Soft Tissue Sarcoma
Conditions
Brief summary
The purpose of this study is to evaluate potential biomarkers and method of action, efficacy and safety of olaratumab in participants with soft tissue sarcoma (STS).
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
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 histologically confirmed diagnosis of STS for which olaratumab and doxorubicin would be appropriate therapy. Participants with a diagnosis of Grade 1 liposarcoma are eligible if there is histological or radiographic evidence of evolution to more aggressive disease. Participants with Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded. Participants must have potentially resectable disease (as assessed by the study investigator) and have a primary tumor lesion deemed amenable to serial biopsy. * For radiotherapy addendum only: Have a histologically confirmed diagnosis of STS of the extremities, Grade 2 or 3, \>5 centimeters, for which olaratumab and radiotherapy would be appropriate therapy. Participants with Kaposi's sarcoma, GIST or myxoid liposarcoma will be excluded. * Have consented to undergo mandatory serial peripheral whole blood and tumor tissue sampling.
Exclusion criteria
* Have active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment. Participants with a history of a CNS metastasis previously treated with curative intent (for example, stereotactic radiation or surgery) that have not progressed on follow-up imaging, have been asymptomatic for at least 60 days and are not receiving systemic corticosteroids and or/anticonvulsants, are eligible. Participants with signs or symptoms of neurological compromise should have appropriate radiographic imaging performed before enrollment to rule out brain metastasis. * Have received prior treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or anthracenediones; the participant has received treatment with olaratumab or has participated in a prior olaratumab trial. * For radiotherapy addendum only: Have received previous radiotherapy in the primary tumor lesion and/or prior treatment with olaratumab or has participated in a prior olaratumab trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Enumeration of Circulating Tumor Cells (CTCs) in Whole Blood | Baseline, End of Cycle 1 (21 days) | Enumeration of CTCs pre- and post- treatment with olaratumab may be a useful biomarker given the predilection for sarcomas to spread hematogenously. |
| Percent Change From Baseline in Gene Expression of Platelet-Derived Growth Factor Receptor Alpha (PGDFRα) and PGDFR Beta (β) in Tumor Tissue | Baseline, End of Cycle 1 (21 days) | Over-activity of PDGF signaling is associated with the development of certain malignant diseases. Olaratumab is an IgG1 antagonist of PDGFRα. |
| Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue | Baseline, End of Cycle 1 (21 days) | PDGF A, PDGF B, PDGF C, and PDGF D are platelet-derived growth factor canonical ligands associated with activation of PDGFR α and β. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Resectable Tumors (Resectability Rate) | Cycle 1 through Cycle 7 (Up to 6 Months) | Resectability rate is obtained when the total number of participants with resectable tumors is divided by the total number of participants. Resectability of a tumor is determined by the surgeon and multi-disciplinary team and dependent on tumor stage and the participants coexisting medical conditions. |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab Monotherapy | Cycle 1 Days 1 and 8: Predose; 5 minutes(m) post-infusion | Summary of Cmax of olaratumab monotherapy on Cycle 1 Day 1 and Day 8 |
| Progression Free Survival (PFS) | Baseline to Objective Progression or Death from Any Cause (Up to 18 Months) | Progression-free survival (PFS) is defined as the time from the date of first study dose to the first date of radiologic disease progression or death due to any cause. Progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression. |
| Number of Participants With Anti-Olaratumab Antibodies | Predose Cycle 1 Day 1 through Follow-Up (Up to 8 Months) | A participant is counted as positive if they had at least one anti-olaratumab antibody positive result during the study. |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab | Cycle 2 Day 1: Predose, 5 minutes(m) post-infusion, 24 hours(h), 96h; Day 8:Predose, 5 m, and 24h, 48h, 96h, and 240h postdose; Cycle 3 Day 1 and Day 8: Predose and 5m post-infusion | Cmax of olaratumab Cycles 2 and 3 Day 1 and 8 of a 21-day cycle. |
| Objective Response Rate (ORR): Percent of Participants With Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) | Baseline to Measured Progressive Disease (Up to 18 Months) | Overall Response Rate (ORR) is defined as the percentage of participants achieving a best overall response of either Complete Response (CR) or Partial Response (PR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as a disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \<10 mm and normalization of tumor marker results; PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. The best overall response is the best response from the start of the treatment until progressive disease (PD)/recurrence. |
| Disease Control Rate (DCR): Percent of Participants Who Exhibit Stable Disease (SD), CR or PR | Baseline to Measured Progressive Disease (Up to 18 Months) | Disease control rate (DCR) is defined as the percentage of participants achieving a best overall response of CR, PR, or SD as determined by RECIST 1.1. CR is defined as a disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \<10 mm and normalization of tumor marker results; PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters; SD is defined as neither sufficient shrinking to qualify as PR nor sufficient increase to qualify for PD. Participants who do not have any post-baseline tumor response assessments for any reason are considered non-responders and are included in the denominator when calculating the response rate. |
Countries
France, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants are considered to have completed the study if they completed one cycle of monotherapy and all 6 cycles of combination therapy.
