Advanced Cancer, Metastatic Cancer
Conditions
Keywords
bladder cancer
Brief summary
The main purpose of this study is to evaluate the safety of the study drug known as LY3076226 in participants with advanced or metastatic cancer.
Interventions
DRUGLY3076226
Administered IV
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
* Have advanced or metastatic cancer and be an appropriate candidate for experimental therapy. * Part B: Have a diagnosis of bladder cancer. * Part B: Have alterations of FGFR3. * Have adequate organ function. * Have discontinued previous treatments for cancer and have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy to Grade ≤1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (v 4.0). * If participant is of reproductive potential, must agree to use medically approved contraceptive precautions during the study and for 3 months following the last dose of study drug. If the participant is a female of childbearing potential, must have had a negative serum or urine pregnancy test within 7 days of the first dose of study drug and must not be breastfeeding.
Exclusion criteria
* Have received treatment within 28 days of the initial dose of study drug with an investigational product or non-approved use of a drug or device (other than the study drug/device used in this study) or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. * Have preexisting corneal disease that may interfere with assessment for potential eye toxicity during the study. * Have preexisting Grade ≥2 skin disorder (for example, erythema, dermatitis). * Have serious preexisting medical conditions (left to the discretion of the investigator). * Have symptomatic central nervous system (CNS) malignancy or metastasis (screening not required). Participants with treated CNS metastases are eligible for this study if they are not currently receiving corticosteroids and/or anticonvulsants, and their disease is asymptomatic and radiographically stable for at least 28 days. * Have current acute or chronic leukemia. * Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required). * Have a second primary malignancy that, in the judgment of the investigator and sponsor, may affect the interpretation of results. Curatively treated nonmelanoma skin cancer or in situ carcinoma of any origin is allowed. * Have Fridericia-corrected QT interval (QTcF) \>480 milliseconds on screening electrocardiogram (ECG). * Have a serious cardiac condition, such as congestive heart failure; New York Heart Association Class III/IV heart disease; unstable angina pectoris; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatment (not including participants with rate-controlled atrial fibrillation).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of LY3076226 | Cycle 1 (21 Days) | The MTD was defined as the highest dose tested that had less than 33% probability of causing a dose limiting toxicity (DLT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Predose: Day 1 (Cycle 1) and 63 (Cycle 3); Postdose: 0.05, 1, 3, 6, 24 and 72 hours | — |
| PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Predose: Day 1 (Cycle 1) and 63 (Cycle 3); Postdose: 0.05, 1, 3, 6, 24 and 72 hours | — |
| Number of Participants With Tumor Response | Baseline through Study Completion (Cycle 3, day 21) | Tumor response was assessed using confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Complete response (CR) was the disappearance of all target and non-target lesions and normalization of tumor marker levels of non-target lesions; partial response (PR) was at least a 30% decrease in the sum of the longest diameter of target lesions. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Part A (dose escalation in advanced cancer): LY3076226 administered intravenously (IV) on day 1 of each 21 day cycle. Part B (dose expansion in advanced urothelial carcinoma): LY3076226 administered IV on day 1 of each 21 day cycle.
Participants by arm
| Arm | Count |
|---|---|
| LY3076226-0.2mg/kg Part A cohort 1 of dose escalation of LY3076226 at 0.2mg/kg. | 1 |
| LY3076226-0.4mg/kg Part A cohort 2 of dose escalation of LY3076226 at 0.4mg/kg. | 1 |
| LY3076226-0.8mg/kg Part A cohort 3 of dose escalation of LY3076226 at 0.8mg/kg. | 1 |
| LY3076226-1.6mg/kg Part A cohort 4 of dose escalation of LY3076226 at 1.6mg/kg. | 3 |
| LY3076226-2.4mg/kg Part A cohort 5 of dose escalation of LY3076226 at 2.4mg/kg. | 3 |
| LY3076226-3.2mg/kg Part A cohort 6 of dose escalation of LY3076226 at 3.2mg/kg. | 4 |
| LY3076226-4.0mg/kg Part A cohort 7 of dose escalation of LY3076226 at 4.0mg/kg. | 3 |
| LY3076226-5.0mg/kg Part A cohort 8 of dose escalation of LY3076226 at 5.0mg/kg. | 6 |
| LY3076226-5.0mg/kg Dose Expansion Part B dose expansion of LY3076226 at 5.0mg/kg. | 3 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 0 | 1 | 3 | 2 | 3 | 3 | 5 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | LY3076226-0.2mg/kg | Total | LY3076226-5.0mg/kg Dose Expansion | LY3076226-5.0mg/kg | LY3076226-4.0mg/kg | LY3076226-3.2mg/kg | LY3076226-2.4mg/kg | LY3076226-1.6mg/kg | LY3076226-0.8mg/kg | LY3076226-0.4mg/kg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 41.0 years | 63.0 years STANDARD_DEVIATION 9.5 | 56.3 years STANDARD_DEVIATION 5.9 | 65.8 years STANDARD_DEVIATION 8.7 | 72.7 years STANDARD_DEVIATION 9.8 | 63.0 years STANDARD_DEVIATION 5.5 | 55.0 years STANDARD_DEVIATION 6.2 | 68.3 years STANDARD_DEVIATION 1.5 | 56.0 years | 73.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 19 Participants | 3 Participants | 5 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 22 Participants | 3 Participants | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Canada | 0 Participants | 7 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 Participants | 18 Participants | 1 Participants | 5 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 13 Participants | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 12 Participants | 2 Participants | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 3 | 0 / 3 | 0 / 4 | 0 / 3 | 0 / 6 | 0 / 3 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 6 / 6 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 | 0 / 1 | 1 / 3 | 1 / 3 | 0 / 4 | 0 / 3 | 1 / 6 | 0 / 3 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of LY3076226
The MTD was defined as the highest dose tested that had less than 33% probability of causing a dose limiting toxicity (DLT).
Time frame: Cycle 1 (21 Days)
Population: All participants enrolled in dose escalation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY3076226 | Maximum Tolerated Dose (MTD) of LY3076226 | 5.0 milligrams |
Secondary
Number of Participants With Tumor Response
Tumor response was assessed using confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Complete response (CR) was the disappearance of all target and non-target lesions and normalization of tumor marker levels of non-target lesions; partial response (PR) was at least a 30% decrease in the sum of the longest diameter of target lesions.
Time frame: Baseline through Study Completion (Cycle 3, day 21)
Population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY3076226 | Number of Participants With Tumor Response | 0 participants |
| LY3076226-0.4mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-0.8mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-1.6mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-2.4mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-3.2mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-4.0mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-5.0mg/kg | Number of Participants With Tumor Response | 0 participants |
| LY3076226-5.0mg/kg Dose Expansion | Number of Participants With Tumor Response | 0 participants |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226
Time frame: Predose: Day 1 (Cycle 1) and 63 (Cycle 3); Postdose: 0.05, 1, 3, 6, 24 and 72 hours
Population: All participants with adequate measurable PK concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY3076226 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 5.35 Micrograms per milliliter(μg/mL) | — |
| LY3076226-0.4mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 10.6 Micrograms per milliliter(μg/mL) | — |
| LY3076226-0.8mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 23.3 Micrograms per milliliter(μg/mL) | — |
| LY3076226-1.6mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 41.9 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 22.2 |
| LY3076226-2.4mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 3 | 62.0 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 34 |
| LY3076226-2.4mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 133 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 123 |
| LY3076226-3.2mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 77.4 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 20.5 |
| LY3076226-3.2mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 3 | 89.8 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 100 |
| LY3076226-4.0mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 3 | 105 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 8.26 |
| LY3076226-4.0mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 104 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 9.37 |
| LY3076226-5.0mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 119 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 16.2 |
| LY3076226-5.0mg/kg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 3 | 144 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 5.6 |
| LY3076226-5.0mg/kg Dose Expansion | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 3 | 95.7 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 22.1 |
| LY3076226-5.0mg/kg Dose Expansion | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3076226 | Cycle 1 | 101 Micrograms per milliliter(μg/mL) | Geometric Coefficient of Variation 22.3 |
Secondary
PK: Area Under the Concentration-Time Curve (AUC) of LY3076226
Time frame: Predose: Day 1 (Cycle 1) and 63 (Cycle 3); Postdose: 0.05, 1, 3, 6, 24 and 72 hours
Population: All participants with adequate measurable PK concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY3076226 | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 13.0 μg per day per mL(μg/day/mL) | — |
| LY3076226-0.4mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 18.8 μg per day per mL(μg/day/mL) | — |
| LY3076226-0.8mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 112 μg per day per mL(μg/day/mL) | — |
| LY3076226-1.6mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 223 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 14.3 |
| LY3076226-2.4mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 503 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 55.5 |
| LY3076226-2.4mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 3 | 374 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 78.2 |
| LY3076226-3.2mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 3 | 758 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 833 |
| LY3076226-3.2mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 424 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 33.2 |
| LY3076226-4.0mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 3 | 688 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 41.2 |
| LY3076226-4.0mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 665 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 14 |
| LY3076226-5.0mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 664 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 29.5 |
| LY3076226-5.0mg/kg | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 3 | 1120 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 18.9 |
| LY3076226-5.0mg/kg Dose Expansion | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 1 | 638 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 17.1 |
| LY3076226-5.0mg/kg Dose Expansion | PK: Area Under the Concentration-Time Curve (AUC) of LY3076226 | Cycle 3 | 801 μg per day per mL(μg/day/mL) | Geometric Coefficient of Variation 27 |