Soft Tissue Sarcoma
Conditions
Brief summary
The main purpose of this study is to evaluate the safety and efficacy of two anti-cancer drugs (gemcitabine and docetaxel) with and without the study drug known as olaratumab in participants with advanced soft tissue sarcoma (STS) or STS that has spread to another part(s) of the body.
Interventions
DRUGOlaratumab
Administered IV
DRUGGemcitabine
Administered IV
DRUGDocetaxel
Administered IV
DRUGPlacebo
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant may have no more than 2 prior lines of systemic therapies (neoadjuvant and adjuvant therapies will not be considered as a prior line of therapy) for advanced or metastatic disease and is suitable to receive gemcitabine and docetaxel therapy. All previous therapies must have completed ≥ 3 weeks (21 days) prior to first dose of study drug. * In the Phase 2 part, prior olaratumab/doxorubicin combination therapy in 1 prior treatment line is allowed. * Prior olaratumab therapy must have been received with doxorubicin as indicated on the olaratumab label. * Prior olaratumab therapy must have included at least 2 full cycles of olaratumab/doxorubicin (that is, a minimum of 4 doses of olaratumab). * Participants, who completed at least 2 cycles of combination olaratumab/doxorubicin therapy then discontinued doxorubicin due to toxicity or maximum dosing and proceeded to olaratumab monotherapy, are eligible. * The most recent dose of olaratumab must have been received within 180 days of randomization in this study. * Availability of tumor tissue is mandatory for study eligibility. The participant must have consented to provide archived formalin-fixed paraffin-embedded tumor tissue or be subject to a pre-treatment re-biopsy of primary or metastatic tumor tissue for future central pathology review and translational research (if archived tissue is unavailable). * The participant has adequate hematologic, organ, and coagulation function within 2 weeks (14 days) prior to enrollment (Phase 1b) or randomization (Phase 2).
Exclusion criteria
* The participant is diagnosed with gastrointestinal stromal tumor (GIST) or Kaposi sarcoma. * The participant has active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment (Phase 1b) or randomization (Phase 2). 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 (Phase 1b) /randomization (Phase 2) to rule out brain metastasis. * The participant has received prior treatment with gemcitabine or docetaxel. Note: Participants previously enrolled in the I5B-MC-JGDJ (NCT02451943) or any other blinded study with olaratumab are not eligible to participate in this trial. * The participant has electively planned or will require major surgery during the course of the study. * Females who are pregnant or breastfeeding. * The participant has an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT) | Cycle 1 (Up To 21 Days) | A Dose Limiting Toxicity is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Febrile neutropenia with documented Grade ≥3 infection or sepsis 2. Grade 4 neutropenia lasting 7 days or longer. 3. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage. 4. Nonhematologic Grade ≥3 toxicity, except for toxicities such as nausea, vomiting, transient electrolyte abnormalities, or diarrhoea that can be controlled with optimal medical management within 48 hours. |
| Phase 2: Overall Survival (OS) (Olaratumab-Naive) | Baseline to Date of Death Due to Any Cause (Up To 38 Months) | OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 8 | T1/2 of Olaratumab. |
| Phase 1b/2: PK: Cmax of Gemcitabine | Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) | Cmax of Gemcitabine. |
| Phase 1b/2: PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC[0-∞]) of Gemcitabine | Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) | AUC\[0-∞\] of Gemcitabine |
| Phase 1b/2: PK: Cmax of Docetaxel | 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 | Cmax of Docetaxel. |
| Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel | 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 | AUC \[0-∞\] of Docetaxel. |
| Phase 1b/2: Population PK: Clearance of Olaratumab | Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8 | Population PK: Clearance of Olaratumab |
| Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab | Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8 | The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2). |
| Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Pre-dose, 5 minutes (min), 1, 4, 4.5, 24, 96, 168, 336 hours (h) post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 8 | Cmax of Olaratumab. |
| Phase 2: Progression Free Survival (PFS) | Baseline to Objective Disease Progression or Death from Any Cause (Up To 38 Months) | PFS was defined as the time from randomization to the first date of radiologic disease progression (as defined by Response Evaluation Criteria In Solid Tumors, Version 1.1 \[RECIST v.1.1\]) or death due to any cause. Progressive disease (PD) was defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Participants who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of randomization if no post-baseline radiographic assessment is available. |
| Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) | Baseline to Objective Disease Progression or Start of New Anti-Cancer Therapy (Up To 38 Months) | ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. |
| Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 38 Months) | DCR is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. |
| Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score | Baseline to Follow-up (Up To 24 Months) | The mBPI-sf is a 11-item instrument used as a multiple-item measure of cancer pain intensity ranging from 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can imagine or completely interferes). Time to first worsening of the mBPI-sf worst pain score (TWP) was defined as the time from the date of randomization to the first date of either a worst pain score increase of greater than or equal to (≥) 2 points from baseline or an analgesic drug class increase of ≥1 level. If the patient has not worsened by either of these criteria, TWP was censored for analysis on the last date the mBPI-sf was administered. |
| Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Baseline to Follow-up (Up to 33 months) | The EORTC QLQ-C30 is a self-reported general cancer instrument consisting of 30 items covered by 1 of 3 dimensions: global health status/quality of life (2 items), functional scales (15 total items addressing either physical, role, emotional, cognitive, or social functioning), symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, or financial impact). Time to first worsening of Symptom Burden was defined as the time from randomization to the first observation of worsening on symptom scales (i.e.,) increase of at least 10 points from baseline. For symptom scales, a linear transformation was used to obtain total score ranging from 0 to 100, a high score represents a high level of symptomatology or problems. |
| Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | Cycle 1 (Day 1), Follow-up (Up to 38 Months) | The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) of health status are each assessed with 5 response options (1=no problem, 2=slight, 3=moderate, 4=severe, and 5=extreme problem) and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status. Additionally, current health status was assessed on a visual analogue scale (VAS) ranging from 0 to 100 with a higher score representing better health status. |
| Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies | Baseline through Follow-Up (Up to 38 Months) | Number of Participants with Treatment Emergent Anti-Olaratumab Antibodies |
| Phase 2: Overall Survival (Olaratumab Pre-Treated) | Baseline to Date of Death Due to Any Cause (Up To 38 Months) | OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact. |
| Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1 | Cmin of Olaratumab. |
Countries
Australia, France, Germany, Hungary, Israel, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Completers included participants who died from any cause.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel Participants received intravenous infusions of olaratumab 15 milligrams per kilogram (mg/kg) on days 1, 8 plus gemcitabine 900 milligrams per meter square (mg/m\^2) on days 1, 8 plus docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 21 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel Participants received intravenous infusions of olaratumab 20 mg/kg on days 1, 8 in combination with gemcitabine 900 mg/m\^2 on days 1, 8 and docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 18 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel Following a protocol amendment, additional participants were enrolled into this group to confirm the safety of the 20 mg/kg dose level prior to opening the Phase 2. Participants received intravenous infusions of olaratumab 20 milligrams per kilogram (mg/kg) on days 1, 8 plus gemcitabine 900 milligrams per meter square (mg/m\^2) on days 1, 8 plus docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 15 |
| Phase 2: Olaratumab + Gemcitabine + Docetaxel (Olaratumab-naive) This cohort included participants who never received olaratumab prior to enrollment. Participants received intravenous infusions of olaratumab loading dose 20 mg/kg on days 1, 8 of cycle 1 followed by 15 mg/kg on days 1, 8 of all subsequent cycles in combination with gemcitabine 900 mg/m\^2 on days 1, 8 and docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 81 |
| Phase 2: Olaratumab + Gemcitabine + Docetaxel (Olaratumab Pre-treated) This cohort included participants who received commercially available olaratumab prior to enrollment. Participants received intravenous infusions of olaratumab loading dose 20 mg/kg on days 1, 8 of cycle 1 followed by 15 mg/kg on days 1, 8 of all subsequent cycles in combination with gemcitabine 900 mg/m\^2 on days 1, 8 and docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 46 |
| Phase 2: Placebo + Gemcitabine + Docetaxel (Olaratumab-naive) This cohort included participants who never received olaratumab prior to enrollment. Participants received intravenous infusions of placebo on days 1, 8 in combination with gemcitabine 900 mg/m\^2 on days 1, 8 and docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 86 |
| Phase 2: Placebo + Gemcitabine + Docetaxel (Olaratumab Pre-treated) This cohort included participants who received commercially available olaratumab prior to enrollment. Participants received intravenous infusions of placebo on days 1, 8 in combination with gemcitabine 900 mg/m\^2 on days 1, 8 and docetaxel 75 mg/m\^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | 43 |
| Total | 310 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 | 1 | 6 | 1 | 5 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 4 | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 3 | 3 | 6 | 3 |
Baseline characteristics
| Characteristic | Total | Phase 2: Placebo + Gemcitabine + Docetaxel (Olaratumab Pre-treated) | Phase 2: Placebo + Gemcitabine + Docetaxel (Olaratumab-naive) | Phase 2: Olaratumab + Gemcitabine + Docetaxel (Olaratumab Pre-treated) | Phase 2: Olaratumab + Gemcitabine + Docetaxel (Olaratumab-naive) | Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel |
|---|---|---|---|---|---|---|---|---|
| Age, Customized <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized <65 years | 227 Participants | 30 Participants | 66 Participants | 27 Participants | 66 Participants | 6 Participants | 12 Participants | 20 Participants |
| Age, Customized >=65 years | 83 Participants | 13 Participants | 20 Participants | 19 Participants | 15 Participants | 9 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 4 Participants | 6 Participants | 4 Participants | 8 Participants | 1 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 264 Participants | 36 Participants | 73 Participants | 39 Participants | 71 Participants | 11 Participants | 18 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 3 Participants | 7 Participants | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 2 Participants | 1 Participants | 8 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 42 Participants | 3 Participants | 10 Participants | 3 Participants | 15 Participants | 0 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 233 Participants | 34 Participants | 70 Participants | 30 Participants | 61 Participants | 13 Participants | 10 Participants | 15 Participants |
| Region of Enrollment Australia | 9 Participants | 0 Participants | 2 Participants | 0 Participants | 6 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment France | 5 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Germany | 24 Participants | 2 Participants | 11 Participants | 4 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Hungary | 11 Participants | 0 Participants | 6 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Israel | 18 Participants | 4 Participants | 7 Participants | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Italy | 6 Participants | 0 Participants | 4 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Poland | 8 Participants | 0 Participants | 2 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Spain | 37 Participants | 2 Participants | 11 Participants | 0 Participants | 9 Participants | 0 Participants | 4 Participants | 11 Participants |
| Region of Enrollment United Kingdom | 31 Participants | 5 Participants | 12 Participants | 3 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 161 Participants | 30 Participants | 28 Participants | 36 Participants | 29 Participants | 14 Participants | 14 Participants | 10 Participants |
| Sex: Female, Male Female | 188 Participants | 28 Participants | 58 Participants | 28 Participants | 48 Participants | 7 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Male | 122 Participants | 15 Participants | 28 Participants | 18 Participants | 33 Participants | 8 Participants | 10 Participants | 10 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 21 | 11 / 18 | 12 / 15 | 54 / 81 | 28 / 45 | 58 / 86 | 28 / 43 |
| other Total, other adverse events | 21 / 21 | 18 / 18 | 15 / 15 | 78 / 81 | 45 / 45 | 81 / 86 | 42 / 43 |
| serious Total, serious adverse events | 6 / 21 | 9 / 18 | 9 / 15 | 44 / 81 | 21 / 45 | 38 / 86 | 23 / 43 |
Outcome results
Primary
Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT)
A Dose Limiting Toxicity is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Febrile neutropenia with documented Grade ≥3 infection or sepsis 2. Grade 4 neutropenia lasting 7 days or longer. 3. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage. 4. Nonhematologic Grade ≥3 toxicity, except for toxicities such as nausea, vomiting, transient electrolyte abnormalities, or diarrhoea that can be controlled with optimal medical management within 48 hours.
