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

Phase 1

Terminated

• Conditions: Triple Negative Breast Cancer (TNBC)
• Interventions: Biological: spartalizumab; Biological: LAG525; Biological: MCS110; Biological: canakinumab; Drug: NIR178; Drug: capmatinib

• Registration Number: NCT03742349
• Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-11-12
• Study First Submitted QC: 2018-11-12
• Study First Posted: 2018-11-15
• Study Start: 2019-01-31
• Primary Completion: 2023-02-06
• Study Completion: 2023-02-06
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-17
• Last Update Posted: 2024-01-19

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 64

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.

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
3: spartalizumab + LAG525 + MCS110	spartalizumab	phase Ib (escalation and expansion)
3: spartalizumab + LAG525 + MCS110	MCS110	phase Ib (escalation and expansion)
4: spartalizumab +LAG525 +canakinumab	spartalizumab	phase Ib (escalation and expansion)
4: spartalizumab +LAG525 +canakinumab	canakinumab	phase Ib (escalation and expansion)
2: spartalizumab +LAG525 +capmatinib	spartalizumab	phase Ib (escalation and expansion)
3: spartalizumab + LAG525 + MCS110	LAG525	phase Ib (escalation and expansion)
4: spartalizumab +LAG525 +canakinumab	LAG525	phase Ib (escalation and expansion)
2: spartalizumab +LAG525 +capmatinib	LAG525	phase Ib (escalation and expansion)
1: spartalizumab + LAG525 + NIR178	spartalizumab	phase Ib (escalation and expansion)
1: spartalizumab + LAG525 + NIR178	LAG525	phase Ib (escalation and expansion)
1: spartalizumab + LAG525 + NIR178	NIR178	phase Ib (escalation and expansion)
2: spartalizumab +LAG525 +capmatinib	capmatinib	phase Ib (escalation and expansion)

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Progression free survival (PFS) per RECIST v1.1 and iRECIST	at month 18	Month 18 is assumed to be study end
PK parameter (Tmax) of MCS110	at month 12	cycle 12
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
Best overall response (BOR)	at month 18	Month 18 is assumed to be study end
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 (Cmax) of LAG525	at month 12	cycle 12
PK parameter (AUC) of LAG525	at month 12	cycle 12
PK parameter (Tmax) of NIR178	at month 12	cycle 12
PK parameter (Cmax) of NIR178	at month 12	cycle 12
PK parameter (AUC) of NIR178	at month 12	cycle 12
PK parameter (Tmax) of capmatinib	at month 12	cycle 12
PK parameter (Cmax) of capmatinib	at month 12	cycle 12
PK parameter (AUC) of capmatinib	at month 12	cycle 12
PK parameter (AUC) of MCS110	at month 12	cycle 12
Changes from baseline of PD markers in tumor tissue (TILs, CD8, PD-L1, LAG-3)	at baseline and at Day 43
PK parameter (Cmax) of canakinumab	at month 12	cycle 12
PK parameter (Tmax) of spartalizumab	at month 12	cycle 12
PK parameter (Cmax) of spartalizumab	at month 12	cycle 12
PK parameter (AUC) of spartalizumab	at month 12	cycle 12
PK parameter (Tmax) of LAG525	at month 12	cycle 12
PK parameter (Cmax) of MCS110	at month 12	cycle 12
PK parameter (Tmax) of canakinumab	at month 12	cycle 12
PK parameter (AUC) of canakinumab	at month 12	cycle 12

Trial Locations

Locations (3)

Columbia University Medical Center- New York Presbyterian Columbia; 🇺🇸 New York, New York, United States

Novartis Investigative Site; 🇪🇸 Valencia, Comunidad Valenciana, Spain

Sarah Cannon Research Institute Sarah Cannon Research; 🇺🇸 Nashville, Tennessee, United States