Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer
Study Details
Study Description
Brief Summary
This randomized phase II trial studies how well lower-dose compared to standard dose regorafenib works in treating patients with colorectal cancer that has spread from the primary site (place where it started) to other places in the body and does not respond to treatment. Regorafenib may stop the growth of colorectal cancer by blocking the growth of new blood vessels necessary for tumor growth and by blocking some of the enzymes needed for cell growth. It is not yet known whether lower-dose or standard dose regorafenib is more effective in treating patients with colorectal cancer. Clobetasol propionate is a steroid cream that is commonly used to treat a variety of skin conditions and may help prevent hand-foot skin reactions in patients receiving regorafenib.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- Evaluate the proportion of patients who complete 2 cycles of protocol treatment and initiate cycle 3 in arm A (pooled arm A1 and A2) and arm B (pooled arm B1 and B2).
SECONDARY OBJECTIVES:
-
Evaluate outcome measures for efficacy in each arm including progression-free survival (PFS), time to progression (TTP), and overall survival (OS).
-
Compare between arms the cumulative dose and dose intensity received within the first two cycles.
-
Evaluate the proportion of patients in each arm that exhibit grade 3 palmar-plantar erythrodysesthesia syndrome (PPES) and/or fatigue, and make comparisons between regorafenib dosing strategies and pre-emptive versus (vs.) reactive strategies to address PPES.
-
Compare quality of life (QOL) between treatment arms (regorafenib dosing strategies and preemptive vs. reactive PPES strategies) as measured by the Hand and Foot Syndrome (HFS)14, Brief Fatigue Inventory (BFI), and Linear Analogue Self-Assessment (LASA) questionnaires.
TERTIARY OBJECTIVES:
-
Evaluate and compare trough minimum concentration (Cmin) pharmacokinetics (PK) during the first 2 treatment cycles for regorafenib and active metabolites M2, M5 between the low dose (dose escalation) and the standard dose cohorts, and correlate with toxicity profile.
-
Evaluate the correlation between PK parameters and tumor response/stable disease after the first two cycles.
-
Evaluate the correlation between PK parameters and PFS and OS. IV. Evaluate if trough (Cmin) concentrations are associated with patient-specific factors (such as ? but not limited to ? age and concomitant medications).
OUTLINE: Patients are randomized to 1 of 4 treatment arms.
ARM A1: Patients receive lower-dose regorafenib PO once daily (QD) on days 1-21 and pre-emptive clobetasol propionate given topically twice daily (BID) for 12 weeks, beginning on day 1 of regorafenib.
ARM A2: Patients receive lower-dose regorafenib PO as in Arm A1 and reactive clobetasol propionate given topically BID beginning on day 1 per physician discretion upon occurrence of PPES grade >= 1.
ARM B1: Patients receive standard dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate as in Arm A1.
ARM B2: Patients receive standard dose regorafenib PO as in Arm B1 and reactive clobetasol propionate as in Arm A2.
In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 2-6 months.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Arm A1 (lower-dose regorafenib, pre-emptive clobetasol) Patients receive lower-dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate given topically BID for 12 weeks, beginning on day 1 of regorafenib. |
Drug: Clobetasol Propionate
Given topically
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Drug: Regorafenib
Given PO
Other Names:
|
Experimental: Arm A2 (lower-dose regorafenib, reactive clobetasol) Patients receive lower-dose regorafenib PO as in Arm A1 and reactive clobetasol propionate given topically BID beginning on day 1 per physician discretion upon occurrence of PPES grade >= 1. |
Drug: Clobetasol Propionate
Given topically
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Drug: Regorafenib
Given PO
Other Names:
|
Experimental: Arm B1 (standard dose regorafenib, pre-emptive clobetasol) Patients receive standard dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate as in Arm A1. |
Drug: Clobetasol Propionate
Given topically
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Drug: Regorafenib
Given PO
Other Names:
|
Experimental: Arm B2 (standard dose regorafenib, reactive clobetasol) Patients receive standard dose regorafenib PO as in Arm B1 and reactive clobetasol propionate as in Arm A2. |
Drug: Clobetasol Propionate
Given topically
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Drug: Regorafenib
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Proportion of Patients in Each Arm Who Complete 2 Cycles of Protocol Treatment and Initiate Cycle 3 [At 8 weeks]
Fisher exact test will be used to detect a difference course 3 between arms (starting low dose [pooled arm A1 and A2] versus [vs.] standard dose [pooled arm B1 and B2]). The proportion of patients who complete 2 courses of protocol treatment and initiate course 3 will be computed by arm with its 95% confidence interval using exact method.
Secondary Outcome Measures
- Overall Survival (OS) [Time from randomization to death due to any cause, assessed up to 2 years]
OS is defined as the time from randomization to death due to any cause and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.
