KRAS Gene MutationPhase 2NCT03520842
Regorafenib and Methotrexate in Treating Participants With Recurrent or Metastatic KRAS Mutated Non-Small Cell Lung Cancer
A Phase 2 study testing Methotrexate, Pharmacokinetic Study and Regorafenib in people with KRAS Gene Mutation and Metastatic Malignant Neoplasm in the Brain, run by Stanford University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- KRAS Gene Mutation, Metastatic Malignant Neoplasm in the Brain, Recurrent Non-Small Cell Lung Carcinoma
- What is being tested?
- Methotrexate, Pharmacokinetic Study and Regorafenib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Aug 2018to 15 Jun 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Stanford University School of Medicine
Palo Alto, California, 94304
About this study
Official title: Study of Regorafenib in Combination With Oral Methotrexate for KRAS Mutated Non-Small Cell Lung Cancer (NSCLC)
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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).
- 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.
- 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
- Being tested
- Methotrexate, Pharmacokinetic Study, Regorafenib
- Medical subject headings
- Brain Neoplasms, Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethotrexateDrug
Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate
Given PO
Pharmacokinetic StudyOther
Also called PHARMACOKINETIC, PK Study
Correlative studies
RegorafenibDrug
Also called BAY 73-4506, Stivarga
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (regorafenib, methotrexate) | Experimental | 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. Receives: Drug: Methotrexate; Other: Pharmacokinetic Study; Drug: Regorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS)
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. PFS was 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
Measured: From first study treatment assessed up to 15 months
Secondary outcomes (5)
Objective Response Rate (ORR)
Objective response rate (ORR; as determined by RECIST v1.1) will be assessed as the proportion (percent) of participants with either complete response (CR; disappearance of all target lesions) or partial response (PR; ≥ 30% decrease in the sum of the longest diameter of target lesions), with exact 95% confidence intervals based on a binomial distribution.
Measured: Up to 24 months
Disease Control Rate (DCR)
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
Measured: At 8 weeks
Number of Participants With Adverse Events
Participants who experienced any treatment emergent adverse event and any ≥ grade 3 adverse event is reported.
Measured: Up to 38 months
Trough Serum Concentration of Methotrexate
Pharmacokinetics (PK) of methotrexate when co-administered with regorafenib, as indicated by the trough serum concentration, was accessed by a fluorescent polarization immunoassay, and is 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 were included.
Measured: Cycle 1, Days 1, 8, 15, and 22
Maximum Serum Concentration (Cmax) of Methotrexate
Pharmacokinetics (PK) of methotrexate when co-administered with regorafenib, as indicated by the maximum serum concentration (Cmax) of methotrexate, was assessed by a fluorescent polarization immunoassay, and is 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 were included in the assessment.
Measured: Cycle 1, Days 1, 8, and 15
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 May 2018
- Study start14 Aug 2018
- Primary completion15 Jun 2022
- Study completion15 Jun 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for KRAS Gene MutationStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Heather Wakelee, Stanford University
- Investigators
- Heather Wakelee, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03520842
- Sponsor's protocol ID
- IRB-43398
- Other IDs
- NCI-2018-00413, LUN0097
- Status last verified
- Jul 2023
- First submitted
- 18 Apr 2018
- Last updated
- 1 Aug 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study of Regorafenib in Combination With Oral Methotrexate for KRAS Mutated Non-Small Cell Lung Cancer (NSCLC)
- ClinicalTrials.gov ID
- NCT03520842
- Acronym / sponsor ID
- IRB-43398
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Study start
- 14 Aug 2018 (actual)
- Primary completion
- 15 Jun 2022 (actual)
- Study completion
- 15 Jun 2022 (actual)
- First posted
- 11 May 2018 (actual)
- Results
- Posted 1 Aug 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- 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).
- 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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (regorafenib, methotrexate) | Experimental | Drug: Methotrexate, Other: Pharmacokinetic Study, Drug: RegorafenibParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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
Key exclusion criteria (22 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethotrexateAlso: Abitrexate, Alpha-Methopterin, Amethopterin, BrimexateGiven PO | Drug | Treatment (regorafenib, methotrexate) |
| Pharmacokinetic StudyAlso: PHARMACOKINETIC, PK StudyCorrelative studies | Other | Treatment (regorafenib, methotrexate) |
| RegorafenibAlso: BAY 73-4506, StivargaGiven PO | Drug | Treatment (regorafenib, methotrexate) |
Primary outcome
Progression Free Survival (PFS)
Time frame: From first study treatment assessed up to 15 months
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. PFS was 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
5 secondary outcomes
Objective Response Rate (ORR)
Time frame: Up to 24 months
Disease Control Rate (DCR)
Time frame: At 8 weeks
Number of Participants With Adverse Events
Time frame: Up to 38 months
Trough Serum Concentration of Methotrexate
Time frame: Cycle 1, Days 1, 8, 15, and 22
Maximum Serum Concentration (Cmax) of Methotrexate
Time frame: Cycle 1, Days 1, 8, and 15
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Aug 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Heather Wakelee principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Methotrexate, Pharmacokinetic Study and Regorafenib in people with KRAS Gene Mutation and Metastatic Malignant Neoplasm in the Brain, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Aug 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) (time frame: From first study treatment assessed up to 15 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2023.