JZAR: A Drug Interaction Study of Tasisulam in Patients With Advanced Cancer or Lymphoma
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Tasisulam and Tolbutamide 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
Administered orally
Drug: Tasisulam
Administered intravenously
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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]
Eligibility Criteria
Criteria
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
- 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).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | Cardiff | South Glamorgan | United Kingdom | CF14 2TL |
| 2 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | Sheffield | Trent | United Kingdom | S10 2SJ |
| 3 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | Leeds | West Yorkshire | United Kingdom | LS9 7TF |
| 4 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | Leicester | United Kingdom | LE1 5WW | |
| 5 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | London | United Kingdom | WC1E 6BT |
Sponsors and Collaborators
- Eli Lilly and Company
Investigators
- Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 13076
- H8K-MC-JZAR
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | All Participants |
|---|---|
| Arm/Group Description | Period 1: 500 milligram (mg) tolbutamide administered once on Day 1 Period 2: 500 mg of tolbutamide and individualized tasisulam dose (based on AUCalb) administered once on Day 1 Period 3: individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on day 4 |
| Period Title: Period 1 : Tolbutamide | |
| STARTED | 4 |
| COMPLETED | 4 |
| NOT COMPLETED | 0 |
| Period Title: Period 1 : Tolbutamide | |
| STARTED | 4 |
| COMPLETED | 2 |
| NOT COMPLETED | 2 |
| Period Title: Period 1 : Tolbutamide | |
| STARTED | 2 |
| COMPLETED | 2 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | All Participants |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 4 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
2
50%
|
| >=65 years |
2
50%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
1
25%
|
| Male |
3
75%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
4
100%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (Count of Participants) | |
| United Kingdom |
4
100%
|
Outcome Measures
| Title | Pharmacokinetics of Tolbutamide, Concurrent Dosing, Area Under the Curve (AUC 0-∞) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants who started Period 2 (tasisulam and tolbutamide). |
| Arm/Group Title | Period 2: Tasisulam and Tolbutamide |
|---|---|
| Arm/Group Description | Period 2: 500 mg of tolbutamide and individualized tasisulam dose (based on AUCalb) administered once on Day 1 |
| Measure Participants | 4 |
| Geometric Mean (Geometric Coefficient of Variation) [nanograms*hour per milliliter (ng*hr/mL)] |
2670000
(20)
|
| Title | Pharmacokinetics of Tolbutamide, Staggered Dosing in Period 3, Area Under the Curve (AUC 0-∞) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants who started period 3 (tasisulam then tolbutamide). |
| Arm/Group Title | Tasisulam and Tolbutamide: Period 3 |
|---|---|
| Arm/Group Description | Period 3: Individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on Day 4. |
| Measure Participants | 2 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng*hr/mL)] |
2700000
(NA)
|
| Title | Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax) |
|---|---|
| Description | |
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants who started Periods 1, 2, or 3. |
| Arm/Group Title | Tolbutamide: Period 1 | Tasisulam and Tolbutamide: Period 2 | Tasisulam and Tolbutamide: Period 3 |
|---|---|---|---|
| Arm/Group Description | Period 1: 500 mg tolbutamide administered once on Day 1 | Period 2: 500 mg of tolbutamide and individualized tasisulam dose (based on AUCalb) administered once on Day 1. | Period 3: individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on Day 4. |
| Measure Participants | 4 | 4 | 2 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)] |
39600
(26)
|
39800
(18)
|
48000
(NA)
|
| Title | Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax) |
|---|---|
| Description | |
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants who started Periods 1, 2, or 3. |
| Arm/Group Title | Period 1: Tolbutamide | Period 2: Tasisulam and Tolbutamide | Period 3: Tasisulam and Tolbutamide |
|---|---|---|---|
| Arm/Group Description | Period 1: 500 mg tolbutamide administered once on Day 1 | Period 2: 500 mg tolbutamide and an individualized tasisulam dose (based on AUCalb) administered once on Day 1. | Period 3: Individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on day 4 (administration day in period 3 could adjusted based on interim pharmacokinetic [PK] analyses) |
| Measure Participants | 4 | 4 | 2 |
| Median (Full Range) [hours] |
2.25
|
5.00
|
5.02
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Tolbutamide | Tasisulam and Tolbutamide | Tasisulam | |||
| Arm/Group Description | Adverse events (AEs) that occurred during Period 1 and during Period 2 when 500 mg tolbutamide was administered orally prior to individualized intravenous dosing (based on AUCalb) of tasisulam. | AEs that occurred during Periods 2 and 3 when both 500 mg oral tolbutamide and individualized intravenous tasisulam (based on AUCalb) were administered. | AEs that occurred during Period 3 Day 1 through Day 4 until just before 500 mg oral tolbutamide was administered on Day 4, 72 hours. | |||
All Cause Mortality |
||||||
| Tolbutamide | Tasisulam and Tolbutamide | Tasisulam | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Tolbutamide | Tasisulam and Tolbutamide | Tasisulam | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/4 (0%) | 1/4 (25%) | 0/2 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal chest pain | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Tolbutamide | Tasisulam and Tolbutamide | Tasisulam | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/4 (75%) | 4/4 (100%) | 1/2 (50%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Thrombocytopenia | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Ear and labyrinth disorders | ||||||
| Tinnitus | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Abdominal distension | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Abdominal pain | 0/4 (0%) | 0 | 2/4 (50%) | 2 | 1/2 (50%) | 1 |
| Constipation | 0/4 (0%) | 0 | 2/4 (50%) | 2 | 0/2 (0%) | 0 |
| Diarrhoea | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Vomiting | 1/4 (25%) | 1 | 0/4 (0%) | 0 | 0/2 (0%) | 0 |
| General disorders | ||||||
| Chest pain | 0/4 (0%) | 0 | 0/4 (0%) | 0 | 1/2 (50%) | 1 |
| Fatigue | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Mucosal inflammation | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Hepatic pain | 1/4 (25%) | 1 | 0/4 (0%) | 0 | 0/2 (0%) | 0 |
| Infections and infestations | ||||||
| Nasopharyngitis | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Rhinitis | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Urinary tract infection | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Hypophosphataemia | 0/4 (0%) | 0 | 1/4 (25%) | 2 | 0/2 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Muscle spasms | 1/4 (25%) | 1 | 0/4 (0%) | 0 | 0/2 (0%) | 0 |
| Musculoskeletal chest pain | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Nervous system disorders | ||||||
| Dizziness | 0/4 (0%) | 0 | 2/4 (50%) | 4 | 0/2 (0%) | 0 |
| Lethargy | 0/4 (0%) | 0 | 2/4 (50%) | 2 | 0/2 (0%) | 0 |
| Neuropathy peripheral | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Presyncope | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Dermatitis acneiform | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Jessner's lymphocytic infiltration | 0/4 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 |
| Night sweats | 1/4 (25%) | 1 | 0/4 (0%) | 0 | 0/2 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Chief Medical Officer |
|---|---|
| Organization | Eli Lilly and Company |
| Phone | 800-545-5979 |
- 13076
- H8K-MC-JZAR