Lungcancer
Conditions
Keywords
Lung cancer, Non small cell lung cancer, non squamous, pemetrexed, carboplatin, binimetinib, chemotherapy, combination chemotherapy, Phase 1, Princess Margaret Cancer Centre, carcinoma
Brief summary
MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. MEK162 is currently being investigated in phase I clinical testing and has been well tolerated up to an MTD of 45mg BID in cancer patients. There has been little change in survival benefit for patients with non-small cell lung cancer in recent years. Emerging new treatment options relying on molecular and genetic markers are being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer with molecular targeted therapies in combination with standard chemotherapy. This study will be targeting patients with KRAS mutations.
Detailed description
OBJECTIVES 1.1 Primary Objectives * To assess the safety of MEK162 administered in combination with carboplatin and pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC). * To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a continuous dosing schedule together with pemetrexed and carboplatin administered on a 3-weekly schedule as first line treatment in advanced NSCLC. * To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung. 1.2 Secondary Objectives * To characterize the population pharmacokinetics of MEK162 administered in combination with carboplatin and pemetrexed (Phase I). * To explore relationships between KRAS mutation (and sub-types) and additional genomic mutations and objective clinical response. 1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined in section 4.3) as measured with NCI CTC AE v4. Phase Ib • Objective response rate (ORR) as per RECIST v1.1. Secondary Phase I • Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs. Phase Ib * Evaluation of response rate (RR), progression-free survival (PFS) and disease control rate (DCR) for patients with and without KRAS mutation in tumor tissue. * Exploratory analysis of KRAS mutation sub-type. Exploratory end-points • A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.
Interventions
DRUGBinimetinib
Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease. MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule.
DRUGPemetrexed
4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
DRUGCarboplatin
4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
Sponsors
Novartis Pharmaceuticals
University Health Network, Toronto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Subjects eligible for enrolment on the study must meet all of the following criteria: * Patients with histologically confirmed non-squamous EGFR wild-type, ALK-rearrangement negative carcinoma of lung. Patients with neuroendocrine carcinoma, mixed small and non-small cell carcinoma or squamous carcinoma are not eligible. * Tissue available for KRAS mutation status analysis. * Patients must have metastatic disease (Incurable stage IIIB/stage IV). * Patients must have clinically and/or radiographically documented measurable disease. At least one site of disease must be unidimensionally measurable by RECIST v1.1 as follows (Eisenhauer et al.): CT-scan, physical exam ≥10 mm Chest X-ray ≥20 mm Lymph node short axis ≥15 mm * All radiology studies must be performed within 28 days prior to registration (35 days if negative). * Lesions in previously irradiated areas should not be selected unless there is clear evidence of progression in such lesions. * Patients may not have received any prior systemic treatment for metastatic NSCLC. Patients who have received adjuvant treatment or chemoradiation for stage III disease should have completed this ≥12 months prior to study enrollment. * Patients with stable CNS metastases are permitted if stability of disease is documented with imaging ≥28 days after treatment completion, are and off corticosteroids by day 1 of study treatment. * Patients may have had prior malignancy if definitively treated and/or, in the opinion of the investigator, the only active malignancy is NSCLC. Patients with mixed small cell lung cancer histology are excluded. Patients who have received radiotherapy to \>30% bone marrow are excluded. Consult PI if unsure whether second malignancies meet requirements specified above. * In patients treated for other malignancy, all prior treatment-related toxicities must be CTCAE v4.0 ≤ Grade 1 (except alopecia) at the time of enrollment. * Able to swallow and retain oral 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. * Patients receiving medications or substances that are inhibitors or inducers of CYP1A2, CYP2A19, CYP2B6, CYP3A4 and/or UGT1A1 and UGT1A9 are eligible but these drugs must be used with caution (Appendix C). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; * Patients must be aged ≥18 years. * Eastern Cooperative Oncology Group (ECOG) performance status ≤1 * Adequate organ and laboratory parameters, defined below. * Laboratory Requirements - within 7 days prior to enrollment: Haematology: absolute granulocytes ≥1.5 × 109/L platelets ≥100 × 109/L Biochemistry: bilirubin ≤1.25 × institutional upper limit of normal AST(SGOT) ≤2.5 × institutional upper limit of normal /ALT(SGPT) or ≤5 × institutional upper limit of normal in the presence of liver metastases creatinine clearance ≥45 mL/min/1.73 m2 -Patients must be able to provide Informed Consent based on the details below: * absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial * before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Exclusion criteria
* History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): * History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). Patients with prior deep venous thrombosis or pulmonary embolism are permitted. * Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR such as: * Evidence of new optic disc cupping * Evidence of new visual field defects on automated perimetry * Intraocular pressure \>21mmHg as measured by tonography * Any serious and/or unstable pre-existing medical (aside from malignancy exception), psychiatric disorder, or other conditions that could interfere with subjects' safety, obtaining informed consent or compliance to the study procedures, in the opinion of the PI. * History of interstitial lung disease or pneumonitis. * Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal metabolic or cardiac disease). * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (e.g. congenital long QT syndrome, family history of long QT syndrome, hypokalemia) or baseline QTcB interval ≥480 msec. * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months or cardiac metastases. * History or evidence of current clinically significant uncontrolled arrhythmias. * History or evidence of current ≥Class II congestive heart failure as defined by New York Heart Association (NYHA). * Known positivity for Hepatitis B surface antigen or Hepatitis C antibody. * Known Human Immunodeficiency Virus (HIV) infection. * Treatment refractory hypertension defined as a blood pressure systolic \>140 mmHg and/or diastolic \>90 mmHg which cannot be controlled by anti-hypertensive therapy. * Subjects with intra-cardiac defibrillators or permanent pacemakers. * Pregnant or nursing (lactating) women are excluded. * Female patient of child bearing potential must have a negative serum or urine pregnancy test. * Women of child-bearing potential must agree to use of appropriate contraceptive methods throughout the study and for 120 days after, These methods include * Total abstinence or 2 barrier methods or a barrier method plus hormonal method from visit 1 to 120 days after the last dose of treatment. * Men must agree to use an appropriate method of contraception starting with first dose of study drug through 120 days after the last dose of treatment (see above). * Whilst not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, baseline audiograms are recommended and should be followed by repeat audiograms prior to cycle 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dose in Milligrams Per Day for Binimetinib. | 22 weeks | To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Per RECIST v1.1. | 22 weeks | The size of tumors in centimeters before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol. Objective response rate (ORR) was defined as the percentage of patients who achieved a complete or partial response as the best overall response. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Analysis of Objective Response Rate, KRAS Mutation Sub-type. | 22 weeks | Exploratory analysis of mutation subtypes using next generation sequencing (NGS). |
| Progression Free Survival Rate | 26 weeks | Evaluation progression-free survival rate (PFS) for patients with and without KRAS mutation in tumor tissue. PFS is defined as the time from start of treatment to disease progression or death. PFS rate is measured over 6 months period (26 weeks). PFS rate is calculated as a percentage of participants achieving a 6 months (26 weeks) period of progression free survival. |
Countries
Canada
Participant flow
Recruitment details
Participants were enrolled based on physician referral, 1st participant was enrolled on 07 March 2017 and last participant was enrolled on 05 December 2018
Pre-assignment details
Out of 16 patients screened, 13 were enrolled who met the eligibility criteria
Participants by arm
| Arm | Count |
|---|---|
| Binimetinib Dose Level 1 Phase I, dose level 1 group:
The dose of MEK162 for dose level 1 group will be 30 mg BID.
Carboplatin will be given every 3 weeks. Pemetrexed will be given every 3 weeks.
Pemetrexed: 4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
Carboplatin: 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
Minimum number of patients is 3.
The rate of subject entry and escalation to the next dose level will depend upon assessment of the safety profile of patients entered at the previous dose level. | 6 |
| Binimetinib Dose Level 2 Phase I, dose level 2 group:
The dose of MEK162 for dose level 2 group will be 45 mg BID. Carboplatin will be given every 3 weeks. Pemetrexed will be given every 3 weeks.
Pemetrexed: 4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
Carboplatin: 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
Minimum number of patients is 3. The rate of subject entry and escalation to the next dose level will depend upon assessment of the safety profile of patients entered at the previous dose level. | 7 |
| Binimetinib Dose Level -1 Dose de-escalation group:
The dose of MEK162 for dose level -1 group will be 30 mg BID. Carboplatin will be given every 3 weeks. Pemetrexed will be given every 3 weeks.
Pemetrexed: 4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
Carboplatin: 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
Minimum number of patients is 3. The rate of subject entry and escalation or de-escalation will depend upon assessment of the safety profile of patients and dose limiting toxicities. | 0 |
| Total | 13 |
Baseline characteristics
| Characteristic | Binimetinib Dose Level 1 | Binimetinib Dose Level 2 | Binimetinib Dose Level -1 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 0 Participants | 9 Participants |
| Age, Continuous | 63.166 years | 56.428 years | — | 59.538 years |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment Canada | 6 participants | 7 participants | — | 13 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | — | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | — | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 7 | 0 / 0 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 0 / 0 |
| serious Total, serious adverse events | 1 / 6 | 3 / 7 | 0 / 0 |
Outcome results
Primary
Recommended Dose in Milligrams Per Day for Binimetinib.
To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.
Time frame: 22 weeks
Population: One patient was not evaluable for DLT; therefore, an additional patient was enrolled at Dose Level 2.~The outcome measure for the recommended does is 30 mg, both arms were combined in the analysis here in order to report 1 recommended single dose (30mg).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Binimetinib Dose Level 1 & 2 (30mg BID & 45mg BID) | Recommended Dose in Milligrams Per Day for Binimetinib. | 30 mg |
Secondary
Objective Response Rate (ORR) as Per RECIST v1.1.
The size of tumors in centimeters before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol. Objective response rate (ORR) was defined as the percentage of patients who achieved a complete or partial response as the best overall response.
Time frame: 22 weeks
Population: Objective response rate (ORR) was defined as the percentage of patients who achieved a complete or partial response as the best overall response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Binimetinib Dose Level 1 & 2 (30mg BID & 45mg BID) | Objective Response Rate (ORR) as Per RECIST v1.1. | 4 Participants |
| Binimetinib Dose Level 2 (45mg BID) | Objective Response Rate (ORR) as Per RECIST v1.1. | 2 Participants |
Other Pre-specified
Exploratory Analysis of Objective Response Rate, KRAS Mutation Sub-type.
Exploratory analysis of mutation subtypes using next generation sequencing (NGS).
Time frame: 22 weeks
Population: Dose levels are combined as mutation information was obtained for the 12 patients in total and segregated in the results by these 2 groups only. Link to published results/ https://doi.org/10.1016/j.lungcan.2021.05.021
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Binimetinib Dose Level 1 & 2 (30mg BID & 45mg BID) | Exploratory Analysis of Objective Response Rate, KRAS Mutation Sub-type. | 62.5 percentage of participants |
| Binimetinib Dose Level 2 (45mg BID) | Exploratory Analysis of Objective Response Rate, KRAS Mutation Sub-type. | 25 percentage of participants |
Other Pre-specified
Progression Free Survival Rate
Evaluation progression-free survival rate (PFS) for patients with and without KRAS mutation in tumor tissue. PFS is defined as the time from start of treatment to disease progression or death. PFS rate is measured over 6 months period (26 weeks). PFS rate is calculated as a percentage of participants achieving a 6 months (26 weeks) period of progression free survival.
Time frame: 26 weeks
Population: Phase Ib. Evaluation of progression-free survival (PFS) rate for patients with and without KRAS mutation in tumor tissue. PFS is defined as the time from start of treatment to disease progression or death.~PFS rate is calculated as a percentage of participants achieving a 6 months (26 weeks) period of progression free survival.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Binimetinib Dose Level 1 & 2 (30mg BID & 45mg BID) | Progression Free Survival Rate | 38.5 percentage of participants |