Solid Tumors
Conditions
Brief summary
The goal of this study is to determine the dose of LY573636-sodium (hereafter referred to as LY573636) that can be administered safely in combination with liposomal doxorubicin in patients with advanced cancer who have failed a prior treatment. The study consists of a dose escalation phase to the maximum tolerated dose (MTD) and a dose confirmation phase in patients with platinum resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have never been treated with doxorubicin.
Interventions
DRUGLY573636-sodium
Individualized dose is dependent on participant's height, weight, gender and is adjusted to target a specific exposure range corrected for a participant's laboratory parameters. Intravenous dosing is done on Day 1 of a 28-day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, cumulative dose of 550 milligrams per square meter (mg/m²) of liposomal doxorubicin or doxorubicin is reached, or other withdrawal criterion is met.
DRUGLiposomal Doxorubicin
40 mg/m² on Day 1, given intravenously of each 28-day cycle Participants may continue on study drug until disease progression, unacceptable toxicity, cumulative dose of 550 mg/m² of liposomal doxorubicin or doxorubicin is reached, or other withdrawal criterion are met.
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
* You must have a histologically confirmed solid malignancy that is unresectable and/or metastatic which has progressed after receiving standard approved chemotherapy * You must have a solid malignancy for which an anthracycline-based regimen is felt to be a reasonable treatment option * You must have measurable disease or non-measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) * You must have a serum albumin level greater than or equal to 3.0 grams/deciliter (g/dL) (30 g/L) * You must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale * You must have tumor progression after receiving standard/approved chemotherapy * You must be reliable and willing to make yourself available for the duration of the study and are willing to follow study procedures * Women must be sterile, post-menopausal or on a contraception and men must be sterile or on contraception * Your test results assessing the function of your blood, kidneys, liver, and heart are satisfactory * Ovarian patients in the confirmation phase must have failed to achieve at least a partial response to a first-line platinum-based therapy (platinum-refractory) or have progression in less than 6 months after a response to a first-line platinum-based therapy (platinum-resistant) * Ovarian patients in the confirmation phase must have measurable disease by RECIST * Ovarian patients in the confirmation phase must be liposomal doxorubicin or doxorubicin naive and not amendable to curative therapy
Exclusion criteria
* You cannot have received other investigational drugs within the last 28 days * You cannot have other on-going serious illnesses including active bacterial, fugal, or viral infections * You cannot have current hematologic malignancies, acute or chronic leukemia, or brain metastasis * You cannot currently be receiving warfarin (Coumadin®) therapy * You cannot have known positive test results in human immunodeficiency, hepatitis B surface antigen or hepatitis C antibodies * You cannot have a history of cardiac disease or clinical evidence of congestive heart failure * Ovarian patients in the confirmation phase who have received 2 or more cytotoxic regimens for platinum-resistant disease * You cannot currently be receiving amiodarone, quinidine, propofol, and clozapine * If you are taking esomeprazole or pantoprazole you must be able to stop taking this medication within 72 hours before and after LY573636 administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose | Predose up to 28 days postdose in Cycle 1 | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD), which is corrected for the participant's predose albumin to identify the albumin-corrected exposure range of LY 573636 when combined with liposomal doxorubicin. MTD is the highest dose with \<33% of participants having a dose-limiting toxicity (DLT) in the first 28-day cycle of treatment. DLT is an adverse event (AE) that is likely related to the study drug or combination and fulfills any 1 of the following: Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity; Gr 3 nonhematologic toxicity (excluding controllable nausea/vomiting or diarrhea and alopecia); Gr 3 electrolyte toxicity that is not resolved with standard treatments. Those who enter the study with Gr 2 hepatic enzyme abnormalities, DLT for an isolated Gr 3 hepatic enzyme abnormality is determined by investigators; a DLT can be declared if a participant experiences increasing toxicity during treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Events | Baseline to study completion up to 18.49 months | Clinically significant events are defined as serious adverse events (SAEs), regardless of causality, during the study including the 30-day follow-up period. A summary of SAEs and other nonserious adverse events is located in the Reported Adverse Event section. Death due to progressive disease was not considered as an SAE. |
| Pharmacokinetics: Maximum Concentration (Cmax) of LY573636 | Predose, 30 minutes (min), 2 hours (h), 4 h, 166 h, 360 h and 698 h postdose in Cycle 1; Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 2; Predose, 166h, 360h and 698 h postdose in Cycle 3 | — |
| Number of Participants With Tumor Response | Baseline to measured progressive disease up to 4.7 months | Number of participants with tumor response = number of participants with complete response (CR) + number of participants with partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in the sum of longest diameter of target lesions. |
| Pharmacokinetics: Area Under the Curve of LY573636 Above the Albumin Corrected Threshold (AUCalb) | Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 1; Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 2; Predose, 166h, 360h and 698 h postdose in Cycle 3 | LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. |
Other
| Measure | Time frame |
|---|---|
| Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | From date of randomization until up to 30 days post study treatment discontinuation, assessed up to 4.7 months |
Countries
United States
Participant flow
Pre-assignment details
The reasons for discontinuation listed in the participant flow are the reasons the participant discontinued treatment and a participant was considered to have completed the trial if they experienced progressive disease or an adverse event.
