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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04935359
Collaborator
(none)
501
72
3
51.1
7
0.1

Study Details

Study Description

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
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.

Study Design

Study Type:
Interventional
Anticipated 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 :
Sep 30, 2021
Anticipated Primary Completion Date :
Jan 1, 2026
Anticipated Study Completion Date :
Jan 1, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

  1. Safety run-in part: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment. [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) [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) [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 [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 [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 [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 [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 [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 [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) [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 [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 [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 [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 [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 [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 [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 [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 [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 [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) [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 [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 [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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)

Contacts and Locations

Locations

Site City State Country Postal Code
1 Highlands Oncology Group Fayetteville Arkansas United States 72703
2 Fort Wayne Medical Oncology/Hematology, Inc. Jefferson Blvd Fort Wayne Indiana United States 46815
3 NYU Clinical Cancer Center New York New York United States 10016
4 US Oncology Research, Dallas Dallas Texas United States 75204
5 Houston Methodist Hospital OPC 26 Houston Texas United States 77030
6 Novartis Investigative Site Adelaide South Australia Australia 5000
7 Novartis Investigative Site Perth Western Australia Australia
8 Novartis Investigative Site Edegem Antwerpen Belgium 2650
9 Novartis Investigative Site Bonheiden Belgium 2820
10 Novartis Investigative Site Leuven Belgium 3000
11 Novartis Investigative Site Cambridge Ontario Canada N1R 3G2
12 Novartis Investigative Site Toronto Ontario Canada M4N 3M5
13 Novartis Investigative Site Brno Czech Republic Czechia 656 53
14 Novartis Investigative Site Novy Jicin Czech Republic Czechia 74101
15 Novartis Investigative Site Hradec Kralove CZE Czechia 500 05
16 Novartis Investigative Site Praha 4 Czechia 140 59
17 Novartis Investigative Site Helsinki Finland 00290
18 Novartis Investigative Site Tampere Finland FIN-33521
19 Novartis Investigative Site Nice Cedex 2 Alpes Maritimes France 06189
20 Novartis Investigative Site Besançon Cedex France 25030
21 Novartis Investigative Site Avignon Cedex France 84082
22 Novartis Investigative Site Creteil France 94010
23 Novartis Investigative Site Dijon France 21000
24 Novartis Investigative Site Lyon Cedex 08 France 69373
25 Novartis Investigative Site Marseille France 13273
26 Novartis Investigative Site Montpellier cedex 5 France 34295
27 Novartis Investigative Site Nantes Cedex 1 France 44093
28 Novartis Investigative Site Paris France 75015
29 Novartis Investigative Site Berlin Germany 13353
30 Novartis Investigative Site Bochum Germany 44791
31 Novartis Investigative Site Essen Germany 45147
32 Novartis Investigative Site Frankfurt Germany 60488
33 Novartis Investigative Site Hamburg Germany 20249
34 Novartis Investigative Site Ulm Germany 89081
35 Novartis Investigative Site Thessaloniki Greece 540 07
36 Novartis Investigative Site Thessaloniki Greece 57001
37 Novartis Investigative Site Budapest Hungary 1097
38 Novartis Investigative Site Budapest Hungary H 1122
39 Novartis Investigative Site Jerusalem Israel 9112001
40 Novartis Investigative Site Ramat Gan Israel 52621
41 Novartis Investigative Site Tel Aviv Israel 6423906
42 Novartis Investigative Site Milano MI Italy 20133
43 Novartis Investigative Site Verona VR Italy 37126
44 Novartis Investigative Site Kashiwa Chiba Japan 277 8577
45 Novartis Investigative Site Koto ku Tokyo Japan 135 8550
46 Novartis Investigative Site Seoul Seocho Gu Korea, Republic of 06591
47 Novartis Investigative Site Seoul Korea, Republic of 03080
48 Novartis Investigative Site Seoul Korea, Republic of 05505
49 Novartis Investigative Site Lorenskog Oslo Norway 1478
50 Novartis Investigative Site Oslo Norway NO 0450
51 Novartis Investigative Site Omsk Russian Federation 644013
52 Novartis Investigative Site Pushkin Saint Petersburg Russian Federation 196603
53 Novartis Investigative Site Banska Bystrica Slovakia 975 17
54 Novartis Investigative Site Bratislava Slovakia 83310
55 Novartis Investigative Site Kosice Slovakia 041 91
56 Novartis Investigative Site Barcelona Catalunya Spain 08035
57 Novartis Investigative Site Santiago de Compostela Galicia Spain 15706
58 Novartis Investigative Site Madrid Spain 28009
59 Novartis Investigative Site Madrid Spain 28034
60 Novartis Investigative Site Madrid Spain 28040
61 Novartis Investigative Site Bellinzona Switzerland 6500
62 Novartis Investigative Site Geneve 14 Switzerland CH 1211
63 Novartis Investigative Site St. Gallen Switzerland 9007
64 Novartis Investigative Site Kaohsiung Taiwan 80756
65 Novartis Investigative Site Taipei Taiwan 10002
66 Novartis Investigative Site Taipei Taiwan 11217
67 Novartis Investigative Site Istanbul Turkey 34722
68 Novartis Investigative Site Izmir Turkey 35040
69 Novartis Investigative Site Sihhiye / Ankara Turkey 06100
70 Novartis Investigative Site Sutton Surrey United Kingdom SM2 5PT
71 Novartis Investigative Site Cambridge United Kingdom CB2 2QQ
72 Novartis Investigative Site Oxford United Kingdom OX3 7LJ

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT04935359
Other Study ID Numbers:
  • CNIS793B12301
  • 2021-000591-10
First Posted:
Jun 23, 2021
Last Update Posted:
Aug 10, 2022
Last Verified:
Aug 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:

Study Results

No Results Posted as of Aug 10, 2022