Clinical Trials /

Regorafenib and Methotrexate in Treating Participants With Recurrent or Metastatic KRAS Mutated Non-Small Cell Lung Cancer

NCT03520842

Description:

This phase II trial studies how well regorafenib works together with methotrexate in treating participants with metastatic non-squamous non-small cell lung cancer with tumors that harbor a KRAS mutation. Regorafenib is a targeted therapy that works on different cancer pathways to stop the growth of tumor cells and stop them from spreading. Methotrexate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving regorafenib and methotrexate together may work in treating participants with KRAS mutated non-small cell lung cancer.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Regorafenib and Methotrexate in Treating Participants With Recurrent or Metastatic KRAS Mutated Non-Small Cell Lung Cancer
  • Official Title: Study of Regorafenib in Combination With Oral Methotrexate for KRAS Mutated Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: LUN0097
  • SECONDARY ID: NCI-2018-00413
  • SECONDARY ID: 43398
  • NCT ID: NCT03520842

Conditions

  • KRAS Gene Mutation
  • Metastatic Malignant Neoplasm in the Brain
  • Recurrent Non-Small Cell Lung Carcinoma
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Treatment (regorafenib, methotrexate)
RegorafenibBAY 73-4506, StivargaTreatment (regorafenib, methotrexate)

Purpose

This phase II trial studies how well regorafenib works together with methotrexate in treating participants with metastatic non-squamous non-small cell lung cancer with tumors that harbor a KRAS mutation. Regorafenib is a targeted therapy that works on different cancer pathways to stop the growth of tumor cells and stop them from spreading. Methotrexate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving regorafenib and methotrexate together may work in treating participants with KRAS mutated non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the progression free survival (PFS) of the combination of regorafenib and
      methotrexate for metastatic KRAS mutated non-small cell lung cancer (NSCLC) patients who have
      received at least 1 prior systemic therapy.

      SECONDARY OBJECTIVES:

      I. To determine the objective response rate (ORR) of the combination of regorafenib and
      methotrexate for metastatic KRAS mutated NSCLC patients who have received at least 1 prior
      systemic therapy.

      II. To determine the disease control rate (DCR) at 8 weeks of the combination of regorafenib
      and methotrexate for metastatic KRAS mutated NSCLC patients who have received at least 1
      prior systemic therapy.

      III. To determine the safety of the combination of regorafenib and methotrexate in metastatic
      KRAS mutated NSCLC patients who have received at least 1 prior systemic therapy, assessed as
      the number of subjects that experience a treatment-emergent adverse event.

      IV. To determine the safety of the combination of regorafenib and methotrexate in metastatic
      KRAS-mutated NSCLC patients who have received at least 1 prior systemic therapy, assessed as
      the number (percent) of participants experiencing any dose-limiting toxicity (DLT).

      V. To determine the pharmacokinetic parameters of methotrexate when combined with regorafenib
      (i.e., trough and maximum serum concentration [Cmax]).

      OUTLINE:

      Participants receive regorafenib orally (PO) once daily (QD) and methotrexate PO twice weekly
      with 2-3 days apart on a 3 week on / 1 week off schedule. Courses repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants will come in for an end of study treatment
      visit.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (regorafenib, methotrexate)ExperimentalParticipants receive regorafenib PO QD on days 1-21, and methotrexate PO twice weekly with 2-3 days apart on a 3 week on/ 1 week off cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Methotrexate
  • Regorafenib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologic or cytologic confirmed diagnosis of recurrent or metastatic non-squamous
             non-small cell lung cancer

          -  Documentation of pathogenic KRAS mutation

          -  Previous receipt of at least one systemic therapy for recurrent or metastatic disease
             OR previous receipt of adjuvant systemic therapy within 6 months of enrollment; there
             is no limit on number of prior therapies allowed

          -  Prior systemic therapy must be completed within 2 weeks of study treatment, with
             either improvement of clinically significant treatment-related toxicities to grade 0-1
             OR stabilized to a new baseline

          -  Previously treated OR asymptomatic non-progressing < 1 cm untreated brain metastases
             are allowed

          -  Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
             version 1.1 criteria

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Absolute neutrophil count (ANC) ≥ 1500/mm^3

          -  Platelet count ≥ 100,000 /mm^3

          -  Hemoglobin (Hb) ≥ 9 g/dL

          -  Serum creatinine ≤ 1.5x upper limit of normal (ULN) OR calculated (Cockcroft Gault
             formula) or measured creatinine clearance ≥ 50 mL/min for patients with creatinine
             levels > 1.5x ULN

          -  Total bilirubin ≤ 1.5x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin
             levels > 1.5x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x ULN (≤ 5x ULN
             for patients with liver involvement of their cancer)

          -  Must be able to swallow and retain oral medication

          -  Women patients of childbearing potential and men patients with women partners of
             childbearing potential must agree to use adequate contraception or agree to abstain
             from heterosexual activity beginning at the time of signing informed consent until at
             least 3 months after the last dose of study treatment; post-menopausal women (defined
             as no menses for at least 1 year) and surgically sterilized women are not considered
             childbearing

        Exclusion Criteria:

          -  Previously treated with regorafenib

          -  Known allergy to regorafenib or methotrexate

          -  Currently receiving another systemic standard or investigational anti-cancer therapy;
             prior investigational therapy must be completed within 4 half-lives (if known) or 2
             weeks, whichever is longer; the maximal washout of investigational therapy will not
             exceed 4 weeks prior to study treatment; bone medications such as bisphosphonates and
             receptor activator of nuclear factor kappa-Β (RANK) ligand inhibitors permitted

