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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

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ClinicalTrials.gov Identifier: NCT04935359
Recruitment Status : Recruiting
First Posted : June 23, 2021
Last Update Posted : June 30, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.


Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Ductal Adenocarcinoma Drug: NIS793 Drug: Nab-paclitaxel Drug: Gemcitabine Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 501 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : September 30, 2021
Estimated Primary Completion Date : January 1, 2026
Estimated Study Completion Date : January 1, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Safety

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
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
Drug: Nab-paclitaxel
Per locally approved formulation

Drug: Gemcitabine
Per locally approved formulation

Drug: Placebo
Dextrose 5% in water (D5W) solution for infusion




Primary Outcome Measures :
  1. Safety run-in part: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment. [ Time Frame: Up to 4 weeks ]
    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

  2. Randomized part: Overall survival (OS) [ Time Frame: From randomization up to death, assessed up to approximately 19 months ]
    OS is defined as the time from date of randomization to date of death due to any cause.


Secondary Outcome Measures :
  1. Percentage of participants with Adverse Events (AEs) [ Time Frame: Up to approximately 19 months ]
    Percentage of participants with AEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments

  2. Percentage of participants with dose interruptions and dose reductions of NIS793 in combination with gemcitabine and nab-paclitaxel [ Time Frame: Up to approximately 19 months ]
    Tolerability measured by the percentage of participants who have dose adjustments (interruptions or reductions) of NIS793

  3. Dose intensity of NIS793 in combination with gemcitabine and nab-paclitaxel [ Time Frame: Up to approximately 19 months ]
    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

  4. Progression-free survival (PFS) by investigator assessment per RECIST 1.1 [ Time Frame: From enrollment (run-in part) or randomization (randomized part) up to disease progression or death, assessed up to approximately 19 months ]
    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.

  5. Overall response rate (ORR) by investigator assessment per RECIST 1.1 [ Time Frame: Up to approximately 19 months ]
    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

  6. Disease control rate (DCR) by investigator assessment per RECIST 1.1 [ Time Frame: Up to approximately 19 months ]
    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

  7. Time to response (TTR) by investigator assessment per RECIST 1.1 [ Time Frame: From enrollment (run-in part) or randomization (randomized part) up to first documented response, assessed up to approximately 19 months ]
    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.

  8. Safety run-in part: Overall Survival (OS) [ Time Frame: From enrollment up to death, assessed up to approximately 19 months ]
    OS is defined as the time from the date of enrollment to date of death due to any cause.

  9. Maximum concentration (Cmax) of NIS793 in combination with gemcitabine and nab-paclitaxel [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    Blood samples will be collected for analysis of Cmax of NIS793

  10. Trough Concentration (Ctrough) of NIS793 in combination with gemcitabine and nab-paclitaxel [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    Blood samples will be collected for analysis of Ctrough of NIS793

  11. Area under the curve from time zero to the last measurable concentration sampling time (AUClast) of NIS793 in combination with gemcitabine and nab-paclitaxel [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    Blood samples will be collected for analysis of AUClast of NIS793

  12. 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 [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    Blood samples will be collected for analysis of AUCtau of NIS793

  13. Time to reach maximum concentration (Tmax) of NIS793 in combination with gemcitabine and nab-paclitaxel [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    Blood samples will be collected for analysis of Tmax of NIS793

  14. Randomized part: NIS793 serum concentration [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    Blood samples will be collected for analysis of NIS793 serum concentration

  15. Randomized part: Change from baseline in the patient reported outcomes measurement information system (PROMIS)-29 profile scores at week 12 [ Time Frame: Week 12 ]
    PROMIS is a commonly used self-reported measurement system of health-related quality of life and physical function. The PROMIS-29 includes 29 items that assess seven domains: physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, pain interference and pain intensity. Questions are ranked on a 5-point response scale, with higher scores at times indicating better quality of life, and at other times indicating poorer quality of life. There is a pain rating scale ranging from 0 to 10, with higher scores indicating higher pain level. Scores will be reported for each domain, as well as for pain rating.

  16. Randomized part: Change from baseline in the European Quality of life questionnaire (EQ-5D-5L) scores (health index and EQ-VAS) at week 12 [ Time Frame: Week 12 ]
    The EQ-5D-5L is a 2-part questionnaire: the descriptive system and the EQ visual analogue scale (EQ-VAS). The first part assesses participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that have 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). The health state index score is calculated based on the responses to the 5 dimensions, providing a single value on a scale from -0.285 to 0.950, with higher scores indicating better health utility. The EQ-VAS records the respondent's self-rated health on a visual analogue scale with endpoints labeled 'the best health you can imagine' and 'the worst health you can imagine'. This scale is numbered from 0 to 100. 100 means the best health you can imagine.

