A Study of Nab-Paclitaxel and Gemcitabine With or Without Olaratumab (LY3012207) in Participants With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of nab-paclitaxel and gemcitabine with or without olaratumab in the treatment of first-line metastatic pancreatic cancer.

Official Title
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A Phase 1b (Open-Label) / Phase 2 (Randomized, Double-Blinded) Study Evaluating Nab-Paclitaxel and Gemcitabine With or Without Olaratumab in the Treatment of First-Line Metastatic Pancreatic Cancer

Conditions
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Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: Olaratumab
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of adenocarcinoma of the exocrine pancreas that is metastatic (Stage IV) and not amenable to resection with curative intent. If present, clinically significant or symptomatic amounts of ascites should be drained prior to Day 1. Have had no prior systemic treatment for metastatic disease. Prior adjuvant or neo-adjuvant chemotherapy or radiochemotherapy (other than nab-paclitaxel) is allowed if completed ≥3 months prior to enrollment and no lingering toxicities are present. Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow. Phase 2: archival tumor tissue or be willing to provide a pre-treatment biopsy. Measurable or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Discontinued all previous treatments for cancer ≥4 weeks prior. Adequate organ function. Life expectancy of at least 3 months. Exclusion Criteria: Serious concomitant systemic disorder. Have received first line treatment for metastatic pancreatic cancer. Received prior treatment with nab-paclitaxel. Have known central nervous system malignancy or metastasis. Current hematologic malignancies. Participated within the last 30 days in a clinical trial involving an investigational product. Women with a positive pregnancy test or lactating. Have endocrine pancreatic tumors or ampullary cancer. Currently enrolled in another clinical trial. Have a known additional malignancy that is progressing or required active treatment within the past 1 year. Known allergy to nab-paclitaxel or gemcitabine or any ingredient of study drug formulations. Are taking certain anti-coagulant medications such as warfarin and are unable to be switched to other similar medicines.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase1b: Olaratumab 15 mg/kg + Nab-paclitaxel + Gemcitabine<br>Participants received intravenous (IV) infusions of olaratumab 15 milligrams per kilogram (mg/kg), nab-paclitaxel 125 milligrams per meter square (mg/m^2) and gemcitabine 1000 mg/m^2 on days 1, 8, 15 of a 28-day cycle until disease progression or a criterion for discontinuation were met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Drug: Nab-paclitaxel<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>|
| Experimental: Phase1b: Olaratumab 20 mg/kg + Nab-paclitaxel + Gemcitabine<br>Participants received intravenous infusions of olaratumab 20 mg/kg, nab-paclitaxel 125 mg/m^2 and gemcitabine 1000 mg/m^2 on days 1, 8, 15 of a 28-day cycle until disease progression or a criterion for discontinuation were met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Drug: Nab-paclitaxel<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>|
| Experimental: Phase1b (cohort expansion): Olaratumab 20 mg/kg + Nab-paclitaxel + Gemcitabine<br>Following a protocol amendment, cohort expansion arm was added in phase 1b with new participants enrolled to confirm the safety of the olaratumab 20 mg/kg dose prior to opening the Phase 2. Participants received intravenous infusions of olaratumab 20 mg/kg, nab-paclitaxel 125 mg/m^2 and gemcitabine 1000 mg/m^2 on days 1, 8, 15 of a 28-day cycle until disease progression or a criterion for discontinuation were met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Drug: Nab-paclitaxel<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>|
| Experimental: Phase 2: Olaratumab + Nab-paclitaxel + Gemcitabine<br>Participants received intravenous infusions of olaratumab 20 mg/kg loading dose on days 1, 8, 15 of cycle 1 followed by 15 mg/kg on days 1, 8, 15 of all subsequent cycles, in combination with nab-paclitaxel 125 mg/m^2 and gemcitabine 1000 mg/m^2 on days 1, 8, 15 of a 28-day cycle until disease progression or a criterion for discontinuation were met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Drug: Nab-paclitaxel<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>|
| Placebo Comparator: Phase 2: Placebo + Nab-paclitaxel + Gemcitabine<br>Participants received intravenous infusions of placebo, nab-paclitaxel 125 mg/m^2 and gemcitabine 1000 mg/m^2 on days 1, 8, 15 of a 28-day cycle until disease progression or a criterion for discontinuation were met. | Drug: Nab-paclitaxel<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>Drug: Placebo<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) | A DLT is defined as an adverse event 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 4.03: Any febrile neutropenia Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by clinically significant hemorrhage Grade 4 neutropenia lasting 7 days or longer Nonhematologic Grade ≥3 toxicity, except for toxicities such as nausea, vomiting, transient electrolyte abnormalities, diarrhea which can be controlled with optimal medical management within 48 hours; non-clinically significant, treatable, or reversible laboratory abnormalities including liver function tests, uric acid, electrolytes, etc. Any other significant toxicity deemed to be dose-limiting (e.g., any toxicity that is possibly related to the study medication that requires the withdrawal of the participant from the study during Cycle 1). | Cycle 1 (Up to 28 days) | 
| Phase 2: Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. If the participant is alive or lost to follow-up at the time of data analysis, OS data will be censored on the last date the participant is known to be alive. For any participant who has withdrawn consent for further follow-up of survival data, OS will be censored at the last date for which the participant consented to be followed for the study. | Baseline to Date of Death from Any Cause (Up To 29 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b/2: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Olaratumab | PK: 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 15, Cycle 3 Day 1, Cycle 3 Day 15 | 
| Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies | Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies | Baseline through Follow-up (Up To 29 Months) | 
| Phase 1b: Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. If the participant is alive or lost to follow-up at the time of data analysis, OS data will be censored on the last date the participant is known to be alive. For any participant who has withdrawn consent for further follow-up of survival data, OS will be censored at the last date for which the participant consented to be followed for the study. | Baseline to Date of Death from Any Cause (Approximately 9 Months) | 
| Phase 2: Progression-Free Survival (PFS) | PFS is 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 in the absence of progressive disease (PD). 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. Participants who did not progress or are lost to follow-up 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. If death or PD occurs after 2 or more consecutive missing radiographic visits, censoring will occur at the date of the last radiographic visit prior to the missed visits. | Baseline to Disease Progression or Death (Up To 26 Months) | 
| Phase 1b/2: Objective Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) | ORR is the best overall tumor response of CR or 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. | Baseline through Disease Progression or Death (Up To 26 Months) | 
| Phase 1b/2: Duration of Response (DoR) | DoR is defined as the time from the date measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the absence of objectively determined disease progression or recurrence. | From Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up To 19 Months) | 
| 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 participant has not worsened by either of these criteria, TWP was censored for analysis on the last date the mBPI-sf was administered. | Baseline through Follow-up (Up To 21 Months) | 
| 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. | Baseline through Follow-up (Up To 21 Months) | 
| 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. | Cycle 1 Day 1, Cycle 7 Day 1 |