Lenvatinib Mesylate and Pembrolizumab in Treating Patients With Metastatic or Recurrent Gastric or Gastroesophageal Cancer

Gastric Adenocarcinoma Clinical Trial

Official title:

A Phase II Study of Lenvatinib, a Multi-Targeted Tyrosine Kinase Inhibitor, Combined With Pembrolizumab for the Treatment of Metastatic Gastroesophageal Cancer Patients Who Have Progressed on First or Subsequent Line Therapies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03413397
• Other study ID #: S17-00626
• Secondary ID: NCI-2017-02333S1
• Status: Recruiting
• Phase: Phase 2
• First received: January 22, 2018
• Last updated: January 22, 2018
• Start date: November 8, 2017
• Est. completion date: November 2021

Study information

• Verified date: January 2018
• Source: New York University School of Medicine
• Contact: Benson Joseph
• Phone: 212-731-5076
• Email: Benson.Joseph[@]nyumc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well lenvatinib mesylate works with pembrolizumab in treating patients with gastric or gastroesophageal cancer that has spread to other places in the body or has come back. Lenvatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving lenvatinib mesylate and pembrolizumab may work better at treating at gastric or gastroesophageal cancer.

Description:

PRIMARY OBJECTIVES:

I. To determine the overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for the combination of lenvatinib mesylate (lenvatinib) and pembrolizumab in patients with metastatic gastroesophageal cancer who have progressed on first or subsequent line(s) therapies.

SECONDARY OBJECTIVES:

I. To determine the progression free survival (PFS), overall survival (OS), and toxicity rates in advanced gastroesophageal patients treated with lenvatinib and pembrolizumab.

TERTIARY OBJECTIVES:

I. To characterize changes in the immune cell phenotype, immune pathway activity, and immune response following lenvatinib only, and then with the addition of pembrolizumab.

OUTLINE:

Patients receive lenvatinib mesylate orally (PO) on days 1-7 of course 1, then on days 1-21 of subsequent courses. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 8 of course 1, then on day 1 of subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 9 and 12 weeks.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 29
• Est. completion date: November 2021
• Est. primary completion date: November 8, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial

• Have histologically or cytologically confirmed metastatic or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma

• Have measurable disease based on RECIST 1.1

• Must have received and have progressed, or are intolerant to at least one systemic regimen (platinum- or fluoropyrimidine-based chemotherapy regimen for metastatic or recurrent disease or progressed within 6 month of completion of adjuvant therapy with a platinum- or fluoropyrimidine-based regimen)

• If Her2 positive, must have received and have progressed or are intolerant to treatment with trastuzumab for metastatic or recurrent disease

• Subjects must consent to provide archival tumor tissue (initial and subsequent tumor biopsy samples, if possible) for correlative biomarker studies

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale

• Adequately controlled blood pressure with or without antihypertensive medications defined as blood pressure (BP) < 140/90 mmHg at screening and no change in antihypertensive mediation within 1 week prior to the screening visit

• Performed within 10 days of treatment initiation: absolute neutrophil count (ANC) >= 1,500 /mcL

• Performed within 10 days of treatment initiation: platelets >= 100,000 / mcL

• Performed within 10 days of treatment initiation: hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

• Performed within 10 days of treatment initiation: serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN

• Performed within 10 days of treatment initiation: serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

• Performed within 10 days of treatment initiation: aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X ULN

• Performed within 10 days of treatment initiation: international normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants

• Performed within 10 days of treatment initiation: activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication

• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

• Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy

• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Has a known history of active TB (Bacillus tuberculosis)

• Hypersensitivity to pembrolizumab or lenvatinib or any of its excipients

• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent

• Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study

• Note: If subject received major surgery, a minimum of four weeks must have passed and they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

• Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24 hours (h) urine collection for quantitative assessment of proteinuria; subjects with urine protein >= 1 g/24h will be ineligible

• Gastrointestinal malabsorption or any other condition in the opinion of the investigator that might affect the absorption of lenvatinib

• Prolongation of corrected QT using Fridericia's formula (QTcF) interval to > 480 ms

• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug

• Arrhythmias requiring class Ia and III antiarrhythmics and/or grade >= 2 bradycardia

• Bleeding disorders or active significant bleeding (i.e. hemoptysis, hematochezia, hematemesis) within 3 weeks

• Thrombotic disorders or use of anticoagulants, such as warfarin, requiring therapeutic international normalized ratio (INR) monitoring; (treatment with low molecular weight heparin (LMWH) or direct acting oral anti-coagulants is allowed)

• History of prior gastrointestinal fistula and/or perforation

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed

• Has known history of, or any evidence of active, non-infectious pneumonitis

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject?s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Has received a live vaccine within 30 days of planned start of study therapy

• Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Related Conditions & MeSH terms

• Adenocarcinoma
• Esophageal Neoplasms
• Gastric Adenocarcinoma
• Gastroesophageal Junction Adenocarcinoma
• Recurrent Gastric Carcinoma
• Stage IV Gastric Cancer AJCC v7
• Stomach Neoplasms

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Lenvatinib Mesylate
Given PO

Biological:
• Pembrolizumab
Given IV

Locations

Country	Name	City	State
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
New York University School of Medicine	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarker analysis	Will consist of descriptive statistical summaries at baseline (means, medians, standard deviations, quantiles, ranges, etc.) and graphical displays (e.g. boxplots). Similar summaries will be provided by changes from baseline and response status for each of the biomarkers under study. Will use non-parametric tests to assess the relationships between PDL1 status, gene expression profiles of interest, and response to combination treatment of pembrolizumab and lenvatinib. Outcome relationships will be largely explorative and descriptive.	Up to 3 years
Primary	Overall response rate defined as partial response (PR) plus complete response (CR), assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria	Best overall response will be calculated as the best response recorded from the start of treatment for each subjects, and will be used for the summaries of objective response. Will be estimated with exact 95% confidence intervals.	Up to 3 years
Secondary	Incidence of adverse events graded by National Cancer Institute Common Terminology Criteria for Adverse Events	Adverse events will be coded using MedDRA (Medical Dictionary for Regulatory Activities).	Up to 30 days after treatment
Secondary	Overall survival	Will be described using Kaplan-Meier curves.	From the start of treatment to the date of subject death (any cause), assessed up to 3 years
Secondary	Progression free survival	Will be described using Kaplan-Meier curves.	From start of treatment to the earlier date of objective disease progression or death due to any cause in the absence of progression, assessed up to 3 years