Clinical Trials /

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

NCT03992456

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-GI-1623
  • SECONDARY ID: NCI-2019-03306
  • SECONDARY ID: ACCRU-GI-1623
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03992456

Conditions

  • 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

Interventions

DrugSynonymsArms
PanitumumabABX-EGF, ABX-EGF Monoclonal Antibody, ABX-EGF, Clone E7.6.3, MoAb ABX-EGF, Monoclonal Antibody ABX-EGF, VectibixArm A (panitumumab)
RegorafenibBAY 73-4506, StivargaArm B (regorafenib, trifluridine and tipiracil hydrochloride)
Trifluridine and Tipiracil HydrochlorideLonsurf, TAS 102, TAS-102, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102Arm B (regorafenib, trifluridine and tipiracil hydrochloride)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (panitumumab)ExperimentalPatients 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.
  • Panitumumab
Arm B (regorafenib, trifluridine and tipiracil hydrochloride)Active ComparatorPatients 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.
  • Regorafenib
  • Trifluridine and Tipiracil Hydrochloride

Eligibility 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.
      
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:Time from randomization to death from any cause, assessed for up to 3 years
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure:Overall response rate (ORR)
Time Frame:At 12 months
Safety Issue:
Description: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.
Measure:Clinical benefit rate
Time Frame:At 6 months
Safety Issue:
Description: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.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Patient-reported quality of life
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

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

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