nis793 with and without the pd-1 inhibitor spartalizumab

• This is a parallel arm, open-label, randomized, multicenter, Phase II study evaluating the safety and efficacy of NIS793 with and without spartalizumab, combined with NG in first-line mPDAC (NCT04390763).

– The study is designed to have a safety run-in period (~6 patients) followed by randomization (~150 patients in a 1:1:1 ratio) (Figure 2)

– A safety review meeting will occur when ≥6 enrolled participants have completed 4 weeks of treatment or discontinued earlier due to dose-limiting toxicity (DLT).

– If after the safety review meeting a decision is made to modify the regimen, another cohort of ≥6 patients will be enrolled in the safety run-in.

• Details of the dosage and administration are shown in Figure 3.

• Crossover between treatment arms is not permitted at any time during the study.

• Participants will have safety evaluations for 150 days (Safety run-in and Arm 1), 90 days (Arm 2), and 30 days (Arm 3) after the last dose of NIS793, spartalizumab, and NG respectively; whichever is longer.

• Study objectives and endpoints are listed in Table 1, and key eligibility criteria are listed in Table 2.

Figure 2: Study Design*,†

SAFETY RUN-IN PART RANDOMIZED PART

NIS793 + spartalizumab + NG

n=at least6 participants

Saf

ety

Rev

iew

Mee

tin

gRANDOMIZE

Arm 1:NIS793 + spartalizumab +

NGn≈50 participants

(excluding safety run-in)

Arm 2:NIS793 +

NGn≈50 participants

Arm 3:NG

n≈50 participants

1:1:1

NG, nab-paclitaxel/gemcitabine* Treatment will continue until unacceptable toxicity, disease progression, discontinuation by investigator’s or patient’s choice, or withdrawal of consent.

†The dose regimen for the randomized part of the study will be determined following the safety review.

Table 1. Objectives and EndpointsObjective(s) Endpoint(s)Primary objective(s) Endpoint(s) for primary objective(s) Safety run-in part:• Assess the safety and tolerability of NIS793

+ spartalizumab in combination with NG

• Incidence of any DLTs that may occur during the first 4 weeks of treatment

• Safety: Incidence and severity of treatment emergent AEs and SAEs, changes between baseline and post-baseline laboratory parameters, vital signs, and ECG parameters

• Tolerability: Dose interruptions, reductions, and dose intensity

Randomized part:• Evaluate the PFS of NIS793 with

spartalizumab in combination with NG versus NG alone

• Evaluate the PFS of NIS793 with NG versus NG alone

• PFS based on RECIST1.1 as per local investigator’s review

Secondary objective(s) Endpoint(s) for secondary objective(s)Randomized part• Evaluate the safety and tolerability in each

treatment arm• Incidence and severity of AEs and SAEs,

including changes in laboratory values, vital signs and ECGs, dose interruptions, reductions, and dose intensity

• Assess the preliminary antitumor activity in each treatment arm

• ORR, DOR, TTP, RECIST 1.1 as per local investigator’s review

• Assess OS in each treatment arm • OS• Assess the CD8 and PD-L1 status of the

participants at screening and on-treatment versus NG

• Change from baseline in CD8 and PD-L1 IHC-related markers

• Characterize the incidence of IG of NIS793 and spartalizumab in combination with NG

• ADA prevalence at baseline and ADA incidence on-treatment (anti-NIS793 and anti-spartalizumab)

• Characterize the PK of NIS793, spartalizumab, and NG in combination treatment or alone

• PK parameters • PK concentration–time profiles

ADA, anti-drug antibody; AE, adverse event; CD8, cluster of differentiation 8; DLT, dose-limiting toxicity; DOR, duration of response; ECG, electrocardiogram; IG, immunogenicity; IHC, immunohistochemistry; NG, nab-paclitaxel/gemcitabine; ORR, overall response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PK, pharmacokinetic; RECIST, Response Evaluation Criteria In Solid Tumors; SAE, serious adverse event; TTP, time to progression.

