Metastatic Pancreatic Ductal Adenocarcinoma
Conditions
Keywords
NIS793, spartalizumab, gemcitabine, nab-paclitaxel, mPDAC, TGFβ, PD-1, Phase II
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
Interventions
BIOLOGICALNIS793
anti-TGFb antibody. NIS793 2100 mg every 2 weeks by intravenous (i.v.) infusion.
BIOLOGICALSpartalizumab
anti-PD-1 antibody. spartalizumab 400 mg every 4 weeks by i.v. infusion.
DRUGgemcitabine
SOC chemotherapy. Gemcitabine (1000 mg/m\^2 on Days 1, 8, and 15) i.v. given as per label.
DRUGnab-paclitaxel
SOC chemotherapy. Nab-paclitaxel (125 mg/m\^2 on Days 1, 8, and 15) i.v. given as per label.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs) | First cycle of treatment (28 days) | A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 where the relationship to study treatment cannot be ruled out and is not clearly related solely to disease, disease progression, inter-current illness or concomitant medications, which occurs within the DLT evaluation period. The DLT evaluation period is the first 28 days of treatment with NIS793 with spartalizumab in combination with gemcitabine/nab-paclitaxel. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. |
| Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | Up to approximately 0.8 years | Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of any study treatment up to 30 days after the date of the last actual administration of any study drug. |
| Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Up to approximately 0.7 years | Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab beyond the first 28 days period of Safety run-in part. |
| Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab | Cycle 1 and Cycle 3. The duration of each cycle was 28 days. | Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. |
| Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Cycle 1 and Cycle 3. The duration of each cycle was 28 days. | Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m\^2 divided by duration of exposure in days and multiplied by 28 days. |
| Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Up to approximately 2 years. Risk changing timepoint=approximately 0.3 years. | PFS was based on local review of tumor assessments, using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was estimated using a Bayesian model. For each comparison (arm 1 versus arm 3 and arm 2 versus arm 3), PFS was modeled using a two-piece hazard model, with specifying hazard rates before and after the possible delayed effect for arms 1 and 2 and constant hazard rate for arm 3. Results in the table as expressed as estimated posterior median hazard rate and one-sided 90% credible interval. |
| Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model | Up to approximately 2 years | PFS was based on local review of tumor assessments, using RECIST 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was analyzed based on the Kaplan-Meier curves and the Cox model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Part: Duration of Response (DOR) Per RECIST v1.1 | Up to approximately 1.7 years | DOR per RECIST v1.1 is defined as the time from the first documented response of CR or PR to the date of the first documented progression or death. DOR only applies to patients with a best overall response of CR or PR by investigator assessment per RECIST v1.1. Participants continuing without progression or death were censored at the date of their last adequate tumor assessment. DOR was analyzed using the Kaplan-Meier method. |
| Randomized Part: Time to Progression (TTP) Per RECIST v1.1 | Up to approximately 1.7 years | TTP per RECIST v1.1 is defined as the time from the date of randomization to the date of event defined as the first documented progression per RECIST v1.1 or death due to underlying cancer. If a participant had no progression or death, the participant was censored at the date of last adequate tumor assessment. DOR was analyzed using the Kaplan-Meier method. |
| Randomized Part: Overall Survival (OS) | Up to approximately 2 years | Overall survival is defined as the time from the date of randomization to the date of death due to any cause. OS was analyzed using the Kaplan-Meier method. |
| Randomized Part: Change From Baseline in PD-L1 Expression | Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days. | The tumor expression of programmed cell death-ligand 1 (PD-L1) was measured by immunohistochemical methods. Results are expressed as absolute change from baseline in PD-L1 expression. |
| Randomized Part: Change From Baseline in CD8 Expression | Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days. | The tumor expression of CD8 was measured by immunohistochemical methods. Results are expressed as absolute change from baseline in CD8 expression. |
| Randomized Part: Number of Participants With Anti-NIS793 Antibodies | Baseline (before first dose) and post-baseline (assessed throughout the treatment up to approximately 1.7 years) | The immunogenicity (IG) against NIS793 was assessed in serum using a validated enhanced electrochemiluminescence immunoassay (ECLIA). Patient anti-drug antibodies (ADA) status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline sample, all of which are ADA-negative samples * ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative post-baseline * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample |
| Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | Cycle 1 and Cycle 3. The duration of each cycle was 28 days | The immunogenicity (IG) against spartalizumab was assessed in serum using a validated a validated homogenous enzyme-linked immunosorbent assay (ELISA). Patient anti-drug antibodies (ADA) status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-inconclusive at baseline: patient who does not qualify as ADA-positive or ADA-negative at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline sample, all of which are ADA-negative samples * ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative post-baseline * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample |
| Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793 | 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 | Pharmacokinetic (PK) parameters were calculated based on NIS793 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Randomized Part: Trough Serum Concentration (Ctrough) of NIS793 | Cycle 1: pre-dose on Day 1. Cycle 3: pre-dose on Day 1 and Day 15 (combined). One cycle=28 days | Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters. |
| Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | 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 | PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab | Cycle 2, 3 and 4: pre-dose on Day 1. One cycle=28 days | Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters. |
| Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | 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 | PK parameters were calculated based on gemcitabine plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | 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 | PK parameters were calculated based on gemcitabine plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine | Cycle 4: pre-dose on Day 1. One cycle=28 days | Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters. |
| Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | 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 | PK parameters were calculated based on nab-paclitaxel plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | 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 | PK parameters were calculated based on nab-paclitaxel plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel | Cycle 4: pre-dose on Day 1. One cycle=28 days | Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters. |
| Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793 | 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 | PK parameters were calculated based on NIS793 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Randomized Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | 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 | PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Up to approximately 1.8 years | Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of any study treatment up to 30 days after the date of the last actual administration of any study drug. |
| Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Up to approximately 1.7 years | Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab in the Randomized part. |
| Randomized Part: Dose Intensity of NIS973 and Spartalizumab | Cycle 1 and Cycle 3. The duration of each cycle was 28 days | Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. |
| Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Cycle 1 and Cycle 3. The duration of each cycle was 28 days | Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m\^2 divided by duration of exposure in days and multiplied by 28 days. |
| Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1 | Up to approximately 1.7 years | ORR is the percentage of patients with a confirmed best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
Countries
Australia, Austria, Belgium, Czechia, Finland, France, Germany, Italy, Singapore, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in 31 investigative sites in 14 countries.
Pre-assignment details
The screening period began once patients had signed the study informed consent. Screening evaluations had to be completed within 21 days prior to the first dose of study treatment (≤ 28 days for baseline radiological assessments). After screening, the treatment period started on Cycle 1 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the safety run-in part | 11 |
| Arm 1: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the randomized part | 50 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel NIS793 2100 mg every 2 weeks i.v. with standard of care chemotherapy in the randomized part | 51 |
| Arm 3: Gemcitabine/Nab-paclitaxel Standard of care chemotherapy in the randomized part | 52 |
| Total | 164 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Randomized Part | Adverse Event | 0 | 11 | 5 | 5 |
| Randomized Part | Death | 0 | 3 | 4 | 2 |
| Randomized Part | Not treated | 0 | 4 | 2 | 7 |
| Randomized Part | Participant Decision | 0 | 5 | 7 | 6 |
| Randomized Part | Physician Decision | 0 | 2 | 2 | 9 |
| Randomized Part | Progressive Disease | 0 | 24 | 31 | 23 |
| Randomized Part | Study terminated by sponsor | 0 | 1 | 0 | 0 |
| Safety run-in Part | Adverse Event | 4 | 0 | 0 | 0 |
| Safety run-in Part | Physician Decision | 1 | 0 | 0 | 0 |
