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Panitumumab, Regorafenib, or TAS-102, in Treating Patients With Metastatic and/or Unresectable RAS Wild-Type Colorectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03992456
Recruitment Status : Not yet recruiting
First Posted : June 20, 2019
Last Update Posted : December 20, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
This phase II trial studies how well retreatment with panitumumab works compared to standard of care regorafenib or trifluridine and tipiracil hydrochloride (TAS-102) in treating patients with colorectal cancer that is negative for RAS wild-type colorectal cancer has spread to other places in the body, and/or cannot be removed by surgery, and is negative for resistance mutations in blood. Treatment with panitumumab may interfere with the ability of tumor cells to grow and spread. Some tumors need growth factors to keep growing. Growth factor antagonists, such as regorafenib, may interfere with the growth factor and stop the tumor from growing. Drugs used in chemotherapy, such as TAS-102, 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. Giving panitumumab may work better in treating patients with colorectal cancer than with the usual treatment of regorafenib or TAS-102.

Condition or disease Intervention/treatment Phase
BRAF V600 Wild Type KRAS Gene Mutation Negative Metastatic Colon Adenocarcinoma Metastatic Colorectal Carcinoma Metastatic Rectal Adenocarcinoma NRAS Gene Mutation Negative Progressive Disease RAS Wild Type Stage IV Colon Cancer AJCC v8 Stage IV Colorectal Cancer AJCC v8 Stage IV Rectal Cancer AJCC v8 Stage IVA Colon Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVA Rectal Cancer AJCC v8 Stage IVB Colon Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVB Rectal Cancer AJCC v8 Stage IVC Colon Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Stage IVC Rectal Cancer AJCC v8 Biological: Panitumumab Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Regorafenib Drug: Trifluridine and Tipiracil Hydrochloride Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) in molecularly selected patients with metastatic colorectal cancer (CRC) receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

SECONDARY OBJECTIVES:

I. To compare the progression free survival (PFS) in molecularly selected patients with metastatic CRC receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

II. To define the objective response rate (ORR) in patients receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

III. To define the clinical benefit rate (CBR = complete response + partial response + stable disease >= 6 months) in patients receiving panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

IV. To compare the safety and tolerability of panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib).

V. Compare quality of life (QOL) between panitumumab rechallenge versus standard therapy (TAS-102 or regorafenib) as measured by the linear analogue self-assessment (LASA) questionnaires.

CORRELATIVE RESEARCH:

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 panitumumab intravenously (IV) over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 1-5 and 8-12, or regorafenib PO once daily (QD) on days 1-21, at the discretion of the treating physician. Treatment repeats every 28 days for a maximum of 24 cycles in the absence of 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PULSE: A Randomized, Phase II Open Label Study of PanitUmumab RechaLlenge Versus Standard Therapy After Progression on Anti-EGFR Therapy in Patients With Metastatic and/or Unresectable RAS Wild-Type Colorectal Cancer
Estimated Study Start Date : December 28, 2019
Estimated Primary Completion Date : August 7, 2021
Estimated Study Completion Date : October 7, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (panitumumab)
Patients receive panitumumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Panitumumab
Given IV
Other Names:
  • ABX-EGF
  • ABX-EGF Monoclonal Antibody
  • ABX-EGF, Clone E7.6.3
  • MoAb ABX-EGF
  • Monoclonal Antibody ABX-EGF
  • Vectibix

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

Other: Questionnaire Administration
Ancillary studies

Active Comparator: Arm B (regorafenib, trifluridine and tipiracil hydrochloride)
Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12, or regorafenib PO QD on days 1-21, at the discretion of the treating physician. Treatment repeats every 28 days for a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity.
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

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

Drug: Trifluridine and Tipiracil Hydrochloride
Given PO
Other Names:
  • Lonsurf
  • TAS 102
  • TAS-102
  • Tipiracil Hydrochloride Mixture with Trifluridine
  • Trifluridine/Tipiracil
  • Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed for up to 3 years ]
    The distribution of overall survival will be estimated using the method of Kaplan-Meier. Overall survival will be compared between the 2 treatment arms using the unstratified log-rank test.


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Time from randomization to documentation of disease progression or death due to any cause, whichever is first, assessed for up to 3 years ]
    The distribution of progression free survival will be estimated using the method of Kaplan-Meier. Progression free survival will be compared between the 2 treatment arms using the log-rank test.

  2. Overall response rate (ORR) [ Time Frame: At 12 months ]
    Defined as the number of patients with a complete response (CR) or partial response (PR) (as defined by the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) divided by the number of evaluable patients in each arm at 12 months post randomization. ORR will be compared between the 2 treatment arms. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.

