Clinical trial NCT04390763: Study of Efficacy and Safety of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)
Official title: A Phase II, Open Label, Randomized, Parallel Arm Study of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy Gemcitabine/Nab-paclitaxel, and Gemcitabine/Nab-paclitaxel Alone in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: NIS793
spartalizumab
gemcitabine
nab-paclitaxel
mPDAC
TGFβ
PD-1
Phase II
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-05-18
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this Phase II study is to assess the efficacy and safety of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in previously untreated mPDAC.

Detailed description: This is a randomized, parallel arms, open-label, multi-center, Phase II study to evaluate the efficacy and safety of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel in participants with first-line metastatic pancreatic ductal adenocarcinoma (mPDAC).

The study started with a Safety Run-in to assess the safety and tolerability of NIS793 in combination with spartalizumab and standard of care (SOC) gemcitabine/nab-paclitaxel. Doses defined for each study treatment, as part of this quadruplet were administered in the Randomized part in the quadruplet/triplet/doublet-based treatment arms.

The Randomized part opened after the Safety Run-in had completed. Participants were randomized in a 1:1:1 ratio to one of the three treatment arms:

* Arm 1: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel
* Arm 2: NIS793 with gemcitabine/nab-paclitaxel
* Arm 3: gemcitabine/nab-paclitaxel

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female ≥ 18 years of age at the time of informed consent.
3. Participants with histologically or cytologically confirmed treatment-naïve metastatic adenocarcinoma of the pancreas with measurable disease as per RECIST 1.1.
4. Participants must have a site of disease amenable to biopsy, and be candidate for tumor biopsy according to the treating institution's guidelines. Participants must be willing to undergo a tumor biopsy at screening and during therapy on the study. In the event a new biopsy cannot be safely performed at study entry, an archival sample (collected \<6 months prior) may be substituted following documented discussion with Novartis.
5. ECOG performance status ≤ 1.

Exclusion Criteria:

1. Previous radiotherapy, surgery (with exception of placement of biliary stent, which is allowed), chemotherapy or any other investigational therapy for the treatment of metastatic pancreatic cancer. Participants having received previous chemotherapy in the adjuvant setting.
2. Participants amenable to potentially curative resection.
3. Participants with a diagnosis of pancreatic neuroendocrine tumors (NETs), acinar, or islet cell tumors.
4. Having out of range laboratory values as pre-defined in the protocol.
5. Participants with MSI-H pancreatic adenocarcinoma.
6. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry.
7. History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
8. The participant exhibits any of the events outlined in the contra-indications or special warnings and precautions sections of gemcitabine and nab-paclitaxel as per locally approved labels.
9. Impaired cardiac function or clinically significant cardiac disease.
10. Known history of testing positive HIV infection.
11. Active HBV or HCV infection. Participants whose disease is controlled under antiviral therapy should not be excluded.
12. History of or current interstitial lung disease or pneumonitis grade ≥ 2
13. High risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding.

Primary outcomes:
measure: Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: First cycle of treatment (28 days)
measure: Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period
timeFrame: Up to approximately 0.8 years
measure: Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel
timeFrame: Up to approximately 0.7 years
measure: Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab
timeFrame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
measure: Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel
timeFrame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
measure: Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model
timeFrame: Up to approximately 2 years. Risk changing timepoint=approximately 0.3 years.
measure: Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model
timeFrame: Up to approximately 2 years
Secondary outcomes:
measure: Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period
timeFrame: Up to approximately 1.8 years
measure: Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel
timeFrame: Up to approximately 1.7 years
measure: Randomized Part: Dose Intensity of NIS973 and Spartalizumab
timeFrame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days
measure: Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel
timeFrame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days
measure: Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1
timeFrame: Up to approximately 1.7 years
measure: Randomized Part: Duration of Response (DOR) Per RECIST v1.1
timeFrame: Up to approximately 1.7 years
measure: Randomized Part: Time to Progression (TTP) Per RECIST v1.1
timeFrame: Up to approximately 1.7 years
measure: Randomized Part: Overall Survival (OS)
timeFrame: Up to approximately 2 years
measure: Randomized Part: Change From Baseline in PD-L1 Expression
timeFrame: Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.
measure: Randomized Part: Change From Baseline in CD8 Expression
timeFrame: Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.
measure: Randomized Part: Number of Participants With Anti-NIS793 Antibodies
timeFrame: Baseline (before first dose) and post-baseline (assessed throughout the treatment up to approximately 1.7 years)
measure: Randomized Part: Number of Participants With Anti-spartalizumab Antibodies
timeFrame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days
measure: Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793
timeFrame: Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 336 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
measure: Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793
timeFrame: Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 336 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
measure: Randomized Part: Trough Serum Concentration (Ctrough) of NIS793
timeFrame: Cycle 1: pre-dose on Day 1. Cycle 3: pre-dose on Day 1 and Day 15 (combined). One cycle=28 days
measure: Randomized Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab
timeFrame: Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 648 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
measure: Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab
timeFrame: Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 648 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
measure: Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab
timeFrame: Cycle 2, 3 and 4: pre-dose on Day 1. One cycle=28 days
measure: Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine
timeFrame: Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
measure: Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine
timeFrame: Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
measure: Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine
timeFrame: Cycle 4: pre-dose on Day 1. One cycle=28 days
measure: Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel
timeFrame: Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
measure: Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel
timeFrame: Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
measure: Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel
timeFrame: Cycle 4: pre-dose on Day 1. One cycle=28 days
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Baltimore
country: United States
facility: Sidney Kimmel CCC At JH
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Cente
state: Massachusetts
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh Cancer Institute
state: Pennsylvania
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Toulouse 4
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References: