EF-36/Keynote B36: A Pilot, Randomized, Open-label Study of Tumor Treating Fields (TTFields, 150 kHz) Concomitant With Pembrolizumab for First Line Treatment of Advanced or Metastatic Non-small Cell Lung Cancer (KEYNOTE B36)

October 4, 2023 updated by: NovoCure GmbH

This is a multicenter, randomized, open-label study of Tumor Treating Fields (TTFields) at 150 kHz to the thorax using the NovoTTF-200T System with IV pembrolizumab in subjects previously untreated for advanced or metastatic, PD-L1 positive non-small cell lung cancer (NSCLC). The primary objective is to evaluate the progression-free survival (PFS) by RECIST 1.1 in subjects with TPS ≥1 percent, 1L metastatic/current advanced NSCLC treated with TTFields concomitant with pembrolizumab compared to those treated with pembrolizumab alone.

The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields) to the region of the malignant tumor, by means of surface, insulated electrode arrays.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

TTFields have demonstrated significant activity in vitro and in NSCLC pre-clinical models, both as a single modality treatment and concomitant with chemotherapies and PD-1 inhibitors. TTFields have demonstrated synergistic activity when administered alongside taxanes; while TTFields used concomitantly with PD-1 inhibition have shown additive effects.

In a pilot study, 42 advanced stage NSCLC patients, who had tumor progression after at least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz) applied to the chest and upper abdomen until disease progression. The combination was well tolerated and the only device-related adverse event was mild to moderate contact dermatitis. Efficacy endpoints were remarkably high compared to historical data for pemetrexed alone.

Preclinical models have been used to assess the potency of TTFields concomitant with checkpoint inhibition. In an in vivo experiment, C57Bl/6 mice had LLC-1 cells injected directly into the lungs. TTFields were applied to the mouse lungs for 7 days in parallel to I.P. injections of anti-PD-1. Concomitant TTFields and anti-PD-1 treatments led to a significant decrease in tumor volume compared to control mice and to mice treated with anti-PD-1 alone. The concomitant treatments also resulted in an increase in the percentage of tumor-infiltrating leukocytes (CD45+). Specifically, there was a significantly higher frequency of macrophages (CD45+/CD11b+/F4/80+) and dendritic cells (CD45+/CD11c+) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1. Concomitant therapy upregulated PD-1 expression on macrophages and dendritic cells in mice, suggesting an adaptive immune response to control the inflammation caused by the treatment. Additionally, cytotoxic T-cells isolated from tumors treated with TTFields and anti-PD-1 demonstrated increased production of IFN-γ. Overall, these findings imply that concomitant TTFields and anti-PD-1 therapy enhanced the immune response, which led to better management of the tumor.

The study will enroll 100 patients, whose tumors are classified as TPS>1% and in whom EGFR or ALK-directed therapy is not indicated, for examination of the effectiveness and safety of TTFields concomitant with pembrolizumab.

In addition, all patients must meet all eligibility criteria.

After a Screening Phase of up to 28 days, subjects will be enrolled to receive TTFields (150 kHz) to the thorax using the NovoTTF-200T device for an average of 18 hours a day concomitant with pembrolizumab 200 mg IV every 3 weeks, or pembrolizumab alone. Each subject will participate in the study for approximately 2 years from the time the subject signs the Informed Consent Form (ICF) through the final contact.

Treatment with TTFields and pembrolizumab will continue for 24 months (TTFields) and until either: (1) 35 study treatments have been administered (pembrolizumab), (2) there is documented disease progression (per iRECIST criteria), (3) unacceptable adverse event(s), (4) intercurrent illness that prevents further administration of treatment, (5) investigator's decision to withdraw the subject, (6) subject withdraws consent, (7) pregnancy of the subject, (8) non-compliance with study treatment or procedure requirements, or (9) administrative/Sponsor decisions.

In case of discontinuation of either of the study treatments due to reasons other than disease progression, the remaining treatment should continue until disease progression or 24 months (TTFields) / 35 cycles (pembrolizumab).

If an alternative anticancer therapy is initiated, the patient will be removed from the study.

Subjects who discontinue all study treatments prior to disease progression will be monitored for disease status in the Observation Phase until: (1) disease progression is confirmed by the site, (2) a non-study cancer treatment is initiated, (3) consent is withdrawn, or (4) the subject is lost to follow-up. Subjects will have post-treatment monthly follow-up by telephone for disease status until death, withdrawing consent, becoming lost to follow-up, or end of the study.

Study Type

Interventional

Enrollment (Estimated)

100

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35209
    • Arizona
      • Glendale, Arizona, United States, 85304
        • Recruiting
        • Palo Verde Cancer Specialists
        • Principal Investigator:
          • Amol Rakkar, MD
        • Contact:
      • Phoenix, Arizona, United States, 85054
        • Recruiting
        • Mayo Clinic
        • Principal Investigator:
          • Vinicius Ernani, MD
        • Contact:
          • Clinical Trials Office
          • Phone Number: 855-776-0015
    • California
      • Long Beach, California, United States, 90806
        • Recruiting
        • Long Beach Memorial Medical Center
        • Contact:
        • Principal Investigator:
          • Nilesh Vora, MD
    • Colorado
      • Colorado Springs, Colorado, United States, 80909
        • Recruiting
        • UCHealth Memorial Hospital
        • Principal Investigator:
          • Robert Hoyer, MD
        • Contact:
    • Florida
      • Lake City, Florida, United States, 32024
        • Recruiting
        • Cancer Care of North Florida
        • Contact:
        • Principal Investigator:
          • Waseemulla Khan, MD
      • Miami, Florida, United States, 33716
        • Recruiting
        • Miami Cancer Insititute - Baptist Health South Florida
        • Contact:
        • Principal Investigator:
          • Rupesh Kotecha, MD
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Recruiting
        • University of Illinois Hospital and Health Sciences System
        • Contact:
    • Indiana
      • Fort Wayne, Indiana, United States, 46845
        • Recruiting
        • Parkview Research Center
        • Contact:
        • Principal Investigator:
          • Charles Vu, MD
      • Indianapolis, Indiana, United States, 46237
        • Recruiting
        • Franciscan St. Francis Health Indianapolis
        • Contact:
        • Principal Investigator:
          • Michael Eaton, MD
    • Kentucky
      • Edgewood, Kentucky, United States, 41017
        • Recruiting
        • Saint Elizabeth Healthcare
        • Contact:
        • Principal Investigator:
          • Colleen Darnell, MD
      • Lexington, Kentucky, United States, 40503
        • Recruiting
        • Baptist Health Oncology Research
        • Principal Investigator:
          • Firas Badin, MD
        • Contact:
    • Michigan
      • Farmington Hills, Michigan, United States, 48334
        • Recruiting
        • Michigan Center of Medical Research
        • Contact:
        • Principal Investigator:
          • Savitha Balaraman, MD
      • Sterling Heights, Michigan, United States, 48314
        • Recruiting
        • Cancer and Leukemia Center
        • Contact:
        • Principal Investigator:
          • Savitha Balaraman, MD
    • Nebraska
      • Lincoln, Nebraska, United States, 68510
    • Nevada
      • Las Vegas, Nevada, United States, 89102
        • Recruiting
        • OptumCare Cancer Care
        • Principal Investigator:
          • John Ellerton, MD
        • Contact:
    • New York
      • Elmira, New York, United States, 14905
        • Recruiting
        • Arnot Ogen Medical Center - Falck Cancer Center
        • Contact:
        • Principal Investigator:
          • Serge Dauphin, MD
    • North Carolina
      • Charlotte, North Carolina, United States, 28210
        • Recruiting
        • Oncology Specialists of Charlotte
        • Contact:
        • Principal Investigator:
          • Justin Favaro, MD
    • Ohio
      • Canton, Ohio, United States, 44718
        • Recruiting
        • Gabrail Cancer Research Center
        • Contact:
        • Principal Investigator:
          • Nashat Gabrail, MD
      • Canton, Ohio, United States, 44710
        • Recruiting
        • Aultman Hospital
        • Contact:
        • Principal Investigator:
          • Raza Khan, MD
    • Pennsylvania
      • Wynnewood, Pennsylvania, United States, 19096
        • Recruiting
        • Lankenau Medical Center
        • Contact:
        • Principal Investigator:
          • Albert DeNittis, MD
    • Tennessee
      • Knoxville, Tennessee, United States, 37909
        • Recruiting
        • Tennessee Cancer Specialists
        • Contact:
        • Principal Investigator:
          • Richard T Lee, MD
    • Texas
      • Dallas, Texas, United States, 75246
        • Recruiting
        • Texas Oncology - Sammons Cancer Center
        • Contact:
        • Principal Investigator:
          • Kartik Konduri, MD
      • Houston, Texas, United States, 77030
        • Recruiting
        • : The University of Texas MD Anderson Cancer Center
        • Contact:
        • Principal Investigator:
          • Aileen Chen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