  3. Clinical benefit rate [ Time Frame: At 6 months ]
    Defined as the number of patients with a complete response (CR), partial response (PR), or stable disease for >= 6 months (as defined by the RECIST 1.1) divided by the number of evaluable patients in each arm. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.

  4. Incidence of adverse events [ Time Frame: Up to 3 years ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. The overall adverse event rates for grade 3 or higher adverse events will be compared using Chi-Square or Fisher?s Exact tests.

  5. Patient-reported quality of life [ Time Frame: Up to 3 years ]
    Patients reported quality of life (QOL) outcomes will be collected using the Linear Analog Self-Assessment (LASA) Questionnaire. Data will be collected each cycle. Mean values of the first question (regarding overall QOL) at each cycle will be plotted, and stratified by arm. Additional analyses using data collected from the LASA questionnaire may be performed.


Other Outcome Measures:
  1. Cell free tumor deoxyribonucleic acid (cfDNA) [ Time Frame: Baseline, at restaging, and at disease progression ]
    A report will be generated for each clinical specimen, which may include (but not limited to) the presence or absence of relevant gene mutations or amplifications, along with the allele frequency. Mutations of interest include KRAS and NRAS exons 2, 3, and 4, BRAF, PIK3CA, EGFR, AKT, PTEN, MAP2K1, and MET. Amplifications of interest include MET, EGFR, KRAS, and ERBB2. Genes and alterations analyzed will be based on best available science at the time of analysis.

  2. Circulating protein studies [ Time Frame: Up to 3 years ]
    Plasma samples will be analyzed for multiple soluble protein analytes, which may include (but not limited to) HGF, c-MET, EGF, HBEGF, TGF-alpha, EGFR, HER2, and CD73.

  3. Tumor tissue studies [ Time Frame: Up to 3 years ]
    Comprehensive mutational analysis will be performed on archived formalin fixed paraffin embedded (FFPE) tumor samples. This analysis may include, but is not limited to Next Generation Sequencing (NGS) and IHC where appropriate.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Registered to Colorectal Cancer Liquid Biopsy Screening Protocol for Molecularly Assigned Therapy (COLOMATE) ACCRU-GI-1611 and:

    • COLOMATE Companion Trial Recommendation Form indicates patient qualifies to be screened for a COLOMATE companion trial.
    • COLOMATE Companion Trial Recommendation Form date of completion is =< 30 days prior to randomization.
  • Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic and/ or unresectable.
  • Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in BRAF codon 600, based on tumor tissue taken from primary or metastatic site prior to receipt of anti EGFR therapy.
  • Disease progression after treatment with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab, or aflibercept), or contraindication to such treatment(s).
  • Disease progression after treatment with an anti-EGFR monoclonal antibody (cetuximab and/or panitumumab) for at least 4 months (minimum of 8 biweekly treatments or 16 weekly treatments at full or partial dose).

    • NOTE: Treatments do not need to be administered consecutively.
    • NOTE: Dose reductions or delays are permitted.
  • Greater than 90 days has elapsed between the most recent treatment with an anti-EGFR therapy (cetuximab or panitumumab) and blood collection for COLOMATE ACCRU-GI-1611.
  • At least one site of disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation.
  • Life expectancy >= 3 months per estimation of investigator.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2.
  • Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support (obtained =< 7 days prior to randomization).
  • Platelet count >= 100,000 /mm^3 (obtained =< 7 days prior to randomization).
  • Hemoglobin > 8.0 g/dL (obtained =< 7 days prior to randomization).
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to randomization).
  • Aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization).
  • Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization).
  • Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula (obtained =< 7 days prior to randomization).
  • Women of child bearing potential and male partners of women of child bearing potential must agree to use two medically accepted methods of contraception, one of them being a barrier method during the study and for 2 months after the last dose of study drug(s).
  • Negative serum pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only.

    • NOTE: Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea >= 12 consecutive months. NOTE: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible treatment.
  • Ability to complete questionnaire(s) by themselves or with assistance.
  • Capable of understanding and complying with the protocol requirements and has signed the informed consent document.
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
  • 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:

  • Radiation therapy, hormonal therapy, biologic therapy, experimental therapy, or chemotherapy for cancer =< 21 days prior to randomization.
  • Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin).
  • Maximum mutant allele frequency (highest allele frequency reported for any gene mutation) (MAF) less than 2% by Guardant360 assay.
  • Detection of at least one of the following gene mutation(s) or amplification(s) by Guardant360 assay.

