Sarcoma, Soft Tissue
Conditions
Brief summary
The purpose of this study is to assess how the body handles olaratumab when it is given with another drug called doxorubicin. The safety and tolerability of these drugs will be studied. Each participant will complete two 21-day cycles in a fixed order. Participants who complete Cycle 2 may continue to receive olaratumab + doxorubicin for an additional six 21-day cycles and then may receive olaratumab alone until discontinuation criteria are met. Screening is required within 21 days prior to first dose. Part B was added in October, 2015 to assess how the body handles a higher dose of olaratumab when given with doxorubicin. Participants may only enroll in one part.
Interventions
DRUGOlaratumab
Administered IV
DRUGDoxorubicin
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histological or cytological evidence of a diagnosis of soft tissue sarcoma (STS) that is advanced and/or metastatic * Have the presence of measurable and/or nonmeasurable disease * Have given written informed consent prior to any study-specific procedures * Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale * Have discontinued previous treatments for cancer and recovered from the acute effects of therapy * Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
Exclusion criteria
* Have received treatment within 28 days of the initial dose of study drug with an investigational product or non-approved use of a drug or device for noncancer indications * Have received prior treatment with doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones * Have active central nervous system (CNS) metastasis. Participants with treated CNS metastases are eligible for this study if they are not currently receiving corticosteroids * Have unstable hepatic disease with a grade equal to or greater than Child-Pugh B * Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis * Have a history of another primary cancer, with the exception of a) curatively resected nonmelanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years prior to study entry * Have a history of chronic heart failure or left ventricular dysfunction * Have a resting heart rate of less than (\<)50 beats per minute (bpm) or greater than (\>)100 bpm * Have a history of radiation therapy involving the mediastinal/pericardial area. Previous radiation therapy is allowed but must not have included whole pelvis radiation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin | Cycle(C)1 and (C)2, Day(D)1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hours (Hrs) Post dose |
| PK: Maximum Concentration (Cmax) Doxorubicin | C1 and C2, D1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hrs Post dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK: Cmax Olaratumab | C1 D10:Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose | PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin. |
| PK: Tmax Olaratumab | C1 D10: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose | Tmax times are relative to the start of the approximately 60-minute IV infusion of olaratumab. PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin. |
| PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin | C1 and C2, D1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hrs Post dose | — |
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | Baseline to Measured Progressive Disease, Study Discontinuation or Death (Up to 24 Months) | The percentage of participants with a best overall response achieving CR or PR (ORR) was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter of target lesions. The methodology for the confidence interval calculation is the exact F method. |
| Percentage of Participants With Olaratumab Antibodies | Preinfusion on Day 1 of Cycles 1 through 3 and Preinfusion on Day 1 of Every Second Cycle Thereafter, Up to 30-Day Follow Up | The formation of anti-drug antibodies (ADA) was assessed using validated ELISAs, following a 4-tier approach. Both the ADA screening assay and the neutralizing antibody assay were validated in accordance with the US Food and Drug Administration (FDA) Guidance for Industry. Participants who had positive samples for treatment emergence due to being \<4-fold difference from baseline or occurred prior to drug exposure are reported. |
| PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab | C1 D10: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose | PK: AUC (0-tLast) with a measurable concentration. PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin. |
Countries
United States
Participant flow
Pre-assignment details
Completers include participants who died or discontinued study treatment due to progressive disease.
Participants by arm
| Arm | Count |
|---|---|
| Part A Doxorubicin Alone: On Cycle 1, Day 1, participants received 75 milligram/square meter (mg/m2) of doxorubicin intravenously (IV).
Olaratumab Alone: On Cycle 1, Day 10, participants received 15 milligram/kilogram (mg/kg) of olaratumab IV.
Olaratumab + Doxorubicin: For Cycles 2 to 8, participants received 15 mg/kg of olaratumab on Days 1 and 8 of each 21-day cycle, IV and 75 mg/m2 of doxorubicin IV immediately following the completion of the olaratumab infusion.
Participants continued to receive olaratumab monotherapy (on days 1 and 8 of each cycle) for Cycle 9 onward, until discontinuation criteria are met. | 25 |
| Part B Doxorubicin Alone: On Cycle 1, Day 1, participants received doxorubicin 75 mg/m2 IV
Olaratumab Alone: On Cycle 1, Day 10, participants received 20 mg/kg of olaratumab IV.
Olaratumab + Doxorubicin:
For Cycle 2, participants received 20 mg of olaratumab on Days 1 and 8 of each 21-day cycle, IV. On Day 1 of Cycle 2, doxorubicin 75 mg/m2 was administered IV immediately following the completion of the olaratumab infusion.
For Cycles 3 - 8, Day 1 and 8, olaratumab 15 mg/kg was administered and on Day 1 doxorubicin 75 mg/m2 was administered IV immediately following the completion of the olaratumab infusion.
Participants continued to receive olaratumab monotherapy (on days 1 and 8 of each cycle) for Cycle 9 onwards, until discontinuation criteria are met. | 24 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Physician and Participant Decision | 1 | 0 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Part A | Part B |
|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 11.8 | 56.7 years STANDARD_DEVIATION 12.6 | 56.1 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 24 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 1 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 | 44 Participants | 22 Participants | 22 Participants |
| Region of Enrollment United States | 49 Participants | 25 Participants | 24 Participants |
| Sex: Female, Male Female | 29 Participants | 15 Participants | 14 Participants |
| Sex: Female, Male Male | 20 Participants | 10 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 25 | 24 / 24 |
| serious Total, serious adverse events | 9 / 25 | 9 / 24 |
Outcome results
Primary
Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin
Time frame: Cycle(C)1 and (C)2, Day(D)1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hours (Hrs) Post dose
Population: All participants who received at least one dose of study drugs and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Doxorubicin Alone | Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin | 2580 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 24 |
| Part A Doxorubicin + 15 mg/kg Olaratumab | Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin | 2570 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 28 |
| Part B Doxorubicin Alone | Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin | 2400 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 21 |
| Part B Doxorubicin + 20 mg/kg Olaratumab | Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin | 2470 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 20 |
90% CI: [0.964, 1.13]
90% CI: [0.957, 1.11]
Primary
PK: Maximum Concentration (Cmax) Doxorubicin
Time frame: C1 and C2, D1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hrs Post dose
Population: All participants who received at least one dose of study drugs and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Doxorubicin Alone | PK: Maximum Concentration (Cmax) Doxorubicin | 2570 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 47 |
| Part A Doxorubicin + 15 mg/kg Olaratumab | PK: Maximum Concentration (Cmax) Doxorubicin | 2330 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 68 |
| Part B Doxorubicin Alone | PK: Maximum Concentration (Cmax) Doxorubicin | 2060 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 53 |
| Part B Doxorubicin + 20 mg/kg Olaratumab | PK: Maximum Concentration (Cmax) Doxorubicin | 2070 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 60 |
90% CI: [0.77, 1.16]
90% CI: [0.801, 1.33]
Secondary
Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
The percentage of participants with a best overall response achieving CR or PR (ORR) was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter of target lesions. The methodology for the confidence interval calculation is the exact F method.
Time frame: Baseline to Measured Progressive Disease, Study Discontinuation or Death (Up to 24 Months)
Population: All participants who received at least one dose of study drug and had a post-baseline lesion response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Doxorubicin Alone | Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 12.0 percentage of participants |
| Part A Doxorubicin + 15 mg/kg Olaratumab | Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 25.0 percentage of participants |
Secondary
Percentage of Participants With Olaratumab Antibodies
The formation of anti-drug antibodies (ADA) was assessed using validated ELISAs, following a 4-tier approach. Both the ADA screening assay and the neutralizing antibody assay were validated in accordance with the US Food and Drug Administration (FDA) Guidance for Industry. Participants who had positive samples for treatment emergence due to being \<4-fold difference from baseline or occurred prior to drug exposure are reported.
Time frame: Preinfusion on Day 1 of Cycles 1 through 3 and Preinfusion on Day 1 of Every Second Cycle Thereafter, Up to 30-Day Follow Up
Population: All participants who received at least one dose of study drug and had evaluable baseline and post-baseline anti-olaratumab antibodies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Doxorubicin Alone | Percentage of Participants With Olaratumab Antibodies | 0 percentage of participants |
| Part A Doxorubicin + 15 mg/kg Olaratumab | Percentage of Participants With Olaratumab Antibodies | 0 percentage of participants |
Secondary
PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab
PK: AUC (0-tLast) with a measurable concentration. PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin.
Time frame: C1 D10: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose
Population: All participants who received at least one dose of study drugs and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Doxorubicin Alone | PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab | 32800 ng∙h/mL | Geometric Coefficient of Variation 21 |
| Part A Doxorubicin + 15 mg/kg Olaratumab | PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab | 32000 ng∙h/mL | Geometric Coefficient of Variation 21 |
| Part B Doxorubicin Alone | PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab | 53800 ng∙h/mL | Geometric Coefficient of Variation 24 |
| Part B Doxorubicin + 20 mg/kg Olaratumab | PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab | 54100 ng∙h/mL | Geometric Coefficient of Variation 20 |
Secondary
PK: Cmax Olaratumab
PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin.
Time frame: C1 D10:Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose
Population: All participants who received at least one dose of study drugs and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Doxorubicin Alone | PK: Cmax Olaratumab | 292 ng/mL | Geometric Coefficient of Variation 19 |
| Part A Doxorubicin + 15 mg/kg Olaratumab | PK: Cmax Olaratumab | 386 ng/mL | Geometric Coefficient of Variation 16 |
| Part B Doxorubicin Alone | PK: Cmax Olaratumab | 512 ng/mL | Geometric Coefficient of Variation 21 |
| Part B Doxorubicin + 20 mg/kg Olaratumab | PK: Cmax Olaratumab | 634 ng/mL | Geometric Coefficient of Variation 26 |
Secondary
PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin
Time frame: C1 and C2, D1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hrs Post dose
Population: All participants who received at least one dose of study drugs and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Doxorubicin Alone | PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin | 0.30 hour (h) |
| Part A Doxorubicin + 15 mg/kg Olaratumab | PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin | 0.31 hour (h) |
| Part B Doxorubicin Alone | PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin | 0.33 hour (h) |
| Part B Doxorubicin + 20 mg/kg Olaratumab | PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin | 0.33 hour (h) |
Secondary
PK: Tmax Olaratumab
Tmax times are relative to the start of the approximately 60-minute IV infusion of olaratumab. PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin.
Time frame: C1 D10: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose
Population: All participants who received at least one dose of study drugs and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Doxorubicin Alone | PK: Tmax Olaratumab | 2.00 h |
| Part A Doxorubicin + 15 mg/kg Olaratumab | PK: Tmax Olaratumab | 2.79 h |
| Part B Doxorubicin Alone | PK: Tmax Olaratumab | 1.67 h |
| Part B Doxorubicin + 20 mg/kg Olaratumab | PK: Tmax Olaratumab | 3.50 h |