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

Study Overview
=================
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.

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

Conditions
-----------------
Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: NIS793
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Drug: Placebo


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety run-in part: NIS793+gemcitabine+nab-paclitaxel<br>In the safety run-in part, participants will receive a combination of NIS793, gemcitabine and nab-paclitaxel. | Drug: NIS793<br>* Concentrate for solution infusion (Liquid in Vial)<br>Drug: Nab-paclitaxel<br>* Per locally approved formulation<br>Drug: Gemcitabine<br>* Per locally approved formulation<br>|
| Experimental: Randomized part: NIS793+gemcitabine+nab-paclitaxel<br>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<br>* Concentrate for solution infusion (Liquid in Vial)<br>Drug: Nab-paclitaxel<br>* Per locally approved formulation<br>Drug: Gemcitabine<br>* Per locally approved formulation<br>Drug: Placebo<br>* Dextrose 5% in water (D5W) solution for infusion<br>|
| Placebo Comparator: Randomized part: placebo+gemcitabine+nab-paclitaxel<br>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<br>* Per locally approved formulation<br>Drug: Gemcitabine<br>* Per locally approved formulation<br>Drug: Placebo<br>* Dextrose 5% in water (D5W) solution for infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mPDAC, NIS793, Pancreas, metastatic pancreatic ductal adenocarcinoma (mPDAC), Nab-paclitaxel, Abraxane, Gemcitabine