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

• ClinicalTrials.gov Identifier: NCT03742349
• Recruitment Status: Terminated
• First Posted: November 15, 2018
• Last Update Posted: February 24, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Triple Negative Breast Cancer (TNBC)	Biological: spartalizumab; Biological: LAG525; Drug: NIR178; Drug: capmatinib; Biological: MCS110; Biological: canakinumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 64 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib, Multicenter, Open-label Dose Escalation and Expansion Platform Study of Select Immunotherapy Combinations in Adult Patients With Triple-negative Breast Cancer
• Actual Study Start Date: January 31, 2019
• Actual Primary Completion Date: February 6, 2023
• Actual Study Completion Date: February 6, 2023

Arms and Interventions

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 Name: 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 Name: PDR001; Biological: LAG525; LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion; Drug: capmatinib; Tablet; Other Name: INC280
Experimental: 3: spartalizumab + LAG525 + MCS110; phase Ib (escalation and expansion)	Biological: spartalizumab; LIVI (Liquid in vial) Concentrate for Solution for infusion; Other Name: 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 Name: PDR001; Biological: LAG525; LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion; Biological: canakinumab; LIVI (Liquid in vial) Solution for injection; Other Name: ACZ885

Outcome Measures

Primary Outcome Measures :

1. Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end
2. Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end
3. Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only) [ Time Frame: at Day 28 ]
   end of first cycle
4. Frequency of dose interuptions [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end
5. Frequency of dose reductions [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end
6. Dose intensities [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end

Secondary Outcome Measures :

1. Best overall response (BOR) [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end
2. Progression free survival (PFS) per RECIST v1.1 and iRECIST [ Time Frame: at month 18 ]
   Month 18 is assumed to be study end
3. Presence of anti-spartalizumab antibodies [ Time Frame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT ]
4. Presence of anti-LAG525 antibodies [ Time Frame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT ]
5. Presence of anti-MCS110 antibodies [ Time Frame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT ]
6. Presence of anti-canakinumab antibodies [ Time Frame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT ]
7. Serum concentration of spartalizumab, LAG525, MCS110, canakinumab [ Time Frame: 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 ]
8. Plasma concentration of NIR178, NJI675, capmatinib [ Time Frame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT ]
9. PK parameter (Tmax) of spartalizumab [ Time Frame: at month 12 ]
   cycle 12
10. PK parameter (Cmax) of spartalizumab [ Time Frame: at month 12 ]
    cycle 12
11. PK parameter (AUC) of spartalizumab [ Time Frame: at month 12 ]
    cycle 12
12. PK parameter (Tmax) of LAG525 [ Time Frame: at month 12 ]
    cycle 12
13. PK parameter (Cmax) of LAG525 [ Time Frame: at month 12 ]
    cycle 12
14. PK parameter (AUC) of LAG525 [ Time Frame: at month 12 ]
    cycle 12
15. PK parameter (Tmax) of NIR178 [ Time Frame: at month 12 ]
    cycle 12
16. PK parameter (Cmax) of NIR178 [ Time Frame: at month 12 ]
    cycle 12
17. PK parameter (AUC) of NIR178 [ Time Frame: at month 12 ]
    cycle 12
18. PK parameter (Tmax) of capmatinib [ Time Frame: at month 12 ]
    cycle 12
19. PK parameter (Cmax) of capmatinib [ Time Frame: at month 12 ]
    cycle 12
20. PK parameter (AUC) of capmatinib [ Time Frame: at month 12 ]
    cycle 12
21. PK parameter (Tmax) of MCS110 [ Time Frame: at month 12 ]
    cycle 12
22. PK parameter (Cmax) of MCS110 [ Time Frame: at month 12 ]
    cycle 12
23. PK parameter (AUC) of MCS110 [ Time Frame: at month 12 ]
    cycle 12
24. PK parameter (Tmax) of canakinumab [ Time Frame: at month 12 ]
    cycle 12
25. PK parameter (Cmax) of canakinumab [ Time Frame: at month 12 ]
    cycle 12
26. PK parameter (AUC) of canakinumab [ Time Frame: at month 12 ]
    cycle 12
27. Changes from baseline of PD markers in tumor tissue (TILs, CD8, PD-L1, LAG-3) [ Time Frame: at baseline and at Day 43 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, New York

Columbia University Medical Center- New York Presbyterian Columbia

New York, New York, United States, 10032

United States, Tennessee

Sarah Cannon Research Institute Sarah Cannon Research

Nashville, Tennessee, United States, 37203

Australia, New South Wales

Novartis Investigative Site

Westmead, New South Wales, Australia, 2145

Hong Kong

Novartis Investigative Site

Shatin, New Territories, Hong Kong

Israel

Novartis Investigative Site

Tel Aviv, Israel, 6423906

Italy

Novartis Investigative Site

Milano, MI, Italy, 20133

Novartis Investigative Site

Milano, MI, Italy, 20141

Japan

Novartis Investigative Site

Kashiwa, Chiba, Japan, 277 8577

Netherlands

Novartis Investigative Site

Amsterdam, Netherlands, 1066 CX

Singapore

Novartis Investigative Site

Singapore, Singapore, 119074

Novartis Investigative Site

Singapore, Singapore, 169610

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Valencia, Comunidad Valenciana, Spain, 46010

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03742349
• Other Study ID Numbers: CADPT01A12101C; 2018-002244-82 ( EudraCT Number )
• First Posted: November 15, 2018
• Last Update Posted: February 24, 2023
• Last Verified: February 2023

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

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Phase Ib, TNBC, advanced, metastatic, immunotherapy, PDR001,; LAG525, NIR178, INC280, MCS110, ACZ885

Additional relevant MeSH terms:

Breast Neoplasms; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Spartalizumab; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Antineoplastic Agents