Advanced Solid Tumor
Conditions
Keywords
notch inhibitor
Brief summary
The purpose of this study is to evaluate the tolerability of the study drug LY3039478 in Japanese participants with advanced solid tumors.
Interventions
DRUGLY3039478
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological or cytological evidence of a diagnosis of solid tumor that is advanced and/or metastatic. * In the judgment of the investigator, participants must be appropriate candidates for experimental therapy after available standard therapies have failed or for whom standard therapy is not appropriate. * Performance status of less than or equal to (≤) 1 on the Eastern Cooperative Oncology Group (ECOG) scale. * Adequate organ function, including hematologic, hepatic, and renal. * Estimated life expectancy of greater than or equal to (≥) 12 weeks.
Exclusion criteria
* Received previous therapy for cancer within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agents, respectively. * Have serious preexisting medical conditions. * Have current or recent (within 3 months of study drug administration) gastrointestinal disease with chronic or intermittent diarrhea. * Have an active bacterial, fungal, and/or known viral infection. * Have known acute or chronic leukemia or current hematologic malignancies that may affect the interpretation of results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With LY3039478 Dose-Limiting Toxicities (DLTs) | Cycle 1 (Up to 28 Days) | DLT was defined as an adverse event (AE) that occurred during Cycle 1 (first 28 days) related to the study drug and met one of the following criteria per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. These criteria included: CTCAE Grade greater than or equal to (≥) 3 non-hematological toxicity, with exceptions for nausea, vomiting, or constipation, and asymptomatic electrolyte disturbances that can be controlled with standard treatment; Grade 4 hematological toxicity of greater than (\>) 5 days duration; Grade ≥ 3 anemia requiring transfusion; any febrile neutropenia; neutropenia needing granulocyte-colony stimulating factors (GCSFs); Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion; Grade 4 thrombocytopenia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR): Percentage of Participants Who Achieved a Complete Response (CR) or Partial Response (PR) | Baseline through Measured Progressive Disease (Up To 100 Weeks) | * The ORR was defined as the percentage of participants achieving either a CR or PR. Tumor response was assessed based on histology: Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was used for solid tumors, and Response Assessment in Neuro-Oncology criteria were used for glioblastoma. * CR was defined as the disappearance of all target lesions, with any pathological lymph nodes (whether target or non-target) showing a reduction in the short axis to \<10 mm. Additionally, tumor marker results were required to have normalized. PR was defined as a decrease of at least 30% in the sum of the diameters of target lesions, using baseline diameters as the reference. |
| Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3039478 | Cycle 1, Day 1 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose); Cycle 1 Day 22 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose) | PK: Cmax of LY3039478 was reported. |
| PK: Area Under the Plasma Concentration-Time Curve (AUC) From 0 to 24 Hours (AUC (0-24)) of LY3039478 | Cycle 1, Day 1 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose); Cycle 1 Day 22 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose) | PK: AUC (0-24) of LY3039478 was reported. |
Countries
Japan
Participant flow
Recruitment details
* This study was a dose-escalation trial that included separate groups of participants who received 25 milligrams (mg) or 50 mg of LY3039478, administered orally three times per week (TIW) in a 28-day cycle. * The dose was escalated from 25 mg to 50 mg only if the frequency of dose-limiting toxicity (DLT) in Cycle 1 (28 days) was less than 33 percent (\<33%) among participants who had received 25 mg LY3039478.
Participants by arm
| Arm | Count |
|---|---|
| 25 mg LY3039478 Participants received 25 mg of LY3039478, administered orally TIW in a 28-day cycle, until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. | 4 |
| 50 mg LY3039478 Participants received 50 mg of LY3039478, administered orally TIW in a 28-day cycle, until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. | 7 |
| Total | 11 |
Baseline characteristics
| Characteristic | 25 mg LY3039478 | Total | 50 mg LY3039478 |
|---|---|---|---|
| Age, Continuous | 64.25 years STANDARD_DEVIATION 5.85 | 65.82 years STANDARD_DEVIATION 12.19 | 66.71 years STANDARD_DEVIATION 15.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 11 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 11 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 4 Participants | 11 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 1 / 7 |
| other Total, other adverse events | 4 / 4 | 6 / 7 |
| serious Total, serious adverse events | 0 / 4 | 0 / 7 |
Outcome results
Primary
Number of Participants With LY3039478 Dose-Limiting Toxicities (DLTs)
DLT was defined as an adverse event (AE) that occurred during Cycle 1 (first 28 days) related to the study drug and met one of the following criteria per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. These criteria included: CTCAE Grade greater than or equal to (≥) 3 non-hematological toxicity, with exceptions for nausea, vomiting, or constipation, and asymptomatic electrolyte disturbances that can be controlled with standard treatment; Grade 4 hematological toxicity of greater than (\>) 5 days duration; Grade ≥ 3 anemia requiring transfusion; any febrile neutropenia; neutropenia needing granulocyte-colony stimulating factors (GCSFs); Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion; Grade 4 thrombocytopenia.
Time frame: Cycle 1 (Up to 28 Days)
Population: All participants with evaluable DLT data in Cycle 1 (the first 28 days) had received greater than or equal to (≥) 75% of the assigned dose during Cycle 1 or had experienced a DLT during Cycle 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 25 mg LY3039478 | Number of Participants With LY3039478 Dose-Limiting Toxicities (DLTs) | 0 Participants |
| 50 mg LY3039478 | Number of Participants With LY3039478 Dose-Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Overall Response Rate (ORR): Percentage of Participants Who Achieved a Complete Response (CR) or Partial Response (PR)
* The ORR was defined as the percentage of participants achieving either a CR or PR. Tumor response was assessed based on histology: Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was used for solid tumors, and Response Assessment in Neuro-Oncology criteria were used for glioblastoma. * CR was defined as the disappearance of all target lesions, with any pathological lymph nodes (whether target or non-target) showing a reduction in the short axis to \<10 mm. Additionally, tumor marker results were required to have normalized. PR was defined as a decrease of at least 30% in the sum of the diameters of target lesions, using baseline diameters as the reference.
Time frame: Baseline through Measured Progressive Disease (Up To 100 Weeks)
Population: All enrolled participants who received at least one dose of LY3039478.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 25 mg LY3039478 | Overall Response Rate (ORR): Percentage of Participants Who Achieved a Complete Response (CR) or Partial Response (PR) | CR | 0 percentage of participants |
| 25 mg LY3039478 | Overall Response Rate (ORR): Percentage of Participants Who Achieved a Complete Response (CR) or Partial Response (PR) | PR | 0 percentage of participants |
| 50 mg LY3039478 | Overall Response Rate (ORR): Percentage of Participants Who Achieved a Complete Response (CR) or Partial Response (PR) | CR | 0 percentage of participants |
| 50 mg LY3039478 | Overall Response Rate (ORR): Percentage of Participants Who Achieved a Complete Response (CR) or Partial Response (PR) | PR | 0 percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3039478
PK: Cmax of LY3039478 was reported.
Time frame: Cycle 1, Day 1 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose); Cycle 1 Day 22 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose)
Population: All enrolled participants who received at least one dose of LY3039478 and had at least one evaluable PK data. Number analyzed refer to participants evaluable at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 25 mg LY3039478 | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3039478 | Cycle 1, Day 1 | 324 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 34 |
| 25 mg LY3039478 | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3039478 | Cycle 1, Day 22 | 429 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 69 |
| 50 mg LY3039478 | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3039478 | Cycle 1, Day 1 | 670 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39 |
| 50 mg LY3039478 | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3039478 | Cycle 1, Day 22 | 416 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 70 |
Secondary
PK: Area Under the Plasma Concentration-Time Curve (AUC) From 0 to 24 Hours (AUC (0-24)) of LY3039478
PK: AUC (0-24) of LY3039478 was reported.
Time frame: Cycle 1, Day 1 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose); Cycle 1 Day 22 (Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose)
Population: All enrolled participants who received at least one dose of LY3039478 and had at least one evaluable PK data. Number analyzed refer to participants evaluable at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 25 mg LY3039478 | PK: Area Under the Plasma Concentration-Time Curve (AUC) From 0 to 24 Hours (AUC (0-24)) of LY3039478 | Cycle 1, Day 1 | 1480 nanograms*hours per milliliter(ng*h/mL) | Geometric Coefficient of Variation 20 |
| 25 mg LY3039478 | PK: Area Under the Plasma Concentration-Time Curve (AUC) From 0 to 24 Hours (AUC (0-24)) of LY3039478 | Cycle 1, Day 22 | 2070 nanograms*hours per milliliter(ng*h/mL) | Geometric Coefficient of Variation 54 |
| 50 mg LY3039478 | PK: Area Under the Plasma Concentration-Time Curve (AUC) From 0 to 24 Hours (AUC (0-24)) of LY3039478 | Cycle 1, Day 1 | 3080 nanograms*hours per milliliter(ng*h/mL) | Geometric Coefficient of Variation 38 |
| 50 mg LY3039478 | PK: Area Under the Plasma Concentration-Time Curve (AUC) From 0 to 24 Hours (AUC (0-24)) of LY3039478 | Cycle 1, Day 22 | 2090 nanograms*hours per milliliter(ng*h/mL) | Geometric Coefficient of Variation 76 |