          -  Leptomeningeal disease as documented by cerebrospinal fluid (CSF) cytology

          -  Clinically significant cardiovascular related disease including:

               -  Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure >
                  90 mmHg on repeated measurements, i.e., 3 or more separate days within one week)
                  despite optimal medical management

               -  Congestive heart failure - New York Heart Association (NYHA) class III or greater

               -  Active coronary artery disease (i.e., unstable or new onset angina within 3
                  months of study treatment; myocardial infarction within 6 months of study
                  treatment)

               -  Clinically significant cardiac arrhythmias other than atrial flutter/fibrillation

               -  Stroke, including transient ischemic attacks, within 6 months of study treatment

               -  Other clinically significant arterial events, except for controlled asymptomatic
                  pulmonary embolism, within 6 months of study treatment

          -  Clinically significant hemorrhage or bleeding event within 1 month of study treatment

          -  Uncontrolled symptomatic pleural effusion or ascites

          -  Known active additional malignancy that is undergoing or expected to undergo systemic
             treatment during duration of study participation

          -  Known history of human immunodeficiency virus (HIV) infection or known current active
             hepatitis B (i.e., hepatitis [Hep] B deoxyribonucleic acid [DNA] positive in prior 3
             months) or hepatitis C infection (i.e., Hep C ribonucleic acid [RNA] positive in prior
             3 months)

          -  Major surgical procedure (e.g., involving the opening of a major body cavity) within 4
             weeks of study treatment; this does not apply to low risk procedures (i.e.,
             thoracentesis; paracentesis; chest tube / PleurX catheter placement; line placement;
             needle biopsy of tumor; and bronchoscopy)

          -  Presence of a clinically significant non-healing wound, non-healing ulcer, or bone
             fracture

          -  Concomitant therapy required at time of first dose of study treatment, including:

               -  Strong CYP3A4 inhibitors and CYP3A4 inducers

               -  Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump
                  inhibitors, and probenecid

          -  Women who are pregnant or breast feeding

          -  Any condition which, in the investigator's opinion, including substance abuse,
             medical, psychological or social conditions that makes the patient unsuitable for
             trial participation or may interfere with the patient's participation in the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS), measured from time of first study treatment until objective tumor progression as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria or death from any cause, whichever occurs earlier.
Time Frame:From first study treatment assessed up to 15 months
Safety Issue:
Description:Progression free survival will be calculated using the Kaplan-Meier method along with 95% confidence interval. RECIST v1.1 criteria are: Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 24 months
Safety Issue:
Description:Objective response rate (ORR) will be assessed as the proportion (percent) of participants with complete response (CR) and partial response (PR), as determined by RECIST v1.1, with exact 95% confidence intervals based on a binomial distribution.
Measure:Disease control rate (DCR)
Time Frame:At 8 weeks
Safety Issue:
Description:Disease control rate (DCR) will be assessed as the proportion of complete responses (CR) + partial responses (PR) + stable disease (SD) after 8 weeks of treatment (+/- 1 week), as determined by using RECIST v1.1
Measure:Incidence of adverse events
Time Frame:Up to 24 months
Safety Issue:
Description:Incidence of adverse events will be assessed as the number (percent) of participants experiencing ANY treatment emergent adverse event. Adverse events will be tabulated by category and severity.
Measure:Dose-limiting toxicities (DLTs)
Time Frame:Up to day 28
Safety Issue:
Description:Will be assessed as the percent of participants experiencing a DLT, which is defined as any of the following occurring: Absolute Neutrophil Count (ANC) <500/mm3 for >7 days Febrile neutropenia [ANC <1000/mm3 temperature of >38.3°C, or ≥38°C sustained for 1+hour] Platelets <25,000/mm3 or ≥Grade 3 thrombocytopenia with bleeding Or any non hematologic treatment related Grade 3 or Grade 4 toxicity, EXCEPT these Grade 3 adverse events: Diarrhea that with dose interruption (DI) + maximal supportive care (MSC) improves to ≤grade 2 in 5 days Nausea/vomiting that with DI+MSC improves to ≤grade 2 in 5 days Mucositis/stomatitis that with DI+MSC improves to ≤grade 2 in 7 days Hand foot skin reaction (HFSR) that with DI+MSC improves to ≤grade 2 in 7 days Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 8x ULN without a bilirubin increase that with DI improves to baseline in 7 days Or any event at the Investigator's discretion
Measure:Trough Serum Concentration of Methotrexate
Time Frame:Day 22
Safety Issue:
Description:Pharmacokinetics (PK) of methotrexate when co-administered with regorafenib, as indicated by the trough serum concentration, will be assessed by a fluorescent polarization immunoassay, and reported as the mean with standard deviation. Participants treated with at least 1 dose of regorafenib and methotrexate and with at least one evaluable baseline pharmacokinetic sample and one follow up trough pharmacokinetic sample treated will be included.
Measure:Maximum Serum Concentration (Cmax) of Methotrexate
Time Frame:Day 15
Safety Issue:
Description:Pharmacokinetics (PK) of methotrexate when co-administered with regorafenib, as indicated by the maximum serum concentration (Cmax) of methotrexate, will be assessed by a fluorescent polarization immunoassay, and reported as the mean with standard deviation. Participants treated with at least 1 dose of regorafenib and methotrexate and with at least one evaluable Cmax pharmacokinetic sample will be included in the assessment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Stanford University

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