Participants by arm
| Arm | Count |
|---|---|
| LY 300 μg/mL + Dox LY573636 targeting a maximum concentration (Cmax) of 300 micrograms per milliliter (μg/mL) (LY 300 μg/mL) as a 2-hour infusion on Day 1 of a 28-day cycle in combination with liposomal doxorubicin (Dox) at a dose of 40 milligrams per square meter (mg/m²) during the Dose-Escalation Phase. | 4 |
| LY 320 μg/mL + Dox LY573636 targeting a Cmax of 320 μg/mL (LY 320 μg/mL) as a 2-hour infusion on Day 1 of a 28-day cycle in combination with liposomal doxorubicin (Dox) at a dose of 40 mg/m² during the Dose-Escalation Phase. | 3 |
| LY 340 μg/mL + Dox LY573636 targeting a Cmax of 340 μg/mL (LY 340 μg/mL) as a 2-hour infusion on Day 1 of a 28-day cycle in combination with liposomal doxorubicin (Dox) at a dose of 40 mg/m² during the Dose-Escalation Phase. | 6 |
| LY 360 μg/mL + Dox LY573636 targeting a Cmax of 360 μg/mL (LY 360 μg/mL) as a 2-hour infusion on Day 1 of a 28-day cycle in combination with liposomal doxorubicin (Dox) at a dose of 40 mg/m² during the Dose-Escalation Phase. | 6 |
| LY 380 μg/mL + Dox LY573636 targeting a Cmax of 380 μg/mL (LY 380 μg/mL) as a 2-hour infusion on Day 1 of a 28-day cycle in combination with liposomal doxorubicin (Dox) at a dose of 40 mg/m² during the Dose-Escalation Phase. | 6 |
| LY Albumin and Day 15 PK Tailored + Dox LY573636 dosing was given as a 2-hour infusion on Day 1 of a 28-day cycle in combination with liposomal doxorubicin (Dox) at a dose of 40 mg/m² during the Dose-Confirmation Phase. LY573636 dose was based on an albumin-corrected exposure (AUCalb) target range of 75th percentile of 3500 hour\*micrograms per milliliter (h\*μg/mL) and the Cycle 1, Day 15 LY573636 total drug level (Day 15 pharmacokinetic \[PK\]) (LY Albumin and Day 15 PK Tailored). | 6 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 2 | 1 | 1 |
| Overall Study | Death | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 4 | 2 | 5 | 4 | 4 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | LY 300 μg/mL + Dox | LY 320 μg/mL + Dox | LY 340 μg/mL + Dox | LY 360 μg/mL + Dox | LY 380 μg/mL + Dox | LY Albumin and Day 15 PK Tailored + Dox | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.39 years STANDARD_DEVIATION 13.6 | 51.54 years STANDARD_DEVIATION 8.55 | 64.65 years STANDARD_DEVIATION 7.53 | 58.57 years STANDARD_DEVIATION 2.71 | 52.24 years STANDARD_DEVIATION 15.08 | 57.82 years STANDARD_DEVIATION 12.97 | 57.54 years STANDARD_DEVIATION 10.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 6 Participants | 5 Participants | 4 Participants | 6 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 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 |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 5 Participants | 6 Participants | 5 Participants | 6 Participants | 28 Participants |
| Region of Enrollment United States | 4 Participants | 3 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 31 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants | 5 Participants | 5 Participants | 6 Participants | 28 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 | 5 / 6 | 3 / 6 | 3 / 6 | 3 / 6 |
Outcome results
Primary
Recommended Phase 2 Dose
Recommended Phase 2 dose was determined by maximum tolerated dose (MTD), which is corrected for the participant's predose albumin to identify the albumin-corrected exposure range of LY 573636 when combined with liposomal doxorubicin. MTD is the highest dose with \<33% of participants having a dose-limiting toxicity (DLT) in the first 28-day cycle of treatment. DLT is an adverse event (AE) that is likely related to the study drug or combination and fulfills any 1 of the following: Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity; Gr 3 nonhematologic toxicity (excluding controllable nausea/vomiting or diarrhea and alopecia); Gr 3 electrolyte toxicity that is not resolved with standard treatments. Those who enter the study with Gr 2 hepatic enzyme abnormalities, DLT for an isolated Gr 3 hepatic enzyme abnormality is determined by investigators; a DLT can be declared if a participant experiences increasing toxicity during treatment.
