Previously Untreated Pancreatic Ductal Adenocarcinoma, Relapsed/Refractory Pancreatic Ductal Adenocarcinoma
Conditions
Brief summary
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.
Interventions
DRUGIdelalisib
Tablets administered orally twice daily
DRUGNab-paclitaxel
125 mg/m\^2 administered intravenously on Days 1, 8 and 15 of each 28 day cycle
DRUGmFOLFOX6
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.
Sponsors
Gilead Sciences
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
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | First dose date up to last dose date (Maximum: 8 weeks) plus 30 days | 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. |
| Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | First dose date up to last dose date (Maximum: 8 weeks) plus 30 days | 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. |
| Idelalisib in Combination With Chemotherapy: Percentage of Participants With Dose Limiting Toxicities (DLTs) | Up to 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 2 years | 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. |
| 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 | — |
| Progression Free Survival (PFS) | Up to 2 years | 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. |
| Overall Survival (OS) | Up to 2 years | Overall survival is defined as the interval from first dose date of study drug to death from any cause. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 30 July 2015. The last study visit occurred on 27 April 2016.
Pre-assignment details
35 participants were screened. The study was terminated. No participants were enrolled in the Idelalisib (IDL) + nab-paclitaxel or IDL + mFOLFOX \[5- fluorouracil (FU), leucovorin and oxaliplatin\] groups.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib 150 mg Participants were administered with idelalisib (IDL) 150 mg tablets orally, twice daily (morning and evening) for 8 weeks. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | All Enrolled but Never Dosed | 4 |
| Overall Study | Death | 1 |
| Overall Study | Study Terminated by Sponsor, Regulatory Agency or Institutional Review Board/ Ethics Committee | 10 |
Baseline characteristics
| Characteristic | Idelalisib 150 mg |
|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 10.7 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants |
| Race/Ethnicity, Customized Race Black | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants |
| Race/Ethnicity, Customized Race White | 11 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 3 / 12 |
Outcome results
Primary
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.
Time frame: Up to 28 days
Population: Due to the early termination of the study, there were no participants enrolled in the Idelalisib Combination arms.
Primary
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.
Time frame: First dose date up to last dose date (Maximum: 8 weeks) plus 30 days
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 100.0 percentage of participants |
Primary
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.
Time frame: First dose date up to last dose date (Maximum: 8 weeks) plus 30 days
Population: Participants in the safety analysis set were analysed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Hemoglobin (Hypo), Hematology | 25.0 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Lymphocytes (Hyper), Hematology | 8.3 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Lymphocytes (Hypo), Hematology | 25.0 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Platelets, Hematology | 8.3 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Alanine Aminotransferase, Chemistry | 58.3 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Albumin, Chemistry | 16.7 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Alkaline Phosphatase, Chemistry | 33.3 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Aspartate Aminotransferase, Chemistry | 66.7 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Bilirubin, Chemistry | 16.7 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Creatinine Clearance, Chemistry | 16.7 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Gamma Glutamyl Transferase, Chemistry | 50.0 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Glucose (Hyper), Chemistry | 16.7 percentage of participants |
| Idelalisib 150 mg | Single-agent IDL: Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Sodium (Hypo), Chemistry | 25.0 percentage of participants |
Secondary
Change From Baseline in FoxP3+ and Cluster Determinant 8+ (CD8+) Cells From Tumor Tissue Samples as a Measure of Pharmacodynamics Activity
Time frame: Up to 2 years
Population: Due to the early termination of the study no pharmacodynamic testing was performed.
Secondary
Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily
Time frame: 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
Population: Participants in the PK Analysis Set with available data were analysed. Due to the early termination of the study, concentration data is reported because there was an insufficient number of participants sampled for PK analysis to generate PK parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (Predose) | NA ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (0.5 h) | 173 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (1 h) | 1220 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (1.5 h) | 1070 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (2 h) | 1700 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (3 h) | 1580 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (4 h) | 1370 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (8 h) | 632 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 8 (Predose) | 2175 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 8 (1.5 h) | 2775 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 15 (Predose) | 2130 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 15 (1.5 h) | 2890 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 2; Day 1 (Predose) | 1046.5 ng/mL |
| Idelalisib 150 mg | Idelalisib Metabolite (GS-563117) Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 2; Day 1 (1.5 h) | 1405 ng/mL |
Secondary
Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily
Time frame: 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
Population: The pharmacokinetic (PK) Analysis Set included all participants in the Full Analysis Set who had the necessary baseline and on-study measurements to provide interpretable results for the specific parameters of interest. Due to the early termination of the study, concentration data is reported because there was an insufficient number of participants sampled for PK analysis to generate PK parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (Predose) | NA ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (0.5 h) | 1110 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (1 h) | 1880 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (1.5 h) | 1690 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (2 h) | 1290 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (3 h) | 795 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (4 h) | 1540 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 1 (8 h) | 251 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 8 (Predose) | 264 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 8 (1.5 h) | 2050 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 15 (Predose) | 275 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 1; Day 15 (1.5 h) | 1605 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 2; Day 1 (Predose) | 178.05 ng/mL |
| Idelalisib 150 mg | Idelalisib Plasma Concentrations Following Idelalisib 150 mg Twice Daily | Cycle 2; Day 1 (1.5 h) | 2180 ng/mL |
Secondary
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.
Time frame: Up to 2 years
Population: Due to early study termination, the prespecified efficacy analyses were not conducted.
Secondary
Overall Survival (OS)
Overall survival is defined as the interval from first dose date of study drug to death from any cause.
Time frame: Up to 2 years
Population: Due to early study termination, the prespecified efficacy analyses were not conducted.
Secondary
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.
Time frame: Up to 2 years
Population: Due to early study termination, the prespecified efficacy analyses were not conducted.