Table 2. Key Eligibility CriteriaKey inclusion criteriaSigned informed consentAged >18 years (patients from Japan aged <20 years require written consent from the participant and their legal representative)Histologically/cytologically confirmed treatment-naïve metastatic adenocarcinoma of the pancreas with measurable disease as per RECIST 1.1Have a site of disease amenable to biopsy and should be candidate for tumor biopsy according to the treating institution’s guidelinesWillingness to undergo a tumor biopsy at screening and during therapyECOG performance status ≤1

Key exclusion criteriaPrevious radiotherapy, surgery (with exception of placement of biliary stent), chemotherapy, or any other investigational therapy for the treatment of metastatic pancreatic cancerParticipants having received previous chemotherapy in the adjuvant setting Participants amenable to potentially curative resection Participants with a diagnosis of PNETs, acinar, or islet cell tumors Patients with out-of-range laboratory values as pre-defined in the protocolParticipants with MSI-H pancreatic adenocarcinoma Presence of symptomatic CNS metastases, or CNS metastases that require local CNS directed therapy, or increasing doses of corticosteroids 2 weeks prior to study entryHistory of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipientsThe participant exhibits any of the events outlined in the contraindications or special warnings and precautions sections of gemcitabine and nab-paclitaxel as per locally approved labelsImpaired cardiac function, HIV infection, active HBV or HCV infection (unless controlled by antiviral therapy), and interstitial lung disease or pneumonitis grade ≥2CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; mAb, monoclonal antibody; MSI-H, microsatellite instability high; PNET, pancreatic neuroendocrine tumor; RECIST, Response Evaluation Criteria In Solid Tumors.

Dosage and administration

Figure 3. Dosage and Administration

NIS793SpartalizumabNab-paclitaxelGemcitabine

Nab-paclitaxelGemcitabine

NIS793Nab-paclitaxelGemcitabine

Day 1Start of cycle

Day 8 Day 15 Day 28End of cycle

Safety run-in part and randomized Arm 1




Day 1Start of cycle


Randomized Arm 2




Day 1Start of cycle


Randomized Arm 3

• In the safety run-in, patients will receive intravenous administration of: NIS793 (2,100 mg) once every 2 weeks with spartalizumab (400 mg) once every 4 weeks with gemcitabine (1,000 mg/m2) on Days 1, 8, and 15 and nab-paclitaxel (125 mg/m2) on Days 1, 8, and 15 (Figure 3). One cycle is 28 days.

Assessments• All assessments are done locally, except biomarker and pharmacokinetic (PK),

pharmacodynamic (PD), immunogenicity (IG) analyses, which are done by central laboratory.

Efficacy• Efficacy will be assessed per Response Evaluation Criteria In Solid Tumors (RECIST)

v1.1 and Response Evaluation Criteria In Solid Tumors For Immunotherapy Trials (iRECIST). Primary endpoint analysis and treatment decisions will be made by the local investigator’s assessment. In addition, radiologic assessments will be collected by an imaging contract research organization designed by Novartis and may be assessed centrally in addition to the local assessment if deemed necessary.

Safety• Safety assessments include monitoring adverse events, physical examinations, vital

signs (blood pressure, pulse rate, and body temperature), Eastern Cooperative Oncology Group (ECOG) performance status, laboratory analysis: hematology, chemistry urinalysis.

• Tumor evaluation as per RECIST 1.1 and iRECIST, electrocardiogram (ECG), cardiac imaging, and troponin and N-terminal pro B-type natriuretic peptide (NTproBNP) analysis.

Other assessments• Additional tests include carbohydrate antigen (CA) 19-9. • PK/PD/IG samples must be drawn before biochemistry and other blood sampling are

performed. PK is assessed for NIS793, spartalizumab, and NG; IG is assessed for NIS793 and spartalizumab; PD is assessed for NIS793.

Trial status• This trial is a multicenter, international study recruiting patients with first-line

metastatic PDAC.• The first patient was enrolled in the study on October 16, 2020. Study enrolment

is ongoing.6

• This study is ongoing and will enrol patients from multiple sites across 15 countries (Figure 4).

Figure 4. Locations of Participating Countries

Japan

Europe

Austria Germany

Belgium Italy

Czech Republic Spain

Finland Switzerland

France United Kingdom

Australia

USA

Asia

Singapore

Taiwan

Japan

Phase II study of the anti–TGF-β NIS793 with and without the PD-1 inhibitor spartalizumab in combination with nab-paclitaxel/gemcitabine (NG) versus NG alone in patients with first-line metastatic pancreatic ductal adenocarcinoma (mPDAC)Peter Grell,1 Chia-Chi Lin,2 Michele Milella,3 Cheng Ean Chee,4 Shivan Sivakumar,5 Katriina Peltola,6 Geraldine Bostel,7 Dragana Jankovic,7 Maria-Athina Altzerinakou,8 Claire Fabre,7 Armando Santoro9

1Masaryk Memorial Cancer Institute, Brno, Czech Republic; 2Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 3Section of Oncology, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy; 4National University Cancer Institute, Singapore, Singapore; 5Churchill Hospital, Oxford, UK; 6Helsinki; University Hospital, Comprehensive Cancer Center, Helsinki, Finland; 7Novartis Institutes for BioMedical Research, Basel, Switzerland; 8Novartis Pharma AG, Rueil-Malmaison, France; 9Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy and Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Hospital, Milan, Italy

Dr Peter Grell | [email protected]

Poster presented at the 2021 ASCO Annual Meeting, held virtually on 4–8 June 2021

This study is sponsored by Novartis Pharma AG

Poster TPS4173

SUMMARY

Scan to obtain:• Poster

https://www.medicalcongress.novartisoncology.com/ASCO/Solid_Tumors/solid_tumors.html#GrellPTPS41737384

Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may notbe reproduced without permission from ASCO® and the author of this poster

INTRODUCTION• Pancreatic ductal adenocarcinoma (PDAC) is an aggressive systemic disease with increasing incidence and dismal

prognosis, despite approved therapies.1 PDAC is estimated to become the second most frequent cause of cancer-related death by 2030 if treatment is not improved.2

• FOLFIRINOX and combined treatment of nab-paclitaxel plus gemcitabine (NG) in metastatic PDAC (mPDAC) showed improved overall survival (OS) in comparison with gemcitabine monotherapy.3,4 Despite these approved chemotherapies, the 5-year OS is still below 10%.5

• Dense fibrotic stroma in this indication is a hallmark of PDAC and is associated with treatment failure.5

Figure 1. Mechanism of Action of NIS793

• Pancreatic stellate cells drive excess extracellular matrix (ECM) protein production via tumor growth factor beta (TGF-β)1 in the desmoplastic stroma and contribute to a fibrotic microenvironment in PDAC.

• PDAC is characterized by resistance to chemotherapy and immunotherapy.

• Increased collagen and hyaluronic acid are mechanical obstacles to the penetration of chemotherapy:

– Activated stellate cells may protect tumor cells from chemotherapy

– Tumor-infiltrating lymphocytes (TILs) are located at the tumor–stroma interface (immune exclusion)

– Matrix stiffness promotes T-cell dysfunction

STUDY DESIGN

Acknowledgments• The authors would like to thank the patients taking part in the trial and their families, and the staff at each site involved

with the study.• The authors would like to thank the study principal investigators: Emiliano Calvo Aller, Thomas Aparicio, Nathan Bahary,

Li-Yuan Bai, Bruno Bockorny, Joelle Collignon, Maria Diab, Thomas Ettrich, Ralph Fritsch, Richard Greil, Rosine Guimbaud, Daniel Horber, Masafumi Ikeda, Daniel Laheru, Teresa Macarulla Mercade, Michael Michael, Gerald Prager, Michele Reni, Jens Siveke, Christoph Springfeld, Wai Meng David Tai, Colin Weekes, and Mark Ka Wong.

• This study is sponsored by Novartis Pharmaceuticals Corporation.• Editorial assistance was provided by Sivanjaa Manoj of ArticulateScience Ltd and was funded by Novartis Pharmaceuticals

Corporation.

• This study is a randomized, parallel arm, open-label, multicenter, Phase II study investigating the safety and efficacy of the combination of NIS793 with and without spartalizumab and NG in participants with first-line mPDAC.

• The primary objective of the safety run-in is to evaluate the safety and tolerability of NIS793 with spartalizumab in combination with NG. The primary objective of the randomized part is to evaluate progression-free survival (PFS) per investigator assessment of NIS793 with and without spartalizumab in combination with NG versus NG alone.

• Secondary objectives include the safety, tolerability, preliminary antitumor activity, OS, and PK of the NIS-based treatment arms compared with NG alone. Other secondary objectives include CD8 and PD-L1 status at screening and on-treatment versus NG.

Disclosures• Peter Grell reports personal consulting fees and travel expenses from Roche and Servier; institutional research funding from Novartis. • Chia-Chi Lin reports personal consulting fees, travel expenses, and honoraria fees from Novartis and Daiichi Sankyo; travel expenses and honoraria fees from Lilly; personal consulting fees only from Boehringer Ingelheim and Blueprint Medicines;

travel expenses only from BeiGene; honoraria fees only from Roche.• Michele Milella reports honoraria fees only from AstraZeneca and MSD.• Cheng Ean Chee has nothing to disclose. • Shivan Sivakumar reports fellowship employment and personal research funding from Bristol Meyers-Squibb.• Katriina Peltola reports an immediate family member employed by Terveystalo; stock ownership of Faron Pharmaceuticals; personal consulting fees, travel expenses, honoraria fees, and institutional research funding from Bristol Meyers-Squibb;

personal consulting fees and honoraria fees from Pfizer; personal consulting fees, expert testimony fees, honoraria fees from Ipsen; personal consulting fees only from Merck; travel expenses and personal research funding from Roche; Personal research funding only from Exelixis, Eisai, and Bayer; personal consulting fees and institutional research funding from Merck-Sharpe Dohme and Novartis.

• Geraldine Bostel and an immediate family member are both Novartis employees, and both report stock ownership of Novartis. • Dragana Jankovic and Claire Fabre are Novartis employees, and report stock ownership of Novartis. • Maria-Athina Altzerinakou is a Novartis employee.• Armando Santoro reports personal consulting fees and speakers’ bureau fees from Bristol Meyers-Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, and ArQule; personal consulting fees only from Sanofi; speakers’ bureau fees only from Takeda,

Roche, AbbVie, Amgen, Celgene, AstraZeneca, Lilly, Sandoz, and Novartis.

References1. Casciani F et al. Chirurgia 2018;113:307–317.2. Åkerberg D et al. J Biomed Eng 2017;10:1–9.3. Lambert A et al. Therap Adv Gastroenterol 2017;10:631–645.4. Von Hoff DD et al. N Engl J Med 2013;369:1691–1703.5. Neuzillet C et al. Oncotarget 2014;5:78–94.6. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04390763. Accessed 27 April 2021.

• TGF-β2 with high affinity (Figure 1). Preclinical data showed TGF-β blockade by NIS793 to target the development of intratumoral fibrosis5 and augment the response of PD-1 blockade.

• Clinical experience with NIS793 is reported in Poster 2509. These are the first-in-human data showing acceptable safety profile of NIS793 in combination with spartalizumab, supporting continued clinical development (NCT02947165).

• Here we present the design for an ongoing study investigating NIS793 with and without spartalizumab combined with NG in the treatment of naïve mPDAC.

nis793 with and without the pd-1 inhibitor spartalizumab

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