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

Metastatic Pancreatic Ductal Adenocarcinoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04935359
• Other study ID #: CNIS793B12301
• Secondary ID: 2021-000591-10
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 30, 2021
• Est. completion date: August 1, 2024

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 511
• Est. completion date: August 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Adenocarcinoma
• Metastatic Pancreatic Ductal Adenocarcinoma

Intervention

Drug:
• NIS793
Concentrate for solution infusion (Liquid in Vial)
• Nab-paclitaxel
Per locally approved formulation
• Gemcitabine
Per locally approved formulation
• Placebo
Dextrose 5% in water (D5W) solution for infusion

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Perth	Western Australia
Belgium	Novartis Investigative Site	Bonheiden
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Brasilia	Distrito Federal
Brazil	Novartis Investigative Site	Ijuí	RS
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Sao Paulo	SP
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Cambridge	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Dalian	Liaoning
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Harbin	Heilongjiang
China	Novartis Investigative Site	Jining	Shandong
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Xian	Shanxi
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Hradec Kralove	CZE
Czechia	Novartis Investigative Site	Novy Jicin	Czech Republic
Czechia	Novartis Investigative Site	Praha 4
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Tampere
France	Novartis Investigative Site	Avignon
France	Novartis Investigative Site	Besancon
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Lyon 08
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montpellier cedex 5
France	Novartis Investigative Site	Nantes Cedex 1
France	Novartis Investigative Site	Nice Cedex 2	Alpes Maritimes
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bochum
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Halle S
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Ulm
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Verona	VR
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Koto ku	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Netherlands	Novartis Investigative Site	Utrecht
Norway	Novartis Investigative Site	Nordbyhagen	Oslo
Norway	Novartis Investigative Site	Oslo
Russian Federation	Novartis Investigative Site	Omsk
Russian Federation	Novartis Investigative Site	Pushkin Saint Petersburg
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Banska Bystrica
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Santiago De Compostela	Galicia
Sweden	Novartis Investigative Site	Malmo
Sweden	Novartis Investigative Site	Umea
Switzerland	Novartis Investigative Site	Bellinzona
Switzerland	Novartis Investigative Site	Geneve 14
Switzerland	Novartis Investigative Site	St. Gallen
Taiwan	Novartis Investigative Site	Kuei Shan Chiang	Taoyuan
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Sihhiye / Ankara
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Oxford
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United States	US Oncology Research Dallas .	Dallas	Texas
United States	Highlands Oncology Group .	Fayetteville	Arkansas
United States	Fort Wayne Medical Oncology Hematology Inc Jefferson Blvd	Fort Wayne	Indiana
United States	Houston Methodist Hospital OPC 26	Houston	Texas
United States	University Of California LA Santa Monica Location	Los Angeles	California
United States	NYU Clinical Cancer Center	New York	New York
United States	NYU Clinical Cancer Center Dept of NYU Clin CancerCenter	New York	New York
United States	Advent Health Cancer Institute	Orlando	Florida
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  China,  Czechia,  Finland,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Norway,  Russian Federation,  Singapore,  Slovakia,  Spain,  Sweden,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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