Malignancy, Metastasis
Conditions
Brief summary
Participants in this single-center, open-label, dose-escalation, Phase 1 study will initially receive intravenous (IV) olaratumab once every 2 weeks or on Days 1 and 8 every 3 weeks for 6 weeks (one cycle). After the first cycle, participants experiencing an overall response of complete response (CR), partial response (PR), or stable disease (SD) will continue to receive olaratumab at their cohort dose and schedule until there is evidence of progressive disease (PD), or until other withdrawal criteria are met.
Interventions
BIOLOGICALOlaratumab
Cohort 1 10 milligrams/kilogram (mg/kg) intravenously (IV) administered on Days 1 and 8, every 3 weeks; Cohort 2 20 mg/kg IV administered every 2 weeks; Cohort 3 15 mg/kg IV administered on Days 1 and 8, every 3 weeks
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Solid tumor that has been histopathologically or cytologically documented * Advanced primary or recurrent solid tumor participants who has not responded to standard therapy or for whom no standard therapy is available * Measurable or nonmeasurable lesions * An Eastern Cooperative Oncology Group Performance Status score of 0-1 * Able to provide informed consent * Has a life expectancy of \>3 months * Adequate hematologic function * Adequate hepatic function * Has adequate renal function * Agrees to use adequate contraception for the duration of study participation and for at least 12 weeks after the last dose of study therapy * Adequate recovery from recent surgery, chemotherapy, and radiation therapy (including palliative radiation therapy). At least 28 days (6 weeks for nitrosoureas or mitomycin C) must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or device, or prior radiation therapy. For treatment with non-approved monoclonal antibodies, a minimum of 8 weeks must have elapsed * Is willing to comply with study procedures until the End-of-Therapy visit
Exclusion criteria
* Received chemotherapy or therapeutic radiotherapy within 28 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, or has ongoing side effects ≥ Grade 2 due to agents administered more than 28 days earlier * Has undergone major surgery \[example (e.g.), laparotomy, thoracotomy, removal of organ(s)\] within 28 days prior to study entry * Elective or planned surgery to be conducted during the trial * Documented and/or symptomatic brain or leptomeningeal metastases (participants who are clinically stable \[no symptoms during the 4 weeks prior to study entry\] with an assessment that no further treatment \[radiation, surgical excision, or administration of steroids\] is required are permitted to enter the study) * Uncontrolled intercurrent illness including, but not limited to: * Active infection requiring systemic antibiotic treatment excluding oral administration \[≥Grade 3 National Cancer Institute - Common Terminology Criteria for Adverse Events \[NCI-CTCAE Version (v) 4.02)\] * Congestive heart failure (Class III or IV per the New York Heart Association classification for heart disease) * Angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months * Uncontrolled hypertension \[systolic blood pressure \>150 millimeters of mercury (mm Hg), diastolic blood pressure \>95 mm Hg\] * Cardiac arrhythmia requiring treatment (NCI-CTCAE v4.02, or asymptomatic sustained ventricular tachycardia * Peripheral neuropathy of any etiology ≥Grade 2 (NCI-CTCAE v4.02); or * Any other serious uncontrolled medical disorder(s) in the opinion of the investigator * Participated in clinical studies of non-approved experimental agents or procedures within 4 weeks prior to study for small molecules, or 8 weeks