng/mL) | — |
Secondary
Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax)
Time frame: 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
Population: All enrolled participants who started Periods 1, 2, or 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Period 2: Tasisulam and Tolbutamide | Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax) | 2.25 hours |
| Tasisulam and Tolbutamide: Period 2 | Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax) | 5.00 hours |
| Tasisulam and Tolbutamide: Period 3 | Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax) | 5.02 hours |
Secondary
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.
Time frame: 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
Population: All enrolled participants who started period 3 (tasisulam then tolbutamide).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Period 2: Tasisulam and Tolbutamide | Pharmacokinetics of Tolbutamide, Staggered Dosing in Period 3, Area Under the Curve (AUC 0-∞) | 2700000 nanogram*hour per milliliter (ng*hr/mL) |