Clinical Trials /

Effect of TTFields (150 kHz) in Non-small Cell Lung Cancer (NSCLC) Patients With 1-10 Brain Metastases Following Radiosurgery (METIS)

NCT02831959

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Effect of TTFields (150 kHz) in Non-small Cell Lung Cancer (NSCLC) Patients With 1-10 Brain Metastases Following Radiosurgery (METIS)
  • Official Title: Pivotal, Open-label, Randomized Study of Radiosurgery With or Without Tumor Treating Fields (TTFields) (150kHz) for 1-10 Brain Metastases From Non-small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: EF-25
  • NCT ID: NCT02831959

Conditions

  • Brain Metastases From Non-small Cell Lung Cancer (NSCLC)

Purpose

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.

Detailed Description

      PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:

      The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in
      vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in
      combination with chemotherapies. TTFields have also shown to inhibit metastatic spread of
      malignant melanoma in in vivo experiment.

      In a pilot study, 42 patients with advanced NSCLC who had 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 (Pless M., et al., Lung
      Cancer 2011). Efficacy endpoints were remarkably high compared to historical data for
      pemetrexed alone.

      In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active
      chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active
      chemotherapy in extending survival, associated with minimal toxicity, good quality of life,
      and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a
      phase III trial of Optune® combined with maintenance temozolomide compared to maintenance
      temozolomide alone has shown that combined therapy led to a significant improvement in both
      progression free survival and overall survival in patients with newly diagnosed glioblastoma
      without the addition of high grade toxicity and without decline in quality of life (Stupp R.,
      et al., JAMA 2015).

      Applying TTFields at 150 kHz to the brain for the treatment of 1-5 brain metastasis from
      NSCLC using the NovoTTF-100M device has been demonstrated to be safe in a pilot study, where
      patients were randomize after local therapy of their brain metastasis by neurosurgery and/or
      stereotactic radiosurgery to receive either NovoTTF-100M treatment or supportive care alone.
      Eighteen (18) patients have been enrolled in the study. There have been no device-related
      serious adverse events (SAE) reported to date (Brozova H., et al., Neuro Oncol 2016).

      DESCRIPTION OF THE TRIAL:

      All patients included in this trial are patients with 1-10 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:

        1. Patients undergo SRS followed by TTFields using the NovoTTF-100M System

        2. 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 intracranial 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:

        -  Surgery

        -  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 intracranial progression if the
      investigator believes it is in the best interest of the patient and patient agrees.

      SCIENTIFIC BACKGROUND:

      Electric fields exert forces on electric charges similar to the way a magnet exerts forces on
      metallic particles within a magnetic field. These forces cause movement and rotation of
      electrically charged biological building blocks, much like the alignment of metallic
      particles seen along the lines of force radiating outwards from a magnet.

      Electric fields can also cause muscles to twitch and if strong enough may heat tissues.
      TTFields are alternating electric fields of low intensity. This means that they change their
      direction repetitively many times a second. Since they change direction very rapidly (150
      thousand times a second), they do not cause muscles to twitch, nor do they have any effects
      on other electrically activated tissues in the body (brain, nerves and heart). Since the
      intensities of TTFields in the body are very low, they do not cause heating.

      The breakthrough finding made by Novocure was that finely tuned alternating fields of very
      low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
      the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
      multiplying, TTFields cause electrically-charged cellular components of these cells to change
      their location within the dividing cell, disrupting their normal function and ultimately
      leading to cell death.. In addition, cancer cells also contain miniature building blocks
      which act as tiny motors in moving essential parts of the cells from place to place. TTFields
      interfere with the normal orientation of these tiny motors related to other cellular
      components since they are electrically-charged as well. As a result of these two effects,
      tumor cell division is slowed, results in cellular death or reverses after continuous
      exposure to TTFields.

      Other cells in the body (normal healthy tissues) are affected much less than cancer cells
      since they multiply at a much slower rate if at all. In addition TTFields can be directed to
      a certain part of the body, leaving sensitive areas out of their reach. Finally, the
      frequency of TTFields applied to each type of cancer is specific and may not damage normally
      dividing cells in healthy tissues.

      In conclusion, TTFields hold the promise of serving as a brand new treatment for brain
      metastases from NSCLC with very few side effects.
    

Trial Arms

NameTypeDescriptionInterventions
NovoTTF-100M deviceExperimentalPatients 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 CareActive ComparatorPatients will undergo SRS alone and be treated with the best known standard of care for Non-Small Cell Lung Cancer metastatic to the brain.

      Eligibility Criteria

              Inclusion Criteria:
      
                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. 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:
      
                     1. largest tumor volume < 10 cc
      
                     2. longest tumor diameter < 3 cm
      
                     3. Cumulative volume of all tumors ≤ 15 cc
      
                6. At least one measurable lesion per RANO-BM (Response Assessment in Neuro-Oncology
                   Brain Metastases) Criteria for brain metastasis
      
                7. 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.
      
                8. Able to operate the NovoTTF-100M device independently or with the help of a caregiver
      
                9. Clinical trials prior to enrollment are allowed, as long as no brain directed therapy
                   was included (current treatment trials are exclusionary)
      
              Exclusion Criteria:
      
                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. Leptomeningeal metastases
      
                7. Recurrent brain metastases
      
                8. Prior WBRT for newly diagnosed brain metastases
      
                9. Severe comorbidities:
      
                     1. Clinically-significant inadequate hematological, hepatic and renal function,
                        defined as: Neutrophil count < 1.5 x 10 9/L and platelet count < 100 x 10^9/L;
                        bilirubin > 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
      
                     2. 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).
      
                     3. 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.
      
                     4. History of cerebrovascular accident (CVA) within 6 months prior to randomization
                        or that is not stable
      
                     5. Active infection or serious underlying medical condition that would impair the
                        ability of the patient to received protocol therapy
      
                     6. 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
      
               10. Implantable electronic medical devices in the brain
      
               11. Known allergies to medical adhesives or hydrogel
      
               12. Currently pregnant or breastfeeding
      
               13. Concurrent brain directed therapy (beyond SRS and NovoTTF-100M as per protocol)
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Time to intracranial progression
      Time Frame:3 years
      Safety Issue:
      Description:

      Secondary Outcome Measures

      Measure:Time to neurocognitive failure
      Time Frame:3 years
      Safety Issue:
      Description:Measured by cognitive decline on a battery of tests: Hopkins Verbal Learning Test (HVLT-R) free recall, delayed recall, and delayed recognition; Controlled Oral Word Association Test (COWAT); and Trail Making Tests (TMT) Parts A and B
      Measure:Overall survival
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Radiological response in the brain
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Time to second intracranial progression
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Time to first and second intracranial progression evaluated in two cohorts, 1-4 brain metastases and 5-10 brain metastases.
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Rate of intracranial progression at 2, 4, 6, 8, 10, 12 months
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Time to distant progression
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Rate of decline in cognitive function at 2, 4, 6, 8, 10, 12 months
      Time Frame:3 years
      Safety Issue:
      Description:Measured by HVLT-R free recall, delayed recall, and delayed recognition; COWAT; and TMT Parts A and B
      Measure:Neurocognitive failure-free survival
      Time Frame:3 years
      Safety Issue:
      Description:Defined from the date of first SRS treatment to neurocognitive failure (as measured by HVLT-R free recall, delayed recall, and delayed recognition; COWAT; and TMT Parts A and B) or death (whichever occurs first), censored at the last neurocognitive assessment on which the patient was reported alive without neurocognitive failure
      Measure:Quality of Life using the EORTC QLQ C30 with BN20 addendum
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:Toxicity during NovoTTF-100M treatment based on incidence and severity of treatment emergent adverse events as evaluated using the CTCAE version 4.0
      Time Frame:3 years
      Safety Issue:
      Description:

      Details

      Phase:Phase 3
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:NovoCure Ltd.

      Trial Keywords

      • Non-Small Cell Lung Cancer
      • NSCLC
      • Brain metastases
      • Treatment
      • Minimal toxicity
      • TTFields
      • TTF
      • Tumor Treating Fields
      • Novocure
      • SRS
      • Stereotactic radiosurgery

      Last Updated

      February 20, 2018