Study of Efficacy and Safety of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) (daNIS-1)

• ClinicalTrials.gov Identifier: NCT04390763
• Recruitment Status: Terminated
• First Posted: May 18, 2020
• Last Update Posted: May 17, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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 untreated mPDAC.

Condition or disease	Intervention/treatment	Phase
Metastatic Pancreatic Ductal Adenocarcinoma	Biological: NIS793; Biological: Spartalizumab; Drug: gemcitabine; Drug: nab-paclitaxel	Phase 2

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 164 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open Label, Randomized, Parallel Arm Study of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy Gemcitabine/Nab-paclitaxel, and Gemcitabine/Nab-paclitaxel Alone in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)
• Actual Study Start Date: October 16, 2020
• Actual Primary Completion Date: April 26, 2024
• Actual Study Completion Date: May 2, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Safety Run-in; Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel	Biological: NIS793; anti-TGFb antibody; Biological: Spartalizumab; anti-PD-1 antibody; Other Name: PDR001; Drug: gemcitabine; SOC chemotherapy; Drug: nab-paclitaxel; SOC chemotherapy; Other Name: abraxane
Experimental: Randomized Arm 1; Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel	Biological: NIS793; anti-TGFb antibody; Biological: Spartalizumab; anti-PD-1 antibody; Other Name: PDR001; Drug: gemcitabine; SOC chemotherapy; Drug: nab-paclitaxel; SOC chemotherapy; Other Name: abraxane
Experimental: Randomized Arm 2; Combination of NIS793 + gemcitabine + nab-paclitaxel	Biological: NIS793; anti-TGFb antibody; Drug: gemcitabine; SOC chemotherapy; Drug: nab-paclitaxel; SOC chemotherapy; Other Name: abraxane
Active Comparator: Randomized Arm 3; gemcitabine + nab-paclitaxel	Drug: gemcitabine; SOC chemotherapy; Drug: nab-paclitaxel; SOC chemotherapy; Other Name: abraxane

Outcome Measures

Primary Outcome Measures :

1. Incidence of DLTs during the Safety Run-in [ Time Frame: 4 weeks ]
   Incidence of DLTs to assess the safety and tolerability of NIS793 + spartalizumab in combination with gemcitabine/nab-paclitaxel
2. Incidence and severity of treatment emergent Adverse Events and Serious Adverse Events in Safety Run-in [ Time Frame: 8 months ]

   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.
3. Dose interruptions/reductions in Safety Run-in [ Time Frame: 8 months ]
   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
4. Dose intensity in Safety Run-in [ Time Frame: 8 months ]
   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
5. Progression-free survival in Randomized part [ Time Frame: 18 months ]
   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

Secondary Outcome Measures :

1. Incidence and severity of Adverse Events and Serious Adverse Events in Randomized part [ Time Frame: 18 months ]

   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.
2. Dose interruption/reduction in Randomized part [ Time Frame: 18 months ]
   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
3. Dose intensity in Randomized part [ Time Frame: 18 months ]
   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
4. Overall response rate per RECIST 1.1 in Randomized part [ Time Frame: 18 months ]
   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
5. Duration of response per RECIST 1.1 in Randomized part [ Time Frame: 18 months ]
   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
6. Time to Progression per RECIST 1.1 in Randomized part [ Time Frame: 18 months ]
   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
7. Overall Survival per RECIST 1.1 in Randomized part [ Time Frame: 18 months ]
   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
8. CD8 and PD-L1 expression in Randomized part [ Time Frame: 18 months ]
   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
9. Antidrug antibodies (ADA) (anti-NIS793 and anti-spartalizumab) expression in Randomized part [ Time Frame: 18 months ]
   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
10. Pharmacokinetic (PK) parameter Cmax in Randomized part [ Time Frame: 12 months ]
    To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel)
11. Pharmacokinetic parameter AUClast in Randomized part [ Time Frame: 12 months ]
    To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel)
12. Pharmacokinetic parameter Ctrough [ Time Frame: 12 months ]
    To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

United States, Georgia

Winship Cancer Institute Main Centre

Atlanta, Georgia, United States, 30322

United States, Maryland

Sidney Kimmel CCC At JH

Baltimore, Maryland, United States, 21231

United States, Massachusetts

Massachusetts General Hospital Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Beth Israel Deaconess Medical Cente

Boston, Massachusetts, United States, 02215

United States, Pennsylvania

Univ of Pittsburgh Cancer Institute HIllman Cancer Center

Pittsburgh, Pennsylvania, United States, 15232

Australia, New South Wales

Novartis Investigative Site

Westmead, New South Wales, Australia, 2145

Australia, Victoria

Novartis Investigative Site

Melbourne, Victoria, Australia, 3000

Austria

Novartis Investigative Site

Salzburg, Austria, 5020

Novartis Investigative Site

Wien, Austria, A-1090

Belgium

Novartis Investigative Site

Liege, Belgium, 4000

Czechia

Novartis Investigative Site

Brno, Czech Republic, Czechia, 656 53

Finland

Novartis Investigative Site

Helsinki, Finland, FIN-00029

France

Novartis Investigative Site

Paris 10, France, 75475

Novartis Investigative Site

Toulouse 4, France, 31054

Germany

Novartis Investigative Site

Essen, Germany, 45147

Novartis Investigative Site

Heidelberg, Germany, 69120

Novartis Investigative Site

Ulm, Germany, 89081

Italy

Novartis Investigative Site

Milano, MI, Italy, 20132

Novartis Investigative Site

Milano, MI, Italy, 20141

Novartis Investigative Site

Rozzano, MI, Italy, 20089

Novartis Investigative Site

Verona, VR, Italy, 37126

Singapore

Novartis Investigative Site

Singapore, Singapore, 119074

Novartis Investigative Site

Singapore, Singapore, 168583

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08036

Novartis Investigative Site

Madrid, Spain, 28050

Switzerland

Novartis Investigative Site

St. Gallen, Switzerland, 9007

Novartis Investigative Site

Zurich, Switzerland, 8091

Taiwan

Novartis Investigative Site

Taichung, Taiwan, 40447

Novartis Investigative Site

Taipei, Taiwan, 10002

United Kingdom

Novartis Investigative Site

Oxford, United Kingdom, OX3 7LJ

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04390763
• Other Study ID Numbers: CNIS793B12201; 2020-000349-14 ( EudraCT Number )
• First Posted: May 18, 2020
• Last Update Posted: May 17, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

NIS793, spartalizumab, gemcitabine, nab-paclitaxel, mPDAC, TGFβ, PD-1, Phase II

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Paclitaxel; Gemcitabine; Spartalizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological