Clinical trial NCT04935359: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: mPDAC
NIS793
Pancreas
metastatic pancreatic ductal adenocarcinoma (mPDAC)
Nab-paclitaxel
Abraxane
Gemcitabine
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-06-23
Enrollment: 511
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Safety run-in part: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.
timeFrame: Up to 4 weeks
measure: Randomized part: Overall survival (OS)
timeFrame: From randomization up to death, assessed up to approximately 19 months
Secondary outcomes:
measure: Percentage of participants with Adverse Events (AEs)
timeFrame: Up to approximately 19 months
measure: Percentage of participants with dose interruptions and dose reductions of NIS793 in combination with gemcitabine and nab-paclitaxel
timeFrame: Up to approximately 19 months
measure: Dose intensity of NIS793 in combination with gemcitabine and nab-paclitaxel
timeFrame: Up to approximately 19 months
measure: Progression-free survival (PFS) by investigator assessment per RECIST 1.1
timeFrame: From enrollment (run-in part) or randomization (randomized part) up to disease progression or death, assessed up to approximately 19 months
measure: Overall response rate (ORR) by investigator assessment per RECIST 1.1
timeFrame: Up to approximately 19 months
measure: Disease control rate (DCR) by investigator assessment per RECIST 1.1
timeFrame: Up to approximately 19 months
measure: Time to response (TTR) by investigator assessment per RECIST 1.1
timeFrame: From enrollment (run-in part) or randomization (randomized part) up to first documented response, assessed up to approximately 19 months
measure: Safety run-in part: Overall Survival (OS)
timeFrame: From enrollment up to death, assessed up to approximately 19 months
measure: Maximum concentration (Cmax) of NIS793 in combination with gemcitabine and nab-paclitaxel
timeFrame: From date of first study drug intake up to approximately 19 months
measure: Trough Concentration (Ctrough) of NIS793 in combination with gemcitabine and nab-paclitaxel
timeFrame: From date of first study drug intake up to approximately 19 months
measure: Area under the curve from time zero to the last measurable concentration sampling time (AUClast) of NIS793 in combination with gemcitabine and nab-paclitaxel
timeFrame: From date of first study drug intake up to approximately 19 months
measure: 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
timeFrame: From date of first study drug intake up to approximately 19 months
measure: Time to reach maximum concentration (Tmax) of NIS793 in combination with gemcitabine and nab-paclitaxel
timeFrame: From date of first study drug intake up to approximately 19 months
measure: Randomized part: NIS793 serum concentration
timeFrame: From date of first study drug intake up to approximately 19 months
measure: Randomized part: Anti-drug antibodies (ADA) against NIS793 prevalence at baseline
timeFrame: Baseline
measure: Randomized part: ADA (anti-NIS793) incidence on treatment
timeFrame: From date of first study drug intake up to approximately 19 months
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: Orlando
country: United States
facility: Advent Health Cancer Institute
state: Florida
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology Hematology Inc
state: Indiana
city: New York
country: United States
facility: NYU Clinical Cancer Center
state: New York
city: Dallas
country: United States
facility: US Oncology Research Dallas
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Bonheiden
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Edegem
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Brasilia
country: Brazil
facility: Novartis Investigative Site
state: Distrito Federal
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Ijui
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Brampton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Cambridge
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Harbin
country: China
facility: Novartis Investigative Site
state: Heilongjiang
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Dalian
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Jining
country: China
facility: Novartis Investigative Site
state: Shandong
city: Xian
country: China
facility: Novartis Investigative Site
state: Shanxi
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Novy Jicin
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Hradec Kralove
country: Czechia
facility: Novartis Investigative Site
state: CZE
city: Praha 4
country: Czechia
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
state: Alpes Maritimes
city: Avignon
country: France
facility: Novartis Investigative Site
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Lyon 08
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Nantes Cedex 1
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bochum
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Halle S
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Nordbyhagen
country: Norway
facility: Novartis Investigative Site
state: Oslo
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Omsk
country: Russian Federation
facility: Novartis Investigative Site
city: Pushkin Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Banska Bystrica
country: Slovakia
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Malmo
country: Sweden
facility: Novartis Investigative Site
city: Umea
country: Sweden
facility: Novartis Investigative Site
city: Bellinzona
country: Switzerland
facility: Novartis Investigative Site
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: