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 |
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Recruitment Status :
Active, not recruiting
First Posted : June 23, 2021
Last Update Posted : April 26, 2024
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Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
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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 |
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 (Clinical Trial) |
| Actual Enrollment : | 511 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 : | June 28, 2024 |
| Estimated Study Completion Date : | June 30, 2024 |
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: NIS793
Concentrate for solution infusion (Liquid in Vial) Drug: Nab-paclitaxel Per locally approved formulation Drug: Gemcitabine Per locally approved formulation |
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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. |
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 |
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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. |
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 :
- 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.
Secondary Outcome Measures :
- 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)
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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:
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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:
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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)
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
Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| 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: | April 26, 2024 |
| Last Verified: | April 2024 |
| 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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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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 Paclitaxel Gemcitabine Antineoplastic Agents, Phytogenic |
Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antimetabolites |