Participants by arm
| Arm | Count |
|---|---|
| Olaratumab + Doxorubicin Cycle 1: olaratumab 20 mg/kg administered intravenously IV on Day 1 and Day 8, followed by up to 6 cycles (Cycle 2 - Cycle 7) of combination therapy with olaratumab and doxorubicin.
Cycle 2: olaratumab 20 mg/kg administered IV on Day 1 and Day 8 and doxorubicin 75 mg/m2 IV on Day 1.
Cycle 3-7: olaratumab 15 mg/kg administered IV on Day 1 and Day 8 and doxorubicin 75 mg/m2 IV on Day 1. | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Progressive disease | 23 |
| Overall Study | Surgical Resection | 10 |
Baseline characteristics
| Characteristic | Olaratumab + Doxorubicin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants |
| Circulating Tumor Cells (CTC) All Population CTC | 2.446 CTC per milliliter STANDARD_DEVIATION 2.797 |
| Circulating Tumor Cells (CTC) Traditional CTC | 2.183 CTC per milliliter STANDARD_DEVIATION 2.631 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| PDGF Canonical Ligands -A, -B, -C, -D PDGF-B | 230.62 relative gene expression units STANDARD_DEVIATION 1151.87 |
| PDGF Canonical Ligands -A, -B, -C, -D PDGF-C | 227.68 relative gene expression units STANDARD_DEVIATION 447.56 |
| PDGF Canonical Ligands -A, -B, -C, -D PDGF-D | 33.22 relative gene expression units STANDARD_DEVIATION 69.99 |
| PDGF Canonical Ligands -A, -B, -C, -D PGDF-A | 12.90 relative gene expression units STANDARD_DEVIATION 18.46 |
| Platelet-Derived Growth Factor Receptor Alpha (PGDFRα ) and PGDFR Beta (β) PGDFRα | 301.68 relative gene expression units STANDARD_DEVIATION 570.79 |
| Platelet-Derived Growth Factor Receptor Alpha (PGDFRα ) and PGDFR Beta (β) PGDFRβ | 812.49 relative gene expression units STANDARD_DEVIATION 1260.23 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 47 Participants |
| Region of Enrollment France | 2 Participants |
| Region of Enrollment Italy | 3 Participants |
| Region of Enrollment Spain | 25 Participants |
| Region of Enrollment United Kingdom | 4 Participants |
| Region of Enrollment United States | 17 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 51 |
| other Total, other adverse events | 50 / 51 |
| serious Total, serious adverse events | 22 / 51 |
Outcome results
Primary
Percent Change From Baseline in Enumeration of Circulating Tumor Cells (CTCs) in Whole Blood
Enumeration of CTCs pre- and post- treatment with olaratumab may be a useful biomarker given the predilection for sarcomas to spread hematogenously.
Time frame: Baseline, End of Cycle 1 (21 days)
Population: All participants who received one cycle of study drug and had evaluable blood samples for CTCs at baseline and post-olaratumab monotherapy.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olaratumab | Percent Change From Baseline in Enumeration of Circulating Tumor Cells (CTCs) in Whole Blood | Traditional CTCs | 846.93 percent change | Standard Deviation 3260.6 |
| Olaratumab | Percent Change From Baseline in Enumeration of Circulating Tumor Cells (CTCs) in Whole Blood | All Population CTCs | 820.11 percent change | Standard Deviation 3263.41 |
Primary
Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue
PDGF A, PDGF B, PDGF C, and PDGF D are platelet-derived growth factor canonical ligands associated with activation of PDGFR α and β.
Time frame: Baseline, End of Cycle 1 (21 days)
Population: All participants who received at least one dose of study drug and had evaluable baseline tissue samples at baseline and post-olaratumab monotherapy.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olaratumab | Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue | Canonical Ligand PDGF - A | 189.37 percent change in gene expression | Standard Deviation 672.91 |
| Olaratumab | Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue | Canonical Ligand PDGF - B | 602.01 percent change in gene expression | Standard Deviation 2798.92 |
| Olaratumab | Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue | Canonical Ligand PDGF - C | 1107.45 percent change in gene expression | Standard Deviation 6053.12 |
| Olaratumab | Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue | Canonical Ligand PDGF - D | 2630.36 percent change in gene expression | Standard Deviation 14425.92 |
Primary
Percent Change From Baseline in Gene Expression of Platelet-Derived Growth Factor Receptor Alpha (PGDFRα) and PGDFR Beta (β) in Tumor Tissue
Over-activity of PDGF signaling is associated with the development of certain malignant diseases. Olaratumab is an IgG1 antagonist of PDGFRα.
Time frame: Baseline, End of Cycle 1 (21 days)
Population: All participants who received at least one dose of study drug and had evaluable tissue samples at baseline and post-olaratumab monotherapy.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olaratumab | Percent Change From Baseline in Gene Expression of Platelet-Derived Growth Factor Receptor Alpha (PGDFRα) and PGDFR Beta (β) in Tumor Tissue | PDGF Receptor α | 6162.86 percent change in gene expression | Standard Deviation 32383.49 |
| Olaratumab | Percent Change From Baseline in Gene Expression of Platelet-Derived Growth Factor Receptor Alpha (PGDFRα) and PGDFR Beta (β) in Tumor Tissue | PDGF Receptor β | 1246.25 percent change in gene expression | Standard Deviation 7024.82 |
Secondary
Disease Control Rate (DCR): Percent of Participants Who Exhibit Stable Disease (SD), CR or PR
Disease control rate (DCR) is defined as the percentage of participants achieving a best overall response of CR, PR, or SD as determined by RECIST 1.1. CR is defined as a disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \<10 mm and normalization of tumor marker results; PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters; SD is defined as neither sufficient shrinking to qualify as PR nor sufficient increase to qualify for PD. Participants who do not have any post-baseline tumor response assessments for any reason are considered non-responders and are included in the denominator when calculating the response rate.
Time frame: Baseline to Measured Progressive Disease (Up to 18 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaratumab | Disease Control Rate (DCR): Percent of Participants Who Exhibit Stable Disease (SD), CR or PR | 52.9 percentage of participants |
Secondary
Number of Participants With Anti-Olaratumab Antibodies
A participant is counted as positive if they had at least one anti-olaratumab antibody positive result during the study.
Time frame: Predose Cycle 1 Day 1 through Follow-Up (Up to 8 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaratumab | Number of Participants With Anti-Olaratumab Antibodies | 1 Participants |
Secondary
Objective Response Rate (ORR): Percent of Participants With Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR)
Overall Response Rate (ORR) is defined as the percentage of participants achieving a best overall response of either Complete Response (CR) or Partial Response (PR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as a disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \<10 mm and normalization of tumor marker results; PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. The best overall response is the best response from the start of the treatment until progressive disease (PD)/recurrence.
Time frame: Baseline to Measured Progressive Disease (Up to 18 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaratumab | Objective Response Rate (ORR): Percent of Participants With Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) | 11.8 percentage of participants |
Secondary
Percentage of Participants With Resectable Tumors (Resectability Rate)
Resectability rate is obtained when the total number of participants with resectable tumors is divided by the total number of participants. Resectability of a tumor is determined by the surgeon and multi-disciplinary team and dependent on tumor stage and the participants coexisting medical conditions.
Time frame: Cycle 1 through Cycle 7 (Up to 6 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaratumab | Percentage of Participants With Resectable Tumors (Resectability Rate) | 35.3 percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab
Cmax of olaratumab Cycles 2 and 3 Day 1 and 8 of a 21-day cycle.
Time frame: Cycle 2 Day 1: Predose, 5 minutes(m) post-infusion, 24 hours(h), 96h; Day 8:Predose, 5 m, and 24h, 48h, 96h, and 240h postdose; Cycle 3 Day 1 and Day 8: Predose and 5m post-infusion
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Olaratumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab | Cycle 2 Day 1 | 624 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 26 |
| Olaratumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab | Cycle 2 Day 8 | 711 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 28 |
| Olaratumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab | Cycle 3 Day 1 | 521 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 30 |
| Olaratumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab | Cycle 3 Day 8 | 601 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 32 |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab Monotherapy
Summary of Cmax of olaratumab monotherapy on Cycle 1 Day 1 and Day 8
Time frame: Cycle 1 Days 1 and 8: Predose; 5 minutes(m) post-infusion
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Olaratumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab Monotherapy | Cycle 1 Day 1 | 510 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 22 |
| Olaratumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab Monotherapy | Cycle 1 Day 8 | 661 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 24 |
Secondary
Progression Free Survival (PFS)
Progression-free survival (PFS) is defined as the time from the date of first study dose to the first date of radiologic disease progression or death due to any cause. Progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression.
Time frame: Baseline to Objective Progression or Death from Any Cause (Up to 18 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaratumab | Progression Free Survival (PFS) | 2.86 months |