Time frame: Cycle 1 (Up To 21 Days)
Population: Phase 1b: All participants who received at least one dose of Olaratumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT) | 1 Participants |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT) | 4 Participants |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT) | 3 Participants |
Primary
Phase 2: Overall Survival (OS) (Olaratumab-Naive)
OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact.
Time frame: Baseline to Date of Death Due to Any Cause (Up To 38 Months)
Population: Phase 2: All randomized participants (including the censored participants). Number of participants censored in Olaratumab + Gemcitabine + Docetaxel (Olaratumab-naive) =30, Placebo + Gemcitabine + Docetaxel (Olaratumab-naive) =28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Overall Survival (OS) (Olaratumab-Naive) | 16.76 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Overall Survival (OS) (Olaratumab-Naive) | 18.04 Months |
p-value: 0.77595% CI: [0.639, 1.397]Log Rank
Secondary
Phase 1b/2: PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC[0-∞]) of Gemcitabine
AUC\[0-∞\] of Gemcitabine
Time frame: Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion)
Population: Phase 1b/2: Zero participants analysed. Due to short half-life of Gemcitabine, there was insufficient quantifiable data in the elimination phase to calculate AUC\[0-∞\] for any of the participants.
Secondary
Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel
AUC \[0-∞\] of Docetaxel.
Time frame: 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8
Population: Phase 1b/2: All participants who received at least one dose of Docetaxel and had evaluable PK data. For phase 2, zero participants analysed due to data not collected for AUC \[0-∞\] of Docetaxel.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel | 4440 nanograms*hours per milliliter | Geometric Coefficient of Variation 103 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel | 2990 nanograms*hours per milliliter | Geometric Coefficient of Variation 83 |
Secondary
Phase 1b/2: PK: Cmax of Docetaxel
Cmax of Docetaxel.
Time frame: 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8
Population: Phase 1b/2: All participants who received at least one dose of Docetaxel and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Docetaxel | 903 Nanograms per milliliter | Geometric Coefficient of Variation 143 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Docetaxel | 1110 Nanograms per milliliter | Geometric Coefficient of Variation 84 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Docetaxel | 1030 Nanograms per milliliter | Geometric Coefficient of Variation 134 |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Docetaxel | 827 Nanograms per milliliter | Geometric Coefficient of Variation 102 |
Secondary
Phase 1b/2: PK: Cmax of Gemcitabine
Cmax of Gemcitabine.
Time frame: Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion)
Population: Phase 1b/2: All participants who received at least one dose of Gemcitabine and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Gemcitabine | 2.79 μg/mL | Geometric Coefficient of Variation 70 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Gemcitabine | 3.49 μg/mL | Geometric Coefficient of Variation 50 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Gemcitabine | 3.01 μg/mL | Geometric Coefficient of Variation 122 |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 1b/2: PK: Cmax of Gemcitabine | 2.35 μg/mL | Geometric Coefficient of Variation 105 |
Secondary
Phase 1b/2: Population PK: Clearance of Olaratumab
Population PK: Clearance of Olaratumab
Time frame: Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8
Population: Phase 1b/2: All participants who received at least one dose of Olaratumab and had evaluable PK data. Phase 1b and phase 2 participants olaratumab PK data was planned to be pooled for the population PK analysis and compared to a validated PK model to confirm that PK parameters were similar to analyses from previous olaratumab studies.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: Population PK: Clearance of Olaratumab | 0.0186 Liter Per Hour |
Secondary
Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab
The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2).
Time frame: Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8
Population: Phase 1b/2: All participants who received at least one dose of Olaratumab and had evaluable PK data. Phase 1b and phase 2 participants olaratumab PK data was planned to be pooled for the population PK analysis and compared to a validated PK model to confirm that PK parameters were similar to analyses from previous olaratumab studies.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab | 5.14 Liter |
Secondary
Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab
Cmax of Olaratumab.
Time frame: Pre-dose, 5 minutes (min), 1, 4, 4.5, 24, 96, 168, 336 hours (h) post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 8
Population: Phase 1b: All participants who received at least one dose of Olaratumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 1 (Day 1) | 432 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 24 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 1 (Day 8) | 460 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 25 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 3 (Day 1) | 523 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 38 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 3 (Day 8) | 513 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 21 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 3 (Day 8) | 689 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 20 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 1 (Day 1) | 572 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 25 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 3 (Day 1) | 644 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 20 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cycle 1 (Day 8) | 697 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 20 |
Secondary
Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab
T1/2 of Olaratumab.