Time frame: Predose up to 28 days postdose in Cycle 1
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY 300 μg/mL + Dox | Recommended Phase 2 Dose | NA micrograms per milliliter (μg/mL) |
| LY 320 μg/mL + Dox | Recommended Phase 2 Dose | NA micrograms per milliliter (μg/mL) |
| LY 340 μg/mL + Dox | Recommended Phase 2 Dose | NA micrograms per milliliter (μg/mL) |
| LY 360 μg/mL + Dox | Recommended Phase 2 Dose | NA micrograms per milliliter (μg/mL) |
| LY 380 μg/mL + Dox | Recommended Phase 2 Dose | NA micrograms per milliliter (μg/mL) |
| LY Albumin and Day 15 PK Tailored + Dox | Recommended Phase 2 Dose | NA micrograms per milliliter (μg/mL) |
Secondary
Number of Participants With Clinically Significant Events
Clinically significant events are defined as serious adverse events (SAEs), regardless of causality, during the study including the 30-day follow-up period. A summary of SAEs and other nonserious adverse events is located in the Reported Adverse Event section. Death due to progressive disease was not considered as an SAE.
Time frame: Baseline to study completion up to 18.49 months
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY 300 μg/mL + Dox | Number of Participants With Clinically Significant Events | 2 Participants |
| LY 320 μg/mL + Dox | Number of Participants With Clinically Significant Events | 0 Participants |
| LY 340 μg/mL + Dox | Number of Participants With Clinically Significant Events | 5 Participants |
| LY 360 μg/mL + Dox | Number of Participants With Clinically Significant Events | 3 Participants |
| LY 380 μg/mL + Dox | Number of Participants With Clinically Significant Events | 3 Participants |
| LY Albumin and Day 15 PK Tailored + Dox | Number of Participants With Clinically Significant Events | 3 Participants |
Secondary
Number of Participants With Tumor Response
Number of participants with tumor response = number of participants with complete response (CR) + number of participants with partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in the sum of longest diameter of target lesions.
Time frame: Baseline to measured progressive disease up to 4.7 months
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY 300 μg/mL + Dox | Number of Participants With Tumor Response | 1 Participants |
| LY 320 μg/mL + Dox | Number of Participants With Tumor Response | 0 Participants |
| LY 340 μg/mL + Dox | Number of Participants With Tumor Response | 1 Participants |
| LY 360 μg/mL + Dox | Number of Participants With Tumor Response | 3 Participants |
| LY 380 μg/mL + Dox | Number of Participants With Tumor Response | 0 Participants |
| LY Albumin and Day 15 PK Tailored + Dox | Number of Participants With Tumor Response | 2 Participants |
Secondary
Pharmacokinetics: Area Under the Curve of LY573636 Above the Albumin Corrected Threshold (AUCalb)
LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636.
Time frame: Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 1; Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 2; Predose, 166h, 360h and 698 h postdose in Cycle 3
Population: Participants who received the study drug and had sufficient pharmacokinetic (PK) data to calculate AUCalb at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY 300 μg/mL + Dox | Pharmacokinetics: Area Under the Curve of LY573636 Above the Albumin Corrected Threshold (AUCalb) | Cycle 1 | 1081.0 hour*micrograms per milliliter (h*µg/mL) | Geometric Coefficient of Variation 163.9 |
| LY 300 μg/mL + Dox | Pharmacokinetics: Area Under the Curve of LY573636 Above the Albumin Corrected Threshold (AUCalb) | Cycle 2 | 413.7 hour*micrograms per milliliter (h*µg/mL) | Geometric Coefficient of Variation 684.3 |
| LY 300 μg/mL + Dox | Pharmacokinetics: Area Under the Curve of LY573636 Above the Albumin Corrected Threshold (AUCalb) | Cycle 3 | 228.4 hour*micrograms per milliliter (h*µg/mL) | Geometric Coefficient of Variation 323.3 |
Secondary
Pharmacokinetics: Maximum Concentration (Cmax) of LY573636
Time frame: Predose, 30 minutes (min), 2 hours (h), 4 h, 166 h, 360 h and 698 h postdose in Cycle 1; Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 2; Predose, 166h, 360h and 698 h postdose in Cycle 3
Population: Participants who received the study drug and had sufficient pharmacokinetic (PK) data to estimate Cmax at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY 300 μg/mL + Dox | Pharmacokinetics: Maximum Concentration (Cmax) of LY573636 | Cycle 1 | 335.1 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 13.9 |
| LY 300 μg/mL + Dox | Pharmacokinetics: Maximum Concentration (Cmax) of LY573636 | Cycle 2 | 284.5 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 15.9 |
| LY 300 μg/mL + Dox | Pharmacokinetics: Maximum Concentration (Cmax) of LY573636 | Cycle 3 | 250.7 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 25.2 |
Other Pre-specified
Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment
Time frame: From date of randomization until up to 30 days post study treatment discontinuation, assessed up to 4.7 months
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY 300 μg/mL + Dox | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 0 Participants |
| LY 320 μg/mL + Dox | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 0 Participants |
| LY 340 μg/mL + Dox | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 0 Participants |
| LY 360 μg/mL + Dox | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 0 Participants |
| LY 380 μg/mL + Dox | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 0 Participants |
| LY Albumin and Day 15 PK Tailored + Dox | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 1 Participants |