    • BRAF mutation mutant allele frequency (MAF) > 0.5%.
    • EGFR mutation (MAF > 0.5%). Note: EGFR S492R, K467, and R451C mutations are not an exclusion.
    • ERBB2 (HER2) mutation (MAF > 0.5%) or amplification.
    • KRAS mutation (MAF > 0.5%) or amplification.
    • MET mutation (MAF > 0.5%) or amplification.
    • NRAS mutation (MAF > 0.5%) or amplification
  • Prior treatment with both TAS-102 and regorafenib (prior treatment with either TAS-102 or regorafenib is permitted).
  • Unable to swallow oral tablets (crushing of study treatment tablets is not allowed).
  • 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. Note: This includes impaired heart function or clinically significant heart disease.
  • Not recovered to baseline or Common Terminology for Adverse Events (CTCAE) version (v)5.0 =< grade 1 from toxicity due to all prior therapies except alopecia, oxaliplatin-related neuropathy, asymptomatic electrolyte abnormalities, and other non-clinically significant adverse events.
  • 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.
  • Patients with known central nervous system (CNS) metastases. Note: Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive (based on repeat imaging >= 30 days after completion of definitive treatment), patients are asymptomatic, and no steroids to control symptoms related to CNS metastases have been administered for at least 30 days.
  • Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to randomization (=< 56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study.
  • Serious, non-healing wound, ulcer, or bone fracture.
  • History of stroke (cerebrovascular accident), transient ischemic attack (TIA), myocardial infarction (MI), unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery =< 6 months prior to randomization.
  • History of cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers, calcium channel blockers, or digoxin =< 6 months prior to randomization.
  • Known history of congestive heart failure ? New York Heart Association (NYHA) >= class II.
  • Known history of human immunodeficiency virus (HIV) seropositivity, acute or chronic active hepatitis B or C infection, or other serious chronic infection requiring ongoing treatment.
  • History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan.
  • Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from colorectal cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor. Note: Subjects surviving a cancer that was curatively treated and without evidence of disease for 3 or more years before randomization are allowed. All cancer treatments must be completed at least 3 years prior to randomization.
  • Uncontrolled hypertension (systolic pressure > 150 mm HG or diastolic pressure > 90 mm Hg [National Cancer Institute (NCI)-CTCAE v5.0]) on repeated measurement despite optimal medical management.
  • Evidence or history of bleeding diathesis or coagulopathy.
  • Any hemorrhage or bleeding event >= NCI CTCAE v5.0 grade 3, =< 4 weeks prior to randomization.
  • Ongoing active infection > grade 2 NCI-CTCAE v5.0.
  • Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulation given during the course of this trial.

    • EXCEPTION: Cetuximab
  • Any known history of malabsorption condition.
  • Substance abuse, medical, psychological or social conditions that may interfere with the subject?s participation in the study or evaluation of the study results.
  • Use of any herbal remedy (e.g. St. John?s wort) =< 7 days prior to randomization.
  • Use of strong CYP3A4 inducers or inhibitors =< 7 days prior to randomization.

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): NCT03992456


Locations
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United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
Contact: Laurie A. Mihalik    480-342-4800    mihalik.laurie@mayo.edu   
Principal Investigator: Tanios S. Bekaii-Saab         
United States, California
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
Contact: Zeno E. Ashai    323-865-0463    zeno.ashai@med.usc.edu   
Principal Investigator: Heinz-Josef Lenz         
United States, District of Columbia
MedStar Georgetown University Hospital
Washington, District of Columbia, United States, 20007
Contact: Brenton Foretich    202-444-2198    bjf53@georgetown.edu   
Principal Investigator: Benjamin A. Weinberg         
United States, Georgia
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States, 30322
Contact: Kim Nguyen    404-778-5680    kim.t.nguyen@emory.edu   
Principal Investigator: Christina S. Wu         
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Contact: Francisco J. Cordero    919-681-3095    francisco.cordero@duke.edu   
Principal Investigator: John H. Strickler         
United States, Wisconsin
Aurora Cancer Care-Milwaukee West
Wauwatosa, Wisconsin, United States, 53226
Contact: Jennifer Mathieu    414-302-2312    jennifer.mathieu@aurora.org   
Principal Investigator: Michael A. Thompson         
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: John H Strickler Academic and Community Cancer Research United

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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT03992456    
Other Study ID Numbers: ACCRU-GI-1623
NCI-2019-03306 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACCRU-GI-1623 ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: June 20, 2019    Key Record Dates
Last Update Posted: December 20, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Adenocarcinoma
Rectal Neoplasms
Colonic Neoplasms
Disease Progression
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
Disease Attributes
Pathologic Processes
Trifluridine
Antineoplastic Agents, Immunological
Panitumumab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antimetabolites