Non-small Cell Lung CancerPhase 2NCT03232892
Trametinib in Patients With Advanced Neurofibromatosis Type 1 (NF1)-Mutant Non-small Cell Lung Cancer
A Phase 2 study testing Trametinib in people with Non-small Cell Lung Cancer, run by University of California, San Francisco at 1 site in United States.
Trial summary
Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer
- What is being tested?
- Trametinib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Feb 2018to 11 Sep 2019
- 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
- Histologically or cytologically confirmed metastatic or unresectable locally advanced, non-squamous, NSCLC.
- Documented non-synonymous somatic mutation in NF1 in any tumor specimen or cell-free DNA assay by Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory.
- Received at least one prior line of cancer therapy for the treatment of NSCLC; this should include at least one of the following: platinum (carboplatin or cisplatin) doublet chemotherapy (acceptable combinations include: paclitaxel, docetaxel, abraxane, pemetrexed, gemcitabine, vinorelbine, or etoposide), anti-PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab), or appropriate targeted therapy in patients with activating EGFR (osimertinib, erlotinib, gefitinib, or afatinib), ALK (alectinib, crizotinib, ceritinib, brigatinib, or loralatinib), or ROS-1 (crizotininb or entrectinib) alterations; therapy may be given as monotherapy or in combination with other cancer therapy (e.g. bevacizumab, ipilumimab)
- Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). Patients whose tumors were found to have an EGFR T790M mutation must also have progressed or been intolerable to treatment with osimertinib.
- Patients with a known Anaplastic lymphoma kinase (ALK)-rearrangement must have progressed or been intolerant to treatment with at least one ALK TKI: crizotinib ceritinib, alectinib,brigatinib, or loralatinib
- Patients with a known ROS-1-rearrangement must have progressed or been intolerant to treatment with crizotinib or entrectinib
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- Patients with PDL1 level of >= 50%, who do not have an ALK-rearrangement or EGFR-mutation, must have progressed or been intolerant to treatment with anti-PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab)
- Documented disease progression or intolerance to treatment either during or after treatment with most recent therapy.
- Willingness to undergo research biopsy.
- Measurable disease defined by RECIST 1.1 criteria.
- Life expectancy of at least 3 months.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
- Age ≥ 18 years.
- Resolution of all acute toxic effects of prior chemotherapy, immunotherapy, radiotherapy or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grade 1.
- Adequate baseline organ function defined as follows:
- Hematologic:
- Absolute neutrophil count: ≥ 1.2 x 10^9/L
- Hemoglobin: ≥ 9 g/dL
- Platelets: ≥ 100 x 10^9/L
- PT/INR and PTT: ≤ 1.5 x upper limit of normal (ULN)
- Hepatic:
- Albumin: ≥ 2.5 g/dL
- Total bilirubin: ≤ 1.5 x ULN
- AST and ALT: ≤ 2.5 x ULN
- Renal:
- Creatine: ≤ 1.5 ULN or
- Calculated creatinine clearance (calculated by the Cockcroft-Gault formula): ≥ 50 mL/min
- Cardiac:
- Left Ventricular Ejection Fraction (LVEF): ≥ lower limit of normal (LLN) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
- Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to study enrollment. The effects of trametinib on the developing human fetus are unknown. For this reason and because animal studies with trametinib have shown reproductive toxicity, women of child-bearing potential and men must agree to use effective methods of contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study participation, and for 4 months following discontinuation of trametinib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration.
- Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
- All prior treatment- related toxicities must be CTCAE (Version 4.03) ≤ Grade 1 (except alopecia) at the time of randomization
- Ability to understand a written informed consent document, and the willingness to sign it.
Who cannot join
- Known mutation in KRAS at position G12, G13, or Q61.
- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Treated brain metastases are allowed as long as they are stable for at least 28 days post-treatment.
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with trametinib . Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib, breastfeeding should be discontinued if the mother is treated with trametinib.
