Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

Sponsor
Academic and Community Cancer Research United (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02368886
Collaborator
National Cancer Institute (NCI) (NIH)
123
Enrollment
22
Locations
4
Arms
122.4
Anticipated Duration (Months)
5.6
Patients Per Site
0
Patients Per Site Per Month

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.

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:
  1. Evaluate outcome measures for efficacy in each arm including progression-free survival (PFS), time to progression (TTP), and overall survival (OS).

  2. Compare between arms the cumulative dose and dose intensity received within the first two cycles.

  3. 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.

  4. 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:
  1. 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.

  2. Evaluate the correlation between PK parameters and tumor response/stable disease after the first two cycles.

  3. 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

Study Type:
Interventional
Actual Enrollment :
123 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Regorafenib Dose Optimization Study (ReDOS): A Phase II Randomized Study of Lower Dose Regorafenib Compared to Standard Dose Regorafenib in Patients With Refractory Metastatic Colorectal Cancer (mCRC)
Actual Study Start Date :
Mar 27, 2015
Actual Primary Completion Date :
Sep 1, 2017
Anticipated Study Completion Date :
Jun 7, 2025

Arms and Interventions

ArmIntervention/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:
  • Olux-E
  • Other: Pharmacological Study
    Correlative studies

    Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Drug: Regorafenib
    Given PO
    Other Names:
  • BAY 73-4506
  • Stivarga
  • 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:
  • Olux-E
  • Other: Pharmacological Study
    Correlative studies

    Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Drug: Regorafenib
    Given PO
    Other Names:
  • BAY 73-4506
  • Stivarga
  • 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:
  • Olux-E
  • Other: Pharmacological Study
    Correlative studies

    Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Drug: Regorafenib
    Given PO
    Other Names:
  • BAY 73-4506
  • Stivarga
  • 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:
  • Olux-E
  • Other: Pharmacological Study
    Correlative studies

    Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Drug: Regorafenib
    Given PO
    Other Names:
  • BAY 73-4506
  • Stivarga
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. 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.

    4. 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).

    5. 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

    6. 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.

    7. 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.

    8. 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

    1. 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

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    SiteCityStateCountryPostal Code
    1Mayo Clinic HospitalPhoenixArizonaUnited States85054
    2Mayo Clinic in ArizonaScottsdaleArizonaUnited States85259
    3USC / Norris Comprehensive Cancer CenterLos AngelesCaliforniaUnited States90033
    4Illinois CancerCare-PeoriaPeoriaIllinoisUnited States61615
    5Northern Indiana Cancer Research ConsortiumSouth BendIndianaUnited States46628
    6Siouxland Regional Cancer CenterSioux CityIowaUnited States51101
    7Dana-Farber Cancer InstituteBostonMassachusettsUnited States02215
    8Mayo ClinicRochesterMinnesotaUnited States55905
    9Metro Minnesota Community Oncology Research ConsortiumSaint Louis ParkMinnesotaUnited States55416
    10Washington University School of MedicineSaint LouisMissouriUnited States63110
    11Missouri Valley Cancer ConsortiumOmahaNebraskaUnited States68106
    12University of Nebraska Medical CenterOmahaNebraskaUnited States68198
    13Roswell Park Cancer InstituteBuffaloNew YorkUnited States14263
    14Hematology Oncology Associates of Central New York-East SyracuseEast SyracuseNew YorkUnited States13057
    15Wake Forest University Health SciencesWinston-SalemNorth CarolinaUnited States27157
    16Ohio State University Comprehensive Cancer CenterColumbusOhioUnited States43210
    17Toledo Clinic Cancer Centers-ToledoToledoOhioUnited States43623
    18Geisinger Medical CenterDanvillePennsylvaniaUnited States17822
    19Wellmont Medical Associates Oncology and Hematology-KingsportKingsportTennesseeUnited States37660
    20University of Washington Medical CenterSeattleWashingtonUnited States98195
    21Saint Vincent Hospital Cancer Center Green BayGreen BayWisconsinUnited States54301
    22Marshfield ClinicMarshfieldWisconsinUnited States54449

    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.
    Responsible Party:
    Academic and Community Cancer Research United
    ClinicalTrials.gov Identifier:
    NCT02368886
    Other Study ID Numbers:
    • RU021407I
    • NCI-2015-00011
    • RU021407I
    • P30CA015083
    First Posted:
    Feb 23, 2015
    Last Update Posted:
    Jan 14, 2022
    Last Verified:
    Aug 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleArm 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 DescriptionIn 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
    STARTED29273433
    COMPLETED28263329
    NOT COMPLETED1114

