Pancreatic Cancer
Conditions
Keywords
Metastatic pancreatic cancer, Metastatic pancreatic adenocarcinoma that is recurrent
Brief summary
Determining the efficacy, based upon overall survival, of ruxolitinib added to capecitabine for the treatment of advanced or metastatic pancreatic cancer.
Detailed description
This was a randomized, double-blinded, placebo-controlled, Phase 3 study, in which approximately 310 participants with advanced or metastatic adenocarcinoma of the pancreas who have failed, or were intolerant to first-line chemotherapy, were to be randomized (1:1) to one of the following treatment groups: * Treatment A (N = 155): Capecitabine + ruxolitinib * Treatment B (N = 155): Capecitabine + placebo Treatment consisted of repeating 21-day cycles. Capecitabine was self-administered for the first 14 days of each cycle, and ruxolitinib/placebo was self-administered daily for each cycle. Treatment for all participants continued as long as the regimen was tolerated, and the participant did not meet discontinuation criteria. Participants who discontinued study treatment before study termination were monitored for safety up to 30-35 days from the end of treatment. All participants were followed for survival until study termination or the safety follow-up visit.
Interventions
DRUGRuxolitinib
5 mg tablets to be administered by mouth twice daily (BID)
DRUGPlacebo
5 mg tablets to be administered by mouth twice daily (BID)
DRUGCapecitabine
150 and 500 mg tablets to be administered by mouth twice daily (BID)
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the pancreas. * Advanced adenocarcinoma of the pancreas that is inoperable or metastatic. * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 * Received 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy). * ≥ 2 weeks elapsed from the completion of previous treatment regimen and participants must have recovered or be at a new stable baseline from any related toxicities. * Radiographically measurable or evaluable disease * Modified Glasgow Prognostic Score (mGPS) of 1 or 2 as defined below: 1. mGPS of 1: C-reactive protein \>10 mg/L and albumin ≥35 g/L 2. mGPS of 2: C-reactive protein \>10 mg/L and albumin \<35 g/L
Exclusion criteria
* Received more than 1 prior regimen for advanced or metastatic disease. * Ongoing radiation therapy, radiation therapy administered within 30 days of enrollment. * Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization). * Prior severe reaction to fluoropyrimidines, known dihydropyrimidine dehydrogenase deficiency (DPD), or other known hypersensitivity to active substances, including fluorouracil (5-FU), or ruxolitinib, or any of their excipients. * Prior treatment with a JAK inhibitor for any indication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization until death due to any cause; up to the data cutoff 11FEB2016. | Overall survival is reported here based on the number of deaths from randomization up to 6-months or to the data cutoff 11FEB2016. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Randomization to disease progression, or death due to any cause if sooner; up to 6-months or to the data cutoff 11FEB2016. | Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, unequivocal progression of non-target lesions, or the appearance of new lesions. |
| Percentage of Participants Achieving Progression Free Survival (PFS) | Randomization to disease progression, or death due to any cause if sooner; up to 6-months or to the data cutoff 11FEB2016. | PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, unequivocal progression of non-target lesions, or the appearance of new lesions. |
| Objective Response Rate (ORR) | Baseline through end of study; up to 6-months or to the data cutoff 11FEB2016. | Objective response rate determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment and was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST) at any post baseline visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) : Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions with no worsening of non-target lesions and no new lesions; Overall Response (OR) = CR + PR. |
| Duration of Response | Baseline through end of study; up to 6-months or to the data cutoff 11FEB2016. | Duration of overall response was defined as the time in months from Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) until the first date Progressive Disease (PD) was objectively documented or until the date of death. |
| Participants With Treatment-Emergent Adverse Events (TEAEs) | Baseline through approximately 30 days post treatment discontinuation; up to 6-months or to the data cutoff 11FEB2016. | A treatment-emergent AE was defined as an event occurring after exposure to at least 1 dose of study drug (ruxolitinib or placebo). A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening). |
Countries
Australia, Belgium, Canada, Germany, Italy, New Zealand, South Korea, Spain, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants with advanced or metastatic adenocarcinoma of the pancreas who had failed or were intolerant to first-line chemotherapy were randomized in the study.
Pre-assignment details
Treatment was started as soon as possible after randomization (within 3 days) and consisted of continuous 21-day cycles. Capecitabine was self-administered for the first 14 days of each cycle, and ruxolitinib/placebo was self-administered for the entire cycle.
Participants by arm
| Arm | Count |
|---|---|
| Ruxolitinib Plus Capecitabine Ruxolitinib 5 mg tablets in combination with Capecitabine 150 mg or 500 mg tablets to be administered by mouth twice daily (BID). | 161 |
| Placebo Plus Capecitabine Placebo 5 mg matching placebo tablets in combination with Capecitabine: 150 mg or 500 mg tablets to be administered by mouth twice daily (BID). | 160 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 16 |
| Overall Study | Death | 13 | 8 |
| Overall Study | Disease progression | 104 | 108 |
| Overall Study | Noncompliance with study treatment | 1 | 0 |
| Overall Study | Other unspecified | 11 | 7 |
| Overall Study | Physician Decision | 7 | 2 |
| Overall Study | Study terminated by the sponsor | 4 | 6 |
| Overall Study | Subject decision | 8 | 9 |
Baseline characteristics
| Characteristic | Ruxolitinib Plus Capecitabine | Placebo Plus Capecitabine | Total |
|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 9.35 | 65.6 years STANDARD_DEVIATION 9.55 | 66.4 years STANDARD_DEVIATION 9.48 |
| Age, Customized ≤ 65 years | 65 participants | 68 participants | 133 participants |
| Age, Customized > 65 years | 96 participants | 92 participants | 188 participants |
| Sex: Female, Male Female | 66 Participants | 64 Participants | 130 Participants |
| Sex: Female, Male Male | 95 Participants | 96 Participants | 191 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 147 / 153 | 145 / 154 |
| serious Total, serious adverse events | 94 / 153 | 83 / 154 |
Outcome results
Primary
Overall Survival (OS)
Overall survival is reported here based on the number of deaths from randomization up to 6-months or to the data cutoff 11FEB2016.
Time frame: Randomization until death due to any cause; up to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of all participants randomized to the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ruxolitinib Plus Capecitabine | Overall Survival (OS) | Observed | 113 Participants |
| Ruxolitinib Plus Capecitabine | Overall Survival (OS) | Censored | 48 Participants |
| Placebo Plus Capecitabine | Overall Survival (OS) | Observed | 124 Participants |
| Placebo Plus Capecitabine | Overall Survival (OS) | Censored | 36 Participants |
95% CI: [0.747, 1.256]
Secondary
Duration of Response
Duration of overall response was defined as the time in months from Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) until the first date Progressive Disease (PD) was objectively documented or until the date of death.
Time frame: Baseline through end of study; up to 6-months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of all participants randomized to the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib Plus Capecitabine | Duration of Response | NA days |
| Placebo Plus Capecitabine | Duration of Response | NA days |
Secondary
Objective Response Rate (ORR)
Objective response rate determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment and was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST) at any post baseline visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) : Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions with no worsening of non-target lesions and no new lesions; Overall Response (OR) = CR + PR.
Time frame: Baseline through end of study; up to 6-months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of all participants randomized to the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib Plus Capecitabine | Objective Response Rate (ORR) | Objective response | 3.7 percentage of participants |
| Ruxolitinib Plus Capecitabine | Objective Response Rate (ORR) | Complete response | 0 percentage of participants |
| Ruxolitinib Plus Capecitabine | Objective Response Rate (ORR) | Partial response | 3.7 percentage of participants |
| Placebo Plus Capecitabine | Objective Response Rate (ORR) | Partial response | 1.9 percentage of participants |
| Placebo Plus Capecitabine | Objective Response Rate (ORR) | Objective response | 1.9 percentage of participants |
| Placebo Plus Capecitabine | Objective Response Rate (ORR) | Complete response | 0 percentage of participants |
Secondary
Participants With Treatment-Emergent Adverse Events (TEAEs)
A treatment-emergent AE was defined as an event occurring after exposure to at least 1 dose of study drug (ruxolitinib or placebo). A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening).
Time frame: Baseline through approximately 30 days post treatment discontinuation; up to 6-months or to the data cutoff 11FEB2016.
Population: The safety evaluable population consisted of all participants exposed to at least 1 dose of study drug (ruxolitinib or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had treatment-related TEAEs | 73 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had Grade 3 or higher TEAEs | 112 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants on concomitant medication due to TEAE | 131 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had any TEAEs | 152 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had SAEs | 94 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants hospitalized because of a TEAE | 89 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants discontinued treatment due to TEAE | 12 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with a dose modification due to TEAE | 68 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with procedure performed due to TEAE | 60 Participants |
| Ruxolitinib Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had a fatal TEAE | 20 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants on concomitant medication due to TEAE | 122 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants hospitalized because of a TEAE | 75 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had Grade 3 or higher TEAEs | 113 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants discontinued treatment due to TEAE | 22 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had a fatal TEAE | 15 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with procedure performed due to TEAE | 46 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had any TEAEs | 152 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had treatment-related TEAEs | 59 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with a dose modification due to TEAE | 48 Participants |
| Placebo Plus Capecitabine | Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants who had SAEs | 83 Participants |
Secondary
Percentage of Participants Achieving Progression Free Survival (PFS)
PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, unequivocal progression of non-target lesions, or the appearance of new lesions.
Time frame: Randomization to disease progression, or death due to any cause if sooner; up to 6-months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of all participants randomized to the study.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ruxolitinib Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 9 months | 2.5 percentage of participants |
| Ruxolitinib Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 3 months | 18.9 percentage of participants |
| Ruxolitinib Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 6 months | 6.1 percentage of participants |
| Ruxolitinib Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 12 months | 2.5 percentage of participants |
| Placebo Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 12 months | NA percentage of participants |
| Placebo Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 9 months | 3.4 percentage of participants |
| Placebo Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 6 months | 5.7 percentage of participants |
| Placebo Plus Capecitabine | Percentage of Participants Achieving Progression Free Survival (PFS) | Survival rate at 3 months | 19.8 percentage of participants |
Secondary
Progression-free Survival (PFS)
Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, unequivocal progression of non-target lesions, or the appearance of new lesions.
Time frame: Randomization to disease progression, or death due to any cause if sooner; up to 6-months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of all participants randomized to the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib Plus Capecitabine | Progression-free Survival (PFS) | 43.0 days |
| Placebo Plus Capecitabine | Progression-free Survival (PFS) | 44.0 days |
95% CI: [0.827, 1.348]