Advanced Cancer
Conditions
Keywords
Metastatic Tumors, Lymphoma
Brief summary
The purpose of this study is to evaluate whether tasisulam acts as an inducer of CYP3A using midazolam as a sensitive and specific probe substrate of CYP3A. The study will also assess the safety and tolerability of tasisulam and midazolam given in combination and document any antitumor activity with tasisulam.
Interventions
DRUGTasisulam
Patient specific dose, administered intravenously, on Day 1 of a 28-day cycle. Minimum of one (1) 28-day cycle. Patients may continue to receive tasisulam until disease progression or until discontinuation criteria are met.
DRUGMidazolam
1.2 milligrams (mg), administered orally once prior to the initiation of tasisulam therapy and once on Day 8 after initiation of tasisulam therapy
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale * 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 an estimated life expectancy, in the judgment of the investigator, of greater than or equal to 12 weeks
Exclusion criteria
* Have received treatment within 30 days of the initial dose of study drug with an experimental agent for non-cancer indications that has not received regulatory approval for any indication * Have symptomatic central nervous system (CNS) malignancy or metastasis (screening not required). Patients with active brain metastasis are excluded * Have current acute or chronic leukemia * Patients who have clinically significant chronic obstructive pulmonary disease (COPD) or other respiratory diseases that may be at risk during periods of conscious sedation under midazolam * Patients with a known history of obstructive sleep apnea, difficult intubation, or syndromes associated with airway abnormalities.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to the Last Time Point With Measurable Concentrations (AUC 0-tlast) | Period 1 and 2: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, 11, 24, 48, and 72 hours post-dose. |
| Midazolam Pharmacokinetics: Maximum Concentration (Cmax) | Period 1 and 2: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, 11, 24, 48, and 72 hours post-dose. |
| Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) | Period 1 and 2: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, 11, 24, 48, and 72 hours post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Tumor Response | Baseline to Day 15 of Maintenance Period up to 3 months | Number of participants with tumor response = number of participants with complete response (CR) + number of participants with partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. |
| Tasisulam Pharmacokinetics: Maximum Concentration (Cmax) | Period 2: Predose, preinfusion start, 1, 1.75, 2 (post end of infusion), 2.5, 3, 4, 6, 8, 24, 48, 72, 120, 168, and 336 hours. | — |
| Tasisulam Pharmacokinetics: Area Under the Concentration-Time Curve Above the Albumin Corrected Threshold (AUCalb) | Period 2: Predose, preinfusion start, 1, 1.75, 2 (post end of infusion), 2.5, 3, 4, 6, 8, 24, 48, 72, 120, 168, and 336 hours. | Tasisulam is highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) tasisulam. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Midazolam + Tasisulam Period 1 (7 days): 1.2 milligrams (mg) midazolam orally on Day 1.
Period 2 (28 days): Tasisulam intravenously to target area under the curve above the albumin corrected threshold (AUCalb) in the range of 1200 to 6400 hour\*micrograms per milliliter (h\*mcg/mL) on Day 1 and 1.2 mg midazolam orally on Day 8.
Maintenance Period (35 days): Tasisulam was dosed intravenously to target AUCalb in the range of 1200 to 6400 h\*mcg/mL on Day 1. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 1 | Sponsor Decision and was not dosed | 1 |
| Period 2 | Sponsor Decision | 1 |
Baseline characteristics
| Characteristic | Midazolam + Tasisulam |
|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 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 | 10 Participants |
| Region of Enrollment France | 10 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 10 | 9 / 10 | 2 / 4 | 2 / 3 |
| serious Total, serious adverse events | 0 / 10 | 1 / 10 | 0 / 4 | 0 / 3 |
Outcome results
Primary
Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity)
Time frame: Period 1 and 2: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, 11, 24, 48, and 72 hours post-dose.
Population: All participants who received study drug and had sufficient pharmacokinetics data to calculate AUC0-infinity. Analysis used data according to the treatment the participants actually received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) | 27.0 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 36 |
| Midazolam + Tasisulam | Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) | 22.8 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 54 |
Primary
Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to the Last Time Point With Measurable Concentrations (AUC 0-tlast)
Time frame: Period 1 and 2: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, 11, 24, 48, and 72 hours post-dose.
Population: All participants who received study drug and had sufficient pharmacokinetics data to calculate AUC0-tlast. Analysis used data according to the treatment the participants actually received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to the Last Time Point With Measurable Concentrations (AUC 0-tlast) | 25.9 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 35 |
| Midazolam + Tasisulam | Midazolam Pharmacokinetics: Area Under the Concentration-Time Curve From Time Zero to the Last Time Point With Measurable Concentrations (AUC 0-tlast) | 22.5 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 55 |
Primary
Midazolam Pharmacokinetics: Maximum Concentration (Cmax)
Time frame: Period 1 and 2: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, 11, 24, 48, and 72 hours post-dose.
Population: All participants who received study drug and had sufficient pharmacokinetics data to estimate Cmax. Analysis used data according to the treatment the participants actually received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Midazolam Pharmacokinetics: Maximum Concentration (Cmax) | 9.07 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41 |
| Midazolam + Tasisulam | Midazolam Pharmacokinetics: Maximum Concentration (Cmax) | 9.48 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51 |
Secondary
Number of Participants With Tumor Response
Number of participants with tumor response = number of participants with complete response (CR) + number of participants with partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions.
Time frame: Baseline to Day 15 of Maintenance Period up to 3 months
Population: All participants who received study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Midazolam | Number of Participants With Tumor Response | 0 Participants |
Secondary
Tasisulam Pharmacokinetics: Area Under the Concentration-Time Curve Above the Albumin Corrected Threshold (AUCalb)
Tasisulam is highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) tasisulam.
Time frame: Period 2: Predose, preinfusion start, 1, 1.75, 2 (post end of infusion), 2.5, 3, 4, 6, 8, 24, 48, 72, 120, 168, and 336 hours.
Population: All participants who received tasisulam and had pharmacokinetics data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Tasisulam Pharmacokinetics: Area Under the Concentration-Time Curve Above the Albumin Corrected Threshold (AUCalb) | 5840 hour*micrograms/milliliter (h*mcg/mL) | Geometric Coefficient of Variation 50 |
Secondary
Tasisulam Pharmacokinetics: Maximum Concentration (Cmax)
Time frame: Period 2: Predose, preinfusion start, 1, 1.75, 2 (post end of infusion), 2.5, 3, 4, 6, 8, 24, 48, 72, 120, 168, and 336 hours.
Population: All participants who received tasisulam and had pharmacokinetics data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Tasisulam Pharmacokinetics: Maximum Concentration (Cmax) | 358 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 17 |