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

Novartis Pharmaceuticals511 enrolled

Overview

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (113)

Highlands Oncology Group

Fayetteville, Arkansas, United States

University of California LA

Los Angeles, California, United States

AdventHealth

Orlando, Florida, United States

Fort Wayne Medical Oncology Hematology Inc

Fort Wayne, Indiana, United States

NYU Clinical Cancer Center

New York, New York, United States

Outcomes

Primary Outcomes

Safety run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) During the First Cycle (4 Weeks) of Treatment.

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle (i.e., 28 days or 4 weeks) of the treatment with NIS793 in combination with gemcitabine/nab-paclitaxel. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5 was used for all grading.

Time frame: Up to 4 weeks

Randomized Part: Overall Survival (OS)

Overall Survival (OS) was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive.

Time frame: From randomization up to death, assessed up to approximately 34 months

Secondary Outcomes

Percentage of Participants With Adverse Events (AEs)

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 30 days after last dose of SOC chemotherapies and up to 90 days after NIS793, whichever is later.

Time frame: Up to approximately 32 months

Percentage of Participants With Dose Interruptions and Dose Reductions of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

No dose reductions were allowed for NIS793 in the Randomized part and beyond the first 28 days period of the Safety Run-in part. Increasing the dosing interval from every 2 weeks (Q2W) to every 2 weeks (Q4W) was allowed. Dose interruption for NIS793 was permitted if adverse drug reaction was suspected to be related to NIS793. If NIS793 was interrupted or delayed for \> 8 weeks due to toxicity that was suspected to be related to treatment, study treatment was permanently discontinued.

Time frame: Up to approximately 32 months

Dose Intensity of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

Dose intensity was computed as the ratio of actual cumulative dose received and actual duration of exposure.

Time frame: Up to approximately 32 months

Progression-Free Survival (PFS)

Progression-Free Survival (PFS) was defined as the time from the enrollment (run-in part) or randomization (randomized part) to the date of the first documented disease progression based on local investigator assessment as per RECIST 1.1 or date of death due to any cause, whichever occurs first. PFS was censored if no PFS event was observed before the analysis cut-off date. The censoring date was the date of the last adequate tumor assessment prior to the analysis cut-off.

Time frame: From enrollment (run-in part) or randomization (randomized part) up to disease progression or death, assessed up to approximately 34 months

Overall Response Rate (ORR)

Overall Response Rate (ORR) was defined as the proportion of participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) as per local review. ORR was evaluated according to RECIST 1.1. The BOR was determined from response assessments undertaken while on treatment.

Time frame: Up to approximately 34 months

Disease Control Rate (DCR)

Disease Control Rate (DCR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) or Non-CR/Non-progressive disease as per local review. DCR was evaluated according to RECIST 1.1.

Time frame: Up to approximately 34 months

Duration of Response (DOR)

Duration of Response (DOR) was defined as the duration of time between the date of first documented response (CR or PR) and the date of first documented progression or death due to any cause.

Time frame: Up to approximately 34 months

Time to Response (TTR)

Time to Response (TTR) was 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 as per local review, which was subsequently confirmed. TTR was evaluated according to RECIST 1.1. Participants without a confirmed CR or PR were censored at the time of PFS event (i.e., disease progression or death due to any cause) for participants with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last adequate tumor assessment for participants without a PFS event.

Time frame: From enrollment (run-in part) or randomization (randomized part) up to first documented response, assessed up to approximately 34 months

Safety run-in Part: Trough Concentration (Ctrough) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Ctrough was listed and summarized using descriptive statistics.

Time frame: Cycles 1 and 3 Day 15 (0 hour (pre-dose)), Cycles 2, 4, 6 and 12 Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.

Safety run-in Part: Maximum Concentration (Cmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax was listed and summarized using descriptive statistics.

Time frame: Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.

Safety run-in Part: Time to Reach Maximum Concentration (Tmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics.

Time frame: Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.

Randomized Part (Chinese Participants With Intensive PK Sampling): Trough Concentration (Ctrough) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected for activity-based pharmacokinetics characterization and Ctrough was summarized using descriptive statistics.

Time frame: Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15, Cycle 4 Day 1 and Cycle 6 Day 1: 0 hour (pre-dose). 1 cycle = 28 days.

Randomized Part (Chinese Participants With Intensive PK Sampling): Maximum Concentration (Cmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

Time frame: Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.

Randomized Part (Chinese Participants With Intensive PK Sampling): Time to Reach Maximum Concentration (Tmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

Time frame: Cycles 1 and 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.

Randomized Part (Chinese Participants With Intensive PK Sampling): Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected for activity-based pharmacokinetics characterization and AUClast was summarized using descriptive statistics.

Time frame: Cycles 1 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.

Randomized Part (Chinese Participants With Intensive PK Sampling): 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

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected and AUCtau was summarized using descriptive statistics.

Time frame: Cycles 3 Day 1: 0 hour (pre-dose) and 1 hour. 1 cycle = 28 days.

Randomized Part (Participants Without Intensive PK Sampling): Trough Concentration (Ctrough) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

For participants without intensive PK sampling, venous whole blood samples were collected for activity-based pharmacokinetics characterization. Ctrough was listed and summarized using descriptive statistics.

Time frame: Cycles 2, 3, 4, 6 and 12 Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.

Randomized Part (Participants Without Intensive PK Sampling): Maximum Concentration (Cmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

For Chinese participants without intensive PK sampling schedule and global participants in the randomized part, for which only sparse PK samples were collected for activity-based pharmacokinetics characterization, Cmax was listed and summarized using descriptive statistics.

Time frame: Cycles 1 and 3: Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.

Randomized Part (Participants Without Intensive PK Sampling): Time to Reach Maximum Concentration (Tmax) of NIS793 in Combination With Gemcitabine and Nab-paclitaxel

For Chinese participants without intensive PK sampling schedule and global participants in the randomized part, for which only sparse PK samples were collected for activity-based pharmacokinetics characterization, Tmax was listed and summarized using descriptive statistics.

Time frame: Cycles 1 and 3: Day 1 (0 hour (pre-dose)). 1 cycle = 28 days.

Randomized Part: Anti-drug Antibodies (ADA) Against NIS793 Prevalence at Baseline

Anti-drug antibodies (ADA) against NIS793 prevalence at baseline refers to the proportion of subjects who have developed antibodies against the drug NIS793 before starting treatment. This is calculated by dividing the number of subjects with ADA-positive samples at baseline by the total number of subjects whose baseline samples were tested for ADA.

Time frame: Baseline

Randomized Part: Anti-drug Antibodies (ADA) Against NIS793 Incidence on Treatment

Anti-drug antibodies (ADA) against NIS793 incidence on treatment refers to the proportion of participants who developed antibodies against the drug NIS793 during the treatment period. This can be categorized into two types: 1. Treatment-induced ADA positive: Participants who were ADA-negative at baseline but became ADA-positive after starting the treatment. 2. Treatment-boosted ADA positive: Participants who were ADA-positive at baseline and showed a significant increase in ADA titer during the treatment.

Time frame: From date of first study drug intake up to approximately 34 months

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

Overview

Conditions

Interventions

Eligibility

Locations (113)

Outcomes

Primary Outcomes

Secondary Outcomes