| Safety run-in Part | Progressive Disease | 6 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Arm 1: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Arm 3: Gemcitabine/Nab-paclitaxel | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.5 years STANDARD_DEVIATION 8.77 | 64.3 years STANDARD_DEVIATION 10.91 | 64.2 years STANDARD_DEVIATION 9.9 | 64.8 years STANDARD_DEVIATION 8.25 | 64.4 years STANDARD_DEVIATION 9.59 |
| Age, Customized 18 - <65 years | 5 Participants | 20 Participants | 23 Participants | 23 Participants | 71 Participants |
| Age, Customized 65 - <85 years | 6 Participants | 30 Participants | 28 Participants | 29 Participants | 93 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 9 Participants | 15 Participants | 15 Participants | 41 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 39 Participants | 35 Participants | 33 Participants | 116 Participants |
| Sex: Female, Male Female | 5 Participants | 21 Participants | 21 Participants | 20 Participants | 67 Participants |
| Sex: Female, Male Male | 6 Participants | 29 Participants | 30 Participants | 32 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 11 | 18 / 50 | 19 / 51 | 4 / 52 | 46 / 164 | 5 / 6 | 15 / 28 | 22 / 30 | 35 / 41 |
| other Total, other adverse events | 11 / 11 | 45 / 46 | 48 / 49 | 40 / 45 | 144 / 151 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 8 / 11 | 34 / 46 | 28 / 49 | 26 / 45 | 96 / 151 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model
PFS was based on local review of tumor assessments, using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was estimated using a Bayesian model. For each comparison (arm 1 versus arm 3 and arm 2 versus arm 3), PFS was modeled using a two-piece hazard model, with specifying hazard rates before and after the possible delayed effect for arms 1 and 2 and constant hazard rate for arm 3. Results in the table as expressed as estimated posterior median hazard rate and one-sided 90% credible interval.
Time frame: Up to approximately 2 years. Risk changing timepoint=approximately 0.3 years.
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Hazard rate before the risk changing timepoint | 2.54 events (progression, death) per year |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Hazard rate after the risk changing timepoint | 1.46 events (progression, death) per year |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Hazard rate before the risk changing timepoint | 1.23 events (progression, death) per year |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Hazard rate after the risk changing timepoint | 2.94 events (progression, death) per year |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Hazard rate before the risk changing timepoint | 2.09 events (progression, death) per year |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Bayesian Model | Hazard rate after the risk changing timepoint | 2.09 events (progression, death) per year |
Bayesian two-piece hazard model
Bayesian two-piece hazard model
Primary
Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model
PFS was based on local review of tumor assessments, using RECIST 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was analyzed based on the Kaplan-Meier curves and the Cox model.
Time frame: Up to approximately 2 years
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model | 3.91 months |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model | 5.52 months |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Progression-Free Survival (PFS) Per RECIST v1.1 - Kaplan-Meier Curves and Cox Model | 4.37 months |
p-value: 0.46Regression, Cox
p-value: 0.38Regression, Cox
Primary
Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel
Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m\^2 divided by duration of exposure in days and multiplied by 28 days.
Time frame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
Population: Patients in the Safety set 1 who received gemcitabine or nab-paclitaxel at each reported treatment cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 3 | 327.6 mg per m^2 per cycle | Standard Deviation 63.65 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 1 | 2425.4 mg per m^2 per cycle | Standard Deviation 698.27 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 3 | 2619.1 mg per m^2 per cycle | Standard Deviation 508.19 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 1 | 303.3 mg per m^2 per cycle | Standard Deviation 87.18 |
Primary
Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab
Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule.
Time frame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
Population: Patients in the Safety set 1 who received NIS793 or spartalizumab at each reported treatment cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab | NIS793 - cycle 1 | 3627.3 mg per cycle | Standard Deviation 980.91 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab | NIS793 - cycle 3 | 4200.0 mg per cycle | Standard Deviation 0 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab | Spartalizumab - cycle 1 | 400.0 mg per cycle | Standard Deviation 0 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Dose Intensity of NIS793 and Spartalizumab | Spartalizumab - cycle 3 | 400.0 mg per cycle | Standard Deviation 0 |
Primary
Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period
Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of any study treatment up to 30 days after the date of the last actual administration of any study drug.
