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

• ClinicalTrials.gov Identifier: NCT02947165
• Recruitment Status: Active, not recruiting
• First Posted: October 27, 2016
• Last Update Posted: May 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Lung Cancer; Hepatocellular Cancer; Colorectal Cancer; Pancreatic Cancer; Renal Cancer	Drug: NIS793; Drug: PDR001	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/Ib, Open-label, Multi-center Dose Escalation Study of NIS793 in Combination With PDR001 in Adult Patients With Advanced Malignancies
• Actual Study Start Date: April 25, 2017
• Estimated Primary Completion Date: June 18, 2021
• Estimated Study Completion Date: June 18, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Incidence of DLTs, AEs, SAEs and dose reductions / interruptions for NIS793 [ Time Frame: Up to 90 days after end of treatment ]
2. Incidence of DLTs, AEs, SAEs and dose reductions/interruptions for NIS793 in combination with PDR001 [ Time Frame: Up to 150 days after end of treatment ]

Secondary Outcome Measures :

1. Best overall response (BOR) [ Time Frame: 48 months ]
   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).
2. Disease control rate (DCR) [ Time Frame: 48 months ]
   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).
3. Overall response rate (ORR) [ Time Frame: 48 months ]
   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).
4. Progression free survival (PFS) [ Time Frame: 48 months ]
   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.
5. Duration of response (DOR) [ Time Frame: 48 months ]
   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).
6. Serum concentration-time profiles of NIS793 single agent and NIS793 in combination with PDR001 [ Time Frame: 48 months ]
   Evaluate serum concentration of NIS793 and PDR001 up to 8 cycles after start of treatment and at end of treatment.
7. Presence of anti-NIS793 and anti-PDR001 antibodies [ Time Frame: 48 months ]
   Assess the emergence of anti-NIS793 and anti-PDR001 antibodies up to 8 cycles after start of treatment and at end of treatment.
8. Concentration of anti-NIS793 and anti-PDR001 antibodies [ Time Frame: 48 months ]
   Assess the concentration of anti-NIS793 and anti-PDR001 antibodies up to 8 cycles after start of treatment and at end of treatment.
9. Area under the curve (AUC) for NIS793 single agent and NIS793 in combination with PDR001. [ Time Frame: 48 months ]
   Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.
10. Cmax for NIS793 single agent and NIS793 in combination with PDR001. [ Time Frame: 48 months ]
    Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.
11. Tmax for NIS793 single agent and NIS793 in combination with PDR001. [ Time Frame: 48 months ]
    Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.
12. Half life of NIS793 as single agent and in combination with PDR001. [ Time Frame: 48 months ]
    Characterize the pharmacokinetic properties of NIS793 given alone and in combination with PDR001.
13. Characterization of tumor infiltrating lymphocytes (TILs) by H&E [ Time Frame: 48 months ]
    Assess change from baseline of immune infiltrates in tumor biopsies after 2 cycles of treatment.
14. Characterization of tumor infiltrating lymphocytes by immunohistochemistry using markers such as CD8 and PD-L1 [ Time Frame: 48 months ]
    Assess change from baseline in immunological markers in tumor biopsies after 2 cycles of treatment.

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. 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.

Contacts and Locations

Locations

United States, Tennessee

Sarah Cannon Research Institute SC

Nashville, Tennessee, United States, 37203

United States, Utah

Huntsman Cancer Institute SC

Salt Lake City, Utah, United States, 84112

Austria

Novartis Investigative Site

Salzburg, Austria, 5020

Canada, Ontario

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 2C1

Germany

Novartis Investigative Site

Ulm, Germany, 89081

Novartis Investigative Site

Wuerzburg, Germany, 97080

Hong Kong

Novartis Investigative Site

Hong Kong, Hong Kong

Italy

Novartis Investigative Site

Milano, MI, Italy, 20132

Novartis Investigative Site

Rozzano, MI, Italy, 20089

Japan

Novartis Investigative Site

Kashiwa, Chiba, Japan, 277 8577

Switzerland

Novartis Investigative Site

St. Gallen, Switzerland, 9007

Taiwan

Novartis Investigative Site

Taipei, Taiwan, 10002

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ 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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02947165
• Other Study ID Numbers: CNIS793X2101; 2016-003044-36 ( EudraCT Number )
• First Posted: October 27, 2016
• Last Update Posted: May 5, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Kidney Neoplasms; Liver Neoplasms; Carcinoma, Hepatocellular; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Urologic Neoplasms; Urogenital Neoplasms; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Diseases