- Progression Free Survival (PFS) [Time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed up to 2 years]
PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.
- Time to Progression (TTP) [Time from randomization to disease progression, where PD is defined by RECIST 1.1, assessed up to 2 years]
TTP is defined as the time from randomization to disease progression, where PD is defined by RECIST 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.
- Cumulative (Total) Dose of Regorafenib Received by Patients in the First Two Cycles [Up to 8 weeks]
Will be summarized with descriptive statistics and compared between regorafenib arms (A vs. B).
- Dose Intensity of Regorafenib Received by Patients in the First Two Cycles as Measured by the Percentage of Planned Dose Received [Up to 8 weeks]
Dose intensity of regorafenib received by patients in the first two cycles as measured by the percentage (%) of planned dose received
- Proportion of Patients Overall and Within Each Arm Experiencing Grade 3 or 4 Hand and Foot Syndrome (HFS) or Fatigue [Up to 2 years]
Will be computed with 95% confidence intervals, and differences between regorafenib dosing strategies (pooled across HFS strategies) tested using a Fisher Exact test. The incidence of grade 3 or 4 HFS will also be descriptively compared between those receiving a pre-specified preemptive vs. reactive approach for hand and foot syndrome (pooled across dosing strategies), and tested using a Fisher Exact test.
- Changes in Quality of Life (QOL) (According to the HFS14 Questionnaire) [Baseline to up to 8 weeks]
Patients will be descriptively compared between treatment arms and between HFS treatment strategies (pre-emptive vs. reactive) according to self-reported outcomes given on the HFS14 questionnaire. Results from the course 1 and 2 HSF14 questionnaires will also be summarized descriptively as they relate to the pre-emptive versus reactive palmar-plantar erythrodysesthesia syndrome (PPES) strategies, with comparisons made within and between arms using the t-test or Wilcoxon rank sum test as appropriate, as well as taking time-dependence into account.
- Changes in QOL (According to the Linear Analogue Self-Assessment [LASA] Questionnaire) [Baseline to up to 8 weeks]
Changes in QOL (according to the LASA questionnaire as measured by the overall QOL question) from baseline will be compared between the treatment arms using the t-test or Wilcoxon rank sum test.
Other Outcome Measures
- Pharmacokinetics (PK) Parameters of Regorafenib Using Liquid Chromatography Mass Spectrometry [Baseline, prior to treatment, days 7, 14, and 21 prior to treatment (course 1), and days 1 and 21 prior to treatment (course 2)]
After quantitation, the average trough concentration, calculated from all available data, will be calculated. This average trough concentration will be correlated with toxicity and efficacy endpoints. Further descriptive characteristics of the pharmacokinetics will also be calculated, an example includes (but is not limited to) within-patient variability in the trough concentrations pharmacokinetic parameters will also be calculated, both overall and within courses, as a ratio of the maximum:minimum value.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Histological or cytological documentation of adenocarcinoma of the colon or rectum
-
Advanced or metastatic colorectal cancer with no curative options available and progression on previous standard therapy, including an EGFR inhibitor if KRAS wild-type
-
Measurable or non-measurable disease
-
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
-
Life expectancy of >= 3 months
-
Absolute neutrophil count (ANC) > 1500/mm^3 (obtained =< 7 days prior to randomization)
-
Platelet count > 100,000/mm^3 (obtained =< 7 days prior to randomization)
-
Hemoglobin > 9.0 g/dL (obtained =< 7 days prior to randomization)
-
Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to randomization)
-
Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization)
-
Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to randomization)
-
International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN (obtained =< 7 days prior to randomization)
-
NOTE: patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
-
Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement of their cancer) (obtained =< 7 days prior to randomization)
-
Negative serum pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only; note: post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test; the definition of adequate contraception will be based on the judgment of the investigator
-
Ability to complete questionnaire(s) by themselves or with assistance
-
Provide informed written consent
-
Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
-
Willing to provide blood samples for correlative research and banking purposes
Exclusion Criteria:
-
Prior treatment with regorafenib
-
Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to randomization
-
Congestive heart failure > New York Heart Association (NYHA) class 2
-
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) or myocardial infarction less than 6 months prior to randomization
-
Cardiac arrhythmias requiring anti-arrhythmic therapy; Note: pace makers, beta blockers, or digoxin are permitted
-
Uncontrolled hypertension; (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
-
History of or current pheochromocytoma
-
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism =< 6 months prior to randomization
-
Ongoing infection > grade 2 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
-
Known history of chronic hepatitis B or C
-
Patients with seizure disorder requiring medication
-
Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of randomization and is clinically stable with respect to the tumor at the time of randomization; note: patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
-
History of organ allograft (including corneal transplant)
-
Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE grade 3 =< 4 weeks prior to randomization
-
Non-healing wound, ulcer, or bone fracture
-
Renal failure requiring hematological (hemo-) or peritoneal dialysis
-
Dehydration CTCAE (version 4.0) grade >= 1
-
Substance abuse, medical, psychological or social conditions that may interfere with the patient?s participation in the study or evaluation of the study results
-
Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
-
Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
-
Persistent proteinuria of Common Toxicity Criteria (CTC) grade 3 or higher (>= 3.5 g/24 hours [hrs])
-
Patients unable to swallow oral medications
-
Any malabsorption condition
-
Unresolved toxicity greater than CTCAE (version 4.0) grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity =< grade 2
-
Albumin levels < 2.5 g/dl
-
Any of the following:
-
Pregnant women
-
Nursing women
-
Men or women of childbearing potential who are unwilling to employ adequate contraception
-
NOTE: men and women of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate
-
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
-
Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
-
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
-
Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 3 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]); note: all cancer treatments for cancers that were distinct in a primary site other than colorectal must be completed at least 3 years prior to randomization (i.e., signature date of the informed consent form)
-
Pleural effusion or ascites that causes respiratory compromise (>= CTCAE version 4.0 grade 2 dyspnea)
-
Concurrent anti-cancer therapy =< 4 weeks from registration (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization)
-
Current use of clobetasol propionate
-
Use of any herbal remedy (e.g. St. John?s wort [Hypericum perforatum])
-
Patients unable to ambulate or who have amputations or paralysis of any extremity
-
History of contact dermatitis to clobetasol propionate or similarly fluorinated steroids or other steroids with the propionate ester
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Mayo Clinic Hospital | Phoenix | Arizona | United States | 85054 |
2 | Mayo Clinic in Arizona | Scottsdale | Arizona | United States | 85259 |
3 | USC / Norris Comprehensive Cancer Center | Los Angeles | California | United States | 90033 |
4 | Illinois CancerCare-Peoria | Peoria | Illinois | United States | 61615 |
5 | Northern Indiana Cancer Research Consortium | South Bend | Indiana | United States | 46628 |
6 | Siouxland Regional Cancer Center | Sioux City | Iowa | United States | 51101 |
7 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
8 | Mayo Clinic | Rochester | Minnesota | United States | 55905 |
9 | Metro Minnesota Community Oncology Research Consortium | Saint Louis Park | Minnesota | United States | 55416 |
10 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
11 | Missouri Valley Cancer Consortium | Omaha | Nebraska | United States | 68106 |
12 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198 |
13 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
14 | Hematology Oncology Associates of Central New York-East Syracuse | East Syracuse | New York | United States | 13057 |
15 | Wake Forest University Health Sciences | Winston-Salem | North Carolina | United States | 27157 |
16 | Ohio State University Comprehensive Cancer Center | Columbus | Ohio | United States | 43210 |
17 | Toledo Clinic Cancer Centers-Toledo | Toledo | Ohio | United States | 43623 |
18 | Geisinger Medical Center | Danville | Pennsylvania | United States | 17822 |
19 | Wellmont Medical Associates Oncology and Hematology-Kingsport | Kingsport | Tennessee | United States | 37660 |
20 | University of Washington Medical Center | Seattle | Washington | United States | 98195 |
21 | Saint Vincent Hospital Cancer Center Green Bay | Green Bay | Wisconsin | United States | 54301 |
22 | Marshfield Clinic | Marshfield | Wisconsin | United States | 54449 |
Sponsors and Collaborators
- Academic and Community Cancer Research United
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Tanios Bekaii-Saab, Academic and Community Cancer Research United
Study Documents (Full-Text)
More Information
Publications
None provided.- RU021407I
- NCI-2015-00011
- RU021407I
- P30CA015083
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy) | Arm A2 (Regorafenib Dose Escalation + Reactive Strategy) | Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy) | Arm B2 (Regorafenib Standard Dose + Reactive Strategy) |
---|---|---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy). | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy). |
Period Title: Overall Study | ||||
STARTED | 29 | 27 | 34 | 33 |
COMPLETED | 28 | 26 | 33 | 29 |
NOT COMPLETED | 1 | 1 | 1 | 4 |
Baseline Characteristics
Arm/Group Title | Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy) | Arm A2 (Regorafenib Dose Escalation + Reactive Strategy) | Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy) | Arm B2 (Regorafenib Standard Dose + Reactive Strategy) | Total |
---|---|---|---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy). | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy). | Total of all reporting groups |
Overall Participants | 28 | 26 | 33 | 29 | 116 |
Age (years) [Median (Full Range) ] | |||||
Median (Full Range) [years] |
65
|
57
|
61
|
62
|
61
|
Sex: Female, Male (Count of Participants) | |||||
Female |
9
32.1%
|
9
34.6%
|
17
51.5%
|
10
34.5%
|
45
38.8%
|
Male |
19
67.9%
|
17
65.4%
|
16
48.5%
|
19
65.5%
|
71
61.2%
|
Race (NIH/OMB) (Count of Participants) | |||||
American Indian or Alaska Native |
0
0%
|
1
3.8%
|
0
0%
|
0
0%
|
1
0.9%
|
Asian |
2
7.1%
|
1
3.8%
|
1
3%
|
1
3.4%
|
5
4.3%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Black or African American |
1
3.6%
|
4
15.4%
|
0
0%
|
4
13.8%
|
9
7.8%
|
White |
25
89.3%
|
19
73.1%
|
31
93.9%
|
24
82.8%
|
99
85.3%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
0
0%
|
1
3.8%
|
1
3%
|
0
0%
|
2
1.7%
|
Region of Enrollment (Count of Participants) | |||||
United States |
28
100%
|
26
100%
|
33
100%
|
29
100%
|
116
100%
|
ECOG Performance Status (Count of Participants) | |||||
0 |
9
32.1%
|
11
42.3%
|
15
45.5%
|
8
27.6%
|
43
37.1%
|
1 |
19
67.9%
|
15
57.7%
|
18
54.5%
|
21
72.4%
|
73
62.9%
|
Outcome Measures
Title | Proportion of Patients in Each Arm Who Complete 2 Cycles of Protocol Treatment and Initiate Cycle 3 |
---|---|
Description | Fisher exact test will be used to detect a difference course 3 between arms (starting low dose [pooled arm A1 and A2] versus [vs.] standard dose [pooled arm B1 and B2]). The proportion of patients who complete 2 courses of protocol treatment and initiate course 3 will be computed by arm with its 95% confidence interval using exact method. |
Time Frame | At 8 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The data for the pre-emptive and reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies (regorafenib dose escalation group (Arms A1 + A2) versus regorafenib standard dose group (Arms B1 + B2)). |
Arm/Group Title | Regorafenib Dose Escalation Group | Regorafenib Standard Dose Group |
---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). |
Measure Participants | 54 | 62 |
Number (95% Confidence Interval) [proportion of patients] |
0.43
|
0.26
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0434 |
Comments | 1-sided | |
Method | Fisher Exact | |
Comments | ||
Method of Estimation | Estimation Parameter | Risk Difference (RD) |
Estimated Value | 0.17 | |
Confidence Interval |
(2-Sided) 95% 0.00 to 0.34 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Overall Survival (OS) |
---|---|
Description | OS is defined as the time from randomization to death due to any cause and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments. |
Time Frame | Time from randomization to death due to any cause, assessed up to 2 years |
Outcome Measure Data
Analysis Population Description |
---|
The data for the pre-emptive and reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies (regorafenib dose escalation group (Arms A1 + A2) versus regorafenib standard dose group (Arms B1 + B2)). |
Arm/Group Title | Regorafenib Dose Escalation Group | Regorafenib Standard Dose Group |
---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). |
Measure Participants | 54 | 62 |
Median (95% Confidence Interval) [months] |
9.8
|
6.0
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1241 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.72 | |
Confidence Interval |
(2-Sided) 95% 0.47 to 1.10 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Progression Free Survival (PFS) |
---|---|
Description | PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments. |
Time Frame | Time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed up to 2 years |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Regorafenib Dose Escalation Group | Regorafenib Standard Dose Group |
---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). |
Measure Participants | 54 | 62 |
Median (95% Confidence Interval) [months] |
2.8
|
2.0
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.3797 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.84 | |
Confidence Interval |
(2-Sided) 95% 0.57 to 1.24 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Time to Progression (TTP) |
---|---|
Description | TTP is defined as the time from randomization to disease progression, where PD is defined by RECIST 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments. |
Time Frame | Time from randomization to disease progression, where PD is defined by RECIST 1.1, assessed up to 2 years |
Outcome Measure Data
Analysis Population Description |
---|
The data for the pre-emptive and reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies (regorafenib dose escalation group (Arms A1 + A2) versus regorafenib standard dose group (Arms B1 + B2)). |
Arm/Group Title | Regorafenib Dose Escalation Group | Regorafenib Standard Dose Group |
---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). |
Measure Participants | 54 | 62 |
Median (95% Confidence Interval) [months] |
2.8
|
2.0
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.4614 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.85 | |
Confidence Interval |
(2-Sided) 95% 0.55 to 1.31 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Cumulative (Total) Dose of Regorafenib Received by Patients in the First Two Cycles |
---|---|
Description | Will be summarized with descriptive statistics and compared between regorafenib arms (A vs. B). |
Time Frame | Up to 8 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The data for the pre-emptive & reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies ((Arms A1 + A2) versus (Arms B1 + B2)). There are patients off-protocol treatment during cycle 1; therefore, we do not have cycle 2 dosing information for those patients who are off-protocol treatment during cycle 1. |
Arm/Group Title | Regorafenib Dose Escalation Group | Regorafenib Standard Dose Group |
---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). |
Measure Participants | 54 | 62 |
Cycle 1 |
91.8
(33.4)
|
133.1
(34.6)
|
Cycle 2 |
121.3
(40.0)
|
117.3
(48.9)
|
Title | Dose Intensity of Regorafenib Received by Patients in the First Two Cycles as Measured by the Percentage of Planned Dose Received |
---|---|
Description | Dose intensity of regorafenib received by patients in the first two cycles as measured by the percentage (%) of planned dose received |
Time Frame | Up to 8 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The data for the pre-emptive & reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies ((Arms A1 + A2) versus (Arms B1 + B2)). |
Arm/Group Title | Regorafenib Dose Escalation Group | Regorafenib Standard Dose Group |
---|---|---|
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy). |
Measure Participants | 54 | 62 |
Median (Standard Deviation) [percentage of planned dose received] |
76.2
(25.3)
|
76.0
(21.0)
|
Title | Proportion of Patients Overall and Within Each Arm Experiencing Grade 3 or 4 Hand and Foot Syndrome (HFS) or Fatigue |
---|---|
Description | Will be computed with 95% confidence intervals, and differences between regorafenib dosing strategies (pooled across HFS strategies) tested using a Fisher Exact test. The incidence of grade 3 or 4 HFS will also be descriptively compared between those receiving a pre-specified preemptive vs. reactive approach for hand and foot syndrome (pooled across dosing strategies), and tested using a Fisher Exact test. |
Time Frame | Up to 2 years |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Changes in Quality of Life (QOL) (According to the HFS14 Questionnaire) |
---|---|
Description | Patients will be descriptively compared between treatment arms and between HFS treatment strategies (pre-emptive vs. reactive) according to self-reported outcomes given on the HFS14 questionnaire. Results from the course 1 and 2 HSF14 questionnaires will also be summarized descriptively as they relate to the pre-emptive versus reactive palmar-plantar erythrodysesthesia syndrome (PPES) strategies, with comparisons made within and between arms using the t-test or Wilcoxon rank sum test as appropriate, as well as taking time-dependence into account. |
Time Frame | Baseline to up to 8 weeks |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Changes in QOL (According to the Linear Analogue Self-Assessment [LASA] Questionnaire) |
---|---|
Description | Changes in QOL (according to the LASA questionnaire as measured by the overall QOL question) from baseline will be compared between the treatment arms using the t-test or Wilcoxon rank sum test. |
Time Frame | Baseline to up to 8 weeks |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Pharmacokinetics (PK) Parameters of Regorafenib Using Liquid Chromatography Mass Spectrometry |
---|---|
Description | After quantitation, the average trough concentration, calculated from all available data, will be calculated. This average trough concentration will be correlated with toxicity and efficacy endpoints. Further descriptive characteristics of the pharmacokinetics will also be calculated, an example includes (but is not limited to) within-patient variability in the trough concentrations pharmacokinetic parameters will also be calculated, both overall and within courses, as a ratio of the maximum:minimum value. |
Time Frame | Baseline, prior to treatment, days 7, 14, and 21 prior to treatment (course 1), and days 1 and 21 prior to treatment (course 2) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Adverse Events
Time Frame | Adverse events were assessed during the active monitoring phase (weekly during Cycles 1 and 2, then every 4 weeks until progression); up to 2 years. The total study duration (accrual and follow-up) is expected to be approximately 2 years. | |||||||
---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | Each CTCAE term is a representation of a specific event used for medical documentation & analysis & is a single MedDRA Lowest Level Term (LLT). All graded AEs are reported for non-cancel patients. Serious AE (SAE) reports may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited AEs, & appear in the SAE table. | |||||||