prior to study entry for non-approved monoclonal antibodies * Received any previous treatment with agents targeting the platelet-derived growth factor (PDGF) or platelet-derived growth factor receptor (PDGFR), approved or non-approved * Known allergy to any of the treatment components (IMC-3G3, histidine, glycine, sodium chloride, mannitol, or polysorbate) * If female, is pregnant (confirmed by urine or serum pregnancy test) or lactating * Known alcohol or drug dependency * Hepatitis B virus (HBV) antigen-, hepatitis C virus (HCV) antibody-, or human immunodeficiency (HIV) antibody-positive \[asymptomatic healthy carriers with detectable HBV-Deoxyribonucleic acid (DNA), HCV-Ribonucleic acid (RNA) may be enrolled into the trial\] * Assessed as inadequate for the study by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | First dose to study completion up to 5.6 months | Data presented are the number of participants who experienced AEs of any grade and AEs of Grade ≥3 as determined by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v) 4.02. A summary of serious adverse events (SAEs) and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
| Number of Participants With SAEs | First dose to study completion up to 5.6 months | A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
| Number of Participants With a Dose- Limiting Toxicity (DLT) in Cycle 1 | First dose through Cycle 1 (6 weeks/cycle) | A DLT is defined as 1 of the following events, if considered by the investigator to be definitely, probably, or possibly related to olaratumab: NCI-CTCAE v4.02 Grade 4 neutropenia lasting \>7 days; NCI-CTCAE v4.02 Grade ≥3 thrombocytopenia with signs of bleeding or requiring platelet transfusions; NCI-CTCAE v4.02 Grade ≥3 neutropenia associated with fever; NCI-CTCAE v4.02 Grade 3 or 4 nonhematologic toxicity, excluding electrolyte abnormality; NCI-CTCAE v4.02 Grade ≥3 skin toxicity despite best preemptive and supportive care; and/or NCI-CTCAE v4.02 Grade ≥3 diarrhea, nausea, or vomiting despite best preemptive and supportive care. |
| Maximum Concentration (Cmax) of Olaratumab Following Multiple Doses | Cycle 2: Pre-dose and up to 336 hours post-dose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serum Anti-Olaratumab Antibody Assessment (Immunogenicity) | First dose to study completion up to 5.6 months | Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. |
| Area Under the Concentration of Olaratumab Versus Time Curve During One Dosing Interval (AUCτ) Following Multiple Doses | Cycle 2: Pre-dose and up to 336 hours post-dose | — |
| Number of Participants With Treatment Related AEs | First dose to study completion up to 5.6 months | Data presented are the number of participants who experienced a treatment related AE of any grade. |
| Terminal Elimination Half-Life (t1/2) of Olaratumab | Cycle 2: Pre-dose and up to 336 hours post-dose | t1/2 is the time it takes for the drug concentration in serum to decrease to half the value observed at the beginning of the time period. |
| Clearance of Olaratumab at Steady State (CLss) | Cycle 2: Pre-dose and up to 336 hours post-dose | CLss is the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time at steady-state. |
| Volume of Distribution at Steady State (Vss) | Cycle 2: Pre-dose and up to 336 hours post-dose | — |
Countries
Japan
Participant flow
Pre-assignment details
There were 3 cohorts and enrollment into the next cohort did not occur until all participants in the previous cohort completed 1 cycle of treatment or discontinued due to dose-limiting toxicity (DLT). Participants who completed Cycle 1 or had DLT during Cycle 1 are considered having completed study.