- History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer and/or subjects with indolent second malignancies are eligible.
- Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
- The subject has received cytotoxic chemotherapy, molecular targeted therapy, or immunotherapy within 21 days before the first dose of study drug (trametinib).
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- Prior treatment with MEK inhibitor.
- History of interstitial lung disease or pneumonitis.
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).
- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to study enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to study enrollment.
- History of retinal vein occlusion (RVO).
- Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
- History or evidence of cardiovascular risk including any of the following:
- LVEF < LLN
- A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480 msec;
- History or evidence of current clinically significant uncontrolled arrhythmias.
- Clarification: Subjects with atrial fibrillation controlled (defined as not requiring change in cardiac drug dosing, emergency room visit, or hospital admission) for > 30 days prior to dosing are eligible.
- History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study enrollment.
- History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association (NYHA).
- Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy;
- Patients with intra-cardiac defibrillators.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94115
About this study
Official title: Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer
Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.
Read the detailed description
This is a phase II, single-arm, open-label, multicenter clinical trial evaluating the efficacy and safety of trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors non-synonymous NF1 mutations and are KRAS wildtype. Eligible patients must have documented disease progression either during or after treatment with most recent therapy and may not have received prior treatment with a MEK inhibitor. Patients with activating alterations in EGFR, ALK, and ROS-1 must also have received appropriate TKI treatment. Patients who meet eligibility criteria will receive trametinib monotherapy and followed for the primary endpoint of objective response rate and additional secondary endpoints. A total of 27 patients will be enrolled into the study, with the goals of obtaining 24 evaluable patients. Patients may continue treatment until disease progression or up to 24 months from the time of study entry or until the study is closed. All patients will be followed for 12 months.
- Conditions
- Non-small Cell Lung Cancer
- Being tested
- Trametinib
- Keywords
- NSCLC, NF-1 mutant
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TrametinibDrug
Also called Mekinist
Trametinib 2mg, once daily, PO, 28-day cycles
| Study group | Role | What they receive |
|---|---|---|
| Trametinib 2.0mg PO daily | Experimental | Trametinib 2.0mg PO daily in 28-day cycles. A maximum of two trametinib dose level reductions are allowed (1.5mg and 1mg) in the case of adverse reactions. Receives: Drug: Trametinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR)
For participants receiving at least one dose of study treatment, the ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.
Measured: Up to 1 year
Secondary outcomes (4)
Duration of Response (DR)
The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).
Measured: Up to 4 years
Disease Control Rate (DCR) According to RECIST Version 1.1 Criteria.
DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).
Measured: Up to 4 years
Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria.
PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.
Measured: Up to 1 year
Overall Survival (OS)
OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.
Measured: Up to 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2017
- Study start13 Feb 2018
- Primary completion11 Sep 2019
- Study completion11 Sep 2019
Why it stopped: Low Accrual
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 Non-small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe 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
- Model description
- Phase 2, single-arm, open label, multicenter clinical trial.
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals, American Cancer Society, Inc.
- Responsible party
- Sponsor
- Investigators
- Collin Blakely, MD, PhD, Study chair, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03232892
- Sponsor's protocol ID
- 166521
- Other IDs
- NCI-2017-02295
- Status last verified
- Nov 2019
- First submitted
- 14 Jul 2017
- Last updated
- 3 Dec 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Will not be shared
Study at a glance
From the registry record, last updated by the sponsor on 3 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer
- ClinicalTrials.gov ID
- NCT03232892
- Acronym / sponsor ID
- 166521
- Conditions
- Non-small Cell Lung Cancer
- Keywords
- NSCLC, NF-1 mutant
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Low Accrual
- Enrolment
- 1 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals, American Cancer Society, Inc.
- Study start
- 13 Feb 2018 (actual)
- Primary completion
- 11 Sep 2019 (actual)
- Study completion
- 11 Sep 2019 (actual)
- First posted
- 28 Jul 2017 (actual)
- Results
- Posted 3 Dec 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.
