Advanced Cancer
Conditions
Keywords
Metastases, Neoplasm, Advanced Cancer, Metastatic Cancer
Brief summary
This study is a multicenter, open-label, dose-escalation phase 1 study of intravenous (IV) LY2495655 in participants with advanced cancer.
Detailed description
This study will consist of the following parts: 1. Dose Escalation - Cohorts of at least 3 participants will be treated with increasing doses of LY2475655 until maximum tolerated dose (MTD) criteria are met in 1 of the 6 dose levels, or the 6th cohort is completed without meeting maximum tolerated dose criteria. 2. Dose Confirmation - Up to 10 more participants will be enrolled to the MTD dose level, or if it was not possible to define the MTD during dose escalation, all clinical and bioanalytical data will be reviewed to select the recommended Phase 2 dose and an up to 10 additional participants will be enrolled to this dose level.
Interventions
DRUGLY2495655
administered intravenously
Sponsors
Eli Lilly and Company
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug * Females with child bearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug * Have an estimated life expectancy of greater than 12 weeks * Have a histological or cytological diagnosis of cancer (with the exception of breast or prostate cancer) that is advanced and/or metastatic, for which no proven effective therapy exists or the participant has declined anticancer therapy OR * Have a histological or cytological diagnosis of metastatic breast or metastatic prostate cancer and receiving stable anti-hormone therapy for at least 2 months * Have adequate hematologic, hepatic, and renal function * 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, or any other investigational therapy, for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) prior to study enrollment and have recovered from the acute effects of therapy. Participants receiving anti-hormone therapy as specified in criteria above are not excluded
Exclusion criteria
* Have received treatment within 30 days of the initial dose of study drug with a drug that has not received regulatory approval for any indication * Have serious preexisting medical conditions other than their cancer (at the discretion of the investigator) * Have central nervous system malignancy or metastasis (screening not required) * Have a history of severe chronic diseases that could interfere with either strength evaluation or body mass assessment during participation in this study including, but not limited to, ischemic disease (affecting the heart, brain, or extremities), uncontrolled hypertension, uncontrolled pain, severe chronic obstructive pulmonary disease, uncompensated heart failure (New York Heart Association Class III or IV), uncontrolled diabetes, or liver cirrhosis (Child-Pugh Class C) * Have a history of inherited or acquired neuromuscular diseases including multiple sclerosis, muscular dystrophies, or myasthenia gravis * Have active systemic inflammatory conditions including rheumatoid arthritis, dermatomyositis, severe arthrosis, or scleroderma * Have unstable bone lesions, or any bone instability, fusion, arthroplasty, tendon repair, synovectomy, and so on, due to any of the before-mentioned conditions or due to accident that could interfere with completion of the physical tests in this protocol * Have chronic glucocorticosteroid use greater than 10 mg of prednisone per day or equivalent * Have known positive test results for hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb). Screening is not required * Have untreated hypothyroidism or hyperthyroidism * Have history of seizures, convulsions (except previous febrile convulsions), or stroke * Present with evidence of major depressive disorder, or history of obsessive compulsive disorder, significant psychiatric disease such as schizophrenia, bipolar disorder, or delirium * Have depressive symptoms associated with their cancer that require treatment with any of the excluded drugs listed in protocol * Have a previous history of discontinuation of a monoclonal antibody therapy due to allergy or severe infusion reaction * Are scheduled to start or already receive any anti-cancer hormone treatments for breast or prostate cancer in the adjuvant or neoadjuvant setting
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Drug-related Adverse Events | Baseline through End of Study (up to 51 months) | A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. An AE is summarized if the onset date is on or after the first dose of study drug and within 30 days after the last dose, or it occurred before the first dose of study drug and worsened while on the therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 and Cycle 4 Days 1 (pre-dose, end of infusion, 2hr, 6hr, 10-12hr after the infusion ends) and Day 2, 3, 5, 8 | AUC(0-336h) is the area under the drug concentration versus time curve within a dosing interval (0-336 hours). Due to the small number per cohort (participants dropping out) calculations of the accumulation factor of exposure for repeated every-other-week dosing were based on simulated area under the drug concentration versus time curve within a dosing interval (AUCτ) instead of observed values. The 90-percentage confidence interval was calculated as the predictive interval. |
| Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 and Cycle 4 Days 1 (pre-dose, end of infusion, 2hr, 6hr, 10-12hr after the infusion ends) and Day 2, 3, 5, 8 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 2 mg LY2495655 2 mg LY2495655 every 2 weeks. Dose Escalation Phase | 4 |
| 7 mg LY2495655 7 mg LY2495655 every 2 weeks. Dose Escalation Phase | 3 |
| 21 mg LY2495655 21 mg LY2495655 every 2 weeks. Dose Escalation Phase | 3 |
| 70 mg LY2495655 70 mg LY2495655 every 2 weeks. Dose Escalation Phase | 3 |
| 100 mg LY2495655 100 mg LY2495655 every 2 weeks. Dose Confirmation Phase | 4 |
| 210 mg LY2495655 210 mg LY2495655 every 2 weeks. Dose Escalation Phase | 3 |
| 300 mg LY2495655 300 mg LY2495655 every 2 weeks. Dose Confirmation Phase | 3 |
| 700 mg LY2495655 700 mg LY2495655 every 2 weeks. Dose Escalation Phase | 6 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 1 | 0 | 2 | 1 | 2 | 1 | 1 | 5 |
| Overall Study | Sponsor Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | 2 mg LY2495655 | 7 mg LY2495655 | 21 mg LY2495655 | 70 mg LY2495655 | 100 mg LY2495655 | 210 mg LY2495655 | 300 mg LY2495655 | 700 mg LY2495655 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 75.0 years STANDARD_DEVIATION 9.2 | 78.1 years STANDARD_DEVIATION 5.9 | 75.9 years STANDARD_DEVIATION 3.6 | 67.1 years STANDARD_DEVIATION 7.8 | 62.9 years STANDARD_DEVIATION 12.5 | 78.8 years STANDARD_DEVIATION 7.2 | 70.7 years STANDARD_DEVIATION 7.3 | 67.9 years STANDARD_DEVIATION 9.6 | 71.4 years STANDARD_DEVIATION 9.3 |
| Race/Ethnicity, Customized African | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 25 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 6 Participants | 29 Participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 4 Participants | 20 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 4 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 2 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 3 | 1 / 3 | 1 / 4 | 2 / 3 | 1 / 3 | 2 / 6 |
Outcome results
Primary
Number of Participants With One or More Drug-related Adverse Events
A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. An AE is summarized if the onset date is on or after the first dose of study drug and within 30 days after the last dose, or it occurred before the first dose of study drug and worsened while on the therapy.
Time frame: Baseline through End of Study (up to 51 months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 1 Participants |
| 7 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 0 Participants |
| 21 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 1 Participants |
| 70 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 0 Participants |
| 100 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 1 Participants |
| 210 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 0 Participants |
| 300 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 0 Participants |
| 700 mg LY2495655 | Number of Participants With One or More Drug-related Adverse Events | 2 Participants |
Secondary
Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655
Time frame: Cycle 1 and Cycle 4 Days 1 (pre-dose, end of infusion, 2hr, 6hr, 10-12hr after the infusion ends) and Day 2, 3, 5, 8
Population: All participants who received at least one dose of study drug and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 6.58 nanomolar (nM) | Geometric Coefficient of Variation 7 |
| 2 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 6.67 nanomolar (nM) | — |
| 7 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 12.6 nanomolar (nM) | Geometric Coefficient of Variation 9 |
| 7 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 11.5 nanomolar (nM) | Geometric Coefficient of Variation 12 |
| 21 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 60.2 nanomolar (nM) | — |
| 21 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 38.3 nanomolar (nM) | Geometric Coefficient of Variation 20 |
| 70 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 101.0 nanomolar (nM) | Geometric Coefficient of Variation 12 |
| 70 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 165.0 nanomolar (nM) | Geometric Coefficient of Variation 16 |
| 100 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 754.0 nanomolar (nM) | Geometric Coefficient of Variation 37 |
| 100 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 1020.0 nanomolar (nM) | — |
| 210 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 221.0 nanomolar (nM) | Geometric Coefficient of Variation 8 |
| 210 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 307.0 nanomolar (nM) | Geometric Coefficient of Variation 24 |
| 300 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 2010.0 nanomolar (nM) | Geometric Coefficient of Variation 31 |
| 300 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 1360.0 nanomolar (nM) | Geometric Coefficient of Variation 27 |
| 700 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 1 | 392.0 nanomolar (nM) | Geometric Coefficient of Variation 14 |
| 700 mg LY2495655 | Pharmacokinetics: Maximum Concentration (Cmax) of LY2495655 | Cycle 4 | 559.0 nanomolar (nM) | Geometric Coefficient of Variation 18 |
Secondary
Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655
AUC(0-336h) is the area under the drug concentration versus time curve within a dosing interval (0-336 hours). Due to the small number per cohort (participants dropping out) calculations of the accumulation factor of exposure for repeated every-other-week dosing were based on simulated area under the drug concentration versus time curve within a dosing interval (AUCτ) instead of observed values. The 90-percentage confidence interval was calculated as the predictive interval.
Time frame: Cycle 1 and Cycle 4 Days 1 (pre-dose, end of infusion, 2hr, 6hr, 10-12hr after the infusion ends) and Day 2, 3, 5, 8
Population: All participants who received at least one dose of study drug and had evaluable pharmacokinetic data. Confidence Interval calculated as predictive interval and summarized from simulated PK profiles in 1000 virtual participants for each dose using a population PK model for LY2495655.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 2 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 0.622 micromolar*hr (µM*hr) |
| 2 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 0.426 micromolar*hr (µM*hr) |
| 7 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 1.62 micromolar*hr (µM*hr) |
| 7 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 2.63 micromolar*hr (µM*hr) |
| 21 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 5.36 micromolar*hr (µM*hr) |
| 21 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 10.0 micromolar*hr (µM*hr) |
| 70 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 39.2 micromolar*hr (µM*hr) |
| 70 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 19.5 micromolar*hr (µM*hr) |
| 100 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 57.6 micromolar*hr (µM*hr) |
| 100 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 28.2 micromolar*hr (µM*hr) |
| 210 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 60.4 micromolar*hr (µM*hr) |
| 210 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 124 micromolar*hr (µM*hr) |
| 300 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 86.8 micromolar*hr (µM*hr) |
| 300 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 179 micromolar*hr (µM*hr) |
| 700 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 1 | 204 micromolar*hr (µM*hr) |
| 700 mg LY2495655 | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC[0-336]) of LY2495655 | Cycle 4 | 424 micromolar*hr (µM*hr) |