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

• ClinicalTrials.gov Identifier: NCT03520842
• Recruitment Status: Active, not recruiting
• First Posted: May 11, 2018
• Last Update Posted: February 28, 2022
• Sponsor: Stanford University
• Information provided by (Responsible Party): Stanford University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
KRAS Gene Mutation; Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer AJCC v7	Drug: Methotrexate; Other: Pharmacokinetic Study; Drug: Regorafenib	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study of Regorafenib in Combination With Oral Methotrexate for KRAS Mutated Non-Small Cell Lung Cancer (NSCLC)
• Actual Study Start Date: August 14, 2018
• Estimated Primary Completion Date: January 1, 2023
• Estimated Study Completion Date: April 1, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (regorafenib, methotrexate); Participants 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.

Drug: Methotrexate; Given PO; Other Names: Abitrexate; 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-19039; Other: Pharmacokinetic Study; Correlative studies; Other Names: PHARMACOKINETIC; PK Study; Drug: Regorafenib; Given PO; Other Names: BAY 73-4506; Stivarga

Outcome Measures

Primary Outcome Measures :

1. 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 ]

   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 :

1. Objective response rate (ORR) [ Time Frame: Up to 24 months ]
   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.
2. Disease control rate (DCR) [ Time Frame: At 8 weeks ]
   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
3. Incidence of adverse events [ Time Frame: Up to 24 months ]

   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.

4. Trough Serum Concentration of Methotrexate [ Time Frame: Day 22 ]
   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.
5. Maximum Serum Concentration (Cmax) of Methotrexate [ Time Frame: Day 15 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologic or cytologic confirmed diagnosis of non-squamous non-small cell lung cancer that is recurrent or metastatic.
• 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

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Palo Alto, California, United States, 94304

Sponsors and Collaborators

Stanford University

Investigators

• Principal Investigator: Heather Wakelee; Stanford University

More Information

• Responsible Party: Stanford University
• ClinicalTrials.gov Identifier: NCT03520842
• Other Study ID Numbers: IRB-43398; NCI-2018-00413 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); LUN0097 ( Other Identifier: OnCore )
• First Posted: May 11, 2018
• Last Update Posted: February 28, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Methotrexate; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors