MEK Inhibitor Combined With Anlotinib in the Treatment of KRAS-mutated Advanced Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase 1 exploratory study. The study plans to enroll 30 eligible patients to receive the MEK inhibitor trametinib (2 mg) in combination with anlotinib (8 mg, 10 mg, 12 mg). Patients participated in safety follow-up after the first course of treatment until 3 months after discontinuation due to PD or toxicity. Dose-limiting toxicities from the first cycle were collected for phase II combination dose determination. Tumor assessments will be performed at screening followed by follow-up every 4 weeks ± 1 week until objective disease progression or unacceptable toxicity is confirmed. Blood samples will be collected for pharmacokinetic analysis and biomarker discovery at baseline and at each periodic assessment.

Detailed Description
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Inclusion criteria Adult patients (age ≥18 years) with histologically or cytologically confirmed IIIB-IV NSCLC (American Joint Committee on Cancer Staging (8th Edition)). Patients must have a performance status of WHO/Eastern Cooperative Oncology Group 0- 1, weight > 30 kg, good organ and bone marrow function, and no drug contraindications in all patients. Duration of treatment Enrolled patients will continue treatment until disease progression, as assessed by the investigator, unless specific treatment discontinuation criteria are met. Study Drug, Dosage, and Administration Trametinib 2mg will be dosed with anlotinib in all patients starting at week 0. Trametinib will be administered according to prescribing information for general use: 2 mg, QD, PO in dose. Anlotinib is available in three dose levels of 12 mg, 10 mg and 8 mg. Dose escalation was designed according to the 3+3 principle. The initial dose is 8 mg, QD, PO, taken for the first 14 days of each 21-day cycle. If no patients developed DLT in the first treatment cycle, the 10 mg dose was explored. If 1 of 3 patients had a DLT, 3 more patients would need to be included for evaluation at this dose. If >1 out of 3 patients in a given dose group develops DLT, it is suggested that a lower dose group can be explored. If no DLT occurred at the 10 mg dose, the 12 mg dose was explored. The dose may be reduced whenever toxicities that cannot be controlled with best supportive care are identified during the study. The dose may be increased to the next dose level if the subject subsequently tolerated that level of treatment well, according to the investigator's judgment. Treatment will be discontinued if subjects cannot tolerate treatment after dose reduction to 8 mg.

Official Title
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A Phase I Clinical Study to Evaluate the Safety and Efficacy of MEK Inhibitor Combined With Anlotinib in the Treatment of Patients With Advanced KRAS Mutant Non-small Cell Lung Cancer

