Clinical trial NCT02368886: Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: Academic and Community Cancer Research United
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2015-02-23
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

I. 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:

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

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

III. 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.

IV. 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:

I. 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.

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

III. 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.

Eligibility 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

Primary outcomes:
measure: Proportion of Patients in Each Arm Who Complete 2 Cycles of Protocol Treatment and Initiate Cycle 3
timeFrame: At 8 weeks
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Time from randomization to death due to any cause, assessed up to 2 years
measure: Progression Free Survival (PFS)
timeFrame: 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
measure: Time to Progression (TTP)
timeFrame: Time from randomization to disease progression, where PD is defined by RECIST 1.1, assessed up to 2 years
measure: Cumulative (Total) Dose of Regorafenib Received by Patients in the First Two Cycles
timeFrame: Up to 8 weeks
measure: Dose Intensity of Regorafenib Received by Patients in the First Two Cycles as Measured by the Percentage of Planned Dose Received
timeFrame: Up to 8 weeks
measure: Proportion of Patients Overall and Within Each Arm Experiencing Grade 3 or 4 Hand and Foot Syndrome (HFS)
timeFrame: 2 years
measure: Quality of Life (QOL) (According to the HFS14 Total Score)
timeFrame: 8 weeks
measure: Changes in QOL (According to the Linear Analogue Self-Assessment [LASA] Questionnaire)
timeFrame: Baseline to 8 weeks
Other outcomes:
measure: Pharmacokinetics (PK) Parameters of Regorafenib Using Liquid Chromatography Mass Spectrometry
timeFrame: Baseline, prior to treatment, days 7, 14, and 21 prior to treatment (course 1), and days 1 and 21 prior to treatment (course 2)
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: South Bend
country: United States
facility: Northern Indiana Cancer Research Consortium
state: Indiana
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro Minnesota Community Oncology Research Consortium
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Missouri Valley Cancer Consortium
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: East Syracuse
country: United States
facility: Hematology Oncology Associates of Central New York-East Syracuse
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Centers-Toledo
state: Ohio
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Kingsport
country: United States
facility: Wellmont Medical Associates Oncology and Hematology-Kingsport
state: Tennessee
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Green Bay
country: United States
facility: Saint Vincent Hospital Cancer Center Green Bay
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
Study officials:
affiliation: Academic and Community Cancer Research United
name: Tanios Bekaii-Saab
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, Dockter TJ, Jacobs NL, Pasche BC, Cleary JM, Meyers JP, Desnoyers RJ, McCune JS, Pedersen K, Barzi A, Chiorean EG, Sloan J, Lacouture ME, Lenz HJ, Grothey A. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Aug;20(8):1070-1082. doi: 10.1016/S1470-2045(19)30272-4. Epub 2019 Jun 28.
citation: Weinberg BA, Hartley ML, Salem ME. Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 2: Approaches Beyond First-Line Therapy, and Novel Biologic Agents Under Investigation. Oncology (Williston Park). 2017 Jul 15;31(7):573-80.