Study of Efficacy and Safety of NIS793 in Combination With Standard of Care (SOC) Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2

A Randomized, Double-blind, Phase III Study, Comparing NIS793 in Combination With Gemcitabine and Nab-paclitaxel Versus (vs.) Placebo Combined With Gemcitabine and Nab-paclitaxel for First Line Treatment of Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2

The purpose of this study is to evaluate the efficacy and safety of NIS793 in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel and placebo in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC).

This study aims to explore whether blockade of Transforming Growth Factor β (TGFβ) in combination with gemcitabine/nab-paclitaxel can reduce fibrosis in PDAC, restore chemo-sensitivity and ultimately lead to improvements in overall survival (OS) and other clinically relevant outcomes.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: NIS793; Drug: Nab-paclitaxel; Drug: Gemcitabine; Drug: Placebo

Detailed Description

This is a randomized, double-blind, multicenter two-arm, phase III study that has two parts:

• Safety run-in part: An open-label safety run-in part will be conducted to confirm recommended phase 3 dose (RP3D) of NIS793 in combination with gemcitabine and nab-paclitaxel. Up to approximately 10 participants will be enrolled at each dose level to achieve at least 6 evaluable participants; however, if the starting dose is not recommended and a lower dose level is tested, 10 additional participants will be enrolled. The decision to open the randomized part will be based on dose confirmation and available safety, relevant PK, and other relevant data from run-in part
• Randomized part: Enrolled participants will be randomized to the two treatment arms.

The study treatment will be administered as a 28-day treatment cycle. Participants will be treated until unacceptable toxicity, disease progression per RECIST 1.1, withdrawal of consent or any other condition of treatment discontinuation specified in the protocol.

Note: As of 07-Jul-2023, treatment with NIS793/placebo was stopped. The trial was unblinded and study participants were allowed to continue with standard of care (SoC) chemotherapy (gemcitabine+ nab-paclitaxel) per investigator assessment.

• Study Type: Interventional
• Enrollment (Actual): 511
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Belgium
  • Bonheiden, Belgium, 2820
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Novartis Investigative Site
• Brazil
  • Distrito Federal
    • Brasilia, Distrito Federal, Brazil, 70200-730
      • Novartis Investigative Site
  • RS
    • Ijuí, RS, Brazil, 98700-000
      • Novartis Investigative Site
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-001
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 04014-002
      • Novartis Investigative Site
• Canada
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • Novartis Investigative Site
    • Cambridge, Ontario, Canada, N1R 3G2
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
• China
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Beijing, China, 100021
    • Novartis Investigative Site
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Guangzhou, China, 510000
    • Novartis Investigative Site
  • Shanghai, China, 200032
    • Novartis Investigative Site
  • Shanghai, China, 200127
    • Novartis Investigative Site
  • Shanghai, China, 200433
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Novartis Investigative Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Novartis Investigative Site
  • Liaoning
    • Dalian, Liaoning, China, 116001
      • Novartis Investigative Site
  • Shandong
    • Jining, Shandong, China, 272000
      • Novartis Investigative Site
  • Shanxi
    • Xian, Shanxi, China, 710061
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Novartis Investigative Site
• Czechia
  • Praha 4, Czechia, 140 59
    • Novartis Investigative Site
  • CZE
    • Hradec Kralove, CZE, Czechia, 500 05
      • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
    • Novy Jicin, Czech Republic, Czechia, 74101
      • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00290
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33521
    • Novartis Investigative Site
• France
  • Avignon, France, 84082
    • Novartis Investigative Site
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Lyon Cedex 08, France, 69373
    • Novartis Investigative Site
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Montpellier cedex 5, France, 34295
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
  • Alpes Maritimes
    • Nice Cedex 2, Alpes Maritimes, France, 06189
      • Novartis Investigative Site
  • Cedex
    • Besançon, Cedex, France, 25030
      • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60488
    • Novartis Investigative Site
  • Halle S, Germany, 06120
    • Novartis Investigative Site
  • Hamburg, Germany, 20249
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Greece
  • Thessaloniki, Greece, 57001
    • Novartis Investigative Site
  • Thessaloniki, Greece, 540 07
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1122
    • Novartis Investigative Site
  • Budapest, Hungary, 1097
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37126
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464 8681
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama-city, Kanagawa, Japan, 241-8515
      • Novartis Investigative Site
  • Osaka
    • Osaka-city, Osaka, Japan, 541-8567
      • Novartis Investigative Site
  • Tokyo
    • Chuo ku, Tokyo, Japan, 104 0045
      • Novartis Investigative Site
    • Koto ku, Tokyo, Japan, 135 8550
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Netherlands
  • Utrecht, Netherlands, 3543 AZ
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, NO 0450
    • Novartis Investigative Site
  • Oslo
    • Nordbyhagen, Oslo, Norway, 1478
      • Novartis Investigative Site
• Russian Federation
  • Omsk, Russian Federation, 644013
    • Novartis Investigative Site
  • Pushkin Saint Petersburg, Russian Federation, 196603
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
    • Novartis Investigative Site
  • Bratislava, Slovakia, 83310
    • Novartis Investigative Site
  • Kosice, Slovakia, 041 91
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Galicia
    • Santiago De Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
• Sweden
  • Malmo, Sweden, SE-205 02
    • Novartis Investigative Site
  • Umea, Sweden, 901 85
    • Novartis Investigative Site
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Novartis Investigative Site
  • Geneve 14, Switzerland, CH 1211
    • Novartis Investigative Site
  • St. Gallen, Switzerland, 9007
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taoyuan
    • Kuei Shan Chiang, Taoyuan, Taiwan, 33305
      • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01250
    • Novartis Investigative Site
  • Istanbul, Turkey, 34722
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Sihhiye / Ankara, Turkey, 06100
    • Novartis Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
    • Novartis Investigative Site
  • Liverpool, United Kingdom, CH63 4JY
    • Novartis Investigative Site
  • London, United Kingdom, EC1A 7BE
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Novartis Investigative Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group .
  • California
    • Los Angeles, California, United States, 90095
      • University Of California Los Angeles Santa Monica Location
  • Florida
    • Orlando, Florida, United States, 32804
      • Advent Health Cancer Institute
  • Indiana
    • Fort Wayne, Indiana, United States, 46815
      • Fort Wayne Medical Oncology/Hematology, Inc. Jefferson Blvd
  • New York
    • New York, New York, United States, 10016
      • Nyu Clinical Cancer Center
    • New York, New York, United States, 10016
      • NYU Clinical Cancer Center Dept of NYU Clin CancerCenter
  • Texas
    • Dallas, Texas, United States, 75204
      • US Oncology Research, Dallas .
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital OPC 26
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Applicable for both Safety run-in and Randomized part

  • Participants aged ≥18 years with histologically or cytologically confirmed (based on local assessment and per local guidelines) mPDAC eligible for treatment in the first line setting and not amenable for potentially curative surgery
  • Presence of at least one measurable lesion assessed by Computerized Tomography (CT) and/or Magnetic Resonance Imaging (MRI) according to RECIST 1.1
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
  • Adequate organ function (assessed by central laboratory for eligibility)
  • Participants must have recovered from treatment-related toxicities of prior anticancer therapies to grade ≤ 1 (CTCAE v 5.0) at time of screening, except alopecia.

Main Exclusion Criteria:

• Applicable for both Safety run-in and Randomized part

  • Previous systemic anti-cancer treatment for metastatic PDAC
  • Pancreatic neuroendocrine (islet) or acinar tumors
  • Participants with known status of microsatellite instability-high (MSI-H) or mismatch repair-deficient pancreatic cancer (if status is not already available, testing is not required at screening).
  • Participant has not recovered from a major surgery performed prior to start of study treatment or has had a major surgery within 4 weeks prior to start of study treatment.
  • Radiation therapy or brain radiotherapy ≤ 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed > 2 weeks prior to start of study treatment).
  • Impaired cardiac function or clinically significant cardio-vascular disease
  • Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study treatment.
  • Participant has conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding.
  • Serious non-healing wounds.
  • Pregnant or breast-feeding women
  • Women of childbearing potential, unless willing to use highly effective contraception methods during treatment and after stopping study treatments as indicated
  • Pre-existing peripheral neuropathy > grade 1 (CTCAE v5.0)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety run-in part: NIS793+gemcitabine+nab-paclitaxel; In the safety run-in part, participants will receive a combination of NIS793, gemcitabine and nab-paclitaxel.	Drug: NIS793; Concentrate for solution infusion (Liquid in Vial); Drug: Nab-paclitaxel; Per locally approved formulation; Drug: Gemcitabine; Per locally approved formulation
Experimental: Randomized part: NIS793+gemcitabine+nab-paclitaxel; Participants will receive a combination of NIS793, gemcitabine and nab-paclitaxel Note: As of 07-Jul-2023, treatment with NIS793/placebo was stopped.	Drug: NIS793; Concentrate for solution infusion (Liquid in Vial); Drug: Nab-paclitaxel; Per locally approved formulation; Drug: Gemcitabine; Per locally approved formulation; Drug: Placebo; Dextrose 5% in water (D5W) solution for infusion
Placebo Comparator: Randomized part: placebo+gemcitabine+nab-paclitaxel; Participants will receive a combination of placebo, gemcitabine and nab-paclitaxel Note: As of 07-Jul-2023, treatment with NIS793/placebo was stopped.	Drug: Nab-paclitaxel; Per locally approved formulation; Drug: Gemcitabine; Per locally approved formulation; Drug: Placebo; Dextrose 5% in water (D5W) solution for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety run-in part: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.	Percentage of participants with DLTs during the first cycle of treatment in the safety run-in part. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness or concomitant medication that occurs within the first cycle of treatment with NIS793 in combination with gemcitabine and nab-paclitaxel	Up to 4 weeks
Randomized part: Overall survival (OS)	OS is defined as the time from date of randomization to date of death due to any cause.	From randomization up to death, assessed up to approximately 19 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants with Adverse Events (AEs)	Percentage of participants with AEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments	Up to approximately 19 months
Percentage of participants with dose interruptions and dose reductions of NIS793 in combination with gemcitabine and nab-paclitaxel	Tolerability measured by the percentage of participants who have dose adjustments (interruptions or reductions) of NIS793	Up to approximately 19 months
Dose intensity of NIS793 in combination with gemcitabine and nab-paclitaxel	Tolerability measured by the dose intensity of NIS793. Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure	Up to approximately 19 months
Progression-free survival (PFS) by investigator assessment per RECIST 1.1	PFS defined as the time from the date of enrollment (run-in part) or randomization (randomized part) to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause.	From enrollment (run-in part) or randomization (randomized part) up to disease progression or death, assessed up to approximately 19 months
Overall response rate (ORR) by investigator assessment per RECIST 1.1	ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1	Up to approximately 19 months
Disease control rate (DCR) by investigator assessment per RECIST 1.1	DCR is the proportion of participants with BOR of CR or PR or stable disease (SD) as per investigator assessment and according to RECIST 1.1	Up to approximately 19 months
Time to response (TTR) by investigator assessment per RECIST 1.1	TTR is defined as the duration of time between the date of enrollment (run-in part) or randomization (randomized part) and the date of first documented response of either CR or PR.	From enrollment (run-in part) or randomization (randomized part) up to first documented response, assessed up to approximately 19 months
Safety run-in part: Overall Survival (OS)	OS is defined as the time from the date of enrollment to date of death due to any cause.	From enrollment up to death, assessed up to approximately 19 months
Maximum concentration (Cmax) of NIS793 in combination with gemcitabine and nab-paclitaxel	Blood samples will be collected for analysis of Cmax of NIS793	From date of first study drug intake up to approximately 19 months
Trough Concentration (Ctrough) of NIS793 in combination with gemcitabine and nab-paclitaxel	Blood samples will be collected for analysis of Ctrough of NIS793	From date of first study drug intake up to approximately 19 months
Area under the curve from time zero to the last measurable concentration sampling time (AUClast) of NIS793 in combination with gemcitabine and nab-paclitaxel	Blood samples will be collected for analysis of AUClast of NIS793	From date of first study drug intake up to approximately 19 months
Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of NIS793 in combination with gemcitabine and nab-paclitaxel	Blood samples will be collected for analysis of AUCtau of NIS793	From date of first study drug intake up to approximately 19 months
Time to reach maximum concentration (Tmax) of NIS793 in combination with gemcitabine and nab-paclitaxel	Blood samples will be collected for analysis of Tmax of NIS793	From date of first study drug intake up to approximately 19 months
Randomized part: NIS793 serum concentration	Blood samples will be collected for analysis of NIS793 serum concentration	From date of first study drug intake up to approximately 19 months
Randomized part: Anti-drug antibodies (ADA) against NIS793 prevalence at baseline	ADA (anti-NIS793) prevalence at baseline is defined as the proportion of participants who have an ADA positive result at baseline	Baseline
Randomized part: ADA (anti-NIS793) incidence on treatment	ADA (anti-NIS793) incidence on treatment is defined as the proportion of participants who are treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)	From date of first study drug intake up to approximately 19 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Estimated): June 28, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: June 21, 2021
• First Submitted That Met QC Criteria: June 21, 2021
• First Posted (Actual): June 23, 2021

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Gemcitabine; Pancreas; Abraxane; Nab-paclitaxel; mPDAC; NIS793; metastatic pancreatic ductal adenocarcinoma (mPDAC)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Gemcitabine
• Other Study ID Numbers: CNIS793B12301; 2021-000591-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No