Gastrointestinal Stromal Tumor (GIST)
Conditions
Brief summary
The purpose of this study is to evaluate the tumor response of stable disease (SD), partial response (PR), or complete response (CR) \[according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1 criteria)\] at 12 weeks in participants with Gastrointestinal Stromal Tumors (GIST) harboring platelet-derived growth factor receptor alpha (PDGFRα) mutations and patients with GIST not harboring PDGFRα mutations.
Interventions
BIOLOGICALOlaratumab
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has histologically or cytologically confirmed, unresectable and/or metastatic GIST * Participant has measurable disease * Participant has documented objective progression following, or intolerance to, treatment with both imatinib and sunitinib * Participant's Eastern Cooperative Oncology Group (ECOG) performance status (PS) is 0 to 2 * Participant has either: 1. prior results from growth factor receptor associated with tyrosine kinase activity (KIT) and PDGFRα mutation analysis that meet analytical criteria as defined for the on-study analysis of these mutations and tumor tissue (from either primary or metastatic tumor) that can be submitted for analysis within 30 days after the first dose of study therapy; or 2. if prior results from KIT and PDGFRα mutation analysis are not available or do not meet analytical criteria as above, then tumor tissue (from either primary or metastatic tumor) must be submitted for genotype testing at the latest 28 days prior to the first dose of study therapy * Participant has adequate hematologic, hepatic, renal and coagulation function * Women of childbearing potential and sexually active males must agree to use adequate contraception prior to study and for at least 12 weeks after the last dose of IMC-3G3 * Participant has a life expectancy of ≥ 3 months
Exclusion criteria
* Participant has untreated central nervous system metastases, and as a result, is clinically unstable with regard to neurologic function * Participant has a history of another primary cancer * Participant has received any investigational therapy within 14 days prior to registration, or is currently enrolled in any other type of medical research * Participant is receiving concurrent treatment with other anticancer therapy * Participant has known human immunodeficiency virus (HIV) infection * Participant has undergone major surgery within 28 days prior to registration * If female, participant is pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Tumor Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Clinical Benefit Rate) at 12 Weeks | 12 weeks | Clinical benefit was defined as CR, PR, or SD using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST, v1.1) criteria. CR: disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm). PR: ≥30% decrease in sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD: neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. PD: increase ≥20% in sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or appearance of 1 or more new lesions was considered progression. Percentage of participants=(participants with CR+PR+SD/participants in group) \*100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CR or PR [Radiographic Objective Response Rate (ORR)] | Baseline up to 35.9 weeks and post study discontinuation 30-day follow-up | The ORR was the best overall response of CR and PR using RECIST, v1.1 criteria. Participants who did not have a tumor response assessment for any reason were considered nonresponders and were included in the denominator that calculated the response rate. Percentage of participants = (number of participants achieving a response/total of participants treated) \* 100. |
| Overall Survival (OS) | Date of first dose of study drug to the date of death from any cause up to 57.3 weeks | OS was defined as the time from the date of first dose of study drug to the date of death from any cause. Participants who were alive at the end of the post-study follow-up or were lost to follow-up were censored on the last date the participant was known to be alive. |
| Number of Participants With Adverse Events (AE) and Participants Who Died | Baseline up to 57.3 weeks and 30-day post study-discontinuation follow-up | Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs, regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The number of participants who died due to an AE or disease progression are also reported. |
| Percentage of Participants With CR, PR or SD [Disease Control Rate (DCR)] | Baseline up to 35.9 weeks | DCR defined as CR, PR or SD using RECIST v1.1 criteria. CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify PD, taking as reference the smallest sum diameter since the treatment started. PD defined as ≥20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or the appearance of 1 or more new lesions was considered progression. Percentage of participants=(number of participants with CR+PR+SD/number of participants in group) \* 100. |
| Maximum Concentration (Cmax) | Day 1 of Cycles 1 and 3 (14-day cycles) | — |
| Progression-Free Survival (PFS) | Baseline to the first date of objectively determined PD or death from any cause up to 35.9 weeks | PFS defined as the duration from date of first dose of study drug until first radiographic documentation of PD using RECIST, v1.1 criteria or death from any cause. PD defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions was progression. Participants who died with no prior PD were considered to have progressed on day of death. Participants who did not progress or were lost to follow-up were censored at date of last radiographic tumor assessment; if no assessment was available censoring was at date of registration. If death or PD occurred after 2 consecutive missing radiographic visits censoring was date of last radiographic visit prior to missed visits. Use of new anticancer therapy prior to PD, censoring was date of last radiographic assessment prior to new therapy. |
| Half Life (t½) | Day 1 of Cycles 1 and 3 (14-day cycles) | — |
| Clearance (CL) | Day 1 of Cycles 1 and 3 (14-day cycles) | — |
| Volume of Distribution at Steady State (Vss) | Day 1 of Cycles 1 and 3 (14-day cycles) | — |
| Percentage of Participants With Human Anti-Olaratumab (IMC-3G3) Antibody Results | Day 1 of Cycles 1, 3, 6, 12 and 18 prior to infusion (14-day cycles) | Participants with Treatment Emergent (TE) anti-olaratumab (IMC-3G3) 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 Curve (AUC) | Day 1 of Cycles 1 and 3 (14-day cycles) | — |
Countries
Belgium, Germany, Netherlands, Poland, Spain, United States
Participant flow
Pre-assignment details
Participants who were considered to have completed Stage 1 of the study discontinued due to progressive disease (PD) or died.
Participants by arm
| Arm | Count |
|---|---|
| PDGFRα Mutation Positive 20 mg/kg of Olaratumab (IMC-3G3) was administered IV on Day 1 of each cycle (14-day cycles) to participants with GIST with genotypes that had a PDGFRα mutation. | 7 |
| PDGFRα Mutation Negative (Wild-Type) 20 mg/kg of Olaratumab (IMC-3G3) was administered IV on Day 1 of each cycle (14-day cycles) to participants with GIST with genotypes that did not have a PDGFRα mutation. | 14 |
| Total | 21 |
Baseline characteristics
| Characteristic | PDGFRα Mutation Negative (Wild-Type) | PDGFRα Mutation Positive | Total |
|---|---|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 9.11 | 64.9 years STANDARD_DEVIATION 7.9 | 54.2 years STANDARD_DEVIATION 11.48 |
| Current M Classification Staging M1 | 13 participants | 6 participants | 19 participants |
| Current M Classification Staging Missing | 1 participants | 1 participants | 2 participants |
| Current N Classification Staging Missing | 3 participants | 1 participants | 4 participants |
| Current N Classification Staging N0 | 8 participants | 5 participants | 13 participants |
| Current N Classification Staging N1 | 3 participants | 0 participants | 3 participants |
| Current N Classification Staging N2 | 0 participants | 1 participants | 1 participants |
| Current T Classification Staging Missing | 1 participants | 1 participants | 2 participants |
| Current T Classification Staging T0 | 2 participants | 2 participants | 4 participants |
| Current T Classification Staging T3 | 4 participants | 0 participants | 4 participants |
| Current T Classification Staging T4 | 2 participants | 2 participants | 4 participants |
| Current T Classification Staging TX | 4 participants | 2 participants | 6 participants |
| Current T Classification Staging Unknown | 1 participants | 0 participants | 1 participants |
| Eastern Cooperative Oncology Group Performance Status(ECOG PS) ECOG PS =0 | 5 participants | 2 participants | 7 participants |
| Eastern Cooperative Oncology Group Performance Status(ECOG PS) ECOG PS =1 | 9 participants | 4 participants | 13 participants |
| Eastern Cooperative Oncology Group Performance Status(ECOG PS) ECOG PS ≥2 | 0 participants | 1 participants | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 7 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Histology-Cell Type Epitheloid Cell | 0 participants | 6 participants | 6 participants |
| Histology-Cell Type Mixed/Combined | 4 participants | 0 participants | 4 participants |
| Histology-Cell Type Other-unspecified | 1 participants | 1 participants | 2 participants |
| Histology-Cell Type Spindle Cell | 9 participants | 0 participants | 9 participants |
| Initial M Stage at Diagnosis M0 | 7 participants | 4 participants | 11 participants |
| Initial M Stage at Diagnosis M1 | 5 participants | 1 participants | 6 participants |
| Initial M Stage at Diagnosis Missing | 1 participants | 2 participants | 3 participants |
| Initial M Stage at Diagnosis MX | 1 participants | 0 participants | 1 participants |
| Initial N Classification Staging at Diagnosis Missing | 2 participants | 2 participants | 4 participants |
| Initial N Classification Staging at Diagnosis N0 | 11 participants | 5 participants | 16 participants |
| Initial N Classification Staging at Diagnosis N1 | 1 participants | 0 participants | 1 participants |
| Initial T Classification Staging at Diagnosis Missing | 1 participants | 2 participants | 3 participants |
| Initial T Classification Staging at Diagnosis T2 | 3 participants | 1 participants | 4 participants |
| Initial T Classification Staging at Diagnosis T3 | 4 participants | 0 participants | 4 participants |
| Initial T Classification Staging at Diagnosis T4 | 1 participants | 3 participants | 4 participants |
| Initial T Classification Staging at Diagnosis Tis | 1 participants | 0 participants | 1 participants |
| Initial T Classification Staging at Diagnosis TX | 4 participants | 1 participants | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 14 Participants | 7 Participants | 21 Participants |
| Region of Enrollment Belgium | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Germany | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Netherlands | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 4 participants | 2 participants | 6 participants |
| Region of Enrollment Spain | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 12 Participants |
