Study of Single Agent Idelalisib Followed by Idelalisib in Combination With Chemotherapy in Adults With Metastatic Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety of single agent idelalisib and to evaluate safety and define the maximum tolerated dose (MTD) of idelalisib in combination with chemotherapy in adults with metastatic pancreatic ductal adenocarcinoma.

Official Title
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A Phase 1b Study of Single Agent Idelalisib Followed by Idelalisib in Combination With Chemotherapy in Subjects With Metastatic Pancreatic Ductal Adenocarcinoma

Conditions
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Previously Untreated Pancreatic Ductal Adenocarcinoma, Relapsed/Refractory Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Idelalisib
* Drug: Nab-paclitaxel
* Drug: mFOLFOX6


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: The presence of metastatic pancreatic adenocarcinoma plus 1 of the following: Histological diagnosis of pancreatic adenocarcinoma confirmed pathologically, OR Pathologist confirmed histological/cytological diagnosis of adenocarcinoma consistent with pancreas origin Measurable disease per response evaluation criteria in solid tumors (RECIST) v1.1 Prior systemic chemotherapy treatment for metastatic pancreatic ductal adenocarcinoma (Arm: idelalisib single agent only) Received one prior line of chemotherapy for metastatic pancreatic ductal adenocarcinoma (Arm: idelalisib + mFOLFOX6 only) Adequate organ function defined as follows: Hepatic: Total bilirubin ≤ 1.25 x upper limit of normal (ULN) (Arm: idelalisib + nab-paclitaxel ); total bilirubin ≤1.5 x ULN (Arm: single agent idelalisib and Arm: idelalisib + mFOLFOX6); aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT), alanine transaminase (ALT) serum glutamic pyruvic transaminase (SGPT) < 2.5 x ULN, and albumin > 3.0 g/dL Hematological: absolute neutrophil count (ANC) > 1,500 cells/cubic millimetre (m^3), platelet > 100,000 cells/mm^3, hemoglobin > 9.0 grams/decilitre (g/dL) Renal: Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance (CrCl) > 30 millilitre (ml)/min as calculated by the Cockcroft-Gault method Able to comprehend and willing to sign the written informed consent form Key Exclusion Criteria: Currently or previously treated with biologic, or immunotherapy Currently or previously treated with conventional chemotherapy, or other agents for metastatic pancreatic ductal adenocarcinoma (Arm: idelalisib + nab-paclitaxel only) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of enrollment Known human immunodeficiency viruses (HIV) infection History of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to enrollment, adequately treated Stage 1 or 2 non-pancreatic cancer currently in complete remission, or any other non-pancreatic cancer that has been in complete remission for ≥ 5 years Diagnosis of pancreatic islet neoplasm, acinar cell carcinoma, non-adenocarcinoma (eg, lymphoma, sarcoma), adenocarcinoma originating from the biliary tree or cystadenocarcinoma History of serious allergic reaction, including anaphylaxis and toxic epidermal necrolysis Presence of peripheral neuropathy ≥ Grade 2 (Arm: idelalisib + nab-paclitaxel and Arm: idelalisib + mFOLFOX6) Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg, unstable angina, congestive heart failure [New York Heart Association > Class III]) within 6 months or enrollment Known hypersensitivity to idelalisib, its metabolites, or formulation excipients Known hypersensitivity to nab-paclitaxel (Arm: idelalisib + nab-paclitaxel), their metabolites, or formulation excipients Known hypersensitivity to 5-fluorouracil, leucovorin, or oxaliplatin (Arm: idelalisib + mFOLFOX6), their metabolites, or formulation excipients Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idelalisib 150 mg<br>Participants were administered with idelalisib (IDL) 150 mg tablets orally, twice daily (morning and evening) for 8 weeks. | Drug: Idelalisib<br>* Tablets administered orally twice daily<br>* Other names: Zydelig®;|
| Experimental: Idelalisib + nab-paclitaxel<br>Participants will receive escalating doses of idelalisib at a dose level of up to 150mg + nab-paclitaxel. | Drug: Idelalisib<br>* Tablets administered orally twice daily<br>* Other names: Zydelig®;Drug: Nab-paclitaxel<br>* 125 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28 day cycle<br>|
| Experimental: Idelalisib + mFOLFOX6<br>Participants will receive escalating doses of idelalisib at a dose level of up to 150mg + mFOLFOX6. | Drug: Idelalisib<br>* Tablets administered orally twice daily<br>* Other names: Zydelig®;Drug: mFOLFOX6<br>* mFOLFOX6 will be administered intravenously on Days 1 and 15 of each 28 day cycle. This regimen consists of levoleucovorin 200 milligram/meter per square (mg/m^2) or racemic leucovorin 400 mg/m^2, oxaliplatin 85 mg/m^2, bolus 5-fluorouracil 400 mg/m^2, and a 46 hour infusion of 5-fluorouracil 2, 400 mg/m^2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | TEAEs were defined as adverse events (AEs) with onset dates on or after the study drug start date and no later than 30 days after the permanent discontinuation of the study drug. It also included the AEs that led to premature discontinuation of study drug. | First dose date up to last dose date (Maximum: 8 weeks) plus 30 days | 
| Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any post baseline time point, up to and including the date of last dose of study drug plus 30 days. If the relevant baseline laboratory value was missing, any abnormality of at least Grade 1 observed within the time frame specified above was considered treatment emergent. Severity grade is defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening). The percentage of participants for any post-baseline abnormal laboratory value in the Grade 1-4 category is reported. The term 'hypo' indicates less than the normal count of a parameter and 'hyper' indicates more than the normal count of a parameter. | First dose date up to last dose date (Maximum: 8 weeks) plus 30 days | 
| Idelalisib in Combination With Chemotherapy: Percentage of Participants With Dose Limiting Toxicities (DLTs) | Dose limiting toxicities were defined as toxicities experienced during the first 28 days of treatment (Cycle 1) that were judged to be clinically significant and at least possibly related to study treatment. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in FoxP3+ and Cluster Determinant 8+ (CD8+) Cells From Tumor Tissue Samples as a Measure of Pharmacodynamics Activity |  | Up to 2 years | 
| Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily |  | Cycle 1, Day 1: Predose and 0.5, 1, 1.5, 2, 3, 4, and 8 hours (h) postdose; Day 8: Predose and 1.5 h postdose; Day 15: Predose and 1.5 h postdose Cycle 2, Day 1: Predose and 1.5 h postdose | 
| Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily |  | Cycle 1, Day 1: Predose and 0.5, 1, 1.5, 2, 3, 4, and 8 h postdose; Day 8: Predose and 1.5 h postdose; Day 15: Predose and 1.5 h postdose Cycle 2, Day 1: Predose and 1.5 h postdose | 
| Overall Response Rate (ORR) | Overall response rate (ORR) was defined as the percentage of participants who achieved a Complete Response (CR) or Partial Response (PR) as assessed by response evaluation criteria in sold tumors (RECIST) v1.1. | Up to 2 years | 
| Overall Survival (OS) | Overall survival is defined as the interval from first dose date of study drug to death from any cause. | Up to 2 years | 
| Progression Free Survival (PFS) | Progression free survival is defined as the interval from first dose date of study drug to the earlier of the first documentation of definitive disease progression or death from any cause. | Up to 2 years |