Participants by arm
| Arm | Count |
|---|---|
| 10 mg/kg Olaratumab 10 mg/kg olaratumab IV administered on Days 1 and 8, every 3 weeks (6-week cycle). Cycles repeated until there was evidence of PD, or until other withdrawal criteria were met. | 3 |
| 20 mg/kg Olaratumab 20 mg/kg olaratumab IV administered on Day 1 every 2 weeks (6-week cycle). Cycles repeated until there was evidence of PD, or until other withdrawal criteria were met. | 7 |
| 15 mg/kg Olaratumab 15 mg/kg olaratumab IV administered on Days 1 and 8, every 3 weeks (6-week cycle). Cycles repeated until there was evidence of PD, or until other withdrawal criteria were met. | 6 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Investigator discontinued therapy | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 10 mg/kg Olaratumab | 20 mg/kg Olaratumab | 15 mg/kg Olaratumab | Total |
|---|---|---|---|---|
| Age, Customized 20 - <65 Years | 1 participants | 6 participants | 4 participants | 11 participants |
| Age, Customized ≥65 Years | 2 participants | 1 participants | 2 participants | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 7 Participants | 6 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 3 participants | 7 participants | 6 participants | 16 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 7 | 0 / 6 |
Outcome results
Primary
Maximum Concentration (Cmax) of Olaratumab Following Multiple Doses
Time frame: Cycle 2: Pre-dose and up to 336 hours post-dose
Population: All participants who received study drug and had pharmacokinetic (PK) data available to calculate Cmax. Due to the limited data, Cmax is not representative of the study population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg/kg Olaratumab | Maximum Concentration (Cmax) of Olaratumab Following Multiple Doses | 603 micrograms/milliliter (µg/mL) | — |
| 20 mg/kg Olaratumab | Maximum Concentration (Cmax) of Olaratumab Following Multiple Doses | 1160 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 91 |
| 15 mg/kg Olaratumab | Maximum Concentration (Cmax) of Olaratumab Following Multiple Doses | 921 micrograms/milliliter (µg/mL) | — |
Primary
Number of Participants With a Dose- Limiting Toxicity (DLT) in Cycle 1
A DLT is defined as 1 of the following events, if considered by the investigator to be definitely, probably, or possibly related to olaratumab: NCI-CTCAE v4.02 Grade 4 neutropenia lasting \>7 days; NCI-CTCAE v4.02 Grade ≥3 thrombocytopenia with signs of bleeding or requiring platelet transfusions; NCI-CTCAE v4.02 Grade ≥3 neutropenia associated with fever; NCI-CTCAE v4.02 Grade 3 or 4 nonhematologic toxicity, excluding electrolyte abnormality; NCI-CTCAE v4.02 Grade ≥3 skin toxicity despite best preemptive and supportive care; and/or NCI-CTCAE v4.02 Grade ≥3 diarrhea, nausea, or vomiting despite best preemptive and supportive care.
Time frame: First dose through Cycle 1 (6 weeks/cycle)
Population: All enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg/kg Olaratumab | Number of Participants With a Dose- Limiting Toxicity (DLT) in Cycle 1 | 0 participants |
| 20 mg/kg Olaratumab | Number of Participants With a Dose- Limiting Toxicity (DLT) in Cycle 1 | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With a Dose- Limiting Toxicity (DLT) in Cycle 1 | 0 participants |
Primary
Number of Participants With Adverse Events (AEs)
Data presented are the number of participants who experienced AEs of any grade and AEs of Grade ≥3 as determined by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v) 4.02. A summary of serious adverse events (SAEs) and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: First dose to study completion up to 5.6 months
Population: All enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/kg Olaratumab | Number of Participants With Adverse Events (AEs) | AE of Any Grade | 3 participants |
| 10 mg/kg Olaratumab | Number of Participants With Adverse Events (AEs) | AE of Grade ≥3 | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Adverse Events (AEs) | AE of Any Grade | 7 participants |
| 20 mg/kg Olaratumab | Number of Participants With Adverse Events (AEs) | AE of Grade ≥3 | 1 participants |
| 15 mg/kg Olaratumab | Number of Participants With Adverse Events (AEs) | AE of Any Grade | 6 participants |
| 15 mg/kg Olaratumab | Number of Participants With Adverse Events (AEs) | AE of Grade ≥3 | 0 participants |
Primary
Number of Participants With SAEs
A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: First dose to study completion up to 5.6 months
Population: All enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg/kg Olaratumab | Number of Participants With SAEs | 0 participants |
| 20 mg/kg Olaratumab | Number of Participants With SAEs | 1 participants |
| 15 mg/kg Olaratumab | Number of Participants With SAEs | 0 participants |
Secondary
Area Under the Concentration of Olaratumab Versus Time Curve During One Dosing Interval (AUCτ) Following Multiple Doses
Time frame: Cycle 2: Pre-dose and up to 336 hours post-dose
Population: All participants who received study drug and had PK data available to calculate AUCτ. Zero participants were analyzed for groups of 10 mg/kg IMC-3G3 and 15 mg/kg IMC-3G3 because of insufficient amount of samples collected. Due to the limited data, AUCτ is not representative of the study population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg/kg Olaratumab | Area Under the Concentration of Olaratumab Versus Time Curve During One Dosing Interval (AUCτ) Following Multiple Doses | 123000 micrograms*hours/milliliter (µg*h/mL) | Geometric Coefficient of Variation 29 |
Secondary
Clearance of Olaratumab at Steady State (CLss)
CLss is the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time at steady-state.