    Baseline Characteristics

    Arm/Group TitleArm 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 DescriptionIn 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 Participants28263329116
    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

    1. Primary Outcome
    TitleProportion of Patients in Each Arm Who Complete 2 Cycles of Protocol Treatment and Initiate Cycle 3
    DescriptionFisher 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 FrameAt 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 TitleRegorafenib Dose Escalation GroupRegorafenib Standard Dose Group
    Arm/Group DescriptionIn 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 Participants5462
    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 Hypothesisp-Value0.0434
    Comments1-sided
    MethodFisher Exact
    Comments
    Method of EstimationEstimation ParameterRisk Difference (RD)
    Estimated Value0.17
    Confidence Interval (2-Sided) 95%
    0.00 to 0.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    TitleOverall Survival (OS)
    DescriptionOS 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 FrameTime 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 TitleRegorafenib Dose Escalation GroupRegorafenib Standard Dose Group
    Arm/Group DescriptionIn 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 Participants5462
    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 Hypothesisp-Value0.1241
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.72
    Confidence Interval (2-Sided) 95%
    0.47 to 1.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    TitleProgression Free Survival (PFS)
    DescriptionPFS 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 FrameTime 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 TitleRegorafenib Dose Escalation GroupRegorafenib Standard Dose Group
    Arm/Group DescriptionIn 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 Participants5462
    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 Hypothesisp-Value0.3797
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.84
    Confidence Interval (2-Sided) 95%
    0.57 to 1.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    TitleTime to Progression (TTP)
    DescriptionTTP 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 FrameTime 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 TitleRegorafenib Dose Escalation GroupRegorafenib Standard Dose Group
    Arm/Group DescriptionIn 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 Participants5462
    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 Hypothesisp-Value0.4614
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.85
    Confidence Interval (2-Sided) 95%
    0.55 to 1.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    TitleCumulative (Total) Dose of Regorafenib Received by Patients in the First Two Cycles
    DescriptionWill be summarized with descriptive statistics and compared between regorafenib arms (A vs. B).
    Time FrameUp 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 TitleRegorafenib Dose Escalation GroupRegorafenib Standard Dose Group
    Arm/Group DescriptionIn 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 Participants5462
    Cycle 1
    91.8
    (33.4)
    133.1
    (34.6)
    Cycle 2
    121.3
    (40.0)
    117.3
    (48.9)
    6. Secondary Outcome
    TitleDose Intensity of Regorafenib Received by Patients in the First Two Cycles as Measured by the Percentage of Planned Dose Received
    DescriptionDose intensity of regorafenib received by patients in the first two cycles as measured by the percentage (%) of planned dose received
    Time FrameUp 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 TitleRegorafenib Dose Escalation GroupRegorafenib Standard Dose Group
    Arm/Group DescriptionIn 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 Participants5462
    Median (Standard Deviation) [percentage of planned dose received]
    76.2
    (25.3)
    76.0
    (21.0)
    7. Secondary Outcome
    TitleProportion of Patients Overall and Within Each Arm Experiencing Grade 3 or 4 Hand and Foot Syndrome (HFS) or Fatigue
    DescriptionWill 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 FrameUp to 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    TitleChanges in Quality of Life (QOL) (According to the HFS14 Questionnaire)
    DescriptionPatients 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 FrameBaseline to up to 8 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Secondary Outcome
    TitleChanges in QOL (According to the Linear Analogue Self-Assessment [LASA] Questionnaire)
    DescriptionChanges 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 FrameBaseline to up to 8 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Other Pre-specified Outcome
    TitlePharmacokinetics (PK) Parameters of Regorafenib Using Liquid Chromatography Mass Spectrometry
    DescriptionAfter 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 FrameBaseline, 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 FrameAdverse 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 TitleArm 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 DescriptionIn 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 (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/28 (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 (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total4/28 (14.3%) 10/26 (38.5%) 10/33 (30.3%) 10/30 (33.3%)
    Blood and lymphatic system disorders
    Anemia1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Cardiac disorders
    Myocardial infarction0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Sinus tachycardia0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Gastrointestinal disorders
    Abdominal pain2/28 (7.1%) 25/26 (19.2%) 53/33 (9.1%) 31/30 (3.3%) 1
    Ascites1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Colitis0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Colonic obstruction1/28 (3.6%) 12/26 (7.7%) 20/33 (0%) 00/30 (0%) 0
    Constipation0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Lower gastrointestinal hemorrhage0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Nausea0/28 (0%) 02/26 (7.7%) 20/33 (0%) 00/30 (0%) 0
    Rectal fistula0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Rectal obstruction0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Vomiting0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    General disorders
    Death NOS0/28 (0%) 01/26 (3.8%) 11/33 (3%) 10/30 (0%) 0
    Fatigue1/28 (3.6%) 11/26 (3.8%) 12/33 (6.1%) 30/30 (0%) 0
    Pain0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Infections and infestations
    Abdominal infection1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Infections and infestations - Other, specify0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Lung infection0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Sepsis0/28 (0%) 01/26 (3.8%) 10/33 (0%) 01/30 (3.3%) 1
    Urinary tract infection1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Investigations
    Alanine aminotransferase increased2/28 (7.1%) 20/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Alkaline phosphatase increased2/28 (7.1%) 20/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Aspartate aminotransferase increased2/28 (7.1%) 20/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Blood bilirubin increased1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    INR increased0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Investigations - Other, specify1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Platelet count decreased1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Metabolism and nutrition disorders
    Anorexia0/28 (0%) 01/26 (3.8%) 10/33 (0%) 01/30 (3.3%) 1
    Dehydration0/28 (0%) 01/26 (3.8%) 12/33 (6.1%) 21/30 (3.3%) 1
    Hyperglycemia1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Hypoalbuminemia1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Hypocalcemia2/28 (7.1%) 20/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Hypokalemia1/28 (3.6%) 11/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Hyponatremia2/28 (7.1%) 20/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Chest wall pain0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Generalized muscle weakness0/28 (0%) 01/26 (3.8%) 11/33 (3%) 10/30 (0%) 0
    Myalgia0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify0/28 (0%) 02/26 (7.7%) 21/33 (3%) 11/30 (3.3%) 1
    Nervous system disorders
    Encephalopathy0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Syncope0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Transient ischemic attacks0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Psychiatric disorders