Detailed description
This is a phase II, single-arm, open-label, multicenter clinical trial evaluating the efficacy and safety of trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors non-synonymous NF1 mutations and are KRAS wildtype. Eligible patients must have documented disease progression either during or after treatment with most recent therapy and may not have received prior treatment with a MEK inhibitor. Patients with activating alterations in EGFR, ALK, and ROS-1 must also have received appropriate TKI treatment. Patients who meet eligibility criteria will receive trametinib monotherapy and followed for the primary endpoint of objective response rate and additional secondary endpoints. A total of 27 patients will be enrolled into the study, with the goals of obtaining 24 evaluable patients. Patients may continue treatment until disease progression or up to 24 months from the time of study entry or until the study is closed. All patients will be followed for 12 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Phase 2, single-arm, open label, multicenter clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Trametinib 2.0mg PO daily | Experimental | Drug: TrametinibTrametinib 2.0mg PO daily in 28-day cycles. A maximum of two trametinib dose level reductions are allowed (1.5mg and 1mg) in the case of adverse reactions. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (33 listed)
- Histologically or cytologically confirmed metastatic or unresectable locally advanced, non-squamous, NSCLC.
- Documented non-synonymous somatic mutation in NF1 in any tumor specimen or cell-free DNA assay by Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory.
- Received at least one prior line of cancer therapy for the treatment of NSCLC; this should include at least one of the following: platinum (carboplatin or cisplatin) doublet chemotherapy (acceptable combinations include: paclitaxel, docetaxel, abraxane, pemetrexed, gemcitabine, vinorelbine, or etoposide), anti-PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab), or appropriate targeted therapy in patients with activating EGFR (osimertinib, erlotinib, gefitinib, or afatinib), ALK (alectinib, crizotinib, ceritinib, brigatinib, or loralatinib), or ROS-1 (crizotininb or entrectinib) alterations; therapy may be given as monotherapy or in combination with other cancer therapy (e.g. bevacizumab, ipilumimab)
- Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). Patients whose tumors were found to have an EGFR T790M mutation must also have progressed or been intolerable to treatment with osimertinib.
- Patients with a known Anaplastic lymphoma kinase (ALK)-rearrangement must have progressed or been intolerant to treatment with at least one ALK TKI: crizotinib ceritinib, alectinib,brigatinib, or loralatinib
Key exclusion criteria (21 listed)
- Known mutation in KRAS at position G12, G13, or Q61.
- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Treated brain metastases are allowed as long as they are stable for at least 28 days post-treatment.
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with trametinib . Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib, breastfeeding should be discontinued if the mother is treated with trametinib.
- History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer and/or subjects with indolent second malignancies are eligible.
- Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
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 |
|---|---|---|
| TrametinibAlso: MekinistTrametinib 2mg, once daily, PO, 28-day cycles | Drug | Trametinib 2.0mg PO daily |
Primary outcome
Objective Response Rate (ORR)
Time frame: Up to 1 year
For participants receiving at least one dose of study treatment, the ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.
4 secondary outcomes
Duration of Response (DR)
Time frame: Up to 4 years
Disease Control Rate (DCR) According to RECIST Version 1.1 Criteria.
Time frame: Up to 4 years
Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria.
Time frame: Up to 1 year
Overall Survival (OS)
Time frame: Up to 1 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Dec 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. Will not be shared
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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.
Collin Blakely, MD, PhD study chair
University of California, San Francisco
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 Trametinib in people with Non-small Cell Lung Cancer, run by University of California, San Francisco 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 33 inclusion and 21 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: stopped early, as of the sponsor's last update on 3 Dec 2019. 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 3 Dec 2019). 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?
Objective Response Rate (ORR) (time frame: Up to 1 year). 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 3 Dec 2019.