Time frame: Up to approximately 0.8 years
Population: Safety set 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related SAEs | 3 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs | 11 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs | 11 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs with grade>=3 | 11 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs with grade>=3 | 8 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | SAEs | 8 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | Fatal SAEs | 1 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related fatal SAEs | 0 Participants |
Primary
Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 where the relationship to study treatment cannot be ruled out and is not clearly related solely to disease, disease progression, inter-current illness or concomitant medications, which occurs within the DLT evaluation period. The DLT evaluation period is the first 28 days of treatment with NIS793 with spartalizumab in combination with gemcitabine/nab-paclitaxel. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Time frame: First cycle of treatment (28 days)
Population: Dose-Determining Set (DDS) including all participants in the Safety run-in part who met the minimum exposure criterion defined in the protocol and had sufficient safety evaluations after 4 weeks of treatment or experienced a DLT during the first 4 weeks of treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs) | Any DLT | 1 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose-Limiting Toxicities (DLTs) | Colitis | 1 Participants |
Primary
Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel
Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab beyond the first 28 days period of Safety run-in part.
Time frame: Up to approximately 0.7 years
Population: Safety set 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose interruption | 9 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose reduction or interruption | 5 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose reduction | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose interruption | 5 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Spartalizumab: At least one dose reduction or interruption | 3 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Spartalizumab: At least one dose reduction | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Spartalizumab: At least one dose interruption | 3 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction or interruption | 9 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction | 2 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose interruption | 9 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction or interruption | 9 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Safety run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction | 3 Participants |
Secondary
Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine
PK parameters were calculated based on gemcitabine plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received gemcitabine and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | Cycle 1 | 7270 h*ng/mL | Standard Deviation 6950 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | Cycle 4 | 5270 h*ng/mL | Standard Deviation 4730 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | Cycle 1 | 9900 h*ng/mL | Standard Deviation 6140 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | Cycle 4 | 5980 h*ng/mL | Standard Deviation 4410 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | Cycle 1 | 8040 h*ng/mL | Standard Deviation 4490 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Gemcitabine | Cycle 4 | 4920 h*ng/mL | Standard Deviation 2830 |
Secondary
Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel
PK parameters were calculated based on nab-paclitaxel plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received nab-paclitaxel and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | Cycle 1 | 15700 h*ng/mL | Standard Deviation 52400 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | Cycle 4 | 5960 h*ng/mL | Standard Deviation 3650 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | Cycle 1 | 5080 h*ng/mL | Standard Deviation 2820 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | Cycle 4 | 5020 h*ng/mL | Standard Deviation 3050 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | Cycle 4 | 4250 h*ng/mL | Standard Deviation 2550 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel | Cycle 1 | 4820 h*ng/mL | Standard Deviation 2500 |
Secondary
Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793
PK parameters were calculated based on NIS793 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received NIS793 and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793 | Cycle 1 | 84700000 h*ng/mL | Standard Deviation 29300000 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793 | Cycle 3 | 153000000 h*ng/mL | Standard Deviation 52300000 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793 | Cycle 1 | 96000000 h*ng/mL | Standard Deviation 26100000 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of NIS793 | Cycle 3 | 151000000 h*ng/mL | Standard Deviation 55000000 |
Secondary
Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab
PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received spartalizumab and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 1 | 10800 h*µg/mL | Standard Deviation 4900 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 3 | 3240 h*µg/mL | Standard Deviation 1900 |
Secondary
Randomized Part: Change From Baseline in CD8 Expression
The tumor expression of CD8 was measured by immunohistochemical methods. Results are expressed as absolute change from baseline in CD8 expression.
Time frame: Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.
