Protocol Summary

Protocol No.: OCR14958

Sponsor Protocol No.: EF-25

Study Title
Pivotal, open-label, randomized study of radiosurgery with or without Tumor Treating Fields (TTFields) for 1-10 brain metastases from non-small cell lung cancer (NSCLC)

Principal Investigator(s)
Tran, David

The study is a prospective, randomized controlled phase III trial, to test the efficacy, safety and neurocognitive outcomes of advanced NSCLC patients, following stereotactic radiosurgery (SRS) for 1-10 brain metastases, treated with NovoTTF-100M compared to supportive treatment alone. 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.

All patients included in this trial are patients with 1-10 supratentorial brain metastases from NSCLC which are amenable to stereotactic radiosurgery (SRS). In addition, all patients must meet all eligibility criteria.

Eligible patients will be randomly assigned to one of two groups:

Patients undergo SRS followed by TTFields using the NovoTTF-100M System
Patients undergo SRS alone and receive supportive care.
Patients in both arms of the study may receive systemic therapy for their NSCLC at the discretion of their treating physician.

Patients will be randomized at a 1:1 ratio. Baseline tests will be performed in patients enrolled in both arms. If assigned to the NovoTTF-100M group, the patients will be treated continuously with the device until second cerebral progression.

On both arms, patients who recur anywhere in the brain will be offered one of the following salvage treatments (according to local practice) including, but not limited to:

Repeat SRS
Whole brain radiotherapy (WBRT)
Patients on the control arm will be offered to cross over to the NovoTTF-100M arm of the study and receive TTFields after salvage therapy for second cerebral progression if the investigator believes it is in the best interest of the patient and patient agrees.

Phase: Phase III

Age Group: Adult

Scope: National

NovoTTF-100M device:
Patients undergo SRS followed by continuous TTFields treatment using the NovoTTF-100M device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the head. The treatment enables the patient to maintain regular daily routine.

Best Standard of Care
Patients will undergo SRS alone and be treated with the best known standard of care for Non-Small Cell Lung Cancer metastatic to the brain.

Detailed Eligibility
1. 18 years of age and older
2. Life expectancy of ≥ 3 months
3. New diagnosis of brain metastases from a histologically or cytologically confirmed primary or metastatic NSCLC tumor within 5 years of registration on the study. If the original histological proof of malignancy is greater than 5 years, then pathological confirmation is required (i.e.: from extra-cranial or intracranial disease).
4. Karnofsky performance status (KPS) ≥ 70
5. Graded Prognostic Assessment (GPA) score ≥ 2.0
6. 1 inoperable brain metastasis or 2- 10 brain lesions per screening MRI, confirmed by contrast enhanced MRI amenable to SRS according to the following criteria:
- largest tumor volume - longest tumor diameter - Cumulative volume of all tumors ≤ 15 cc
7. At least one measurable lesion per RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) Criteria for brain metastasis
8. Patients must be receiving optimal therapy for their extracranial disease according to local practice at each center. Patients may continue on systemic therapy while receiving TTFields.
9. Able to operate the NovoTTF-100M device independently or with the help of a caregiver
10. Clinical trials prior to enrollment are allowed, as long as no brain directed therapy was included (current treatment trials are exclusionary)

1. Patients who are known to have somatic tumor mutations in the following genes, for which targeted agents are available that directly affect the treatment of brain metastasis: Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ROS-1 proto-oncogene, and proto-oncogene B-RAF
2. Patients who have a single, operable brain metastasis
3. Patients with significant edema leading to risk of brain herniation
4. Patients with midline shift > 10mm
5. Patients with intractable seizures
6. Infratentorial metastases
7. Leptomeningeal metastases
8. Recurrent brain metastases or brain metastases previously treated with surgery and/or radiosurgery and/or brain radiotherapy
9. Prior surgical resection or WBRT for newly diagnosed brain metastases (needle biopsy for diagnosis establishment is allowed)
10. Severe comorbidities:
- Clinically-significant inadequate hematological, hepatic and renal function, defined as: Neutrophil count 1.5 x upper limit of normal (ULN); aspartate transaminase (AST) and/or alanine aminotransferase (ALT) > 2.5 x ULN or > 5 x ULN if patient has documented liver metastases; and serum creatinine > 1.5 x ULN
- History of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea).
- History of arrhythmia that is symptomatic or requires treatment. Patients with atrial fibrillation or flutter controlled by medication are not excluded from participation in the trial.
- History of cerebrovascular accident (CVA) within 6 months prior to randomization or that is not stable
- Active infection or serious underlying medical condition that would impair the ability of the patient to received protocol therapy
- History of any psychiatric condition that might impair patient's ability to understand or comply with the requirements of the study or to provide consent
11. Implantable electronic medical devices in the brain
12. Known allergies to medical adhesives or hydrogel
13. Currently pregnant or breastfeeding
14. Concurrent brain directed therapy (beyond SRS and NovoTTF-100M as per protocol)

Applicable Disease Sites

Brain and Nervous System
Lung Cancer

Participating Institutions
UF Gainesville

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