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 (KEYNOTE B36)

  • STATUS
    Recruiting
  • End date
    Aug 18, 2024
  • participants needed
    66
  • sponsor
    NovoCure GmbH
Updated on 18 September 2022
measurable disease
pembrolizumab
EGFR
lung carcinoma

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.

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.

Details
Condition Non-small Cell Lung Cancer
Treatment NovoTTF-200T
Clinical Study IdentifierNCT04892472
SponsorNovoCure GmbH
Last Modified on18 September 2022

Eligibility

Yes No Not Sure

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
Clear my responses

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