Study of Efficacy and Safety of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)

Study Overview
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Brief Summary
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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 untreated mPDAC.

Official Title
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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)

Conditions
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Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Biological: NIS793
* Biological: Spartalizumab
* Drug: gemcitabine
* Drug: nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Male or female ≥ 18 years of age at the time of informed consent. Participants with histologically or cytologically confirmed treatment-naïve metastatic adenocarcinoma of the pancreas with measurable disease as per RECIST 1.1. 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. ECOG performance status ≤ 1. Exclusion Criteria: 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. Participants amenable to potentially curative resection. Participants with a diagnosis of pancreatic neuroendocrine tumors (NETs), acinar, or islet cell tumors. Having out of range laboratory values as pre-defined in the protocol. Participants with MSI-H pancreatic adenocarcinoma. 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. History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients. 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. Impaired cardiac function or clinically significant cardiac disease. Known history of testing positive HIV infection. Active HBV or HCV infection. Participants whose disease is controlled under antiviral therapy should not be excluded. History of or current interstitial lung disease or pneumonitis grade ≥ 2 High risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-in<br>Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel | Biological: NIS793<br>* anti-TGFb antibody<br>Biological: Spartalizumab<br>* anti-PD-1 antibody<br>* Other names: PDR001;Drug: gemcitabine<br>* SOC chemotherapy<br>Drug: nab-paclitaxel<br>* SOC chemotherapy<br>* Other names: abraxane;|
| Experimental: Randomized Arm 1<br>Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel | Biological: NIS793<br>* anti-TGFb antibody<br>Biological: Spartalizumab<br>* anti-PD-1 antibody<br>* Other names: PDR001;Drug: gemcitabine<br>* SOC chemotherapy<br>Drug: nab-paclitaxel<br>* SOC chemotherapy<br>* Other names: abraxane;|
| Experimental: Randomized Arm 2<br>Combination of NIS793 + gemcitabine + nab-paclitaxel | Biological: NIS793<br>* anti-TGFb antibody<br>Drug: gemcitabine<br>* SOC chemotherapy<br>Drug: nab-paclitaxel<br>* SOC chemotherapy<br>* Other names: abraxane;|
| Active Comparator: Randomized Arm 3<br>gemcitabine + nab-paclitaxel | Drug: gemcitabine<br>* SOC chemotherapy<br>Drug: nab-paclitaxel<br>* SOC chemotherapy<br>* Other names: abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLTs during the Safety Run-in | Incidence of DLTs to assess the safety and tolerability of NIS793 + spartalizumab in combination with gemcitabine/nab-paclitaxel | 8 months | 
| Incidence and severity of treatment emergent Adverse Events and Serious Adverse Events in Safety Run-in | Safety and tolerability measured by appearance of (or worsening of any pre-existing condition) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient signed informed consent. A Serious Adverse Event (SAE) is defined as one of the following: Is fatal or life threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect Is medical significant Requires inpatient hospitalization or prolongation of existing hospitalization. | 8 months | 
| Dose interruptions/reductions in Safety Run-in | Tolerability of NIS793 + spartalizumab in combination with gemcitabine/nab-paclitaxel measured by the number of subjects with at least one dose interruption/reduction of study treatment and reason | 8 months | 
| Dose intensity in Safety Run-in | Tolerability of NIS793 + spartalizumab in combination with gemcitabine/nab-paclitaxel measured by the dose intensity of study treatment for subjects with non-zero duration of exposure computed as the ratio of dose intensity and planned dose intensity | 8 months | 
| Progression-free survival in Randomized part | PFS as per Response Evaluation Criteria in Solid Tumors (RECIST1.1) as per local Investigator's review, to evaluate the PFS of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of Adverse Events and Serious Adverse Events in Randomized part | Safety and tolerability measured by appearance of (or worsening of any pre-existing condition) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient signed informed consent. A Serious Adverse Event (SAE) is defined as one of the following: Is fatal or life threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect Is medical significant Requires inpatient hospitalization or prolongation of existing hospitalization. | 18 months | 
| Overall response rate per RECIST 1.1 in Randomized part | ORR per RECIST 1.1 to assess the preliminary anti-tumor activity of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel | 18 months | 
| Duration of response per RECIST 1.1 in Randomized part | DOR per RECIST 1.1 to assess the preliminary anti-tumor activity of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel | 18 months | 
| Time to Progression per RECIST 1.1 in Randomized part | TTP per RECIST 1.1 to assess the preliminary anti-tumor activity of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel | 18 months | 
| Overall Survival per RECIST 1.1 in Randomized part | OS per RECIST 1.1 to assess the preliminary anti-tumor activity of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel | 18 months | 
| CD8 and PD-L1 expression in Randomized part | Change from baseline in CD8 and PD-L1 IHC related markers to assess the CD8 and PD-L1 status of the participants at screening and on treatment versus gemcitabine/nab-paclitaxel | 18 months | 
| Antidrug antibodies (ADA) (anti-NIS793 and anti-spartalizumab) expression in Randomized part | Antidrug antibodies (ADA) prevalence at baseline and ADA incidence on-treatment (anti-NIS793 and anti-spartalizumab) to characterize the incidence of immunogenicity of NIS793 and spartalizumab in combination with gemcitabine/nab-paclitaxel | 18 months | 
| Pharmacokinetic (PK) parameter Cmax in Randomized part | To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel) | 12 months | 
| Pharmacokinetic parameter AUClast in Randomized part | To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel) | 12 months | 
| Pharmacokinetic parameter Ctrough | To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel) | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NIS793, spartalizumab, gemcitabine, nab-paclitaxel, mPDAC, TGFβ, PD-1, Phase II