Study of Safety and Efficacy of Novel Immunotherapy Combinations in Patients With Triple Negative Breast Cancer (TNBC).

A Phase Ib, Multicenter, Open-label Dose Escalation and Expansion Platform Study of Select Immunotherapy Combinations in Adult Patients With Triple-negative Breast Cancer

This is a Phase Ib, open label, dose escalation study of spartalizumab + LAG525 in combination with NIR178, capmatinib, MCS110, or canakinumab, followed by a dose expansion in adult patients with advanced or metastatic TNBC.

During the dose-escalation part of each treatment arm, patients will be treated with fixed doses of spartalizumab + LAG525 in combination with partner investigational drugs to be escalated until the MTD is reached or a lower RDE is established: NIR178, capmatinib, MCS110, or canakinumab. It is anticipated that other partner study drugs may be added in the future by protocol amendment.

After the determination of the MTD/RDE for a particular treatment arm, dose expansion may begin in that arm in order to further assess safety, tolerability, PK/PD, and anti-tumor activity of each combination at the MTD/RDE. Dose expansion arms may initiate only after consideration by the Investigators and Novartis of all available toxicity information, the assessment of risk to future patients from the BLRM, and the available PK, preliminary efficacy, and PD information. There is no requirement for dose-escalation treatment arms reaching an MTD/RDE to proceed to dose expansion.

Study Overview

• Status: Terminated
• Conditions: Triple Negative Breast Cancer (TNBC)
• Intervention / Treatment: Biological: spartalizumab; Biological: LAG525; Drug: NIR178; Drug: capmatinib; Biological: MCS110; Biological: canakinumab

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
• Hong Kong
  • Shatin, New Territories, Hong Kong
    • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center- New York Presbyterian Columbia
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Sarah Cannon Research

Participation Criteria

Eligibility Criteria

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

Description

Main Inclusion Criteria:

• Patients with advanced/metastatic TNBC (defined as HER-2 negative with <1% of tumor cell nuclei immunoreactive for estrogen receptor (ER) and progesterone receptor (PR)), with measurable disease as determined by RECIST version 1.1 (refer to Appendix 16.1). Tumor lesions previously irradiated or subjected to other loco-regional therapy will only be considered measurable if there is documented disease progression at the treated site prior to study entry.
• Patients should have received standard chemotherapy for advanced or metastatic disease but should not have received more than 2 prior lines of chemotherapy. Neoadjuvant or adjuvant chemotherapy will count as one prior line.
• Patients must have received prior systemic treatment that included taxane-based chemotherapy for neoadjuvant or metastatic disease.
• Patients must have a site of disease amenable to core needle biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at screening, and during therapy on the study. Exceptions may be considered after documented discussion with Novartis. Patients with available archival tumor tissue obtained ≤6 months prior to study treatment initiation do not need to undergo a new tumor biopsy at screening, if the patient has not received any anti-cancer therapy since the biopsy was taken, and if adequate tissue is available.

Main exclusion criteria applicable to all treatment arms:

• Patient has received prior treatment with anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (any line of therapy).
• Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within 2 weeks prior to initiating study treatment.
• History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
• Impaired cardiac function or clinically significant cardiac disease.
• HIV infection.
• Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, including those with inactive disease for patients receiving either capmatinib, MCS110 or canakinumab.
• Active, known or suspected autoimmune disease.
• History of or current interstitial lung disease or pneumonitis grade ≥ 2.
• Subjects with tuberculosis (TB), for patients receiving either MCS110 or canakinumab.