    Confusion0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Renal and urinary disorders
    Urinary retention1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Dyspnea0/28 (0%) 01/26 (3.8%) 11/33 (3%) 12/30 (6.7%) 2
    Pleural effusion0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Respiratory failure0/28 (0%) 01/26 (3.8%) 10/33 (0%) 01/30 (3.3%) 1
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysesthesia syndrome0/28 (0%) 01/26 (3.8%) 20/33 (0%) 00/30 (0%) 0
    Rash maculo-papular0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Vascular disorders
    Thromboembolic event1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (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 (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total28/28 (100%) 24/26 (92.3%) 31/33 (93.9%) 30/30 (100%)
    Blood and lymphatic system disorders
    Anemia4/28 (14.3%) 58/26 (30.8%) 157/33 (21.2%) 106/30 (20%) 8
    Blood and lymphatic system disorders - Other, specify0/28 (0%) 00/26 (0%) 00/33 (0%) 02/30 (6.7%) 3
    Thrombotic thrombocytopenic purpura0/28 (0%) 01/26 (3.8%) 50/33 (0%) 00/30 (0%) 0
    Cardiac disorders
    Sinus tachycardia0/28 (0%) 00/26 (0%) 01/33 (3%) 11/30 (3.3%) 1
    Ear and labyrinth disorders
    Tinnitus0/28 (0%) 00/26 (0%) 01/33 (3%) 20/30 (0%) 0
    Endocrine disorders
    Hypothyroidism0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Eye disorders
    Watering eyes1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Gastrointestinal disorders
    Abdominal pain2/28 (7.1%) 31/26 (3.8%) 13/33 (9.1%) 32/30 (6.7%) 2
    Ascites0/28 (0%) 01/26 (3.8%) 30/33 (0%) 00/30 (0%) 0
    Constipation2/28 (7.1%) 21/26 (3.8%) 11/33 (3%) 14/30 (13.3%) 5
    Diarrhea14/28 (50%) 3010/26 (38.5%) 2017/33 (51.5%) 3710/30 (33.3%) 24
    Dry mouth2/28 (7.1%) 71/26 (3.8%) 10/33 (0%) 03/30 (10%) 3
    Dyspepsia0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Dysphagia0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Flatulence0/28 (0%) 00/26 (0%) 01/33 (3%) 50/30 (0%) 0
    Gastroesophageal reflux disease0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Gastrointestinal disorders - Other, specify0/28 (0%) 00/26 (0%) 00/33 (0%) 02/30 (6.7%) 2
    Mucositis oral1/28 (3.6%) 14/26 (15.4%) 55/33 (15.2%) 75/30 (16.7%) 7
    Nausea8/28 (28.6%) 1612/26 (46.2%) 2116/33 (48.5%) 4313/30 (43.3%) 17
    Oral pain0/28 (0%) 00/26 (0%) 02/33 (6.1%) 23/30 (10%) 5
    Stomach pain0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Vomiting5/28 (17.9%) 77/26 (26.9%) 89/33 (27.3%) 125/30 (16.7%) 6
    General disorders
    Chills1/28 (3.6%) 21/26 (3.8%) 31/33 (3%) 12/30 (6.7%) 2
    Edema limbs1/28 (3.6%) 11/26 (3.8%) 11/33 (3%) 10/30 (0%) 0
    Fatigue25/28 (89.3%) 7220/26 (76.9%) 5326/33 (78.8%) 8327/30 (90%) 72
    Fever1/28 (3.6%) 20/26 (0%) 01/33 (3%) 13/30 (10%) 3
    General disorders and administration site conditions - Other, specify0/28 (0%) 00/26 (0%) 02/33 (6.1%) 32/30 (6.7%) 4
    Non-cardiac chest pain0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Pain4/28 (14.3%) 41/26 (3.8%) 12/33 (6.1%) 21/30 (3.3%) 1
    Hepatobiliary disorders
    Hepatic failure0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Hepatobiliary disorders - Other, specify0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Infections and infestations
    Sinusitis1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Urinary tract infection0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Alanine aminotransferase increased2/28 (7.1%) 44/26 (15.4%) 46/33 (18.2%) 133/30 (10%) 3
    Alkaline phosphatase increased3/28 (10.7%) 44/26 (15.4%) 47/33 (21.2%) 135/30 (16.7%) 6
    Aspartate aminotransferase increased2/28 (7.1%) 35/26 (19.2%) 88/33 (24.2%) 168/30 (26.7%) 9
    Blood bilirubin increased3/28 (10.7%) 55/26 (19.2%) 59/33 (27.3%) 109/30 (30%) 10
    Creatinine increased0/28 (0%) 02/26 (7.7%) 21/33 (3%) 13/30 (10%) 4
    Investigations - Other, specify1/28 (3.6%) 81/26 (3.8%) 12/33 (6.1%) 53/30 (10%) 4
    Lymphocyte count decreased1/28 (3.6%) 14/26 (15.4%) 52/33 (6.1%) 34/30 (13.3%) 6
    Platelet count decreased4/28 (14.3%) 42/26 (7.7%) 36/33 (18.2%) 82/30 (6.7%) 2
    Weight loss2/28 (7.1%) 33/26 (11.5%) 96/33 (18.2%) 95/30 (16.7%) 5
    White blood cell decreased1/28 (3.6%) 21/26 (3.8%) 13/33 (9.1%) 31/30 (3.3%) 1
    Metabolism and nutrition disorders
    Anorexia8/28 (28.6%) 116/26 (23.1%) 76/33 (18.2%) 1013/30 (43.3%) 20
