Cancer
Conditions
Brief summary
The purpose of this study is to assess the effect LY2603618 on a protein \[enzyme cytochrome P (CYP) 2D6\] which is involved in the metabolic pathway of Desipramine in participants with cancer. This is a drug interaction study so the treatment of the disease will not be the main purpose of the study. The study involves two single doses of 50 milligrams (mg), 1 tablet by mouth, on Day 1 of Period 1 and 2. In Period 1 Desipramine will be administered alone. In Period 2 Desipramine will be administered in combination with LY2603618. LY2603618 will be administered as a 275mg intravenous (IV) infusion over 1 hour (hr). Desipramine will be administered at the end of the LY2603618 infusion. Information about any side effects that may occur will also be collected.
Interventions
DRUGLY2603618
Administered intravenously as a 1-hour infusion.
DRUGDesipramine
Administered orally
DRUGPemetrexed
Administered intravenously as a 10-minute infusion.
DRUGGemcitabine
Administered intravenously as a 30-minute infusion.
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 a histological or cytological diagnosis of cancer (solid tumor), with clinical or radiologic evidence of locally advanced and/or metastatic disease, for which no life-prolonging therapy exists (that is, refractory to standard therapy and/or therapies known to provide clinical benefit, or for which no standard therapy exists). Note: Participants who have had progressive disease after receiving pemetrexed for metastatic disease are excluded from receiving the combination with pemetrexed during the safety extension study. Participants who have had progressive disease after receiving gemcitabine for metastatic disease are excluded from receiving the combination with gemcitabine during the safety extension study. * Have a body surface area (BSA) greater than or equal to 1.37 square meters (m²) * Have given written informed consent prior to any study-specific procedures * 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 treatments for cancer, including chemotherapy, radiotherapy, anticancer hormone therapy or other investigational therapy for at least 30 days prior to study entry and recovered from the acute effects of therapy (at least 42 days for mitomycin-C or nitrosoureas, or 60 days for biologics) * Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures * Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for at least 3 months following the last dose of study drug * Females with childbearing potential: Have had a negative serum pregnancy test less than or equal to 7 days before the first dose of study drug and must also not be breastfeeding * Have an estimated life expectancy, in the judgment of the investigator, that will permit the participant to complete 1 full cycle of treatment beyond the drug interaction portion of the study (approximately 8 weeks) * Are able to swallow tablets * Prior radiation therapy for treatment of cancer is allowed to \<25% of the bone marrow and participants must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry.
Exclusion criteria
* Have received treatment within 28 days of the initial dose of study drug with an experimental agent for noncancer indications that has not received regulatory approval for any indication * Poor metabolizer (PM) status for CYP2D6 (genotyped) * Have previously completed or withdrawn from this study or any other study investigating LY2603618 or any other checkpoint kinase one (Chk1) inhibitor * Have known allergy to gemcitabine, pemetrexed, desipramine or LY2603618 or any ingredient of gemcitabine, pemetrexed, desipramine or LY2603618 (like Captisol®) * Have serious preexisting medical conditions (left to the discretion of the investigator) other than advanced cancer * 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 90 days. * Have current hematologic malignancies or either 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 QTc interval of \>500 milliseconds (msec) on screening electrocardiogram (ECG) * Have ECG abnormalities on the screening ECG such as significant conduction abnormalities, ischemic changes (such as prior Q-wave myocardial infarction and/or marked ischemic ST- and T-wave), arrhythmias (such as persistent or paroxysmal ventricular or supraventricular arrhythmias, including atrial fibrillation), or other ECG abnormalities that would put the participant at unnecessary risk in the opinion of the investigator * Drugs with narrow therapeutic windows and that are also known substrates of CYP2D6 or drugs that are classified as sensitive substrates of CYP2D6 are excluded * Drugs or herbal supplements that are known inhibitors of CYP2D6 are excluded during the study, and during the 30-day period (or a minimum of 5 half-lives, whichever is less) prior to study start * Participants who have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females), or participants unwilling to stop alcohol consumption for 24 hours before the study through the end of the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Plasma Pharmacokinetics of LY2603618: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)] | Period 2 only: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours post dose |
| Plasma Pharmacokinetics of LY2603618: the Maximum Concentration of LY2603618 in the Plasma (Cmax) | Period 2 only: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours post dose |
| Plasma Pharmacokinetics of Desipramine: the Maximum Concentration of Desipramine in the Plasma (Cmax) | Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose |
| Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of Desipramine [AUC(0-tlast)] | Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose |
| Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)] | Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose |
| Plasma Pharmacokinetics of LY2603618: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of LY2603618 [AUC(0-tlast)] | Period 2 only: Predose 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours post dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Tumor Response | Baseline to study completion up to 11 cycles of 21-day cycles | Tumor response is complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (Version 1.1). CR is the disappearance of all target and non-target lesions and PR is a ≥30% decrease in sum of longest diameter of target lesions. Number of participants with a tumor response is the total number of participants with CR or PR. |
Countries
United States
Participant flow
Pre-assignment details
This was a nonrandomized, open-label, fixed-sequence, 2-period study followed by a continued access phase.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Single 50-milligram (mg) oral dose of desipramine on Day 1 of Study Period 1. Single 275-mg intravenous infusion over one hour of LY2603618 followed by single 50-mg oral dose of desipramine on Day 1 of Study Period 2.
