Effect of Tumor Treating Fields (TTFields, 150 kHz) as Front-Line Treatment of Locally-advanced Pancreatic Adenocarcinoma Concomitant With Gemcitabine and Nab-paclitaxel (PANOVA-3)

Study Description

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Brief Summary:

Brief 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 gemcitabine and nab-paclitaxel, for front line treatment of locally-advanced pancreatic adenocarcinoma.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
Pancreas Adenocarcinoma	Device: NovoTTF-100L(P); Drug: Gemcitabine; Drug: nab paclitaxel	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	556 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pivotal, Randomized, Open-label Study of Tumor Treating Fields (TTFields, 150kHz) Concomitant With Gemcitabine and Nab-paclitaxel for Front-line Treatment of Locally-advanced Pancreatic Adenocarcinoma
Actual Study Start Date :	May 10, 2018
Estimated Primary Completion Date :	December 2022
Estimated Study Completion Date :	December 2022

Arms and Interventions

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Arm	Intervention/treatment
Experimental: NovoTTF-100L(P); Patients receive TTFields using the NovoTTF-100L(P) System together with gemcitabine and nab-Paclitaxel	Device: NovoTTF-100L(P); Patients receive continuous TTFields treatment using the NovoTTF-100L(P) device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the torso. The treatment enables the patient to maintain regular daily routine.; Other Name: TTFields; Drug: Gemcitabine; Gemcitabine 1000 mg/m^2 over 30 minute infusion will be administered immediately after nab-paclitaxel on Days 1, 8 and 15 of each 28-day cycle.; Drug: nab paclitaxel; nab-paclitaxel 125 mg/m^2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle.
Active Comparator: Best Standard of Care; Patients receive best standard of care with gemcitabine and nab-Paclitaxel	Drug: Gemcitabine; Gemcitabine 1000 mg/m^2 over 30 minute infusion will be administered immediately after nab-paclitaxel on Days 1, 8 and 15 of each 28-day cycle.; Drug: nab paclitaxel; nab-paclitaxel 125 mg/m^2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle.

Outcome Measures

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Primary Outcome Measures :

1. Overall survival [ Time Frame: 4 years ]

Secondary Outcome Measures :

1. Progression-free survival [ Time Frame: 4 years ]
2. Local progression-free survival [ Time Frame: 4 years ]
3. Objective response rate [ Time Frame: 4 years ]
4. One-year survival rate [ Time Frame: 4 years ]
5. Quality of life [ Time Frame: 4 years ]
   Quality of life will be assessed using the EORTC QLQ C-30 questionnaire with EORTC QLQ-PAN26 (Pancreatic Cancer symptom) supplement.
6. Pain-free survival [ Time Frame: 4 years ]
   Pain-free survival will measured as the duration between the time of randomization until a greater than or equal to two-point decline from a baseline measurement in a patient self-reported visual analogue scale (VAS) is recorded or death, whichever occurs first.
7. Puncture-free survival [ Time Frame: 4 years ]
8. Resectability rate [ Time Frame: 4 years ]
9. Toxicity profile [ Time Frame: 4 years ]
   Toxicity profile in patients treated with TTFields in combination with gemcitabine and nab-paclitaxel compared to the toxicity profile of patients treated with chemotherapy alone, measured by the rate of treatment-emergent toxicities in both arms. Adverse events will be collected and recorded based on the revised Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. 18 years of age and older
2. Life expectancy of ≥ 3 months
3. Histological/cytological diagnosis of de novo adenocarcinoma of the pancreas

4. Unresectable, locally advanced stage disease according to the following criteria:

   • Head/uncinate process:

     1. Solid tumor contact with SMA>180°
     2. Solid tumor contact with the CA>180°
     3. Solid tumor contact with the first jejunal SMA branch
     4. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus)
     5. Contact with most proximal draining jejunal branch into SMV

   • Body and tail

     1. Solid tumor contact of >180° with the SMA or CA
     2. Solid tumor contact with the CA and aortic involvement
     3. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus)
   • No distant metastasis, including non-regional lymph node metastasis
   • No borderline resectable (per Al-Hawary MM, et al., Radiology 201414)
5. ECOG score 0-2
6. Amenable and assigned by the investigator to receive therapy with gemcitabine and nab-paclitaxel
7. Able to operate the NovoTTF-100L(P) System independently or with the help of a caregiver
8. Signed informed consent form for the study protocol

Exclusion Criteria:

1. Prior palliative treatment (e.g. surgery, radiation) to the tumor
2. Cancer requiring anti-tumor treatment within the 5 years before inclusion, excluding treated stage I prostate cancer, in situ cervical or uterus cancer, in situ breast cancer and non-melanomatous skin cancer.

3. Serious co-morbidities:

   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 Upper Limit of Normal (ULN); AST and/or ALT > 2.5 x ULN; 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 receive 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.
4. Concurrent anti-tumor therapy beyond gemcitabine and nab-paclitaxel
5. Implantable electronic medical devices in the torso, such as pacemakers
6. Known severe hypersensitivities to medical adhesives or hydrogel, or to one of the chemotherapies used in this trial.
7. Pregnancy or breast-feeding (female patients with reproductive potential and their partners must accept to use effective contraception throughout the entire study period and for 3 months after the end of treatment). All patients who are capable of becoming pregnant must take a pregnancy test which is negative within 72 hours before beginning treatment. The definition of effective contraception is left up to the decision of the investigator.
8. Unable to follow the protocol for medical, psychological, familial, geographic or other reasons.
9. Admitted to an institution by administrative or court order.

Contacts and Locations

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Contacts

Contact: Lori A. Ladd	+1 603 389 2158	patientinfo@novocure.com

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Sponsors and Collaborators

NovoCure Ltd.

More Information

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Publications:

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.

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.

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.

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.

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.

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.

Giladi M, Schneiderman RS, Porat Y, Munster M, Itzhaki A, Mordechovich D, Cahal S, Kirson ED, Weinberg U, Palti Y. Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology. 2014 Jan-Feb;14(1):54-63. doi: 10.1016/j.pan.2013.11.009. Epub 2013 Dec 4.

Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718. Erratum in: JAMA. 2018 May 1;319(17):1824.

Responsible Party:	NovoCure Ltd.
ClinicalTrials.gov Identifier:	NCT03377491 History of Changes
Other Study ID Numbers:	EF-27
First Posted:	December 19, 2017
Last Update Posted:	December 13, 2018
Last Verified:	November 2018

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		Yes
Device Product Not Approved or Cleared by U.S. FDA:		Yes

Keywords provided by NovoCure Ltd.:

Locally Advanced Pancreatic Adenocarcinoma; TTFields; Tumor Treating Fields; Gemcitabine	nab-Paclitaxel; Minimal toxicity; TTF; Novocure

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Paclitaxel; Gemcitabine; Albumin-Bound Paclitaxel; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators	Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs