Neoplasm Metastasis
Conditions
Brief summary
The primary purpose of this study is to assess the safety and tolerability of LY2940680 up to the global recommended dose in Japanese participants with advanced solid cancers.
Interventions
DRUGLY2940680
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histological or cytological evidence of a diagnosis of solid tumor that is advanced and/or metastatic. The participant must be, in the judgment of the investigator, an appropriate candidate for the experimental therapy after available standard therapies have failed to provide clinical benefit for their disease * Have the presence of measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors Guideline Version 1.1 * Have adequate organ function * Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, cancer-related hormonal therapy for at least 3 weeks (6 weeks for mitomycin-C or nitrosoureas, 2 weeks for palliative radiation therapy for bone metastasis) prior to study enrollment, and have recovered from the acute effects of any such therapy * Males must agree to use medically approved barrier contraceptive precautions during the study and for 6 months following the last dose of study drug * Females with child bearing potential must agree to use medically approved contraceptive precautions during the study and for 6 months following the last dose of study drug; have had a negative serum pregnancy test ≤7 days before the first dose of study drug * A breastfeeding woman must not be breastfeeding. If a female who stops breastfeeding enters the study, the female must stop breastfeeding from the day of the first study drug administration until at least 6 months after the last administration * Have an estimated life expectancy, in the judgment of the investigator, which will permit the participant to complete 2 cycles of treatment * Are able to swallow tablets
Exclusion criteria
* Have received treatment within 21 days of the study enrollment with any agent that has not received regulatory approval for any indication * Have symptomatic central nervous system (CNS) malignancy or metastasis. Participants with treated brain metastases are eligible if they are clinically stable with regard to neurologic function and off steroids after cranial irradiation ending at least 14 days prior to enrollment, or after surgical resection performed at least 28 days prior to enrollment * Have known current hematologic malignancies or acute or chronic leukemia * Have a known active fungal, bacterial, and/or known viral infection including human immunodeficiency (HIV) or viral (A, B, or C) hepatitis, potentially affecting the conduct of this study * Have a second primary malignancy that in the judgment of the investigator and sponsor may affect the interpretation of results * Have QTc interval of \>470 milliseconds (msec) on screening electrocardiogram (ECG) * Have serious preexisting medical conditions or serious concomitant systemic disorders that, in the opinion of the investigator, would preclude participation in this study * Have received any medication that is a strong inhibitor of cytochrome P4503A4 (CYP3A4) within 7 days prior to receiving study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With LY2940680 Dose-Limiting Toxicities (DLT) | Cycle 1 (28 Days) | DLT was defined as an AE during Cycle 1 that is possibly related to the study drug and meets any one of the following criteria based on NCI CTCAE,version 4.0): Grade(Gr) 3 nonhematological toxicity(tox) with exceptions for made for nausea(ns),vomiting(vm),constipation(cp),diarrhea(dr),fatigue(ft),anorexia(an),alopecia or electrolyte-abnormality(eab) that is manageable with appropriate care.If \>Gr 3 ns,vm,cp,dr,ft,an,or eab persists for\>2 days with maximal supportive intervention,the event was declared a DLT.Transient(≤5 days) Gr 3 liver enzyme elevations,without evidence of other hepatic injury.Gr 3 thrombocytopenia(throm) requiring platelet transfusion or Gr 4 throm.Gr 4 neutropenia of \>5 days duration.Febrile neutropenia(ANC\<1,000/mm3 with a single temperature(temp) of \>38.3 degrees C or a sustained temp of ≥38 degrees C for more than one hour).Tox requiring dose omissions of \>5 days or significant & deemed by the primary investigator(PI) & sponsor(sp) to be dose limiting . |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | Cycle1 Day1: Predose, 0.5,1,2,4, 6, 8, 10-12 hours; Cycle 1 Day15: Predose, 0.5,1,2,4, 6, 8, 10-12 hours | Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556). |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | Cycle1 Day1: Predose, 0.5,1,2,4, 6, 8, 10-12 hours; Cycle 1 Day15: Predose, 0.5,1,2,4, 6, 8, 10-12 hours | Pharmacokinetics (PK): Area Under the Concentration time Curve From 0 to 24 Hours (AUC\[0-24\]) of LY2940680 and a Major Metabolite of LSN3185556. |
| Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | Baseline Until Disease Progression or Death Due to Any Cause (Up to 29 Months) | Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and all target and non-target lymph nodes were non-pathological or normal in size (\<10 millimeter \[mm\] short axis). PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameters. ORR calculated as: (sum of the number of participants with PRs and CRs) divided by (number of evaluable participants) multiplied by 100. |
| Pharmacodynamic (PD): Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin | Baseline, Cycle 1 Day15 | Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin. |
Countries
Japan
Participant flow
Pre-assignment details
Study completers were participants who were Dose-Limiting Toxicities (DLT) evaluable and discontinued the treatment due to any reason.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: 100 mg LY2940680 Cohort 1: 100 mg LY2940680 administered orally once daily in 28-day cycles.
Treatment with LY2940680 continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. | 3 |
| Cohort 2: 200 mg LY2940680 Cohort 2: 200 mg LY2940680 administered orally daily in 28-day cycles.
Treatment with LY2940680 continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. | 3 |
| Cohort 3: 400 mg LY2940680 Cohort 3: 400 mg LY2940680 administered orally once daily in 28-day cycles.
Treatment with LY2940680 continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. | 13 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Progressive Disease | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Cohort 1: 100 mg LY2940680 | Total | Cohort 3: 400 mg LY2940680 | Cohort 2: 200 mg LY2940680 |
|---|---|---|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 7.02 | 62.9 years STANDARD_DEVIATION 10.95 | 60.7 years STANDARD_DEVIATION 11.93 | 72.0 years STANDARD_DEVIATION 4.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 19 Participants | 13 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 3 Participants | 19 Participants | 13 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 16 Participants | 13 Participants | 2 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 / 3 | 3 / 3 | 13 / 13 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 4 / 13 |
Outcome results
Primary
Number of Participants With LY2940680 Dose-Limiting Toxicities (DLT)
DLT was defined as an AE during Cycle 1 that is possibly related to the study drug and meets any one of the following criteria based on NCI CTCAE,version 4.0): Grade(Gr) 3 nonhematological toxicity(tox) with exceptions for made for nausea(ns),vomiting(vm),constipation(cp),diarrhea(dr),fatigue(ft),anorexia(an),alopecia or electrolyte-abnormality(eab) that is manageable with appropriate care.If \>Gr 3 ns,vm,cp,dr,ft,an,or eab persists for\>2 days with maximal supportive intervention,the event was declared a DLT.Transient(≤5 days) Gr 3 liver enzyme elevations,without evidence of other hepatic injury.Gr 3 thrombocytopenia(throm) requiring platelet transfusion or Gr 4 throm.Gr 4 neutropenia of \>5 days duration.Febrile neutropenia(ANC\<1,000/mm3 with a single temperature(temp) of \>38.3 degrees C or a sustained temp of ≥38 degrees C for more than one hour).Tox requiring dose omissions of \>5 days or significant & deemed by the primary investigator(PI) & sponsor(sp) to be dose limiting .
Time frame: Cycle 1 (28 Days)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: 100 mg LY2940680 | Number of Participants With LY2940680 Dose-Limiting Toxicities (DLT) | 0 Participants |
| Cohort 2: 200 mg LY2940680 | Number of Participants With LY2940680 Dose-Limiting Toxicities (DLT) | 0 Participants |
| Cohort 3: 400 mg LY2940680 | Number of Participants With LY2940680 Dose-Limiting Toxicities (DLT) | 3 Participants |
Secondary
Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])
Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and all target and non-target lymph nodes were non-pathological or normal in size (\<10 millimeter \[mm\] short axis). PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameters. ORR calculated as: (sum of the number of participants with PRs and CRs) divided by (number of evaluable participants) multiplied by 100.
Time frame: Baseline Until Disease Progression or Death Due to Any Cause (Up to 29 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: 100 mg LY2940680 | Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | 0 Participants |
| Cohort 2: 200 mg LY2940680 | Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | 1 Participants |
| Cohort 3: 400 mg LY2940680 | Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | 0 Participants |
Secondary
Pharmacodynamic (PD): Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin
Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin.
Time frame: Baseline, Cycle 1 Day15
Population: All participants who received at least one dose of study drug and evaluable PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: 100 mg LY2940680 | Pharmacodynamic (PD): Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin | 92.73 percentage change | Standard Deviation 0.928 |
| Cohort 2: 200 mg LY2940680 | Pharmacodynamic (PD): Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin | 89.24 percentage change | Standard Deviation 2.096 |
| Cohort 3: 400 mg LY2940680 | Pharmacodynamic (PD): Percentage Change From Baseline in Gene Expression Level of Hedgehog (Hh) Regulated Genes (Gli1) in Skin | 92.86 percentage change | Standard Deviation 8.053 |
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556
Pharmacokinetics (PK): Area Under the Concentration time Curve From 0 to 24 Hours (AUC\[0-24\]) of LY2940680 and a Major Metabolite of LSN3185556.
Time frame: Cycle1 Day1: Predose, 0.5,1,2,4, 6, 8, 10-12 hours; Cycle 1 Day15: Predose, 0.5,1,2,4, 6, 8, 10-12 hours
Population: All participants who received at least one dose of study drug who had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LY2940680:Cycle 1 Day 1 | 7.96 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 31 |
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LY2940680:Cycle 1 Day 15 | 14.7 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 78 |
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LSN3185556:Cycle 1 Day 1 | 13.2 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 48 |
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LSN3185556:Cycle 1 Day 15 | 31.8 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 126 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LSN3185556:Cycle 1 Day 15 | 79.7 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 15 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LY2940680:Cycle 1 Day 1 | 20.3 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 22 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LSN3185556:Cycle 1 Day 1 | 24.6 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 5 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LY2940680:Cycle 1 Day 15 | 42.9 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 40 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LSN3185556:Cycle 1 Day 15 | 235 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 48 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LY2940680:Cycle 1 Day 15 | 142 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 61 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LSN3185556:Cycle 1 Day 1 | 50.1 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 30 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Area Under the Concentration Time Curve From 0 to 24 Hours (AUC[0-24]) of LY2940680 and a Major Metabolite of LSN3185556 | LY2940680:Cycle 1 Day 1 | 43.1 microgram*hour per milliliter(µg*h/mL) | Geometric Coefficient of Variation 26 |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556)
Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556).
Time frame: Cycle1 Day1: Predose, 0.5,1,2,4, 6, 8, 10-12 hours; Cycle 1 Day15: Predose, 0.5,1,2,4, 6, 8, 10-12 hours
Population: All participants who received at least one dose of study drug who had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LY2940680:Cycle 1 Day 1 | 0.841 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 8 |
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LSN3185556:Cycle 1 Day 15 | 2.12 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 84 |
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LSN3185556:Cycle 1 Day 1 | 0.925 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 45 |
| Cohort 1: 100 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LY2940680:Cycle 1 Day 15 | 1.41 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 51 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LSN3185556:Cycle 1 Day 1 | 1.49 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 8 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LY2940680:Cycle 1 Day 15 | 3.10 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 21 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LSN3185556:Cycle 1 Day 15 | 4.10 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 22 |
| Cohort 2: 200 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LY2940680:Cycle 1 Day 1 | 1.81 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 5 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LSN3185556:Cycle 1 Day 15 | 13.7 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 50 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LY2940680:Cycle 1 Day 1 | 3.84 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 29 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LY2940680:Cycle 1 Day 15 | 9.08 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 40 |
| Cohort 3: 400 mg LY2940680 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680 and a Major Metabolite of LY2940680 (LSN3185556) | LSN3185556:Cycle 1 Day 1 | 3.02 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 30 |