CRC (Colorectal Cancer)
Conditions
Keywords
Metastatic Colorectal Cancer, Colon Cancer, Ruxolitinib, adenocarcinoma, regorafenib, Jakavi ®, Jakafi ®, Stivarga ®
Brief summary
The purpose of this study was to determine if ruxolitinib, in combination with regorafenib, is safe and effective in the treatment of metastatic colorectal cancer.
Detailed description
The study consisted of an open-label, Part 1 safety run-in (consisting of 1 to 3 cohorts of 9 subjects each), to confirm the safety of the regorafenib/ruxolitinib combination in subjects with relapsed or refractory metastatic colorectal cancer (CRC). If determined to be tolerable, Part 2 was to proceed as a randomized, double-blind study evaluating ruxolitinib or placebo in combination with regorafenib in subjects with relapsed or refractory metastatic CRC previously treated with fluoropyrimidine, oxaliplatin, and/or irinotecan based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy and if Kirsten rat sarcoma (KRAS) wild type an anti-epidermal growth factor receptor (EGFR) therapy. Subjects in the safety run-in received open-label ruxolitinib and regorafenib; for the randomized, double-blind portion of the study all subjects received regorafenib and either ruxolitinib or placebo in a 1:1 blinded manner. Treatment for all subjects consisted of repeating 28-day cycles. Regorafenib was self-administered for the first 21 days of each cycle, and ruxolitinib/placebo was self-administered during the entire 28-day cycle. Treatment cycles continued as long as the regimen is tolerated, and the subject does not meet the discontinuation criteria. When subjects discontinued regorafenib, ruxolitinib or placebo they remained in the study and were followed for subsequent treatment regimens which were initiated and survival.
Interventions
DRUGRuxolitinib
5 mg tablets to be administered by mouth Ruxolitinib 20 mg twice a day (BID) (Part 1) (NOTE: The starting dose for the randomized portion of study (Part 2) was 15 mg BID based on results from Part 1.)
DRUGRegorafenib
Regorafenib 160mg once daily for the first 21 days of each 28-day cycle. (NOTE: Dose interruptions and modifications for regorafenib are expected when toxicities occur in which dose interruptions or modifications are appropriate.)
DRUGPlacebo
5 mg matching placebo tablets to be administered by mouth
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 colon or rectum that is metastatic. * Previous treatment with fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapy, an anti-VEGF therapy (if no contraindication) and if KRAS wild type and no contraindication, an anti-EGFR therapy. * Radiographically measurable or evaluable disease (per RECIST v1.1) * Life expectancy of ≥ 12 weeks. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * Three or more weeks have elapsed from the completion of previous treatment regimen and subjects must have recovered or be at a new stable baseline from any related toxicities. * Prior radiotherapy to disease sites is allowed with certain protocol-defined restrictions.
Exclusion criteria
* Prior treatment with regorafenib. * Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. * Active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), diverticulitis, or other gastrointestinal conditions with increased risk of perforation or gastrointestinal bleeding. * Recent history (≤ 3 months) or ongoing partial or complete bowel obstruction unless due to disease under study and corrected with surgery. * Blood pressure ≥ 140/90 mmHg. * Active bleeding diathesis or history of any major bleeding (eg, requiring transfusion of red blood cells (RBCs), central nervous system (CNS) bleeding, or significant hemoptysis within 6 months of enrollment. Subjects with bleeding secondary to underlying disease (including gastrointestinal (GI) perforation or fistula) that has been corrected by surgery or alternative procedure may be included. * Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class II, III, or IV congestive heart failure, and arrhythmia requiring therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline until death due to any cause; up to 16 months or data cut-off 11 FEB 2016. | Overall survival is defined as the time from randomization to death due to any cause. Participants without death observed at the time of the analysis will be censored at last date known to be alive. The median overall survival time was estimated using the Kaplan-Meier method. Overall survival was compared between treatment groups using log-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline through disease progression, or death due to any cause if sooner; up to 16 months or data cut-off 11 FEB 2016. | 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 Longest Diameter (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. |
| Overall Response Rate (ORR) | Baseline through end of study; up to 16 months or data cut-off 11 FEB 2016. | Response defined per Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR)=disappearance of all target and non-target lesions without new lesion; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions, non-target lesion not progressed, and no new lesion; Progressive Disease=20% increase in sum of longest diameter of target lesions, or non-target lesion progression, or identification of new lesion; Stable Disease=small changes that do not meet above criteria. ORR was defined as the proportion of participants who achieved a best response of either CR or PR. ORR=number of participants with CR or PR/number of participants randomized. |
| Duration of Response | Baseline through end of study; up to 16 months or data cut-off 11 FEB 2016. | Duration of response is defined as the time from response (CR/PR) 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. |
| Percentage of Participants Achieving Disease Control | Baseline through end of study; up to 16 months or data cut-off 11 FEB 2016. | Disease control as measured by the percentage of participants whose best response was complete response (CR), partial response (PR), or stable disease (SD) per RECIST v.1.1. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline through approximately 30 days post treatment discontinuation;up to 16 months or data cut-off 27JAN 2016 for Substudy 1 and up to the data cut-off of 11FEB2016 for Substudy 2. | TEAEs were defined as any adverse event (AE) during the study that began or worsened on or after the date of first dose of investigational product. |
Countries
Australia, France, Germany, Israel, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
In Substudy 1, the first subject was enrolled on 29 OCT 2014, and the last subject was enrolled on 23 JUL 2015. In Substudy 2, the first subject was enrolled on 05 NOV 2014, and the last subject was enrolled on 02 OCT 2015.
Pre-assignment details
Substudy 1; 4 participants were assigned a randomization number but were not given study drug because of clinical deterioration or withdrawal of consent. Substudy 2; 9 participants were assigned a randomization number, but weren't given study drug due to clinical deterioration, withdrawal of consent or not meeting all of the eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Substudy 1: Ruxolitinib + Regorafenib Ruxolitinib 15 mg BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle. | 87 |
| Substudy 1: Placebo + Regorafenib Placebo BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle. | 88 |
| Substudy 2: Ruxolitinib + Regorafenib Ruxolitinib 15 mg BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle. | 110 |
| Substudy 2: Placebo + Regorafenib Placebo BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle. | 111 |
| Total | 396 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 17 | 10 | 10 |
| Overall Study | Death | 9 | 3 | 2 | 1 |
| Overall Study | Did not receive study med | 2 | 2 | 4 | 5 |
| Overall Study | Disease progression | 53 | 55 | 68 | 73 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Noncompliance | 0 | 1 | 0 | 0 |
| Overall Study | Other, unspecified | 2 | 1 | 3 | 4 |
| Overall Study | Patient decision, inc. consent withdrawn | 4 | 5 | 5 | 6 |
| Overall Study | Physician Decision | 4 | 2 | 3 | 2 |
| Overall Study | Protocol deviation | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Substudy 1: Placebo + Regorafenib | Substudy 2: Ruxolitinib + Regorafenib | Substudy 2: Placebo + Regorafenib | Total | Substudy 1: Ruxolitinib + Regorafenib |
|---|---|---|---|---|---|
| Age, Continuous | 59.5 years | 59.0 years | 59.2 years | 59.6 years | 60.8 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 10 Participants | 9 Participants | 21 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 6 Participants | 7 Participants | 27 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 5 Participants | 11 Participants | 35 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 4 Participants | 8 Participants | 0 Participants |
| Race (NIH/OMB) White | 70 Participants | 84 Participants | 80 Participants | 304 Participants | 70 Participants |
| Sex: Female, Male Female | 32 Participants | 48 Participants | 54 Participants | 168 Participants | 34 Participants |
| Sex: Female, Male Male | 56 Participants | 62 Participants | 57 Participants | 228 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 85 / 85 | 86 / 86 | 106 / 106 | 105 / 106 |
| serious Total, serious adverse events | 49 / 85 | 42 / 86 | 37 / 106 | 37 / 106 |
Outcome results
Primary
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. Participants without death observed at the time of the analysis will be censored at last date known to be alive. The median overall survival time was estimated using the Kaplan-Meier method. Overall survival was compared between treatment groups using log-rank test.
Time frame: Baseline until death due to any cause; up to 16 months or data cut-off 11 FEB 2016.
Population: Intent-to-treat (ITT) population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Substudy 1: Ruxolitinib + Regorafenib | Overall Survival (OS) | 4.6 months |
| Substudy 1: Placebo + Regorafenib | Overall Survival (OS) | 5.3 months |
| Substudy 2: Ruxolitinib + Regorafenib | Overall Survival (OS) | 11.4 months |
| Substudy 2: Placebo + Regorafenib | Overall Survival (OS) | 10.9 months |
p-value: 0.58895% CI: [0.73, 1.49]Log Rank
p-value: 0.13695% CI: [0.48, 1.23]Log Rank
Secondary
Duration of Response
Duration of response is defined as the time from response (CR/PR) 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.
Time frame: Baseline through end of study; up to 16 months or data cut-off 11 FEB 2016.
Population: No data displayed because outcome measure has not been analyzed. Duration of response analyses was not done since there were no responders in Substudy 1 and very few responders in Substudy 2 at data cutoff (27JAN2016 for Substudy 1 and 11Feb2016 for Substudy 2). Duration of response analysis was not done in both substudies.
Secondary
Overall Response Rate (ORR)
Response defined per Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR)=disappearance of all target and non-target lesions without new lesion; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions, non-target lesion not progressed, and no new lesion; Progressive Disease=20% increase in sum of longest diameter of target lesions, or non-target lesion progression, or identification of new lesion; Stable Disease=small changes that do not meet above criteria. ORR was defined as the proportion of participants who achieved a best response of either CR or PR. ORR=number of participants with CR or PR/number of participants randomized.
Time frame: Baseline through end of study; up to 16 months or data cut-off 11 FEB 2016.
Population: Intent-to-treat (ITT) population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Substudy 1: Ruxolitinib + Regorafenib | Overall Response Rate (ORR) | 0.0 percentage of responders |
| Substudy 1: Placebo + Regorafenib | Overall Response Rate (ORR) | 0.0 percentage of responders |
| Substudy 2: Ruxolitinib + Regorafenib | Overall Response Rate (ORR) | 2.7 percentage of responders |
| Substudy 2: Placebo + Regorafenib | Overall Response Rate (ORR) | 4.5 percentage of responders |
Secondary
Percentage of Participants Achieving Disease Control
Disease control as measured by the percentage of participants whose best response was complete response (CR), partial response (PR), or stable disease (SD) per RECIST v.1.1.
Time frame: Baseline through end of study; up to 16 months or data cut-off 11 FEB 2016.
Population: Intent-to-treat (ITT) population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Substudy 1: Ruxolitinib + Regorafenib | Percentage of Participants Achieving Disease Control | 40.2 percentage of participants |
| Substudy 1: Placebo + Regorafenib | Percentage of Participants Achieving Disease Control | 34.1 percentage of participants |
| Substudy 2: Ruxolitinib + Regorafenib | Percentage of Participants Achieving Disease Control | 61.8 percentage of participants |
| Substudy 2: Placebo + Regorafenib | Percentage of Participants Achieving Disease Control | 36.9 percentage of participants |
Secondary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as any adverse event (AE) during the study that began or worsened on or after the date of first dose of investigational product.
Time frame: Baseline through approximately 30 days post treatment discontinuation;up to 16 months or data cut-off 27JAN 2016 for Substudy 1 and up to the data cut-off of 11FEB2016 for Substudy 2.
Population: Safety Population consists of all enrolled participants that received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Substudy 1: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with Grade 3/4 TEAEs | 82.4 percentage of participants |
| Substudy 1: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any TEAEs | 100.0 percentage of participants |
| Substudy 1: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who discontinued drug due to of TEAEs | 14.1 percentage of participants |
| Substudy 1: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any serious TEAE | 57.6 percentage of participants |
| Substudy 1: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with a fatal TEAE | 15.3 percentage of participants |
| Substudy 1: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any serious TEAE | 48.8 percentage of participants |
| Substudy 1: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with a fatal TEAE | 9.3 percentage of participants |
| Substudy 1: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who discontinued drug due to of TEAEs | 19.8 percentage of participants |
| Substudy 1: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any TEAEs | 100.0 percentage of participants |
| Substudy 1: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with Grade 3/4 TEAEs | 81.4 percentage of participants |
| Substudy 2: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any serious TEAE | 34.9 percentage of participants |
| Substudy 2: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any TEAEs | 100.0 percentage of participants |
| Substudy 2: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with Grade 3/4 TEAEs | 77.4 percentage of participants |
| Substudy 2: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with a fatal TEAE | 1.9 percentage of participants |
| Substudy 2: Ruxolitinib + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who discontinued drug due to of TEAEs | 11.3 percentage of participants |
| Substudy 2: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with a fatal TEAE | 3.8 percentage of participants |
| Substudy 2: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with Grade 3/4 TEAEs | 72.6 percentage of participants |
| Substudy 2: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any TEAEs | 99.1 percentage of participants |
| Substudy 2: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any serious TEAE | 34.9 percentage of participants |
| Substudy 2: Placebo + Regorafenib | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who discontinued drug due to of TEAEs | 10.4 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 Longest Diameter (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: Baseline through disease progression, or death due to any cause if sooner; up to 16 months or data cut-off 11 FEB 2016.
Population: Intent-to-treat (ITT) population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Substudy 1: Ruxolitinib + Regorafenib | Progression Free Survival (PFS) | 2.2 months |
| Substudy 1: Placebo + Regorafenib | Progression Free Survival (PFS) | 2.1 months |
| Substudy 2: Ruxolitinib + Regorafenib | Progression Free Survival (PFS) | 3.5 months |
| Substudy 2: Placebo + Regorafenib | Progression Free Survival (PFS) | 2.0 months |