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

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

The purpose of this study was 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 aimed to explore whether blockade of Transforming Growth Factor β (TGFβ) in combination with gemcitabine/nab-paclitaxel could reduce fibrosis in PDAC, restore chemo-sensitivity and ultimately lead to improvements in overall survival (OS) and other clinically relevant outcomes.

This was a randomized, double-blind, multicenter, two- group, phase III study that consisted of two parts: a Safety Run-in part and a Randomized part.

The decision to open the randomized part of the study was based on dose confirmation and available safety, relevant PK, and other clinical and laboratory data from the Safety Run-in part.

The open-label Safety Run-in part was conducted to confirm the recommended phase 3 dose (RP3D) of NIS793 in combination with gemcitabine and nab-paclitaxel. The safety run-in part started with one treatment regimen - NIS793 (2100 mg intravenous (i.v.) every 2 weeks (Q2W)) in combination with gemcitabine and nab-paclitaxel during the DLT assessment period. Dose limiting toxicity assessment period is defined as first cycle (i.e. 28 days, or 4 weeks) of dosing of the study treatment.

The Randomized part randomized participants 1:1 to one of the two treatment groups:

• Investigational group (Arm A); combination of NIS793, gemcitabine and nab-paclitaxel
• Control group (Arm B): combination of placebo, gemcitabine and nab-paclitaxel

Participants were stratified at randomization by Eastern Cooperative Oncology Group Performance Status (ECOG-PS) (0 or 1), presence of liver metastasis (yes vs. no), and region (North America, Europe and Australia vs. other countries).

Cross-over to the other treatment group was not allowed during the study duration.

The study treatment was administered as a 28-day treatment cycle. NIS793 was administered at a flat dose as confirmed in the Safety Run-in part on day 1 and 15 (e.g., 2100 mg i.v. Q2W or 2100 mg i.v. Q4W, if Q2W was considered as not tolerable in Safety Run-in part). Gemcitabine (1000 mg/m² on days 1, 8 and 15) and nab-paclitaxel (125 mg/m² on days 1, 8 and 15) were administered as per label.

As of 7-Jul-2023, the administration of NIS793/placebo was stopped for all participants following the recommendation from Data Monitoring Committee (DMC). Following the recommendation to stop administration of NIS793/placebo, the DMC encouraged to continue administration of gemcitabine/nab-paclitaxel to all participants per investigator's assessment, and the collection of additional follow-up data to better characterize the safety of NIS793 in combination with gemcitabine/nab-paclitaxel.

The study was considered complete when each participant completed at least 12 months of follow-up from randomization date, died, withdrew consent, or was lost to follow-up, whichever occurred first or, in the event of an early study termination. At which time, any study participant continuing with standard of care chemotherapy (gemcitabine + nab-paclitaxel) was transitioned off the study.

Key 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.

Key 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)

Other Inclusion/Exclusion criteria may apply.