Time frame: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 8
Population: Phase 1b: All participants who received at least one dose of Olaratumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 1 (Day 1) | 4.60 days | Geometric Coefficient of Variation 34 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 1 (Day 8) | 6.25 days | Geometric Coefficient of Variation 25 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 3 (Day 8) | 5.82 days | Geometric Coefficient of Variation 30 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 3 (Day 1) | 5.17 days | Geometric Coefficient of Variation 36 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 3 (Day 8) | 6.39 days | Geometric Coefficient of Variation 32 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 1 (Day 1) | 4.29 days | Geometric Coefficient of Variation 28 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 1 (Day 8) | 6.62 days | Geometric Coefficient of Variation 27 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | Cycle 3 (Day 1) | 6.36 days | Geometric Coefficient of Variation 41 |
Secondary
Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab
Cmin of Olaratumab.
Time frame: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1
Population: Phase 1b: All participants who received at least one dose of Olaratumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cycle 1 (Day 1) | 95.9 μg/mL | Geometric Coefficient of Variation 37 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cycle 1 (Day 8) | 64.3 μg/mL | Geometric Coefficient of Variation 64 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cycle 3 (Day 1) | 137 μg/mL | Geometric Coefficient of Variation 40 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cycle 1 (Day 1) | 142 μg/mL | Geometric Coefficient of Variation 38 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cycle 1 (Day 8) | 93.3 μg/mL | Geometric Coefficient of Variation 47 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cycle 3 (Day 1) | 252 μg/mL | Geometric Coefficient of Variation 36 |
Secondary
Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD)
DCR is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
Time frame: Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 38 Months)
Population: Phase 2: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 74.1 Percentage of participants |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 72.1 Percentage of participants |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 67.4 Percentage of participants |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 62.8 Percentage of participants |
p-value: 0.772495% CI: [0.558, 2.194]Exact Mantel-Haenszel test
p-value: 0.650895% CI: [0.513, 2.911]Exact Mantel-Haenszel test
Secondary
Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L)
The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) of health status are each assessed with 5 response options (1=no problem, 2=slight, 3=moderate, 4=severe, and 5=extreme problem) and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status. Additionally, current health status was assessed on a visual analogue scale (VAS) ranging from 0 to 100 with a higher score representing better health status.
Time frame: Cycle 1 (Day 1), Follow-up (Up to 38 Months)
Population: Phase 2: All randomized participants who completed EQ-5D-5L.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Follow-up (Up to 38 Months)] | 68.7 score on a scale | Standard Deviation 16.5 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Follow-up (Up to 38 Months)] | 0.74 score on a scale | Standard Deviation 0.21 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Cycle 1 (Day 1)] | 0.80 score on a scale | Standard Deviation 0.17 |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Cycle 1 (Day 1)] | 73.5 score on a scale | Standard Deviation 18.9 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Follow-up (Up to 38 Months)] | 63.0 score on a scale | Standard Deviation 21.6 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Follow-up (Up to 38 Months)] | 0.71 score on a scale | Standard Deviation 0.26 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Cycle 1 (Day 1)] | 0.81 score on a scale | Standard Deviation 0.17 |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Cycle 1 (Day 1)] | 72.7 score on a scale | Standard Deviation 18.1 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Follow-up (Up to 38 Months)] | 74.8 score on a scale | Standard Deviation 21.8 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Cycle 1 (Day 1)] | 0.83 score on a scale | Standard Deviation 0.15 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Cycle 1 (Day 1)] | 76.2 score on a scale | Standard Deviation 19.6 |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Follow-up (Up to 38 Months)] | 0.80 score on a scale | Standard Deviation 0.2 |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Follow-up (Up to 38 Months)] | 0.76 score on a scale | Standard Deviation 0.24 |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - Index Value [Cycle 1 (Day 1)] | 0.83 score on a scale | Standard Deviation 0.22 |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Follow-up (Up to 38 Months)] | 70.8 score on a scale | Standard Deviation 24.2 |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L - VAS Score [Cycle 1 (Day 1)] | 70.3 score on a scale | Standard Deviation 23.8 |
Secondary
Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies
Number of Participants with Treatment Emergent Anti-Olaratumab Antibodies
Time frame: Baseline through Follow-Up (Up to 38 Months)
Population: Phase 2: All randomized participants who received at least one dose of Olaratumab and had evaluable immunogenicity data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies | 0 Participants |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies | 0 Participants |
Secondary
Phase 2: Overall Survival (Olaratumab Pre-Treated)
OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact.
Time frame: Baseline to Date of Death Due to Any Cause (Up To 38 Months)
Population: Phase 2: All randomized participants (including the censored participants). Number of participants censored in Olaratumab + Gemcitabine + Docetaxel (Olaratumab Pre-Treated) = 20, Placebo + Gemcitabine + Docetaxel (Olaratumab Pre-Treated) =15.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Overall Survival (Olaratumab Pre-Treated) | 19.84 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Overall Survival (Olaratumab Pre-Treated) | 17.31 Months |
p-value: 0.14895% CI: [0.385, 1.158]Log Rank
Secondary
Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR])
ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions.
Time frame: Baseline to Objective Disease Progression or Start of New Anti-Cancer Therapy (Up To 38 Months)
Population: Phase 2: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) | 32.1 Percentage of participants |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) | 23.3 Percentage of participants |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) | 30.4 Percentage of participants |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) | 14 Percentage of participants |
p-value: 0.189195% CI: [0.794, 3.179]Exact Mantel-Haenszel test
p-value: 0.064295% CI: [0.923, 7.71]Exact Mantel-Haenszel test
Secondary
Phase 2: Progression Free Survival (PFS)
PFS was defined as the time from randomization to the first date of radiologic disease progression (as defined by Response Evaluation Criteria In Solid Tumors, Version 1.1 \[RECIST v.1.1\]) or death due to any cause. Progressive disease (PD) was defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Participants who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of randomization if no post-baseline radiographic assessment is available.
Time frame: Baseline to Objective Disease Progression or Death from Any Cause (Up To 38 Months)
Population: Phase 2: All randomized participants (including the censored participants). Number of participants censored in Olaratumab + Gemcitabine + Docetaxel (Olaratumab-naive)=20 Placebo + Gemcitabine + Docetaxel (Olaratumab-naive)=21, Olaratumab + Gemcitabine + Docetaxel (Olaratumab pre-treated)=12, Placebo + Gemcitabine + Docetaxel (Olaratumab pre-treated)=16.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Progression Free Survival (PFS) | 7.62 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Progression Free Survival (PFS) | 4.37 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Progression Free Survival (PFS) | 5.45 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Progression Free Survival (PFS) | 4.17 Months |
p-value: 0.05595% CI: [0.476, 1.007]Log Rank
p-value: 0.48295% CI: [0.49, 1.398]Log Rank
Secondary
Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales.
The EORTC QLQ-C30 is a self-reported general cancer instrument consisting of 30 items covered by 1 of 3 dimensions: global health status/quality of life (2 items), functional scales (15 total items addressing either physical, role, emotional, cognitive, or social functioning), symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, or financial impact). Time to first worsening of Symptom Burden was defined as the time from randomization to the first observation of worsening on symptom scales (i.e.,) increase of at least 10 points from baseline. For symptom scales, a linear transformation was used to obtain total score ranging from 0 to 100, a high score represents a high level of symptomatology or problems.
Time frame: Baseline to Follow-up (Up to 33 months)
Population: Phase 2: All randomized participants who had baseline and at least one post-baseline assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Financial difficulties | NA Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Pain | 4.67 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Dyspnoea | 2.14 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Insomnia | 5.32 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Appetite loss | 1.12 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Constipation | 3.25 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Diarrhoea | 1.41 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Fatigue | 0.95 Months |
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Nausea and vomiting | 3.78 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Pain | 0.99 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Constipation | 2.86 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Dyspnoea | 2.14 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Financial difficulties | 7.66 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Insomnia | 4.24 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Diarrhoea | 1.81 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Appetite loss | 2.56 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Fatigue | 0.95 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Nausea and vomiting | 2.46 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Dyspnoea | 2.33 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Insomnia | 1.91 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Fatigue | 0.85 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Appetite loss | 1.41 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Constipation | 4.63 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Nausea and vomiting | 3.98 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Diarrhoea | 3.55 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Financial difficulties | 7.29 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Pain | 2.43 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Insomnia | 5.09 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Nausea and vomiting | 13.17 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Financial difficulties | NA Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Fatigue | 0.76 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Dyspnoea | 2.79 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Pain | 3.06 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Appetite loss | 1.97 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Diarrhoea | 3.52 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | Constipation | 3.81 Months |
Comparison: Fatiguep-value: 0.33295% CI: [0.834, 1.764]Log Rank
Comparison: Nausea and vomitingp-value: 0.38995% CI: [0.514, 1.287]Log Rank
Comparison: Painp-value: 0.0295% CI: [0.386, 0.926]Log Rank
Comparison: Dyspnoeap-value: 0.82195% CI: [0.622, 1.442]Log Rank
Comparison: Insomniap-value: 0.81295% CI: [0.574, 1.509]Log Rank
Comparison: Appetite lossp-value: 0.16295% CI: [0.893, 2.055]Log Rank
Comparison: Constipationp-value: 0.61995% CI: [0.55, 1.413]Log Rank
Comparison: Diarrhoeap-value: 0.59795% CI: [0.746, 1.724]Log Rank
Comparison: Financial difficultiesp-value: 0.3895% CI: [0.425, 1.381]Log Rank
Comparison: Fatiguep-value: 0.87795% CI: [0.635, 1.723]Log Rank
Comparison: Nausea and vomitingp-value: 0.79195% CI: [0.568, 2.139]Log Rank
Comparison: Painp-value: 0.48795% CI: [0.454, 1.443]Log Rank
Comparison: Dyspnoeap-value: 0.97695% CI: [0.556, 1.85]Log Rank
Comparison: Insomniap-value: 0.11195% CI: [0.882, 3.25]Log Rank
Comparison: Appetite lossp-value: 0.7695% CI: [0.62, 1.979]Log Rank
Comparison: Constipationp-value: 0.74795% CI: [0.586, 2.135]Log Rank
Comparison: Diarrhoeap-value: 0.3395% CI: [0.726, 2.576]Log Rank
Comparison: Financial difficultiesp-value: 0.41195% CI: [0.636, 2.965]Log Rank
Secondary
Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score
The mBPI-sf is a 11-item instrument used as a multiple-item measure of cancer pain intensity ranging from 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can imagine or completely interferes). Time to first worsening of the mBPI-sf worst pain score (TWP) was defined as the time from the date of randomization to the first date of either a worst pain score increase of greater than or equal to (≥) 2 points from baseline or an analgesic drug class increase of ≥1 level. If the patient has not worsened by either of these criteria, TWP was censored for analysis on the last date the mBPI-sf was administered.
Time frame: Baseline to Follow-up (Up To 24 Months)
Population: Phase 2: All randomized participants who had baseline and at least one post-baseline assessment (including the censored participants). Number of participants censored in Olaratumab + Gemcitabine + Docetaxel (Olaratumab-naive) = 30, Placebo + Gemcitabine + Docetaxel (Olaratumab-naive)=23, Olaratumab + Gemcitabine + Docetaxel (Olaratumab pre-treated)=17, Placebo + Gemcitabine + Docetaxel (Olaratumab pre-treated)=8.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score | 3.61 Months |
| Phase 1b: Cohort 2 - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score | 2.27 Months |
| Phase 1b: Cohort 2 Expansion - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score | 3.15 Months |
| Phase 2: Placebo + Gemcitabine + Docetaxel | Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score | 2.20 Months |
p-value: 0.07395% CI: [0.419, 1.041]Log Rank
p-value: 0.22595% CI: [0.395, 1.253]Log Rank