Phase I/Ib Study of NIS793 in Combination With PDR001 in Patients With Advanced Malignancies.

A Phase I/Ib, Open-label, Multi-center Dose Escalation Study of NIS793 in Combination With PDR001 in Adult Patients With Advanced Malignancies

To characterize the safety and tolerability of NIS793 as single agent and in combination with PDR001 and to identify recommended doses for future studies.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Colorectal Cancer; Pancreatic Cancer; Lung Cancer; Renal Cancer; Hepatocellular Cancer
• Intervention / Treatment: Drug: NIS793; Drug: PDR001

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C1
      • Novartis Investigative Site
• Germany
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute SC
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute SC

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Written informed consent must be obtained prior to any screening procedures.
2. Patient (male or female) ≥ 18 years of age.
3. Escalation: Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST version 1.1 who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists.

4. Expansion: Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who have progressed despite standard therapy following their last prior therapy or are intolerant to standard therapy and fit into one of the following groups: Group 1: NSCLC resistant to anti-PD-1/PD-L1; Group 2: TNBC; Group 3: HCC; Group 4: MSS-CRC; Group 5: pancreatic; Group 6 ccRCC resistant to anti-PD-1/PD-L1.

   Resistance to anti-PD-1/PD-L1 therapy is defined as: Documented progressive disease occurring while on/or within 6 months after anti-PD-1 and/or anti-PD-L1 agent (single or combination) received as the last therapy prior to enrollment.

5. ECOG Performance Status ≤ 2.
6. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy. Patient must be willing to undergo a new tumor biopsy at screening, and during therapy on this study. Exceptions may be made on a case by case basis after documented discussion with Novartis.

Exclusion Criteria:

1. History of severe hypersensitivity reactions to study treatment ingredients or other monoclonal antibodies and components of study drug.
2. Patients with active, known or suspected autoimmune disease. Note: Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
3. HIV infection.
4. Active HBV or HCV infection.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NIS793	Drug: NIS793; Anti-TGF beta antibody tested on a Q3W regimen or alternative Q2W regimen.
Experimental: NIS793 + PDR001	Drug: NIS793; Anti-TGF beta antibody tested on a Q3W regimen or alternative Q2W regimen.; Drug: PDR001; Anti-PD-1 antibody tested on a Q3W regimen or alternative Q4W regimen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of DLTs, AEs, SAEs and dose reductions / interruptions for NIS793	Up to 90 days after end of treatment
Incidence of DLTs, AEs, SAEs and dose reductions/interruptions for NIS793 in combination with PDR001	Up to 150 days after end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response (BOR)	Evaluate the anti-tumor activity per RECIST as well as per immune related Response Criteria (irRC) of NIS793 as single agent and in combination with PDR001 every 2 cycles from start of treatment until cycle 9 then every 3 cycles until end of treatment (if applicable).	48 months
Disease control rate (DCR)	Evaluate the anti-tumor activity per RECIST as well as per immune related Response Criteria (irRC) of NIS793 as single agent and in combination with PDR001every 2 cycles from start of treatment until cycle 9 then every 3 cycles until end of treatment (if applicable).	48 months
Overall response rate (ORR)	Evaluate the anti-tumor activity per RECIST as well as per immune related Response Criteria (irRC) of NIS793 as single agent and in combination with PDR001 every2 cycles from start of treatment until cycle 9 then every 3 cycles until end of treatment (if applicable).	48 months
Progression free survival (PFS)	Evaluate the anti-tumor activity per RECIST as well as per immune related Response Criteria (irRC) of NIS793 as single agent and in combination with PDR001 every 2 cycles from start of treatment until cycle 9 then every 3 cycles until end of treatment. During disease progression f/u, every 8 weeks for 40 weeks, then every 12 weeks.	48 months
Duration of response (DOR)	Evaluate the anti-tumor activity per RECIST as well as per immune related Response Criteria (irRC) of NIS793 as single agent and in combination with PDR001 every 2 cycles from start of treatment until cycle 9 then every 3 cycles until end of treatment (if applicable).	48 months
Serum concentration-time profiles of NIS793 single agent and NIS793 in combination with PDR001	Evaluate serum concentration of NIS793 and PDR001 up to 8 cycles after start of treatment and at end of treatment.	48 months
Presence of anti-NIS793 and anti-PDR001 antibodies	Assess the emergence of anti-NIS793 and anti-PDR001 antibodies up to 8 cycles after start of treatment and at end of treatment.	48 months
Concentration of anti-NIS793 and anti-PDR001 antibodies	Assess the concentration of anti-NIS793 and anti-PDR001 antibodies up to 8 cycles after start of treatment and at end of treatment.	48 months
Area under the curve (AUC) for NIS793 single agent and NIS793 in combination with PDR001.	Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.	48 months
Cmax for NIS793 single agent and NIS793 in combination with PDR001.	Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.	48 months
Tmax for NIS793 single agent and NIS793 in combination with PDR001.	Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.	48 months
Half life of NIS793 as single agent and in combination with PDR001.	Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.	48 months
Characterization of tumor infiltrating lymphocytes (TILs) by H&E	Assess change from baseline of immune infiltrates in tumor biopsies after 2 cycles of treatment.	48 months
Characterization of tumor infiltrating lymphocytes by immunohistochemistry using markers such as CD8 and PD-L1	Assess change from baseline in immunological markers in tumor biopsies after 2 cycles of treatment.	48 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Dodagatta-Marri E, Meyer DS, Reeves MQ, Paniagua R, To MD, Binnewies M, Broz ML, Mori H, Wu D, Adoumie M, Del Rosario R, Li O, Buchmann T, Liang B, Malato J, Arce Vargus F, Sheppard D, Hann BC, Mirza A, Quezada SA, Rosenblum MD, Krummel MF, Balmain A, Akhurst RJ. alpha-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by alpha-TGFbeta antibody to promote durable rejection and immunity in squamous cell carcinomas. J Immunother Cancer. 2019 Mar 4;7(1):62. doi: 10.1186/s40425-018-0493-9.

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2017
• Primary Completion (Actual): June 18, 2021
• Study Completion (Actual): June 18, 2021

Study Registration Dates

• First Submitted: October 18, 2016
• First Submitted That Met QC Criteria: October 25, 2016
• First Posted (Estimate): October 27, 2016

Study Record Updates

• Last Update Posted (Actual): January 31, 2022
• Last Update Submitted That Met QC Criteria: January 28, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Kidney Neoplasms; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immune Checkpoint Inhibitors; Spartalizumab
• Other Study ID Numbers: CNIS793X2101; 2016-003044-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No