Clinical Trials /

Regorafenib, With Cetuximab or Panitumumab, for the Treatment of Unresectable, Locally Advanced, or Metastatic Colorectal Cancer

NCT04117945

Description:

This phase II trial how well regorafenib and anti-EGFR therapy (cetuximab or panitumumab) works for the treatment of patients with colorectal cancer that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic). Regorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab or panitumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The purpose of this research study is to compare the effects, good and/or bad, of taking regorafenib follow by cetuximab or panitumumab, to those that receive cetuximab or panitumumab before regorafenib.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Regorafenib, With Cetuximab or Panitumumab, for the Treatment of Unresectable, Locally Advanced, or Metastatic Colorectal Cancer
  • Official Title: A Randomized Phase II Study of Regorafenib Followed by Anti-EGFR Monoclonal Antibody Therapy Versus the Reverse Sequencing for Metastatic Colorectal Cancer Patients Previously Treated With Fluoropyrimidine, Oxaliplatin and Irinotecan (REVERCE II)

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-GI-1809
  • SECONDARY ID: NCI-2019-06518
  • SECONDARY ID: ACCRU-GI-1809
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04117945

Conditions

  • BRAF V600E Negative
  • KRAS Gene Mutation Negative
  • Locally Advanced Unresectable Colorectal Adenocarcinoma
  • Metastatic Colorectal Adenocarcinoma
  • NRAS Gene Mutation Negative
  • Stage III Colorectal Cancer AJCC v8
  • Stage IIIA Colorectal Cancer AJCC v8
  • Stage IIIB Colorectal Cancer AJCC v8
  • Stage IIIC Colorectal Cancer AJCC v8
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8

Interventions

DrugSynonymsArms
CetuximabCetuximab Biosimilar CDP-1, Cetuximab Biosimilar CMAB009, Cetuximab Biosimilar KL 140, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225Arm B (cetuximab, panitumumab, irinotecan)
IrinotecanArm B (cetuximab, panitumumab, irinotecan)
PanitumumabABX-EGF, ABX-EGF Monoclonal Antibody, ABX-EGF, Clone E7.6.3, MoAb ABX-EGF, Monoclonal Antibody ABX-EGF, VectibixArm B (cetuximab, panitumumab, irinotecan)
RegorafenibBAY 73-4506, StivargaArm A (regorafenib)

Purpose

This phase II trial how well regorafenib and anti-EGFR therapy (cetuximab or panitumumab) works for the treatment of patients with colorectal cancer that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic). Regorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab or panitumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The purpose of this research study is to compare the effects, good and/or bad, of taking regorafenib follow by cetuximab or panitumumab, to those that receive cetuximab or panitumumab before regorafenib.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare the overall survival between evaluable patients who were randomized to receive
      regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive
      anti-EGFR monoclonal antibody followed by regorafenib.

      SECONDARY OBJECTIVES:

      I. To compare the first progression free survival (PFS1) of patients between evaluable
      patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody
      therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib
      II. To compare the second progression free survival (PFS2) of patients between evaluable
      patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody
      therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

      III. To compare the sequential treatment progression free survival (stPFS) of patients
      between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR
      monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody
      followed by regorafenib.

      IV. To assess the frequency and severity of adverse events between evaluable patients who
      were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy
      compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

      V. To compare the objective response rate (ORR), while on initial treatment, between
      evaluable patients who were randomized to receive regorafenib followed by anti-EGFR
      monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody
      followed by regorafenib VI. To compare the objective response rate (ORR), while on sequential
      treatment, between evaluable patients who were randomized to receive regorafenib followed by
      anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal
      antibody prior to regorafenib.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To assess plasma pharmacodynamics biomarkers of response and resistance to therapy.

      II. To explore any correlation between tissue and blood based biomarkers and clinical
      outcomes.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Cycles repeat
      every 28 days in the absence of disease progression or unacceptable toxicity. Per the
      treating physician's discretion, patients who experience disease progression may initiate a
      treatment regimen consisting of cetuximab or panitumumab intravenously (IV) over 30-90
      minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as
      determined by the study doctor. Cycles repeat every 28 days until disease progression or
      unacceptable toxicity.