Arm/Group Title | Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy) | Arm A2 (Regorafenib Dose Escalation + Reactive Strategy) | Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy) | Arm B2 (Regorafenib Standard Dose + Reactive Strategy) | ||||
Arm/Group Description | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy). | In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy). | In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy). | ||||
All Cause Mortality |
||||||||
Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy) | Arm A2 (Regorafenib Dose Escalation + Reactive Strategy) | Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy) | Arm B2 (Regorafenib Standard Dose + Reactive Strategy) | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/28 (0%) | 3/26 (11.5%) | 3/33 (9.1%) | 2/30 (6.7%) | ||||
Serious Adverse Events |
||||||||
Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy) | Arm A2 (Regorafenib Dose Escalation + Reactive Strategy) | Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy) | Arm B2 (Regorafenib Standard Dose + Reactive Strategy) | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 4/28 (14.3%) | 10/26 (38.5%) | 10/33 (30.3%) | 10/30 (33.3%) | ||||
Blood and lymphatic system disorders | ||||||||
Anemia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Cardiac disorders | ||||||||
Myocardial infarction | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Sinus tachycardia | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Gastrointestinal disorders | ||||||||
Abdominal pain | 2/28 (7.1%) | 2 | 5/26 (19.2%) | 5 | 3/33 (9.1%) | 3 | 1/30 (3.3%) | 1 |
Ascites | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Colitis | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Colonic obstruction | 1/28 (3.6%) | 1 | 2/26 (7.7%) | 2 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Constipation | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Lower gastrointestinal hemorrhage | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Nausea | 0/28 (0%) | 0 | 2/26 (7.7%) | 2 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Rectal fistula | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Rectal obstruction | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Vomiting | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
General disorders | ||||||||
Death NOS | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Fatigue | 1/28 (3.6%) | 1 | 1/26 (3.8%) | 1 | 2/33 (6.1%) | 3 | 0/30 (0%) | 0 |
Pain | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Infections and infestations | ||||||||
Abdominal infection | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Infections and infestations - Other, specify | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Lung infection | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Sepsis | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Urinary tract infection | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Investigations | ||||||||
Alanine aminotransferase increased | 2/28 (7.1%) | 2 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Alkaline phosphatase increased | 2/28 (7.1%) | 2 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Aspartate aminotransferase increased | 2/28 (7.1%) | 2 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Blood bilirubin increased | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
INR increased | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Investigations - Other, specify | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Platelet count decreased | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Metabolism and nutrition disorders | ||||||||
Anorexia | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Dehydration | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 2/33 (6.1%) | 2 | 1/30 (3.3%) | 1 |
Hyperglycemia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Hypoalbuminemia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Hypocalcemia | 2/28 (7.1%) | 2 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Hypokalemia | 1/28 (3.6%) | 1 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Hyponatremia | 2/28 (7.1%) | 2 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||||||
Back pain | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Chest wall pain | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Generalized muscle weakness | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Myalgia | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 0/28 (0%) | 0 | 2/26 (7.7%) | 2 | 1/33 (3%) | 1 | 1/30 (3.3%) | 1 |
Nervous system disorders | ||||||||
Encephalopathy | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Syncope | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Transient ischemic attacks | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Psychiatric disorders | ||||||||
Confusion | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Renal and urinary disorders | ||||||||
Urinary retention | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||||||