Other eligibility criteria apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: spartalizumab + LAG525 + NIR178; phase Ib (escalation and expansion)	Biological: spartalizumab; LIVI (Liquid in vial) Concentrate for Solution for infusion; Other Names: PDR001; Biological: LAG525; LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion; Drug: NIR178; Capsule
Experimental: 2: spartalizumab +LAG525 +capmatinib; phase Ib (escalation and expansion)	Biological: spartalizumab; LIVI (Liquid in vial) Concentrate for Solution for infusion; Other Names: PDR001; Biological: LAG525; LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion; Drug: capmatinib; Tablet; Other Names: INC280
Experimental: 3: spartalizumab + LAG525 + MCS110; phase Ib (escalation and expansion)	Biological: spartalizumab; LIVI (Liquid in vial) Concentrate for Solution for infusion; Other Names: PDR001; Biological: LAG525; LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion; Biological: MCS110; LIVI (Liquid in vial) Concentrate for Solution for infusion
Experimental: 4: spartalizumab +LAG525 +canakinumab; phase Ib (escalation and expansion)	Biological: spartalizumab; LIVI (Liquid in vial) Concentrate for Solution for infusion; Other Names: PDR001; Biological: LAG525; LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion; Biological: canakinumab; LIVI (Liquid in vial) Solution for injection; Other Names: ACZ885

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety	Month 18 is assumed to be study end	at month 18
Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety	Month 18 is assumed to be study end	at month 18
Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)	end of first cycle	at Day 28
Frequency of dose interuptions	Month 18 is assumed to be study end	at month 18
Frequency of dose reductions	Month 18 is assumed to be study end	at month 18
Dose intensities	Month 18 is assumed to be study end	at month 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response (BOR)	Month 18 is assumed to be study end	at month 18
Progression free survival (PFS) per RECIST v1.1 and iRECIST	Month 18 is assumed to be study end	at month 18
Presence of anti-spartalizumab antibodies		at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
Presence of anti-LAG525 antibodies		at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
Presence of anti-MCS110 antibodies		at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
Presence of anti-canakinumab antibodies		at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
Serum concentration of spartalizumab, LAG525, MCS110, canakinumab		at Day 1, Day 8, Day 15, Day 29, Day 57, Day 65, Day 70, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
Plasma concentration of NIR178, NJI675, capmatinib		at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
PK parameter (Tmax) of spartalizumab	cycle 12	at month 12
PK parameter (Cmax) of spartalizumab	cycle 12	at month 12
PK parameter (AUC) of spartalizumab	cycle 12	at month 12
PK parameter (Tmax) of LAG525	cycle 12	at month 12
PK parameter (Cmax) of LAG525	cycle 12	at month 12
PK parameter (AUC) of LAG525	cycle 12	at month 12
PK parameter (Tmax) of NIR178	cycle 12	at month 12
PK parameter (Cmax) of NIR178	cycle 12	at month 12
PK parameter (AUC) of NIR178	cycle 12	at month 12
PK parameter (Tmax) of capmatinib	cycle 12	at month 12
PK parameter (Cmax) of capmatinib	cycle 12	at month 12
PK parameter (AUC) of capmatinib	cycle 12	at month 12
PK parameter (Tmax) of MCS110	cycle 12	at month 12
PK parameter (Cmax) of MCS110	cycle 12	at month 12
PK parameter (AUC) of MCS110	cycle 12	at month 12
PK parameter (Tmax) of canakinumab	cycle 12	at month 12
PK parameter (Cmax) of canakinumab	cycle 12	at month 12
PK parameter (AUC) of canakinumab	cycle 12	at month 12
Changes from baseline of PD markers in tumor tissue (TILs, CD8, PD-L1, LAG-3)		at baseline and at Day 43

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Results

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2019
• Primary Completion (Actual): February 6, 2023
• Study Completion (Actual): February 6, 2023

Study Registration Dates

• First Submitted: November 12, 2018
• First Submitted That Met QC Criteria: November 12, 2018
• First Posted (Actual): November 15, 2018

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Phase Ib, TNBC, advanced, metastatic, immunotherapy, PDR001,; LAG525, NIR178, INC280, MCS110, ACZ885
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Spartalizumab
• Other Study ID Numbers: CADPT01A12101C; 2018-002244-82 (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