Population: Participants in the Full Analysis Set (FAS) who had a valid assessment of CD8 tumor expression at both baseline and on-treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Change From Baseline in CD8 Expression | 10.1 percentage of CD8 marker area expression | Standard Deviation 11.01 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Change From Baseline in CD8 Expression | 1.4 percentage of CD8 marker area expression | Standard Deviation 2.64 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Change From Baseline in CD8 Expression | 2.1 percentage of CD8 marker area expression | Standard Deviation 1.82 |
Secondary
Randomized Part: Change From Baseline in PD-L1 Expression
The tumor expression of programmed cell death-ligand 1 (PD-L1) was measured by immunohistochemical methods. Results are expressed as absolute change from baseline in PD-L1 expression.
Time frame: Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.
Population: Participants in the Full Analysis Set (FAS) who had a valid assessment of PD-L1 tumor expression at both baseline and on-treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Change From Baseline in PD-L1 Expression | 7.625 percentage of PD-L1 positive tumor cells | Standard Deviation 10.4193 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Change From Baseline in PD-L1 Expression | 7.917 percentage of PD-L1 positive tumor cells | Standard Deviation 17.0572 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Change From Baseline in PD-L1 Expression | 4.000 percentage of PD-L1 positive tumor cells | Standard Deviation 8.9443 |
Secondary
Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel
Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m\^2 divided by duration of exposure in days and multiplied by 28 days.
Time frame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days
Population: Patients in the Safety set 2 who received gemcitabine or nab-paclitaxel at each reported treatment cycle
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 1 | 2442.3 mg per m^2 per cycle | Standard Deviation 675.34 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 3 | 2293.9 mg per m^2 per cycle | Standard Deviation 710.08 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 1 | 305.7 mg per m^2 per cycle | Standard Deviation 84.91 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 3 | 286.2 mg per m^2 per cycle | Standard Deviation 86.45 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 3 | 296.2 mg per m^2 per cycle | Standard Deviation 88.06 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 1 | 2644.8 mg per m^2 per cycle | Standard Deviation 543.43 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 1 | 330.7 mg per m^2 per cycle | Standard Deviation 67.95 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 3 | 2426.5 mg per m^2 per cycle | Standard Deviation 696.1 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 3 | 299.1 mg per m^2 per cycle | Standard Deviation 70.08 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 3 | 2445.3 mg per m^2 per cycle | Standard Deviation 561.36 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Nab-paclitaxel - cycle 1 | 298.8 mg per m^2 per cycle | Standard Deviation 80.96 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of Gemcitabine and Nab-paclitaxel | Gemcitabine - cycle 1 | 2392.1 mg per m^2 per cycle | Standard Deviation 651 |
Secondary
Randomized Part: Dose Intensity of NIS973 and Spartalizumab
Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule.
Time frame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days
Population: Patients in the Safety set 2 who received NIS793 or spartalizumab at each reported treatment cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of NIS973 and Spartalizumab | NIS793 - cycle 1 | 3515.2 mg per cycle | Standard Deviation 995.32 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of NIS973 and Spartalizumab | NIS793 - cycle 3 | 3796.2 mg per cycle | Standard Deviation 844.03 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of NIS973 and Spartalizumab | Spartalizumab - cycle 1 | 400.0 mg per cycle | Standard Deviation 0 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of NIS973 and Spartalizumab | Spartalizumab - cycle 3 | 400.0 mg per cycle | Standard Deviation 0 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of NIS973 and Spartalizumab | NIS793 - cycle 1 | 3857.1 mg per cycle | Standard Deviation 784.22 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Dose Intensity of NIS973 and Spartalizumab | NIS793 - cycle 3 | 3550.0 mg per cycle | Standard Deviation 982.59 |
Secondary
Randomized Part: Duration of Response (DOR) Per RECIST v1.1
DOR per RECIST v1.1 is defined as the time from the first documented response of CR or PR to the date of the first documented progression or death. DOR only applies to patients with a best overall response of CR or PR by investigator assessment per RECIST v1.1. Participants continuing without progression or death were censored at the date of their last adequate tumor assessment. DOR was analyzed using the Kaplan-Meier method.