Adult respiratory distress syndrome | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Dyspnea | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 2/30 (6.7%) | 2 |
Pleural effusion | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Respiratory failure | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Skin and subcutaneous tissue disorders | ||||||||
Palmar-plantar erythrodysesthesia syndrome | 0/28 (0%) | 0 | 1/26 (3.8%) | 2 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Rash maculo-papular | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Vascular disorders | ||||||||
Thromboembolic event | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||
Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy) | Arm A2 (Regorafenib Dose Escalation + Reactive Strategy) | Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy) | Arm B2 (Regorafenib Standard Dose + Reactive Strategy) | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 28/28 (100%) | 24/26 (92.3%) | 31/33 (93.9%) | 30/30 (100%) | ||||
Blood and lymphatic system disorders | ||||||||
Anemia | 4/28 (14.3%) | 5 | 8/26 (30.8%) | 15 | 7/33 (21.2%) | 10 | 6/30 (20%) | 8 |
Blood and lymphatic system disorders - Other, specify | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 2/30 (6.7%) | 3 |
Thrombotic thrombocytopenic purpura | 0/28 (0%) | 0 | 1/26 (3.8%) | 5 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Cardiac disorders | ||||||||
Sinus tachycardia | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 1/30 (3.3%) | 1 |
Ear and labyrinth disorders | ||||||||
Tinnitus | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 2 | 0/30 (0%) | 0 |
Endocrine disorders | ||||||||
Hypothyroidism | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Eye disorders | ||||||||
Watering eyes | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Gastrointestinal disorders | ||||||||
Abdominal pain | 2/28 (7.1%) | 3 | 1/26 (3.8%) | 1 | 3/33 (9.1%) | 3 | 2/30 (6.7%) | 2 |
Ascites | 0/28 (0%) | 0 | 1/26 (3.8%) | 3 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Constipation | 2/28 (7.1%) | 2 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 4/30 (13.3%) | 5 |
Diarrhea | 14/28 (50%) | 30 | 10/26 (38.5%) | 20 | 17/33 (51.5%) | 37 | 10/30 (33.3%) | 24 |
Dry mouth | 2/28 (7.1%) | 7 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 3/30 (10%) | 3 |
Dyspepsia | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Dysphagia | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Flatulence | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 5 | 0/30 (0%) | 0 |
Gastroesophageal reflux disease | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Gastrointestinal disorders - Other, specify | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 2/30 (6.7%) | 2 |
Mucositis oral | 1/28 (3.6%) | 1 | 4/26 (15.4%) | 5 | 5/33 (15.2%) | 7 | 5/30 (16.7%) | 7 |
Nausea | 8/28 (28.6%) | 16 | 12/26 (46.2%) | 21 | 16/33 (48.5%) | 43 | 13/30 (43.3%) | 17 |
Oral pain | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 2/33 (6.1%) | 2 | 3/30 (10%) | 5 |
Stomach pain | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Vomiting | 5/28 (17.9%) | 7 | 7/26 (26.9%) | 8 | 9/33 (27.3%) | 12 | 5/30 (16.7%) | 6 |
General disorders | ||||||||
Chills | 1/28 (3.6%) | 2 | 1/26 (3.8%) | 3 | 1/33 (3%) | 1 | 2/30 (6.7%) | 2 |
Edema limbs | 1/28 (3.6%) | 1 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Fatigue | 25/28 (89.3%) | 72 | 20/26 (76.9%) | 53 | 26/33 (78.8%) | 83 | 27/30 (90%) | 72 |
Fever | 1/28 (3.6%) | 2 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 3/30 (10%) | 3 |
General disorders and administration site conditions - Other, specify | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 2/33 (6.1%) | 3 | 2/30 (6.7%) | 4 |
Non-cardiac chest pain | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Pain | 4/28 (14.3%) | 4 | 1/26 (3.8%) | 1 | 2/33 (6.1%) | 2 | 1/30 (3.3%) | 1 |
Hepatobiliary disorders | ||||||||
Hepatic failure | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Hepatobiliary disorders - Other, specify | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Infections and infestations | ||||||||
Sinusitis | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Urinary tract infection | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Investigations | ||||||||
Activated partial thromboplastin time prolonged | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Alanine aminotransferase increased | 2/28 (7.1%) | 4 | 4/26 (15.4%) | 4 | 6/33 (18.2%) | 13 | 3/30 (10%) | 3 |
Alkaline phosphatase increased | 3/28 (10.7%) | 4 | 4/26 (15.4%) | 4 | 7/33 (21.2%) | 13 | 5/30 (16.7%) | 6 |
Aspartate aminotransferase increased | 2/28 (7.1%) | 3 | 5/26 (19.2%) | 8 | 8/33 (24.2%) | 16 | 8/30 (26.7%) | 9 |
Blood bilirubin increased | 3/28 (10.7%) | 5 | 5/26 (19.2%) | 5 | 9/33 (27.3%) | 10 | 9/30 (30%) | 10 |
Creatinine increased | 0/28 (0%) | 0 | 2/26 (7.7%) | 2 | 1/33 (3%) | 1 | 3/30 (10%) | 4 |
Investigations - Other, specify | 1/28 (3.6%) | 8 | 1/26 (3.8%) | 1 | 2/33 (6.1%) | 5 | 3/30 (10%) | 4 |
Lymphocyte count decreased | 1/28 (3.6%) | 1 | 4/26 (15.4%) | 5 | 2/33 (6.1%) | 3 | 4/30 (13.3%) | 6 |
Platelet count decreased | 4/28 (14.3%) | 4 | 2/26 (7.7%) | 3 | 6/33 (18.2%) | 8 | 2/30 (6.7%) | 2 |
Weight loss | 2/28 (7.1%) | 3 | 3/26 (11.5%) | 9 | 6/33 (18.2%) | 9 | 5/30 (16.7%) | 5 |
White blood cell decreased | 1/28 (3.6%) | 2 | 1/26 (3.8%) | 1 | 3/33 (9.1%) | 3 | 1/30 (3.3%) | 1 |
Metabolism and nutrition disorders | ||||||||
Anorexia | 8/28 (28.6%) | 11 | 6/26 (23.1%) | 7 | 6/33 (18.2%) | 10 | 13/30 (43.3%) | 20 |
Dehydration | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 2/33 (6.1%) | 2 | 2/30 (6.7%) | 2 |
Hyperglycemia | 0/28 (0%) | 0 | 1/26 (3.8%) | 2 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Hyperkalemia | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 1/30 (3.3%) | 1 |
Hypermagnesemia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Hypoalbuminemia | 3/28 (10.7%) | 6 | 2/26 (7.7%) | 2 | 3/33 (9.1%) | 5 | 4/30 (13.3%) | 5 |
Hypocalcemia | 2/28 (7.1%) | 3 | 2/26 (7.7%) | 3 | 0/33 (0%) | 0 | 4/30 (13.3%) | 4 |
Hypokalemia | 2/28 (7.1%) | 5 | 0/26 (0%) | 0 | 3/33 (9.1%) | 4 | 3/30 (10%) | 3 |
Hyponatremia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 6/33 (18.2%) | 8 | 5/30 (16.7%) | 5 |
Hypophosphatemia | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Metabolism and nutrition disorders - Other, specify | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 2/30 (6.7%) | 2 |
Musculoskeletal and connective tissue disorders | ||||||||
Arthritis | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 2 | 0/30 (0%) | 0 |
Back pain | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 3/33 (9.1%) | 4 | 2/30 (6.7%) | 2 |
Bone pain | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Chest wall pain | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 2 | 0/30 (0%) | 0 |
Generalized muscle weakness | 3/28 (10.7%) | 4 | 2/26 (7.7%) | 2 | 1/33 (3%) | 2 | 1/30 (3.3%) | 1 |
Musculoskeletal and connective tissue disorder - Other, specify | 1/28 (3.6%) | 3 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Myalgia | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 4/33 (12.1%) | 5 | 3/30 (10%) | 3 |
Myositis | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Pain in extremity | 1/28 (3.6%) | 1 | 3/26 (11.5%) | 3 | 2/33 (6.1%) | 4 | 1/30 (3.3%) | 2 |
Nervous system disorders | ||||||||
Cognitive disturbance | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Dizziness | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 1/30 (3.3%) | 2 |
Dysgeusia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 1/33 (3%) | 3 | 2/30 (6.7%) | 2 |
Encephalopathy | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Headache | 3/28 (10.7%) | 3 | 2/26 (7.7%) | 6 | 3/33 (9.1%) | 7 | 0/30 (0%) | 0 |
Paresthesia | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 2 | 0/30 (0%) | 0 |
Peripheral motor neuropathy | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Peripheral sensory neuropathy | 5/28 (17.9%) | 6 | 1/26 (3.8%) | 1 | 4/33 (12.1%) | 8 | 2/30 (6.7%) | 4 |
Psychiatric disorders | ||||||||
Insomnia | 2/28 (7.1%) | 2 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Psychiatric disorders - Other, specify | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Renal and urinary disorders | ||||||||
Hematuria | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Urinary frequency | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||||||
Atelectasis | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Cough | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 2/33 (6.1%) | 3 | 0/30 (0%) | 0 |
Dyspnea | 3/28 (10.7%) | 5 | 3/26 (11.5%) | 7 | 5/33 (15.2%) | 5 | 4/30 (13.3%) | 4 |
Epistaxis | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Hiccups | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Hoarseness | 4/28 (14.3%) | 11 | 4/26 (15.4%) | 8 | 5/33 (15.2%) | 6 | 3/30 (10%) | 3 |
Hypoxia | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 0/30 (0%) | 0 |
Pleuritic pain | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Productive cough | 1/28 (3.6%) | 2 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Sinus disorder | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Skin and subcutaneous tissue disorders | ||||||||
Alopecia | 1/28 (3.6%) | 1 | 0/26 (0%) | 0 | 4/33 (12.1%) | 9 | 2/30 (6.7%) | 2 |
Dry skin | 1/28 (3.6%) | 3 | 1/26 (3.8%) | 1 | 2/33 (6.1%) | 7 | 1/30 (3.3%) | 1 |
Nail discoloration | 0/28 (0%) | 0 | 1/26 (3.8%) | 1 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Pain of skin | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 1/30 (3.3%) | 1 |
Palmar-plantar erythrodysesthesia syndrome | 18/28 (64.3%) | 37 | 17/26 (65.4%) | 43 | 22/33 (66.7%) | 61 | 22/30 (73.3%) | 42 |
Pruritus | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 1/30 (3.3%) | 1 |
Rash maculo-papular | 8/28 (28.6%) | 16 | 2/26 (7.7%) | 3 | 8/33 (24.2%) | 12 | 8/30 (26.7%) | 11 |
Skin and subcutaneous tissue disorders - Other, specify | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 1/33 (3%) | 1 | 1/30 (3.3%) | 1 |
Vascular disorders | ||||||||
Hot flashes | 0/28 (0%) | 0 | 0/26 (0%) | 0 | 0/33 (0%) | 0 | 1/30 (3.3%) | 1 |
Hypertension | 21/28 (75%) | 46 | 14/26 (53.8%) | 36 | 17/33 (51.5%) | 62 | 19/30 (63.3%) | 44 |
Thromboembolic event | 0/28 (0%) | 0 | 1/26 (3.8%) | 2 | 0/33 (0%) | 0 | 0/30 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Tanios Bekaii-Saab, M.D. |
---|---|
Organization | Mayo Clinic Arizona |
Phone | 507/266-0800 |
Bekaii-Saab.Tanios@mayo.edu |
- RU021407I
- NCI-2015-00011
- RU021407I
- P30CA015083