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

• ClinicalTrials.gov Identifier: NCT04935359
• Recruitment Status: Active, not recruiting
• First Posted: June 23, 2021
• Last Update Posted: April 26, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 21, 2021
• First Posted Date: June 23, 2021
• Last Update Posted Date: April 26, 2024
• Actual Study Start Date: September 30, 2021
• Estimated Primary Completion Date: June 28, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 21, 2021)

• 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
• 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 16, 2023)

• 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
• 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
• 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
• 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.
• 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
• 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
• 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.
• 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.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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)

Original Secondary Outcome Measures (submitted: June 21, 2021)

• 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
• 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
• 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
• 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.
• 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
• 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
• 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.
• 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.
• 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
• 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
• 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
• 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
• 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
• 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
• 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.
• 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.
• 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
• 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).
• 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
• 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)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Metastatic Pancreatic Ductal Adenocarcinoma

Intervention

• 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

Study Arms

• 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.
  Interventions:

  • Drug: NIS793
  • Drug: Nab-paclitaxel
  • Drug: Gemcitabine
• 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.

  Interventions:

  • Drug: NIS793
  • Drug: Nab-paclitaxel
  • Drug: Gemcitabine
  • Drug: Placebo
• 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.

  Interventions:

  • Drug: Nab-paclitaxel
  • Drug: Gemcitabine
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 7, 2023): 511
• Original Estimated Enrollment (submitted: June 21, 2021): 490
• Estimated Study Completion Date: June 30, 2024
• Estimated Primary Completion Date: June 28, 2024 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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, United States

Administrative Information

• NCT Number: NCT04935359
• Other Study ID Numbers: CNIS793B12301; 2021-000591-10 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2024