Pancreatic Cancer
Conditions
Keywords
Pancreatic cancer, MM-398, Metastatic pancreatic cancer, First line pancreatic cancer treatment
Brief summary
This is an open-label, phase 2 non-comparative study to assess the safety, tolerability, and preliminary efficacy of nal-IRI in combination with other anticancer therapies in patients not previously treated for metastatic pancreatic adenocarcinoma. This study will assess the following regimen: • nal-IRI + 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatin The study will be conducted in two parts: Part 1, consisting of an initial dose exploration (Part 1A) followed by dose expansion (Part 1B) of the irinotecan liposome injection +5-FU/LV + oxaliplatin regimen and Part 2, consisting of a comparison of irinotecan liposome injection-containing regimen versus nab-paclitaxel plus gemcitabine. The comparative Part 2 was removed in a protocol amendment, dated 11 April 2018 (Version 6.0), before it was initiated, as this comparative part of the study is being undertaken as a stand-alone phase III study D-US-60010-001. This CSR only pertains to the single-arm dose exploration and dose expansion Part 1 results and no further reference is made to the comparative Part 2.
Interventions
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting * Unresectable, locally advanced or metastatic disease; diagnosed within 6 weeks prior to screening * At least one tumor lesion measurable by CT or MRI scan (according to RECIST v1.1) * ECOG performance status of 0 or 1 at screening and within 72 hours prior to first dose if first dose occurs more than 72 hours post-screening * Adequate hematological, hepatic, renal and cardiac function * Recovered from the effects of any prior surgery or radiotherapy * Patient has a Karnofsky performance status (KPS) ≥ 70 at Screening, and within 72 hours prior to date of first dose if first dose occurs more than 72 hours after screening (Part 1B only)
Exclusion criteria
* Prior treatment of pancreatic cancer in the metastatic setting (or locally advanced setting) with surgery (placement of stent is allowed), radiotherapy, chemotherapy or investigational therapy * Prior treatment of pancreatic cancer with chemotherapy in adjuvant setting, except those where at least 12 months have elapsed since completion of the last dose and no persistent treatment-related toxicities present * Uncontrolled Central Nervous System (CNS) metastases * Clinically significant gastrointestinal disorder * History of any second malignancy in the last 3 years. Patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible * Presence of any contraindications for nal-IRI, irinotecan, 5-FU, leucovorin, oxaliplatin * Use of strong CYP3A4 or inducers or presence of any other contra indications for irinotecan * Pregnant or breast feeding * Neuroendocrine or acinar pancreatic carcinoma * Serum albumin \< 3 g/dL at screening visit and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening * Patients with symptoms and signs of clinically unacceptable deterioration of primary disease at time of screening * Previous treatment with irinotecan-based, nab-paclitaxel-based or gemcitabine-based resulting in disease progression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT) | From the start of the first study treatment (Cycle 1 Day 1) up to 14 days after the second dose of study treatment, maximum of 42 days | Adverse events (AEs) were considered to be DLTs if they occurred during the safety evaluation period (i.e, 28 days of Cycle 1; or 14 days after the second dose of study treatment if there was a treatment delay) and were deemed related to the study treatment regimen. Any AE that was related to disease progression was not considered a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) | RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter (maximum of 278 weeks). | The PFS was defined as the time from date of first study treatment to the first documented radiographical progression of disease (PD), per investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, or death from any cause, whichever comes first. The PFS was calculated using Kaplan-Meier technique. |
| Overall Response Rate (ORR) | RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks). | The ORR was defined as the percentage of participants with a BOR characterized as either a CR or PR relative to the total number of evaluable participants using RECIST Version 1.1. Evaluable participants were defined as treated participants with measurable disease at baseline. |
| Best Overall Response (BOR) | RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks). | The BOR was defined as the best response (complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) recorded from the start of study treatment until disease progression or start of new anticancer therapy using RECIST Version 1.1. |
| Median Overall Survival (OS) | RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks). | The OS was the time from date of first study treatment to the date of death from any cause. Participant survival data were collected from all available sources. The OS was calculated using Kaplan-Meier technique. |
| Median Duration of Response (DoR) | RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks). | The DoR was defined as the time from the first date of response (CR or PR) to first date of documented radiographical PD, per investigator using RECIST Version 1.1. This only applied to participants with CR or PR. If a participant was given a new anticancer therapy prior to first response, DoR was not calculated. The DoR was calculated using Kaplan-Meier technique. |
| Disease Control Rate (DCR) | At Week 16 | The DCR was defined as percentage of participants with CR or PR or SD or Non-PD/Non-CR, per RECIST Version 1.1 relative to total number of treated participants with measurable disease at baseline. |
Countries
Australia, Spain, United States
Participant flow
Recruitment details
This Phase 2 non-comparative, open-label study was conducted in previously untreated metastatic pancreatic cancer participants at 15 investigational sites in Australia, Spain and USA between 19 October 2015 and 15 February 2021.
