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

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ClinicalTrials.gov Identifier: NCT02368886
Recruitment Status : Active, not recruiting
First Posted : February 23, 2015
Last Update Posted : May 8, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

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
Colon Adenocarcinoma Rectal Adenocarcinoma Stage III Colorectal Cancer AJCC v7 Stage IIIA Colorectal Cancer AJCC v7 Stage IIIB Colorectal Cancer AJCC v7 Stage IIIC Colorectal Cancer AJCC v7 Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7 Drug: Clobetasol Propionate Other: Pharmacological Study Other: Quality-of-Life Assessment Drug: Regorafenib Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
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 : March 27, 2015
Actual Primary Completion Date : September 1, 2017
Estimated Study Completion Date : June 22, 2019

Resource links provided by the National Library of Medicine


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 Name: Olux-E

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: 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 Name: Olux-E

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: 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 Name: Olux-E

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: 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 Name: Olux-E

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Drug: Regorafenib
Given PO
Other Names:
  • BAY 73-4506
  • Stivarga




Primary Outcome Measures :
  1. Proportion of patients in each arm who complete 2 courses of treatment and who intend to initiate course 3 if no progression is noted on the planned disease evaluation [ Time Frame: 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 [poled 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 Frame: Time from randomization to death due to any cause, assessed up to 2 years ]
    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 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 ]
    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 Frame: Time from randomization to disease progression, where PD is defined by RECIST 1.1, assessed up to 2 years ]
    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 courses [ Time Frame: Up to 8 weeks ]
    Will be summarized with descriptive statistics and compared between regorafenib arms (A vs. B) using the t-test (if approximately normally distributed) or the Wilcoxon rank sum test (if not approximately normally distributed).

  5. Dose intensity of regorafenib received by patients in the first two courses [ Time Frame: Up to 8 weeks ]
    Will be summarized with descriptive statistics and compared between regorafenib arms (A vs. B) using the t-test (if approximately normally distributed) or the Wilcoxon rank sum test (if not approximately normally distributed).

  6. Proportion of patients overall and within each arm experiencing grade 3 or 4 Hand and Foot Syndrome (HFS) or fatigue [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ 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) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02368886


  Show 22 Study Locations
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Tanios Bekaii-Saab Academic and Community Cancer Research United

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT02368886     History of Changes
Other Study ID Numbers: RU021407I
NCI-2015-00011 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RU021407I ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: February 23, 2015    Key Record Dates
Last Update Posted: May 8, 2019
Last Verified: February 2019

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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:
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Colorectal Neoplasms
Colonic Neoplasms
Adenocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Clobetasol
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs