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A Phase1b multicenter open-label dose escalation and expansion platform study of select immunotherapy combinations in adult patients with triple negative breast cancer

Study of safety and efficacy of novel immunotherapy combinations in patients with triple negative breast cancer(TNBC)

64

The combination of a backbone [spartalizumab (PDR001) + LAG525] and a partner [NIR178, capmatinib (INC280), MCS110, or canakinumab (ACZ885)] constituted a treatment arm. All of the participants were female (100%) with an average age of 52.3 (SD: 11.67) years. NIR178 arm: Six out of 24 patients were Asian. The median age of all patients in this arm was 57.5 years (range: 40 to 82 years). capmatinib arm: Two out of 13 patients were Asian. The median age of all patients in this arm was 52.0 years (range: 34 to 78 years). MCS110 arm: One out of 10 patients was Asian. The median age of all patients in this arm was 44.0 years (range: 29 to 57 years). canakinumab arm: Eight out of 17 patients were Asian. The median age of all patients in this arm was 54.0 years (range: 30 to 67 years).

A total 64 patients (NIR178 arm: 24 patients, capmatinib arm: 13 patients, MCS110 arm: 10 patients, canakinumab arm: 17 patients) had been enrolled in the study. Overall, all patients had been discontinued the study due to progressive disease (48 patients), physician decision (9 patients), adverse event (AE, 6 patients), or subject decision (1 patient). Novartis decided to halt recruitment in the MCS110 arm on 16 April 2020 due to discontinuation of the development program for MCS110, and in the capmatinib arm on 20 July 2020 due to limited anti-tumor activity observed in this treatment arm. Expansion parts of all four treatment arms were not initiated.

All patients experienced at least one AE in all four treatment arms. NIR178 arm: Twelve out of twenty-four patients (50%) AEs were grade >=3 of which 10 (41.7%) were considered treatment related. Most frequently reported AEs (>=20%) during the on-treatment period were alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, constipation, nausea, abdominal pain, anaemia, diarrhoea, fatigue, and pyrexia. Twenty-one (87.5%) patients reported at least one AE suspected to be related to the study drug during the on-treatment period of which 10 (41.7%) reported grade >=3 AEs. Total of 10 patients (41.7%) reported the serious adverse events (SAEs). Seven (29.2%) patients reported at least one SAE suspected to be related to the study drug. Four out of 20 patients experienced dose limiting toxicities (DLTs, 6 events) during Cycle 1. capmatinib arm: Nine out of thirteen patients (69.2%) reported grade >=3 AEs of which 6 patients (46.2%) were treatment related. Most frequently reported AEs (>=20%) during the on-treatment period were vomiting, ALT increased, anaemia, AST increased, nausea, oedema peripheral, pyrexia, dyspnoea, fatigue, and pruritus. All patients reported at least one AE suspected to be related to the study drug during the on-treatment period of which 6 patients (46.2%) reported grade >=3 AEs. Total of 8 patients (61.5%) reported the SAEs. Five patients (38.5%) reported at least one SAE suspected to be related to the study drug. Four out of 10 patients experienced DLTs (6 events). MCS110 arm: Six out of ten patients (60%) reported grade >=3 AEs of which 4 patients (40%) had treatment related grade >=3 AEs. The most frequently reported AEs (>=20%) during the on-treatment period were AST increased, asthenia, blood creatine phosphokinase increased, rash, ALT increased, cough, lipase increased, periorbital oedema, pruritus, pyrexia, blepharitis, dyspepsia, headache, leukopenia, nausea, neutrophil count decreased, pain in extremity, and rash pruritic. Nine patients (90%) reported at least one AE suspected to be related to the study drug during the on-treatment period of whom 4 patients (40%) reported grade >=3 AEs. Total of 4 patients (40%) reported the SAEs. No SAE suspected to be related to the study drug was reported. No DLTs were reported. canakinumab arm: Twelve out of seventeen patients (70.6%) reported grade >=3 AEs of which 5 patients (29.4%) had treatment related grade >=3 AEs. Most frequently reported AEs during the on-treatment period were nausea and fatigue. Eleven patients (64.7%) reported at least one AE suspected to be related to the study drug during the on-treatment period of which 5 patients (29.4%) reported grade >=3 AEs. Total of 10 patients (58.8%) reported the SAEs. Five patients (29.4%) reported at least one SAE suspected to be related to the study drug. No DLTs were reported

NIR178 arm: When administered along with different doses of NIR178, no apparent effect on mean exposure [geometric mean AUC(0-672)] of spartalizumab and LAG525 was apparent. capmatinib arm: The mean exposures [geometric mean AUC(0-672)] for spartalizumab and LAG525 were generally similar when the compared across the 2 doses of capmatinib on C1D1. MS110 arm: Minor accumulation was observed for spartalizumab (Racc ~1.31) and LAG525 (Racc ~1.20) following Q4W dosing with these drugs. canakinumab arm: With Q4W dosing some accumulation was observed for both spartalizumab (Racc ~1.80) and LAG525 (Racc ~1.51). No notable ADA prevalence and incidence were observed in all four treatment arms of the study. In both NIR178 arm and canakinumab arm, the estimated median Progression-Free Survival (PFS) per RECIST v1.1 were 1.9 months (90% CI: 1.2 to 10, 1.4 to 8.2). Mean (SD) change from baseline in PD-L1 expression in tumor tissue by measuring by % positive immune cells from SP142 assay were -1.3% (7.23) for NIR178 arm, 4.7% (5.01) for capmatinib arm, 1.4% (1.80) for MCS110 arm, and 0.8% (1.15) for canakinumab arm.

The safety profile was well characterized in all four treatment arms evaluated in this study. Overall, the doses and combinations explored were manageable and no significant safety concerns were identified. The PK of each agent was generally comparable with its PK as a single agent and there was no clear evidence of any PK drug-drug interaction. However, results should be interpreted with caution given limited data, particularly at steady state.

No

Yonemura Masataka

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

rinshoshiken.toroku2@novartis.com

Yonemura Masataka

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

+81-120-003-293

rinshoshiken.toroku2@novartis.com

completed

Feb. 22, 2019

Interventional

A Phase Ib, multicenter, open-label dose escalation and expansion platform study.

treatment purpose

1

Patients with advanced/metastatic TNBC (defined as HER-2 negative with under 1% of tumor cell nuclei immunoreactive for estrogen receptor (ER) and progesterone receptor (PR), with measurable disease as determined by RECIST version 1.1.
Patients should have documented disease progression following, or intolerance to, no more than 2 prior lines of chemotherapy for advanced or metastatic disease. Neoadjuvant and/or adjuvant chemotherapy administered with curative intent will count as one prior line of therapy, if disease recurred within 12 months of the last treatment.
Patients must have received prior systemic treatment that included taxane-based chemotherapy for (neo)adjuvant 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 institutions guidelines.

Patients with a history of treatment with anti-LAG-3, anti-PD-1, anti-PD-L1 or anti-PD-L2 antibodies.
Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy.
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. For patients with inactive HBV or HCV infection (hepatitis controlled under antiviral therapy), see study drug-specific exclusion criteria. For dose expansion, patients whose disease is controlled under antiviral therapy should not be excluded.
Active, known or suspected autoimmune disease.
History of or current interstitial lung disease or pneumonitis over grade 2.
Subjects with tuberculosis (TB) (patients receiving MCS110 or canakinumab)

Both

Triple negative breast cancer

Arm 1: Spartalizumab + LAG525 in combination with NIR178
Arm 2: Spartalizumab + LAG525 in combination with capmatinib
Arm 3: Spartalizumab + LAG525 in combination with MCS110
Arm 4: Spartalizumab + LAG525 in combination with canakinumab

safety
Incidence and severity of AEs and SAEs,Incidence and nature of DLTs in first cycle.

efficacy
pharmacokinetics
Best overall response (BOR) and PFS per RECIST.

Jan. 08, 2019