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Trametinib
* Drug: Anlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in the study subjects should fulfill the following criteria: Age: 18-75 years old, both male and female; ECOG score 0 or 1 point; According to the eighth edition of the International Anti-Cancer Alliance/American Cancer Staging System, patients with stage IIIB-IV non-small cell lung cancer diagnosed by histopathology or cytology Patients with KRAS gene mutation confirmed by the central laboratory; Before the study drug is administered, the previous chemotherapy, immunotherapy or radiotherapy must have been completed for at least 4 weeks, and all related toxic reactions (except for hair loss) have been restored before the study drug is administered (recovered to ≤ Grade 1 or Baseline level); Must be willing to provide tumor tissue samples archived or freshly obtained within 6 months before signing the informed consent form, and the tissue sections should not be less than 6-8 pieces (if less than 6 pieces need to be negotiated with the sponsor, they can be included in the group after consent) According to the RECIST v1.1 standard, patients must have measurable target lesions that can be examined by CT or MRI Patients need to meet the following laboratory test results, which need to be completed within 14 days before the first administration: 1) Routine blood test (no blood transfusion or correction with hematopoietic stimulating factor drugs within 14 days before screening): Hemoglobin ( HB) ≥90 g/L; Absolute neutrophil count (ANC) ≥2.0×109/L; Absolute lymphocyte count (LC) ≥0.5×109/L; Platelet count (PLT) ≥100×109/ L; White blood cell count (WBC) ≥4.0×109/L and ≤15×109/L. 2) Biochemical examination (no blood transfusion or albumin within 14 days before screening): AST and ALT≤2.5 ULN (if there is tumor liver metastasis, ≤5 ULN); ALP≤2.5 ULN (if there is tumor bone metastasis, ≤5 ULN) ; TBiL≤1.5 ULN; ALB≥30 g/L; Cr≤1.5 ULN, and creatinine clearance (CrCL)≥60 mL/min (Cockcroft-Gault formula); APTT≤1.5 ULN, and INR or PT≤1.5 ULN ( Did not receive anticoagulation therapy); Women of childbearing age must undergo a serum pregnancy study within 3 days before the first medication, and the result is negative. Women of childbearing age and men whose partners are women of childbearing age must agree to use high-efficiency methods of contraception during the study period and within 180 days after the last administration of the study drug Volunteer to participate in clinical research, good compliance, and signed informed consent. Exclusion Criteria: Subjects must not enter the study if any of the following exclusion criteria are fulfilled: Have previously received specific MEK inhibitors or treatment programs containing Anlotinib; Those who have participated in other clinical trials and used other trial-related drugs within 4 weeks before the start of study administration; Concomitant treatment with other anti-tumor drugs during the study period (hormone therapy is acceptable); Patients with active central nervous system (CNS) damage (ie, imaging instability, symptomatic damage). Note: For patients receiving stereotactic radiotherapy or surgical treatment, no brain disease progression during the period of 3 months or more can be selected; Within 4 weeks before the start of the study treatment, the occurrence of grade 3 bleeding symptoms specified in the National Cancer Institute's Common Terminology Standards for Adverse Events (NCI CTCAE v4.03); Concomitant diseases or infectious diseases that have not been controlled; For pre-menopausal women (postmenopausal women must have been menopausal for at least 12 months to be considered infertile) serum pregnancy test results are positive or judged by the investigator, during the study period and at least 30 days after the last administration of the study drug, Willing to become pregnant, breastfeeding, or unwilling to use effective contraceptive measures (including female spouses of male subjects of childbearing age); Other severe, acute, or chronic clinical or mental diseases or laboratory abnormalities that may increase the risk of participating in research and research medication, or may interfere with the interpretation of research results. There are EGFR mutations and ALK fusions; Intravenous or oral drugs that are being received and cannot be stopped at least 2 weeks before the start of the study treatment and during the study period and the protocol forbidden to affect CYP isoenzymes (strong inducers, strong inhibitors and enzyme substrates of CYP2C9 and CYP 2C19) (Appendix 17-3, 17-4); Inability to swallow capsules or intractable nausea and vomiting, malabsorption, extracorporeal bile shunt, or any significant small bowel resection that may prevent the full absorption of the study drug; ECG QTcB ≥480msec corrected by Bazetts formula at screening or a history of congenital long QT syndrome; Within 6 months before study administration, any of the following conditions occurred: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, severe arrhythmia requiring medication , Uncontrollable hypertension, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; Active/chronic human immunodeficiency virus (HIV), syphilis, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. Active/chronic HBV infection is defined as HBsAg or HBV DNA positive, and chronic HCV is defined as anti-HCV antibody or HCV RNA positive; Interstitial lung disease or interstitial pneumonia, including clinically significant radiation pneumonia (that is, affecting daily life activities or requiring intervention and treatment); Medical history of allogeneic bone marrow transplantation or organ transplantation; Existence of other active malignant tumors, or a history of other malignant tumors other than NSCLC in the past 5 years, excluding any type of carcinoma in situ, skin basal cell carcinoma or squamous cell carcinoma that has been cured in the past Known to have chronic liver disease;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anlotinib + Trametinib<br>Anlotinib given orally, once daily in 21-day cycle (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21) plus trametinib 2 milligrams (mg) given orally, once daily. | Drug: Trametinib<br>* Trametinib 2 mg given orally, once daily<br>Drug: Anlotinib<br>* Anlotinib capsules given orally, dose ranging from 8 mg to 12 mg once daily in 21-day cycle (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21). The initial dose is 8 mg, QD, PO, taken for the first 14 days of each 21-day cycle. If no patients developed DLT in the first treatment cycle, the 10 mg dose was explored. If 1 of 3 patients had a DLT, 3 more patients would need to be included for evaluation at this dose. If >1 out of 3 patients in a given dose group develops DLT, it is suggested that a lower dose group can be explored. If no DLT occurred at the 10 mg dose, the 12 mg dose was explored.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | DLT defined as any of the following events occurring during the study related to drugs : （1） ≥grade 3 non-hematologic toxicity, except for the following conditions: Nausea, vomiting, diarrhea, constipation, electrolyte imbalance that downgrade within 1 week after supportive treatment； Grade 3 fatigue ≤ 7 days duration； Grade 3 hypertension that can be controlled within 1 week by medication； Alopecia, fever caused by tumor or infection, and elevated alkaline phosphatase; （2）Grade 4 neutropenia, thrombocytopenia, and hemoglobin reduction confirmed by at least 2 tests within 2 days; Grade 3 thrombocytopenia with bleeding tendency confirmed by at least 2 tests within 2 days; （3）Grade 3 neutropenia with fever confirmed at least 2 times within 2 days (neutrophil count <1.0×109 / L; fever ≥38.5℃) （5）Decreased ventricular ejection fraction ≥ grade 2 ； （6）Retinal vein occlusion (RVO), uveitis ≥ grade 2 , and other more serious ocular toxicity | Baseline up to 21 days | 
| Maximum tolerated dose (MTD) | MTD defined as the highest dose level at which less than or equal to 2 of 6 subjects experience dose limiting toxicity (DLT) | Baseline up to 21 days | 
| Determine the Recommended Phase II Dose (RP2D) | The RP2D defined as the lower dose level to MTD based on the safety profile | Up to approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS-Progression Free Survival (PFS) | The time from the start of systemic treatment date to the date of first documented disease progression (event: disease progression - DP, based on RECIST, death, adverse events, which provide to disqualification from further therapy). | Up to approximately 18 months | 
| Overall response rate (ORR) according to RECIST Version 1.1 | According to RECIST 1.1, the proportion of subjects whose tumors were assessed as CR+PR by subcenter imaging evaluation was recorded from the time they were first treated until disease progression or initiation of a new anticancer treatment. | Up to approximately 18 months | 
| Disease control rate (DCR) | Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) and Stable Disease (SD) | Up to approximately 18 months | 
| Overall survival (OS) | OS defined as the time from randomization to death from any cause. Participants who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive | Up to approximately 24 months | 
| Adverse Event (AE) | adverse event caused by the combination | up to approximately 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS Mutations; anlotinib; MEK inhibitor