  17. Randomized part: Time-to-deterioration in domain scores in the PROMIS-29 profile [ Time Frame: From randomization up to deterioration or death, assessed up to approximately 19 months ]
    A clinically meaningful deterioration or worsening in the domain will be defined according to change from baseline scores according to minimally important differences (MID) estimates for each domain. Time-to-deterioration is defined as the time from baseline to the date of deterioration event or death due to any cause. The event of deterioration is defined as the change from baseline (worsening) of the corresponding PROMIS-29 score ≥MID, with no later change below the thereshold

  18. Randomized part: Time-to-deterioration in EQ-5D-5L scores (health index and EQ-VAS) [ Time Frame: From randomization up to deterioration, assessed up to approximately 19 months ]

    The EQ-5D-5L is a 2-part questionnaire: the descriptive system and the EQ-VAS. The first part assesses participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that have 5 levels. The health state index score is calculated based on the responses to the 5 dimensions, providing a single value on a scale from -0.285 to 0.950, with higher scores indicating better health. The EQ-VAS records the respondent's self-rated health on a visual analogue scale with endpoints labeled 'the best health you can imagine' and 'the worst health you can imagine'. This scale is numbered from 0 to 100. 100 means the best health you can imagine.

    Time-to-deterioration is defined as the time from baseline to the date of deterioration event or death due to any cause. The event of deterioration is defined as the change from baseline (worsening) in the corresponding index score ≥ 7 (EuroQol visual analogue scale) or ≥8 (health index).


  19. Randomized part: Anti-drug antibodies (ADA) against NIS793 prevalence at baseline [ Time Frame: Baseline ]
    ADA (anti-NIS793) prevalence at baseline is defined as the proportion of participants who have an ADA positive result at baseline

  20. Randomized part: ADA (anti-NIS793) incidence on treatment [ Time Frame: From date of first study drug intake up to approximately 19 months ]
    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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • 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, acinar, or islet 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04935359


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, Arkansas
Highlands Oncology Group Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: London Hall    479-587-1700    lhall@hogonc.com   
Principal Investigator: Joseph T. Beck         
United States, Texas
US Oncology Research, Dallas Recruiting
Dallas, Texas, United States, 75204
Contact: Penny R Watkins       penny.watkins@usoncology.com   
Principal Investigator: Scott Paulson         
Australia, South Australia
Novartis Investigative Site Recruiting
Adelaide, South Australia, Australia, 5000
Australia, Western Australia
Novartis Investigative Site Recruiting
Perth, Western Australia, Australia
Belgium
Novartis Investigative Site Recruiting
Edegem, Antwerpen, Belgium, 2650
Novartis Investigative Site Recruiting
Bonheiden, Belgium, 2820
Novartis Investigative Site Recruiting
Leuven, Belgium, 3000
Canada, Ontario
Novartis Investigative Site Recruiting
Cambridge, Ontario, Canada, N1R 3G2
Czechia
Novartis Investigative Site Recruiting
Brno, Czech Republic, Czechia, 656 53
Novartis Investigative Site Recruiting
Novy Jicin, Czech Republic, Czechia, 74101
Novartis Investigative Site Recruiting
Hradec Kralove, CZE, Czechia, 500 05
Novartis Investigative Site Recruiting
Praha 4, Czechia, 140 59
Finland
Novartis Investigative Site Recruiting
Helsinki, Finland, 00290
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 13353
Novartis Investigative Site Recruiting
Bochum, Germany, 44791
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Frankfurt, Germany, 60488
Novartis Investigative Site Recruiting
Hamburg, Germany, 20249
Israel
Novartis Investigative Site Recruiting
Jerusalem, Israel, 9112001
Italy
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20133
Novartis Investigative Site Recruiting
Verona, VR, Italy, 37126
Japan
Novartis Investigative Site Recruiting
Kashiwa, Chiba, Japan, 277 8577
Novartis Investigative Site Recruiting
Koto ku, Tokyo, Japan, 135 8550
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03080
Norway
Novartis Investigative Site Recruiting
Lorenskog, Oslo, Norway, 1478
Novartis Investigative Site Recruiting
Oslo, Norway, NO 0450
Russian Federation
Novartis Investigative Site Active, not recruiting
Omsk, Russian Federation, 644013
Novartis Investigative Site Active, not recruiting
Pushkin Saint Petersburg, Russian Federation, 196603
Slovakia
Novartis Investigative Site Recruiting
Banska Bystrica, Slovakia, 975 17
Novartis Investigative Site Recruiting
Bratislava, Slovakia, 83310
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Santiago de Compostela, Galicia, Spain, 15706
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
Novartis Investigative Site Recruiting
Madrid, Spain, 28034
Novartis Investigative Site Recruiting
Madrid, Spain, 28040
Switzerland
Novartis Investigative Site Recruiting
Geneve 14, Switzerland, CH 1211
Taiwan
Novartis Investigative Site Recruiting
Taipei, Taiwan, 10002
United Kingdom
Novartis Investigative Site Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Novartis Investigative Site Recruiting
Cambridge, United Kingdom, CB2 2QQ
Novartis Investigative Site Recruiting
Oxford, United Kingdom, OX3 7LJ
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04935359    
Other Study ID Numbers: CNIS793B12301
2021-000591-10 ( EudraCT Number )
First Posted: June 23, 2021    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
mPDAC
NIS793
Pancreas
metastatic pancreatic ductal adenocarcinoma (mPDAC)
Nab-paclitaxel
Abraxane
Gemcitabine
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
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