22 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of stage III or metastatic NSCLC without EGFR sensitizing mutation or ALK translocation
  • Age ≥ 22 years
  • Have a PD-L1 positive (TPS≥1%) tumor by local laboratory assessment
  • Have evaluable (measureable or non-measureable) disease in thorax per RECIST 1.1
  • ECOG performance status of 0 to 1
  • Have not received prior treatments for metastatic or current advanced NSCLC. Palliative treatment is allowed and subjects who received adjuvant, neoadjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease are eligible if therapy completed at least 12 months prior to the development of metastatic or current advanced disease.
  • Life expectancy of at least 3 months
  • Able to operate the NovoTTF-200T device

Exclusion Criteria:

  • Has known active or untreated CNS metastases and/or carcinomatous meningitis
  • Has an EGFR sensitizing mutation and/ or ALK translocation
  • Can be treated with curative intent with either surgical resection and/or chemoradiation
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another stimulatory or co-inhibitory T cell receptor within the past 12 months
  • Has received prior systemic anti-cancer therapy for metastatic or current advanced NSCLC (palliative radiotherapy is allowed)
  • Being unable to operate the NovoTTF-200T device independently or with the help of a caregiver
  • Pregnancy or breastfeeding
  • Received live vaccine in the past 30 days or had major surgery in the last 3 weeks
  • Is expected to require any other form of systemic or localized antineoplastic therapy while on study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm 1: Treatment Group
Pembrolizumab (MK-3475) and TTFields
Device: NovoTTF-200T
All patients enrolled in this group will receive TTFields treatment, delivered for at an average of least 18 hours a day using NovoTTF-200T concomitant with pembrolizumab, a standard immunotherapy agent, which is delivered intravenously.
Drug: Pembrolizumab (MK-3475) 200 mg
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)
Experimental: Arm 2: Control Group
Pembrolizumab (MK-3475)
Drug: Pembrolizumab (MK-3475) 200 mg
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival
Time Frame: 24 months
PFS will be measured from the date of enrollment to date of progression (in months) based on RECIST 1.1 criteria. The analysis will include stratification by PD-L1 expression, TPS≥1-49% and TPS≥50%, as a secondary outcome.
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: 24 months
Survival will be measured from date of enrollment until date of death. The analysis will include patients with PD-L1 expression TPS≥1-49 percent and TPS≥50 percent
24 months
Duration of response (DOR)
Time Frame: 24 months
The analysis will be defined as the time from response to progression/death (P/D) based on RECIST 1.1 criteria
24 months
Objective Response Rate (ORR)
Time Frame: 24 months
Percentage of patients who have a partial or complete response to therapy based on RECIST 1.1 criteria
24 months
Disease control rate (DCR)
Time Frame: 18 weeks
Will be defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response (CR), partial response (PR), and stable disease (SD) by RECIST 1.1 at 18 weeks
18 weeks
Safety and Tolerability: adverse events (AEs)
Time Frame: 24 months
Will be defined as the incidence, frequency and severity of adverse events (AEs) noted in patients treated.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NovoCure GmbH

Collaborators

Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 12, 2021

Primary Completion (Estimated)

July 1, 2024

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

May 13, 2021

First Submitted That Met QC Criteria

May 18, 2021

First Posted (Actual)

May 19, 2021

Study Record Updates

Last Update Posted (Actual)

October 6, 2023

Last Update Submitted That Met QC Criteria

October 4, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EF- 36
  • KEYNOTE-B36 (Other Identifier: Merck Sharp & Dohme Corp)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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