Time frame: Cycle 2: Pre-dose and up to 336 hours post-dose
Population: All participants who received study drug and had PK data available to calculate CLss. Zero participants were analyzed for groups of 10 mg/kg IMC-3G3 and 15 mg/kg IMC-3G3 because of insufficient amount of samples collected. Due to limited data, CLss is not representative of the study population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg/kg Olaratumab | Clearance of Olaratumab at Steady State (CLss) | 0.163 milliliters/hour/kilogram (mL/h/kg) | Geometric Coefficient of Variation 29 |
Secondary
Number of Participants With Serum Anti-Olaratumab Antibody Assessment (Immunogenicity)
Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20.
Time frame: First dose to study completion up to 5.6 months
Population: All participants who received at least one dose of study drug and had evaluable baseline and evaluable post-baseline antibody data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg/kg Olaratumab | Number of Participants With Serum Anti-Olaratumab Antibody Assessment (Immunogenicity) | 0 participants |
Secondary
Number of Participants With Treatment Related AEs
Data presented are the number of participants who experienced a treatment related AE of any grade.
Time frame: First dose to study completion up to 5.6 months
Population: All enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Any treatment related AE | 1 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Proteinuria | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Aspartate aminotransferase increased | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Rash | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Tumour haemorrhage | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Fibrin D dimer increased | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Leukopenia | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Hyperglycaemia | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Hypertension | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Dermatitis | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Diarrhoea | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Anaemia | 0 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Cough | 1 participants |
| 10 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Fatigue | 0 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Hypertension | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Any treatment related AE | 6 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Anaemia | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Leukopenia | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Diarrhoea | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Fatigue | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Aspartate aminotransferase increased | 2 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Fibrin D dimer increased | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Hyperglycaemia | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Tumour haemorrhage | 1 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Proteinuria | 3 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Cough | 0 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Dermatitis | 0 participants |
| 20 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Rash | 1 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Fatigue | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Hypertension | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Proteinuria | 1 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Diarrhoea | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Rash | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Cough | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Leukopenia | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Any treatment related AE | 1 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Fibrin D dimer increased | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Dermatitis | 1 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Hyperglycaemia | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Aspartate aminotransferase increased | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Anaemia | 0 participants |
| 15 mg/kg Olaratumab | Number of Participants With Treatment Related AEs | Tumour haemorrhage | 0 participants |
Secondary
Terminal Elimination Half-Life (t1/2) of Olaratumab
t1/2 is the time it takes for the drug concentration in serum to decrease to half the value observed at the beginning of the time period.
Time frame: Cycle 2: Pre-dose and up to 336 hours post-dose
Population: All participants who received study drug and had PK data available to calculate t1/2. Due to limited data and the relatively short duration of sample collection, t1/2 is not representative of the study population.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 10 mg/kg Olaratumab | Terminal Elimination Half-Life (t1/2) of Olaratumab | NA days |
| 20 mg/kg Olaratumab | Terminal Elimination Half-Life (t1/2) of Olaratumab | 7.33 days |
| 15 mg/kg Olaratumab | Terminal Elimination Half-Life (t1/2) of Olaratumab | 8.25 days |
Secondary
Volume of Distribution at Steady State (Vss)
Time frame: Cycle 2: Pre-dose and up to 336 hours post-dose
Population: Zero participants were analyzed because of insufficient amount of samples collected.