| Type of Cancer-Gastrointestinal Stromal Tumor | 14 participants | 7 participants | 21 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 13 / 14 |
| serious Total, serious adverse events | 2 / 7 | 3 / 14 |
Outcome results
Primary
Percentage of Participants With Tumor Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Clinical Benefit Rate) at 12 Weeks
Clinical benefit was defined as CR, PR, or SD using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST, v1.1) criteria. CR: disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm). PR: ≥30% decrease in sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD: neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. PD: increase ≥20% in sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or appearance of 1 or more new lesions was considered progression. Percentage of participants=(participants with CR+PR+SD/participants in group) \*100.
Time frame: 12 weeks
Population: All participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDGFRα Mutation Positive | Percentage of Participants With Tumor Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Clinical Benefit Rate) at 12 Weeks | 42.9 percentage of participants |
| PDGFRα Mutation Negative (Wild-Type) | Percentage of Participants With Tumor Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Clinical Benefit Rate) at 12 Weeks | 14.3 percentage of participants |
Secondary
Area Under the Curve (AUC)
Time frame: Day 1 of Cycles 1 and 3 (14-day cycles)
Population: Zero participants were analyzed. AUC was not reported. AUC could not be calculated due to an insufficient number of olaratumab serum concentrations.
Secondary
Clearance (CL)
Time frame: Day 1 of Cycles 1 and 3 (14-day cycles)
Population: Zero participants were analyzed. CL was not reported. CL could not be calculated due to an insufficient number of olaratumab serum concentrations.
Secondary
Half Life (t½)
Time frame: Day 1 of Cycles 1 and 3 (14-day cycles)
Population: Zero participants were analyzed. t1/2 was not reported. t1/2 could not be calculated due to an insufficient number of olaratumab serum concentrations.
Secondary
Maximum Concentration (Cmax)
Time frame: Day 1 of Cycles 1 and 3 (14-day cycles)
Population: All participants who had evaluable pharmacokinetic (PK) Cmax results at the specific time point. Due to the limited data, Cmax is not representative of the study population.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PDGFRα Mutation Positive | Maximum Concentration (Cmax) | Day 1 Cycle 1 (n=2) | 392.9 nanograms per milliliter (ng/mL) |
| PDGFRα Mutation Positive | Maximum Concentration (Cmax) | Day 1 Cycle 3 (n=1) | 483.9 nanograms per milliliter (ng/mL) |
Secondary
Number of Participants With Adverse Events (AE) and Participants Who Died
Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs, regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The number of participants who died due to an AE or disease progression are also reported.
Time frame: Baseline up to 57.3 weeks and 30-day post study-discontinuation follow-up
Population: All participants who received any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PDGFRα Mutation Positive | Number of Participants With Adverse Events (AE) and Participants Who Died | SAEs | 2 participants |
| PDGFRα Mutation Positive | Number of Participants With Adverse Events (AE) and Participants Who Died | AEs | 7 participants |
| PDGFRα Mutation Positive | Number of Participants With Adverse Events (AE) and Participants Who Died | Died Due to AE | 0 participants |
| PDGFRα Mutation Positive | Number of Participants With Adverse Events (AE) and Participants Who Died | Died Due to Disease Progression | 0 participants |
| PDGFRα Mutation Negative (Wild-Type) | Number of Participants With Adverse Events (AE) and Participants Who Died | Died Due to Disease Progression | 1 participants |
| PDGFRα Mutation Negative (Wild-Type) | Number of Participants With Adverse Events (AE) and Participants Who Died | SAEs | 3 participants |
| PDGFRα Mutation Negative (Wild-Type) | Number of Participants With Adverse Events (AE) and Participants Who Died | Died Due to AE | 1 participants |
| PDGFRα Mutation Negative (Wild-Type) | Number of Participants With Adverse Events (AE) and Participants Who Died | AEs | 13 participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first dose of study drug to the date of death from any cause. Participants who were alive at the end of the post-study follow-up or were lost to follow-up were censored on the last date the participant was known to be alive.