Time frame: Up to approximately 1.7 years
Population: Participants in the Full Analysis Set (FAS) with CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Duration of Response (DOR) Per RECIST v1.1 | 7.75 months |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Duration of Response (DOR) Per RECIST v1.1 | 4.86 months |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Duration of Response (DOR) Per RECIST v1.1 | 11.70 months |
Secondary
Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine
PK parameters were calculated based on gemcitabine plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received gemcitabine and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | Cycle 1 | 9830 ng/mL | Standard Deviation 8580 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | Cycle 4 | 7950 ng/mL | Standard Deviation 5650 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | Cycle 1 | 12000 ng/mL | Standard Deviation 6850 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | Cycle 4 | 8830 ng/mL | Standard Deviation 6150 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | Cycle 1 | 10600 ng/mL | Standard Deviation 6170 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine | Cycle 4 | 7000 ng/mL | Standard Deviation 4210 |
Secondary
Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel
PK parameters were calculated based on nab-paclitaxel plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received nab-paclitaxel and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | Cycle 1 | 9990 ng/mL | Standard Deviation 37100 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | Cycle 4 | 4570 ng/mL | Standard Deviation 4910 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | Cycle 1 | 4120 ng/mL | Standard Deviation 3370 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | Cycle 4 | 4050 ng/mL | Standard Deviation 2410 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | Cycle 1 | 3490 ng/mL | Standard Deviation 1760 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel | Cycle 4 | 2900 ng/mL | Standard Deviation 1370 |
Secondary
Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793
Pharmacokinetic (PK) parameters were calculated based on NIS793 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received NIS793 and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793 | Cycle 1 | 603000 ng/mL | Standard Deviation 181000 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793 | Cycle 3 | 821000 ng/mL | Standard Deviation 235000 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793 | Cycle 1 | 622000 ng/mL | Standard Deviation 192000 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Serum Concentration (Cmax) of NIS793 | Cycle 3 | 784000 ng/mL | Standard Deviation 286000 |
Secondary
Randomized Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab
PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: 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
Population: Participants in the pharmacokinetic analysis set (PAS) who received spartalizumab and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 109 µg/mL | Standard Deviation 22.4 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 120 µg/mL | Standard Deviation 38 |
Secondary
Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period
Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of any study treatment up to 30 days after the date of the last actual administration of any study drug.
Time frame: Up to approximately 1.8 years
Population: Safety set 2
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs | 45 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs | 45 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs with grade>=3 | 42 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs with grade>=3 | 34 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | SAEs | 32 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related SAEs | 19 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Fatal SAEs | 3 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related fatal SAEs | 1 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs with grade>=3 | 42 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Fatal SAEs | 1 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs with grade>=3 | 37 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | SAEs | 26 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related SAEs | 12 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs | 49 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs | 45 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related fatal SAEs | 0 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs with grade>=3 | 35 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs | 38 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | AEs | 43 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related AEs with grade>=3 | 24 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Fatal SAEs | 4 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related SAEs | 12 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | SAEs | 26 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With AEs and SAEs During the On-treatment Period | Treatment-related fatal SAEs | 0 Participants |
Secondary
Randomized Part: Number of Participants With Anti-NIS793 Antibodies
The immunogenicity (IG) against NIS793 was assessed in serum using a validated enhanced electrochemiluminescence immunoassay (ECLIA). Patient anti-drug antibodies (ADA) status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline sample, all of which are ADA-negative samples * ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative post-baseline * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample
Time frame: Baseline (before first dose) and post-baseline (assessed throughout the treatment up to approximately 1.7 years)
