Effect of Tumor Treating Fields (TTFields) (150 kHz) as Second Line Treatment of Non-small Cell Lung Cancer (NSCLC) in Combination With PD-1 Inhibitors or Docetaxel (LUNAR)

Non-Small Cell Lung Cancer Clinical Trial

— LUNAR  

Official title:

LUNAR: Pivotal, Randomized, Open-label Study of Tumor Treating Fields (TTFields) (150 kHz) in Combination With PD-1 Inhibitors or Docetaxel, for Second Line Treatment of Non-small Cell Lung Cancer (NSCLC)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02928588
• Other study ID #: EF-24
• Status: Not yet recruiting
• Phase: Phase 3
• First received: October 6, 2016
• Last updated: October 6, 2016
• Start date: November 2016
• Est. completion date: November 2020

Study information

• Verified date: October 2016
• Source: NovoCure Ltd.
• Contact: Birgit Allmendinger
• Email: BAllmendinger[@]novocure.com
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The study is a prospective, randomized controlled phase III trial aimed to test the efficacy and safety of Tumor Treating Fields (TTFields) in combination with PD-1 inhibitors or docetaxel, for second line treatment of Non-small Cell Lung Cancer (NSCLC) .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:

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 and PD-1 inhibitors. TTFields have been demonstrated to act synergistically with taxanes and have been shown to be additive when combined with PD-1 inhibitors. In addition, TTFields have 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). 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.

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).

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with squamous or non-squamous, unresectable, locally advanced or metastatic NSCLC who had disease progression while on or after front-line treatment. In addition, all patients must meet all eligibility criteria.

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

1. Patients receive docetaxel or PD-1 inhibitor in combination with TTFields using the NovoTTF-100L System.

2. Patients receive docetaxel or PD-1 inhibitor without TTFields.

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-100L group, the patients will be treated continuously with the device until irPD in the thorax/liver (lung cancer progression based on Imune Related Response Criteria (irRC)).

On both arms, patients who have irPD will switch to a third line treatment according to local practice.

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 NSCLC with very few side effects.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 512
• Est. completion date: November 2020
• Est. primary completion date: November 2020
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 18 years of age and older

2. Life expectancy of = 3 months

3. Histological diagnosis of squamous or non-squamous, unresectable, locally advanced or metastatic NSCLC

4. Diagnosis of first radiological progression according to RECIST Criteria V1.1 while on or after front-line treatment, within 14 days of randomization

5. ECOG Score of 0-1

6. Assigned by the physician to receive either docetaxel or PD-1 inhibitor per standard of care regimens

7. Able to operate the NovoTTF-100L device independently or with the help of a caregiver

8. Signed informed consent for the study protocol

Exclusion Criteria:

1. Presence of brain metastasis or leptomeningeal spread of the disease

2. Prior surgery or radiation therapy in the lungs (except for palliation purposes)

3. Severe comorbidities:

1. Clinically significant (as determined by the investigator) hematological, hepatic and renal dysfunction, defined as: Neutrophil count < 1.5 x 10^9/L and platelet count < 100 x 10^9/L; bilirubin > 1.5 x ULN; AST and/or 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

7. Any other malignancy requiring anti-tumor treatment in the past three years, excluding treated stage I prostate cancer, in situ cervical cancer, in situ breast cancer and non-melanomatous skin cancer

4. Concurrent treatment with other experimental treatments for NSCLC while on the study

5. Implantable electronic medical devices (e.g. pacemaker, defibrilator) in the upper torso

6. Known allergies to medical adhesives or hydrogel

7. Pregnancy or breast-feeding (patients with reproductive potential must use effective contraception methods throughout the entire study period, as determined by their investigator/gynecologist)

8. Admitted to an institution by administrative or court order

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Device:
• NovoTTF-100L
Patients receive continuous TTFields treatment using the NovoTTF-100L device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the chest. The treatment enables the patient to maintain regular daily routine.

Drug:
• PD1 inhibitors or docetaxel
Patients receive standard of care with PD1 inhibitors or docetaxel

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
NovoCure Ltd.

References & Publications (9)

Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Sci Rep. 2015 Dec 11;5:18046. doi: 10.1038/srep18046. — View Citation

Giladi M, Voloshin T, Shteingauz A, Munster M, Blat R, Porat Y, Schneiderman RS, Cahal S, Itzhaki A, Kirson E, Weinberg U, Palti Y. Alternating electric fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. J Immunol. 2016;196(1 Supplement):75.26-75.26.

Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y. Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol. 2014 Oct;41 Suppl 6:S35-41. doi: 10.1053/j.seminoncol.2014.09.006. Epub 2014 Sep 8. — View Citation

Kirson ED, Dbalý V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7. Epub 2007 Jun 5. — View Citation

Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009;26(7):633-40. doi: 10.1007/s10585-009-9262-y. Epub 2009 Apr 23. — View Citation

Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004 May 1;64(9):3288-95. — View Citation

Pless M, Droege C, von Moos R, Salzberg M, Betticher D. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013 Sep;81(3):445-50. doi: 10.1016/j.lungcan.2013.06.025. Epub 2013 Jul 23. — View Citation

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.2015.16669. — View Citation

Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbalý V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202. doi: 10.1016/j.ejca.2012.04.011. Epub 2012 May 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival of patients treated with TTFields + docetaxel or PD-1 inhibitors vs. docetaxel or PD-1 alone (superiority)		4 years	No
Primary	Co-primary outcome (will be tested only if the primary endpoint fails): Overall survival of patients treated with TTFields + docetaxel vs. PD-1 inhibitors alone (non-inferiority)		4 years	No
Secondary	Overall survival of patients treated with TTFields + docetaxel vs. docetaxel alone (superiority)		4 years	No
Secondary	Overall survival of patients treated with TTFields + PD-1 inhibitors vs. PD- 1 inhibitors alone (superiority)		4 years	No
Secondary	Progression-free survival of patients treated with docetaxel or PD-1 inhibitors + TTFields vs. docetaxel or PD-1 inhibitors alone, based on the Immune-Related Response Criteria (irRC)		4 years	No
Secondary	Best overall radiological response rate (based on Immune-Related Response Criteria (irRC)) of patients treated with TTFields + docetaxel or PD-1 inhibitors vs. docetaxel or PD-1 inhibitors alone		4 years	No
Secondary	Quality of life of patients treated with TTFields+ docetaxel or PD-1 inhibitors vs. docetaxel or PD-1 inhibitors alone, using the EORTC QLQ C30 questionnaire with LC13 addendum		4 years	No
Secondary	Adverse events, severity and frequency, in patients treated with TTFields+ docetaxel or PD-1 inhibitors vs. docetaxel or PD-1 inhibitors alone		4 years	Yes