    Dehydration0/28 (0%) 00/26 (0%) 02/33 (6.1%) 22/30 (6.7%) 2
    Hyperglycemia0/28 (0%) 01/26 (3.8%) 20/33 (0%) 01/30 (3.3%) 1
    Hyperkalemia0/28 (0%) 01/26 (3.8%) 11/33 (3%) 11/30 (3.3%) 1
    Hypermagnesemia1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Hypoalbuminemia3/28 (10.7%) 62/26 (7.7%) 23/33 (9.1%) 54/30 (13.3%) 5
    Hypocalcemia2/28 (7.1%) 32/26 (7.7%) 30/33 (0%) 04/30 (13.3%) 4
    Hypokalemia2/28 (7.1%) 50/26 (0%) 03/33 (9.1%) 43/30 (10%) 3
    Hyponatremia1/28 (3.6%) 10/26 (0%) 06/33 (18.2%) 85/30 (16.7%) 5
    Hypophosphatemia0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Metabolism and nutrition disorders - Other, specify1/28 (3.6%) 10/26 (0%) 00/33 (0%) 02/30 (6.7%) 2
    Musculoskeletal and connective tissue disorders
    Arthritis0/28 (0%) 00/26 (0%) 01/33 (3%) 20/30 (0%) 0
    Back pain0/28 (0%) 01/26 (3.8%) 13/33 (9.1%) 42/30 (6.7%) 2
    Bone pain0/28 (0%) 01/26 (3.8%) 11/33 (3%) 10/30 (0%) 0
    Chest wall pain0/28 (0%) 00/26 (0%) 01/33 (3%) 20/30 (0%) 0
    Generalized muscle weakness3/28 (10.7%) 42/26 (7.7%) 21/33 (3%) 21/30 (3.3%) 1
    Musculoskeletal and connective tissue disorder - Other, specify1/28 (3.6%) 30/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Myalgia0/28 (0%) 01/26 (3.8%) 14/33 (12.1%) 53/30 (10%) 3
    Myositis0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Pain in extremity1/28 (3.6%) 13/26 (11.5%) 32/33 (6.1%) 41/30 (3.3%) 2
    Nervous system disorders
    Cognitive disturbance0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Dizziness0/28 (0%) 00/26 (0%) 01/33 (3%) 11/30 (3.3%) 2
    Dysgeusia1/28 (3.6%) 10/26 (0%) 01/33 (3%) 32/30 (6.7%) 2
    Encephalopathy0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Headache3/28 (10.7%) 32/26 (7.7%) 63/33 (9.1%) 70/30 (0%) 0
    Paresthesia0/28 (0%) 00/26 (0%) 01/33 (3%) 20/30 (0%) 0
    Peripheral motor neuropathy0/28 (0%) 01/26 (3.8%) 10/33 (0%) 01/30 (3.3%) 1
    Peripheral sensory neuropathy5/28 (17.9%) 61/26 (3.8%) 14/33 (12.1%) 82/30 (6.7%) 4
    Psychiatric disorders
    Insomnia2/28 (7.1%) 21/26 (3.8%) 10/33 (0%) 01/30 (3.3%) 1
    Psychiatric disorders - Other, specify0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Renal and urinary disorders
    Hematuria0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Urinary frequency0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Cough1/28 (3.6%) 10/26 (0%) 02/33 (6.1%) 30/30 (0%) 0
    Dyspnea3/28 (10.7%) 53/26 (11.5%) 75/33 (15.2%) 54/30 (13.3%) 4
    Epistaxis0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Hiccups0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Hoarseness4/28 (14.3%) 114/26 (15.4%) 85/33 (15.2%) 63/30 (10%) 3
    Hypoxia0/28 (0%) 00/26 (0%) 01/33 (3%) 10/30 (0%) 0
    Pleuritic pain0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Productive cough1/28 (3.6%) 20/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Sinus disorder1/28 (3.6%) 10/26 (0%) 00/33 (0%) 00/30 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia1/28 (3.6%) 10/26 (0%) 04/33 (12.1%) 92/30 (6.7%) 2
    Dry skin1/28 (3.6%) 31/26 (3.8%) 12/33 (6.1%) 71/30 (3.3%) 1
    Nail discoloration0/28 (0%) 01/26 (3.8%) 10/33 (0%) 00/30 (0%) 0
    Pain of skin0/28 (0%) 00/26 (0%) 01/33 (3%) 11/30 (3.3%) 1
    Palmar-plantar erythrodysesthesia syndrome18/28 (64.3%) 3717/26 (65.4%) 4322/33 (66.7%) 6122/30 (73.3%) 42
    Pruritus0/28 (0%) 00/26 (0%) 01/33 (3%) 11/30 (3.3%) 1
    Rash maculo-papular8/28 (28.6%) 162/26 (7.7%) 38/33 (24.2%) 128/30 (26.7%) 11
    Skin and subcutaneous tissue disorders - Other, specify0/28 (0%) 00/26 (0%) 01/33 (3%) 11/30 (3.3%) 1
    Vascular disorders
    Hot flashes0/28 (0%) 00/26 (0%) 00/33 (0%) 01/30 (3.3%) 1
    Hypertension21/28 (75%) 4614/26 (53.8%) 3617/33 (51.5%) 6219/30 (63.3%) 44
    Thromboembolic event0/28 (0%) 01/26 (3.8%) 20/33 (0%) 00/30 (0%) 0

    Limitations/Caveats

    [Not Specified]

    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/TitleTanios Bekaii-Saab, M.D.
    OrganizationMayo Clinic Arizona
    Phone507/266-0800
    EmailBekaii-Saab.Tanios@mayo.edu
    Responsible Party:
    Academic and Community Cancer Research United
    ClinicalTrials.gov Identifier:
    NCT02368886
    Other Study ID Numbers:
    • RU021407I
    • NCI-2015-00011
    • RU021407I
    • P30CA015083
    First Posted:
    Feb 23, 2015
    Last Update Posted:
    Jan 14, 2022
    Last Verified:
    Aug 1, 2021