Population: Participants in the safety set 2 who received NIS793 and had a non-missing baseline ADA sample and at least one non-missing post-baseline ADA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA-negative post-baseline | 41 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA- inconclusive post-baseline | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA-positive at baseline | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | Treatment-induced ADA-positive | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA-negative at baseline | 41 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | Treatment-induced ADA-positive | 0 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA-negative at baseline | 44 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA-positive at baseline | 0 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA- inconclusive post-baseline | 0 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-NIS793 Antibodies | ADA-negative post-baseline | 44 Participants |
Secondary
Randomized Part: Number of Participants With Anti-spartalizumab Antibodies
The immunogenicity (IG) against spartalizumab was assessed in serum using a validated a validated homogenous enzyme-linked immunosorbent assay (ELISA). Patient anti-drug antibodies (ADA) status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-inconclusive at baseline: patient who does not qualify as ADA-positive or ADA-negative at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline sample, all of which are ADA-negative samples * ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative post-baseline * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample
Time frame: Cycle 1 and Cycle 3. The duration of each cycle was 28 days
Population: Participants in the safety set 2 who received spartalizumab and had a non-missing baseline ADA sample and at least one non-missing post-baseline ADA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | ADA-negative at baseline | 40 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | ADA- inconclusive at baseline | 1 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | ADA-positive at baseline | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | ADA-negative post-baseline | 35 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | ADA- inconclusive post-baseline | 2 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | Treatment-induced ADA-positive | 4 Participants |
Secondary
Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel
Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab in the Randomized part.
Time frame: Up to approximately 1.7 years
Population: Safety set 2
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction | 25 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose reduction or interruption | 35 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction | 26 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose interruption | 35 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose reduction | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction or interruption | 39 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Spartalizumab: At least one dose reduction or interruption | 21 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Spartalizumab: At least one dose reduction | 0 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Spartalizumab: At least one dose interruption | 21 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction or interruption | 38 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose interruption | 35 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose interruption | 34 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction | 23 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose reduction or interruption | 31 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose reduction | 0 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | NIS793: At least one dose interruption | 31 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction or interruption | 41 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose interruption | 36 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction or interruption | 43 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction | 27 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose interruption | 37 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction | 19 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose interruption | 32 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction | 19 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose interruption | 29 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Gemcitabine: At least one dose reduction or interruption | 32 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of NIS793, Spartalizumab, Gemcitabine and Nab-paclitaxel | Nab-paclitaxel: At least one dose reduction or interruption | 34 Participants |
Secondary
Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1
ORR is the percentage of patients with a confirmed best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 1.7 years
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1 | 22.0 percentage of participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1 | 31.4 percentage of participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Overall Response Rate (ORR) Per RECIST v1.1 | 15.4 percentage of participants |
Secondary
Randomized Part: Overall Survival (OS)
Overall survival is defined as the time from the date of randomization to the date of death due to any cause. OS was analyzed using the Kaplan-Meier method.
Time frame: Up to approximately 2 years
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Overall Survival (OS) | 10.7 months |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Overall Survival (OS) | 8.5 months |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Overall Survival (OS) | 10.1 months |
Secondary
Randomized Part: Time to Progression (TTP) Per RECIST v1.1
TTP per RECIST v1.1 is defined as the time from the date of randomization to the date of event defined as the first documented progression per RECIST v1.1 or death due to underlying cancer. If a participant had no progression or death, the participant was censored at the date of last adequate tumor assessment. DOR was analyzed using the Kaplan-Meier method.
Time frame: Up to approximately 1.7 years
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Time to Progression (TTP) Per RECIST v1.1 | 3.94 months |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Time to Progression (TTP) Per RECIST v1.1 | 5.59 months |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Time to Progression (TTP) Per RECIST v1.1 | 5.36 months |
Secondary
Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine
Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Time frame: Cycle 4: pre-dose on Day 1. One cycle=28 days
Population: Participants in the pharmacokinetic analysis set (PAS) who received gemcitabine and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine | 0 ng/mL | Standard Deviation 0 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine | 0 ng/mL | Standard Deviation 0 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Gemcitabine | 0 ng/mL | Standard Deviation 0 |
Secondary
Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel
Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Time frame: Cycle 4: pre-dose on Day 1. One cycle=28 days
Population: Participants in the pharmacokinetic analysis set (PAS) who received nab-paclitaxel and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel | 455 ng/mL | Standard Deviation 1320 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel | 2.13 ng/mL | Standard Deviation 10.4 |
| Arm 3: Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Nab-paclitaxel | 3.25 ng/mL | Standard Deviation 5.08 |
Secondary
Randomized Part: Trough Serum Concentration (Ctrough) of NIS793
Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Time frame: Cycle 1: pre-dose on Day 1. Cycle 3: pre-dose on Day 1 and Day 15 (combined). One cycle=28 days
Population: Participants in the pharmacokinetic analysis set (PAS) who received NIS793 and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of NIS793 | Cycle 1 | 137000 ng/mL | Standard Deviation 51700 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of NIS793 | Cycle 3 | 289000 ng/mL | Standard Deviation 121000 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of NIS793 | Cycle 1 | 156000 ng/mL | Standard Deviation 50100 |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of NIS793 | Cycle 3 | 291000 ng/mL | Standard Deviation 126000 |
Secondary
Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab
Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Time frame: Cycle 2, 3 and 4: pre-dose on Day 1. One cycle=28 days
Population: Participants in the pharmacokinetic analysis set (PAS) who received spartalizumab and had an available value for the outcome measure. PAS consisted of all patients who received one dose (complete infusion) of the planned treatments and provided at least one valid primary PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab | Cycle 2 | 22.3 µg/mL | Standard Deviation 8.67 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab | Cycle 3 | 31.9 µg/mL | Standard Deviation 11.7 |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | Randomized Part: Trough Serum Concentration (Ctrough) of Spartalizumab | Cycle 4 | 30.5 µg/mL | Standard Deviation 14.3 |
Post Hoc
All-Collected Deaths
On-treatment and post-treatment safety follow-up (FU) deaths were collected from first dose of study treatment to 90 days after last dose of NIS793, 150 days after last dose of spartalizumab and 30 days after last dose of gemcitabine and nab-paclitaxel, whichever was longer. Survival FU deaths were collected from 91 days after last dose of NIS793, 151 days after last dose of spartalizumab and 31 days after last dose of gemcitabine and nab-paclitaxel, whichever was longer, until end of study. All deaths refer to the sum of pre-treatment deaths, on-treatment and post-treatment safety FU deaths, and survival FU deaths.
Time frame: On-treatment and post-treatment safety FU deaths: up to approximately 1 year (run-in part) and 1.9 years (randomized part). Survival FU deaths: up to approximately 1.8 years (run-in part) and 2 years (randomized part)
Population: Safety set 1 (safety run-in) and Full Analysis Set (randomized part)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | All-Collected Deaths | On-treatment and post-treatment safety FU deaths | 5 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | All-Collected Deaths | All deaths | 10 Participants |
| Run-in: NIS793 + Spartalizumab + Gemcitabine/Nab-paclitaxel | All-Collected Deaths | Survival FU deaths | 5 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | All-Collected Deaths | On-treatment and post-treatment safety FU deaths | 18 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | All-Collected Deaths | All deaths | 33 Participants |
| Arm 2: NIS793 + Gemcitabine/Nab-paclitaxel | All-Collected Deaths | Survival FU deaths | 15 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | All-Collected Deaths | Survival FU deaths | 22 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | All-Collected Deaths | On-treatment and post-treatment safety FU deaths | 19 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | All-Collected Deaths | All deaths | 41 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | All-Collected Deaths | On-treatment and post-treatment safety FU deaths | 4 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | All-Collected Deaths | All deaths | 39 Participants |
| Arm 3: Gemcitabine/Nab-paclitaxel | All-Collected Deaths | Survival FU deaths | 35 Participants |