      ARM B: Patients receive cetuximab or panitumumab IV over 30-90 minutes on days 1 and 15.
      Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
      Per the treating physician's discretion, patients who experience disease progression may
      initiate a treatment regimen consisting of regorafenib PO QD on days 1-21. Cycles repeat
      every 28 days until disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, and then every 3
      months for up to 3 years after randomization.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (regorafenib)ExperimentalPatients receive regorafenib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If received as initial treatment, patients who experience disease progression may switch over to the other treatment regimen, per treating physician discretion.
  • Regorafenib
Arm B (cetuximab, panitumumab, irinotecan)ExperimentalPatients receive cetuximab or panitumumab IV over 30-90 minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If received as initial treatment, patients who experience disease progression may switch over to the other treatment regimen, per treating physician discretion.
  • Cetuximab
  • Irinotecan
  • Panitumumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven, unresectable distant metastatic or locally advanced colorectal
             adenocarcinoma

          -  KRAS, NRAS wild type

          -  BRAF v600E wildtype

          -  Measurable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

          -  Life expectancy of >= 3 months per estimation of treating physician

          -  Absolute neutrophil count (ANC) >= 1200/mm^3 (obtained =< 7 days prior to
             randomization)

          -  Platelet count >= 75,000/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
                  treating physician

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

          -  Disease progression on or intolerable to any of the following: fluoropyrimidine,
             oxaliplatin and irinotecan

          -  Able to swallow and retain oral medication

          -  Willing to provide tissue and blood samples for correlative research purposes

          -  Willing to allow transfer of tissue and blood samples, clinical information, and
             outcome data collected from this trial for future research

        Exclusion Criteria:

          -  Prior treatment with regorafenib, cetuximab or panitumumab

          -  Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days
             prior to randomization

          -  Congestive heart failure > New York Heart Association (NYHA) class 2.

               -  NOTE: Class 3 is defined as marked limitation in activity due to symptoms, even
                  during less-than-ordinary activity, e.g., walking short distances (20-100m). They
                  are comfortable at rest. Class 4 is defined as patients with severe limitations.
                  Experiences symptoms even while at rest. Mostly bed bound

          -  Unstable angina (angina symptoms at rest), new-onset angina (begun =< 3 months prior
             to randomization) or myocardial infarction =< 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 (v)5.0

          -  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
             v5.0 grade 3 =< 4 weeks prior to randomization

          -  Non-healing wound, ulcer, or bone fracture

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the patient?s participation in the study or evaluation of the study results

          -  High-frequency microsatellite instability (MSI-H) patients who have not received prior
             PD-1 monoclonal antibody (mAb) therapy

          -  Concurrent anti-cancer therapy =< 3 weeks from randomization (chemotherapy, radiation
             therapy, surgery, immunotherapy, biologic therapy, or tumor embolization)

          -  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

          -  History of known persistent proteinuria of CTCAE v5.0 grade 3 or higher (>= 3.5 g/24
             hrs)

          -  Any malabsorption condition

          -  Unresolved toxicity greater than CTCAE v5.0 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 because this study involves an agent that has known genotoxic,
             mutagenic and teratogenic effects:

               -  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 treating physician, 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

          -  Known history of human immunodeficiency virus (HIV) infection or active hepatitis B or
             C infection requiring treatment with antiviral therapy

          -  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 =< 3 years prior to randomization EXCEPT for cervical cancer
             in-situ, treated ductal carcinoma in situ of the breast, curatively treated
             nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial
             bladder tumor (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 v5.0 grade 2
             dyspnea)

          -  Any condition which, in the treating physician?s opinion, makes the subject unsuitable
             for trial participation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:The median OS and 95% confidence intervals in each arm will be reported.

Secondary Outcome Measures

Measure:First progression-free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:The median first PFS and 95% confidence intervals in each arm will be reported.
Measure:Second PFS
Time Frame:Up to 3 years
Safety Issue:
Description:The median second PFS and 95% confidence intervals in each arm will be reported.
Measure:Sequential treatment PFS
Time Frame:Up to 3 years
Safety Issue:
Description:The median PFS while on sequential treatment and 95% confidence intervals in each arm will be reported.
Measure:Objective response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Point estimates and the corresponding 95% confidence intervals for the true success proportions in each arm will be reported.
Measure:Sequential treatment objective response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Point estimates and the corresponding 95% confidence intervals for the true success proportions will be reported.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:The number of patients who experience a grade 3 or higher adverse event (Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0), regardless of attribution, will be reported by arm.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Academic and Community Cancer Research United

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