Pre-assignment details
This study was divided into 2 parts: Part 1 (dose exploration \[Part 1A\] followed by dose expansion \[Part 1B\] of the irinotecan liposome injection + 5 fluorouracil \[5-FU\]/leucovorin \[LV\] + oxaliplatin regimen) and Part 2 (comparison of irinotecan liposome injection-containing regimen versus \[vs\] nab-paclitaxel plus gemcitabine). Overall, 56 participants were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Dose Exploration: Cohort 1 Participants received irinotecan liposome injection 70 mg/m\^2 followed by oxaliplatin 60 mg/m\^2 followed by LV 400 mg/m\^2 and then 5-FU 2400 mg/m\^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 7 |
| Dose Exploration: Cohort -1 Participants received irinotecan liposome injection 50 mg/m\^2 followed by oxaliplatin 60 mg/m\^2 followed by LV 400 mg/m\^2 and then 5-FU 2400 mg/m\^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 7 |
| Dose Exploration: Cohort -2B Participants received irinotecan liposome injection 50 mg/m\^2 followed by oxaliplatin 85 mg/m\^2 followed by LV 400 mg/m\^2 and then 5-FU 2400 mg/m\^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 10 |
| Dose Exploration: Cohort -3 Participants received irinotecan liposome injection 55 mg/m\^2 followed by oxaliplatin 70 mg/m\^2 followed by LV 400 mg/m\^2 and then 5-FU 2400 mg/m\^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 7 |
| Dose Expansion: Cohort -1 Participants received irinotecan liposome injection 50 mg/m\^2 followed by oxaliplatin 60 mg/m\^2 followed by LV 400 mg/m\^2 and then 5-FU 2400 mg/m\^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 25 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 5 | 7 | 8 | 7 | 17 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Sponsor Decision | 1 | 0 | 1 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Dose Exploration: Cohort 1 | Dose Exploration: Cohort -1 | Dose Exploration: Cohort -2B | Dose Exploration: Cohort -3 | Dose Expansion: Cohort -1 | Total |
|---|---|---|---|---|---|---|
| Age, Customized < 65 years | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 19 Participants | 34 Participants |
| Age, Customized >= 65 years | 3 Participants | 3 Participants | 7 Participants | 3 Participants | 6 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 Participants | 7 Participants | 10 Participants | 7 Participants | 21 Participants | 52 Participants |
| Race/Ethnicity, Customized Not Reportable | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 7 Participants | 9 Participants | 7 Participants | 21 Participants | 50 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 2 Participants | 2 Participants | 14 Participants | 28 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 8 Participants | 5 Participants | 11 Participants | 28 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 7 | 7 / 7 | 8 / 10 | 7 / 7 | 17 / 25 |
| other Total, other adverse events | 7 / 7 | 7 / 7 | 10 / 10 | 7 / 7 | 25 / 25 |
| serious Total, serious adverse events | 6 / 7 | 2 / 7 | 7 / 10 | 4 / 7 | 15 / 25 |
Outcome results
Primary
Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)
Adverse events (AEs) were considered to be DLTs if they occurred during the safety evaluation period (i.e, 28 days of Cycle 1; or 14 days after the second dose of study treatment if there was a treatment delay) and were deemed related to the study treatment regimen. Any AE that was related to disease progression was not considered a DLT.
Time frame: From the start of the first study treatment (Cycle 1 Day 1) up to 14 days after the second dose of study treatment, maximum of 42 days
Population: Safety population included participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Exploration: Cohort 1 | Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT) | 2 Participants |
| Dose Exploration: Cohort -1 | Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT) | 1 Participants |
| Dose Exploration: Cohort -2B | Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT) | 2 Participants |
| Dose Exploration: Cohort -3 | Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT) | 0 Participants |
Secondary
Best Overall Response (BOR)
The BOR was defined as the best response (complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) recorded from the start of study treatment until disease progression or start of new anticancer therapy using RECIST Version 1.1.
Time frame: RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).
Population: Safety population included participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Exploration: Cohort 1 | Best Overall Response (BOR) | 2 Participants |
| Dose Exploration: Cohort -1 | Best Overall Response (BOR) | 6 Participants |
| Dose Exploration: Cohort -2B | Best Overall Response (BOR) | 4 Participants |
| Dose Exploration: Cohort -3 | Best Overall Response (BOR) | 4 Participants |
| Dose Expansion: Cohort -1 | Best Overall Response (BOR) | 20 Participants |
| Cohort -1: Pooled | Best Overall Response (BOR) | 26 Participants |
Secondary
Disease Control Rate (DCR)
The DCR was defined as percentage of participants with CR or PR or SD or Non-PD/Non-CR, per RECIST Version 1.1 relative to total number of treated participants with measurable disease at baseline.
Time frame: At Week 16
Population: Safety population included participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Exploration: Cohort 1 | Disease Control Rate (DCR) | 42.9 percentage of participants |
| Dose Exploration: Cohort -1 | Disease Control Rate (DCR) | 71.4 percentage of participants |
| Dose Exploration: Cohort -2B | Disease Control Rate (DCR) | 40.0 percentage of participants |
| Dose Exploration: Cohort -3 | Disease Control Rate (DCR) | 28.6 percentage of participants |
| Dose Expansion: Cohort -1 | Disease Control Rate (DCR) | 72.0 percentage of participants |
| Cohort -1: Pooled | Disease Control Rate (DCR) | 71.9 percentage of participants |
Secondary
Median Duration of Response (DoR)
The DoR was defined as the time from the first date of response (CR or PR) to first date of documented radiographical PD, per investigator using RECIST Version 1.1. This only applied to participants with CR or PR. If a participant was given a new anticancer therapy prior to first response, DoR was not calculated. The DoR was calculated using Kaplan-Meier technique.
Time frame: RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).
Population: Safety population included participants who received at least 1 dose of any study treatment. Only participants with DoR events were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Exploration: Cohort -1 | Median Duration of Response (DoR) | 28.4 months |
| Dose Exploration: Cohort -2B | Median Duration of Response (DoR) | NA months |
| Dose Expansion: Cohort -1 | Median Duration of Response (DoR) | 9.4 months |
| Cohort -1: Pooled | Median Duration of Response (DoR) | 9.4 months |
Secondary
Median Overall Survival (OS)
The OS was the time from date of first study treatment to the date of death from any cause. Participant survival data were collected from all available sources. The OS was calculated using Kaplan-Meier technique.
Time frame: RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).
Population: Safety population included participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Exploration: Cohort 1 | Median Overall Survival (OS) | 12.6 months |
| Dose Exploration: Cohort -1 | Median Overall Survival (OS) | 12.5 months |
| Dose Exploration: Cohort -2B | Median Overall Survival (OS) | 16.6 months |
| Dose Exploration: Cohort -3 | Median Overall Survival (OS) | 5.8 months |
| Dose Expansion: Cohort -1 | Median Overall Survival (OS) | 12.7 months |
| Cohort -1: Pooled | Median Overall Survival (OS) | 12.6 months |
Secondary
Median Progression Free Survival (PFS)
The PFS was defined as the time from date of first study treatment to the first documented radiographical progression of disease (PD), per investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, or death from any cause, whichever comes first. The PFS was calculated using Kaplan-Meier technique.
Time frame: RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter (maximum of 278 weeks).
Population: Safety population included participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Exploration: Cohort 1 | Median Progression Free Survival (PFS) | 9.7 months |
| Dose Exploration: Cohort -1 | Median Progression Free Survival (PFS) | 32.3 months |
| Dose Exploration: Cohort -2B | Median Progression Free Survival (PFS) | 9.2 months |
| Dose Exploration: Cohort -3 | Median Progression Free Survival (PFS) | 3.8 months |
| Dose Expansion: Cohort -1 | Median Progression Free Survival (PFS) | 9.2 months |
| Cohort -1: Pooled | Median Progression Free Survival (PFS) | 9.2 months |
Secondary
Overall Response Rate (ORR)
The ORR was defined as the percentage of participants with a BOR characterized as either a CR or PR relative to the total number of evaluable participants using RECIST Version 1.1. Evaluable participants were defined as treated participants with measurable disease at baseline.
Time frame: RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).
Population: Safety population included participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Exploration: Cohort 1 | Overall Response Rate (ORR) | 0 percentage of participants |
| Dose Exploration: Cohort -1 | Overall Response Rate (ORR) | 42.9 percentage of participants |
| Dose Exploration: Cohort -2B | Overall Response Rate (ORR) | 30.0 percentage of participants |
| Dose Exploration: Cohort -3 | Overall Response Rate (ORR) | 14.3 percentage of participants |
| Dose Expansion: Cohort -1 | Overall Response Rate (ORR) | 32.0 percentage of participants |
| Cohort -1: Pooled | Overall Response Rate (ORR) | 34.4 percentage of participants |