Time frame: Date of first dose of study drug to the date of death from any cause up to 57.3 weeks
Population: All participants who received any study drug. Participants censored: PDGFRα Mutant=4, PDGFRα Wild-type=4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PDGFRα Mutation Positive | Overall Survival (OS) | NA weeks |
| PDGFRα Mutation Negative (Wild-Type) | Overall Survival (OS) | 24.9 weeks |
Secondary
Percentage of Participants With CR or PR [Radiographic Objective Response Rate (ORR)]
The ORR was the best overall response of CR and PR using RECIST, v1.1 criteria. Participants who did not have a tumor response assessment for any reason were considered nonresponders and were included in the denominator that calculated the response rate. Percentage of participants = (number of participants achieving a response/total of participants treated) \* 100.
Time frame: Baseline up to 35.9 weeks and post study discontinuation 30-day follow-up
Population: All participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDGFRα Mutation Positive | Percentage of Participants With CR or PR [Radiographic Objective Response Rate (ORR)] | 0 percentage of participants |
| PDGFRα Mutation Negative (Wild-Type) | Percentage of Participants With CR or PR [Radiographic Objective Response Rate (ORR)] | 0 percentage of participants |
Secondary
Percentage of Participants With CR, PR or SD [Disease Control Rate (DCR)]
DCR defined as CR, PR or SD using RECIST v1.1 criteria. CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify PD, taking as reference the smallest sum diameter since the treatment started. PD defined as ≥20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or the appearance of 1 or more new lesions was considered progression. Percentage of participants=(number of participants with CR+PR+SD/number of participants in group) \* 100.
Time frame: Baseline up to 35.9 weeks
Population: All participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDGFRα Mutation Positive | Percentage of Participants With CR, PR or SD [Disease Control Rate (DCR)] | 71.4 percentage of participants |
| PDGFRα Mutation Negative (Wild-Type) | Percentage of Participants With CR, PR or SD [Disease Control Rate (DCR)] | 28.6 percentage of participants |
Secondary
Percentage of Participants With Human Anti-Olaratumab (IMC-3G3) Antibody Results
Participants with Treatment Emergent (TE) anti-olaratumab (IMC-3G3) 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: Day 1 of Cycles 1, 3, 6, 12 and 18 prior to infusion (14-day cycles)
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) |
|---|---|---|
| PDGFRα Mutation Positive | Percentage of Participants With Human Anti-Olaratumab (IMC-3G3) Antibody Results | 5.3 percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS defined as the duration from date of first dose of study drug until first radiographic documentation of PD using RECIST, v1.1 criteria or death from any cause. PD defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions was progression. Participants who died with no prior PD were considered to have progressed on day of death. Participants who did not progress or were lost to follow-up were censored at date of last radiographic tumor assessment; if no assessment was available censoring was at date of registration. If death or PD occurred after 2 consecutive missing radiographic visits censoring was date of last radiographic visit prior to missed visits. Use of new anticancer therapy prior to PD, censoring was date of last radiographic assessment prior to new therapy.
Time frame: Baseline to the first date of objectively determined PD or death from any cause up to 35.9 weeks
Population: All participants who received any study drug. Censored participants: PDGFRα Mutant=2, PDGFRα Wild-Type=0.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PDGFRα Mutation Positive | Progression-Free Survival (PFS) | 32.1 weeks |
| PDGFRα Mutation Negative (Wild-Type) | Progression-Free Survival (PFS) | 6.1 weeks |
Secondary
Volume of Distribution at Steady State (Vss)
Time frame: Day 1 of Cycles 1 and 3 (14-day cycles)
Population: Zero participants were analyzed. Vss was not reported. Vss could not be calculated due to an insufficient number of olaratumab serum concentrations.