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 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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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)

Locations (113)

Highlands Oncology Group

Fayetteville, Arkansas, United States

University of California LA

Los Angeles, California, United States

Advent Health Cancer Institute

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.

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

Time frame: 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.

Time frame: From randomization up to death, assessed up to approximately 19 months

Secondary Outcomes

Percentage of participants with Adverse Events (AEs)

Percentage of participants with AEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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