Participants may have received additional doses of LY2603618 in combination as follows: 1000 milligrams per square meter (mg/m²) intravenous administration over 30 minutes of gemcitabine on Days 1, 8 and 15 and 230-mg intravenous infusion over one hour of LY2603618 on Days 2, 9 and 16 of 28-day cycles during continued access phase OR 500-mg/m² intravenous administration over 10 minutes of pemetrexed on Day 1 and 275-mg intravenous infusion over one hour of LY2603618 on Day 2 of 21-day cycles during continued access phase.
Participants were allowed to continue to receive the combination therapy until fulfilling one of the criteria for discontinuation, such as unacceptable toxicity or disease progression. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Continued Access Phase | Death | 0 | 0 | 1 | 1 |
| Continued Access Phase | Progression of Disease | 0 | 0 | 8 | 4 |
| Continued Access Phase | Protocol Violation | 0 | 0 | 0 | 2 |
| Continued Access Phase | Withdrawal by Subject | 0 | 0 | 3 | 0 |
| Period 2 | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 58.3 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 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 | 7 Participants |
| Race (NIH/OMB) More than one race | 1 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 | 12 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 9 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 | 8 / 20 | 12 / 19 | 12 / 12 | 7 / 7 |
| serious Total, serious adverse events | 0 / 20 | 1 / 19 | 4 / 12 | 2 / 7 |
Outcome results
Primary
Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)]
Time frame: Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose
Population: All participants who received desipramine and had pharmacokinetic data collected to calculate the AUC(0-∞) of desipramine in Periods 1 and 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2603618 | Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)] | Period 1 | 655 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 84 |
| LY2603618 | Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)] | Period 2 | 687 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 80 |
Primary
Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of Desipramine [AUC(0-tlast)]
Time frame: Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose
Population: All participants who received desipramine and had pharmacokinetic data collected to calculate AUC(0-tlast) of desipramine in Periods 1 and 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2603618 | Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of Desipramine [AUC(0-tlast)] | Period 1 | 619 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 76 |
| LY2603618 | Plasma Pharmacokinetics of Desipramine: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of Desipramine [AUC(0-tlast)] | Period 2 | 653 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 72 |
Primary
Plasma Pharmacokinetics of Desipramine: the Maximum Concentration of Desipramine in the Plasma (Cmax)
Time frame: Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose
Population: All participants who received desipramine and had pharmacokinetic data collected to calculate the Cmax of desipramine in Periods 1 and 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2603618 | Plasma Pharmacokinetics of Desipramine: the Maximum Concentration of Desipramine in the Plasma (Cmax) | Period 1 | 21.2 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 67 |
| LY2603618 | Plasma Pharmacokinetics of Desipramine: the Maximum Concentration of Desipramine in the Plasma (Cmax) | Period 2 | 22.8 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 62 |
Primary
Plasma Pharmacokinetics of LY2603618: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)]
Time frame: Period 2 only: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours post dose
Population: All participants who received LY2603618 and had pharmacokinetic data collected to calculate the AUC(0-∞) of LY2603618 in Period 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2603618 | Plasma Pharmacokinetics of LY2603618: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)] | 53700 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 55 |
Primary
Plasma Pharmacokinetics of LY2603618: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of LY2603618 [AUC(0-tlast)]
Time frame: Period 2 only: Predose 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours post dose
Population: All participants who received LY2603618 and had pharmacokinetic data collected to calculate the AUC(0-tlast) of LY2603618 in Period 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2603618 | Plasma Pharmacokinetics of LY2603618: the Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Observed Plasma Concentration of LY2603618 [AUC(0-tlast)] | 53000 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 52 |
Primary
Plasma Pharmacokinetics of LY2603618: the Maximum Concentration of LY2603618 in the Plasma (Cmax)
Time frame: Period 2 only: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours post dose
Population: All participants who received LY2603618 and had pharmacokinetic data collected to calculate the Cmax of LY2603618 in Period 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2603618 | Plasma Pharmacokinetics of LY2603618: the Maximum Concentration of LY2603618 in the Plasma (Cmax) | 5950 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 39 |
Secondary
Number of Participants With a Tumor Response
Tumor response is complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (Version 1.1). CR is the disappearance of all target and non-target lesions and PR is a ≥30% decrease in sum of longest diameter of target lesions. Number of participants with a tumor response is the total number of participants with CR or PR.
Time frame: Baseline to study completion up to 11 cycles of 21-day cycles
Population: All participants who received at least 1 dose of study drug and had tumor response measured during continued access phase.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY2603618 | Number of Participants With a Tumor Response | 1 Participants |
| LY2603618 + Pemetrexed (Continued Access) | Number of Participants With a Tumor Response | 0 Participants |