KEYNOTE B36: Effect of Tumor Treating Fields (TTFields) (150 kHz) Concurrent With Pembrolizumab for Treatment of Advanced Non-small Cell Lung Cancer (NSCLC)

Sponsor

NovoCure GmbH (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04892472

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Locations

Arm

36.7

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, single arm, open-label study of Tumor Treating Fields (TTFields) at 150 kHz to the thorax using the NovoTTF-200T System concomitant with IV pembrolizumab in subjects previously untreated for their advanced or metastatic intrathoracic, PD-L1 positive non-small cell lung cancer (NSCLC). The primary objective is to evaluate the objective response rate (ORR) by RECIST 1.1 in subjects with TPS ≥1 percent.

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

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer	Device: NovoTTF-200T	Phase 2

Detailed Description

TTFields have demonstrated significant activity in in-vitro and NSCLC pre-clinical models, both as a single modality treatment and in combination with chemotherapies and PD-1 inhibitors. With taxanes, TTFields have been demonstrated to act synergistically, while TTFields have been shown to be additive when combined with PD-1 inhibition.

In a pilot study of 42 patients with advanced NSCLC who had tumor progression after at least one line of prior chemotherapy, all participants 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.

The potency of TTFields combined with checkpoint inhibition has been investigated in pre-clinical models. In an in-vivo experiment, C57Bl/6 mice were injected directly into the lungs with LLC-1 cells. Application of TTFields to the mouse lungs was maintained for 7 days and parallel to the ongoing I.P. injection of anti-PD-1. The combined treatment of TTFields and anti-PD-1 led to a significant decrease in tumor volume as compared to control mice and to mice treated with anti-PD-1 alone. The combined treatment 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 DCs (CD45+/CD11c+) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1. The PD-L1 expression levels of these cells were increased as compared to the control group suggesting an adaptive immune attempt to limit the inflammatory response elicited by the combined treatment. Compatibly, cytotoxic T-cells isolated from tumors treated with TTFields and anti-PD-1 demonstrated increased production of IFN-γ. 061

Taken together, these results suggest that the combination of TTFields and anti-PD-1 augmented the immune response resulting in improved tumor control.

The study will enroll 66 patients, whose tumors are classified as TPS>1% and in whom EGFR or ALK-directed therapy is not indicated, are projected to be enrolled in this study for examination of the effectiveness and safety of TTFields concomitant with pembrolizumab.

In addition, all patients must meet all eligibility criteria.

Subjects will be enrolled after a Screening Phase of up to 28 days to receive TTFields at 150 kHz to the thorax using the NovoTTF-200T System for at least 18 hours a day on average concomitant with pembrolizumab 200 mg IV every 3 weeks. 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 Design

Study Type:

Interventional

Anticipated Enrollment :

66 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 12, 2021

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study Arm Pembrolizumab and TTFields	Device: NovoTTF-200T All patients enrolled in the study will receive TTFields treatment, delivered for at least 18 hours a day on average using NovoTTF-200T together with pembrolizumab, a standard immunotherapy agent, which is delivered intravenously. Other Names: Drug: Pembrolizumab

Arm

Intervention/Treatment

Experimental: Study Arm

Pembrolizumab and TTFields

Device: NovoTTF-200T

All patients enrolled in the study will receive TTFields treatment, delivered for at least 18 hours a day on average using NovoTTF-200T together with pembrolizumab, a standard immunotherapy agent, which is delivered intravenously.

Other Names:

Drug: Pembrolizumab

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [24 months]
ORR will be measured from the date of enrollment to date of progression (in months) based on RECIST 1.1 criteria. The analysis will include patients with PD-L1 expression TPS≥1-49 percent and TPS≥50 percent as a Secondary Outcome

Secondary Outcome Measures

Overall survival (OS) [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
Progression Free Survival (PFS) [24 months]
The analysis will be estimated proportions of patients who are progression-free based on the RECIST 1.1 criteria following the time of enrollment. The analysis will include patients with PD-L1 expression TPS≥1-49 percent and TPS≥50 percent
Progression Free Survival at 6 months (PFS6) [6 months]
The analysis will be estimated proportions of patients who are progression-free at 6 months based on the RECIST 1.1 criteria following the time of enrollment
1-year survival rates [12 months]
The analyses will be performed based on estimated proportions of patients who are alive at one year following enrollment
Duration of response (DOR) [24 months]
The analysis will be defined as the time from response to progression/death (P/D) based on RECIST 1.1 criteria
Disease control rate (DCR) [24 months]
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
Safety and Tolerability: adverse events (AEs) [24 months]
Will be defined as the incidence, frequency and severity of adverse events (AEs) noted in patients treated with TTFields concomitant with pembrolizumab, as well as their association with study treatments

Eligibility Criteria

Criteria

Ages Eligible for Study:

22 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed, newly diagnosed unresectable stage III or metastatic (M1a) intrathoracic NSCLC without EGFR sensitizing mutation or ALK translocation
Age ≥ 22 years
Have a PD-L1 positive (TPS≥1%) tumor by local laboratory assessment
Measurable disease by RECIST 1.1
ECOG performance status of 0 to 1
Have not received prior systemic treatments for NSCLC.
Life expectancy of at least 3 months
Able to operate the NovoTTF-200T system

Exclusion Criteria:

Has an extrathoracic metastasis (i.e. M component is M1b or M1c)
Has an EGFR sensitizing mutation and/ or ALK translocation
If Stage III, can be treated with curative intent with either surgical resection and/or chemoradiation
Has received prior systemic anti-cancer therapy or prior radiotherapy for NSCLC (palliative radiotherapy is allowed)
Being unable to operate the NovoTTF-200T device independently or with the help of a caregiver
Pregnancy or breastfeeding
Significant illnesses not associated with the primary disease
Implanted electronic devices (e.g. pacemaker) in the upper torso

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Alabama Research	Birmingham	Alabama	United States	35209
2	Palo Verde Cancer Specialists	Glendale	Arizona	United States	85304
3	Mayo Clinic	Phoenix	Arizona	United States	85054
4	Long Beach Memorial Medical Center	Long Beach	California	United States	90806
5	UCHealth Memorial Hospital	Colorado Springs	Colorado	United States	80909
6	Cancer Care of North Florida	Lake City	Florida	United States	32024
7	Miami Cancer Insititute - Baptist Health South Florida	Miami	Florida	United States	33716
8	AdventHealth Orlando Research Institute	Orlando	Florida	United States	32804
9	Parkview Research Center	Fort Wayne	Indiana	United States	46845
10	Baptist Health Oncology Research	Lexington	Kentucky	United States	40503
11	Central Maine Medical Center	Lewiston	Maine	United States	04240
12	Michigan Center of Medical Research	Farmington Hills	Michigan	United States	48334
13	Cancer and Leukemia Center	Sterling Heights	Michigan	United States	48314
14	OptumCare Cancer Care	Las Vegas	Nevada	United States	89102
15	Arnot Ogen Medical Center - Falck Cancer Center	Elmira	New York	United States	14905
16	Oncology Specialists of Charlotte	Charlotte	North Carolina	United States	28210
17	Aultman Hospital	Canton	Ohio	United States	44710
18	Gabrail Cancer Research Center	Canton	Ohio	United States	44718
19	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
20	Tennessee Cancer Specialists	Knoxville	Tennessee	United States	37909
21	Texas Oncology - Sammons Cancer Center	Dallas	Texas	United States	75246
22	: The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030