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.

Start Date31 Jan 2019

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

KCT0003237 / CompletedPhase 2IIT

Biomarker study of PDR001 in combination with MCS110 in gastric cancer

Start Date21 Jan 2019

Sponsor / Collaborator

Seoul National University Hospital

NCT03694977 / Unknown statusPhase 2IIT

Biomarker Study of PDR001 in Combination With MCS110 in Gastric Cancer

Current status of treatment options in advanced gastric cancer.
The cytotoxic chemotherapy, usually fluoropyrimidine + platinum combination regimen is current standard of care. In case of HER2(+) gastric cancer, the addition of trastuzumab on top of cytotoxic chemotherapy is standard of care.
In second-line setting, the cytotoxic chemotherapy in combination with Ramucirumab improved the patients' survival compared with cytotoxic chemotherapy alone.
There are few treatment options for gastric cancer patients who have been treated with more than two lines of palliative chemotherapy. Patients with good performance status even after failure to 2 kinds of palliative chemotherapy still need the active anticancer treatment options. Therefore, this is the high unmet medical need.
Current status of immunotherapy development in gastric cancer
The importance of tumor microenvironment
The role of polarized macrophage in TME
The role of polarized macrophage in gastric cancer
Potential of combination of PD1 inhibitor and CSF-1 inhibitor
Based on these rationales, we hypothesized that the combination of PD1 inhibitor and CSF1R inhibitor might be synergistic in gastric cancer. However, the exact in vivo immune modulation by each inhibitor has not been revealed so far. Therefore, we will conduct this "biomarker study of PDR001 in combination with MCS110 in gastric cancer" to see the biologic dynamic modulation with MCS110 and combination (MCS110/PDR001) and to see preliminary efficacy signal with this combination.
Primary objective: To see biomarker changes (PDL1, TAM, TIL) by MCS110 monotherapy and MCS110/PDR001 combination (To see the biomarker changes by MCS110 monotherapy at first, then, by MCS110/PDR001 combination in gastric cancer) Secondary objective: To see preliminary efficacy (ORR, irRR, PFS, DOR, DCR, OS) and safety.

Start Date17 Jan 2019

Sponsor / Collaborator

Seoul National University Hospital

100 Clinical Results associated with Lacnotuzumab

100 Translational Medicine associated with Lacnotuzumab

100 Patents (Medical) associated with Lacnotuzumab

Literatures (Medical) associated with Lacnotuzumab

01 Jun 2024·Molecular Oral Microbiology

Effects of IL‐34 and anti‐IL‐34 neutralizing mAb on alveolar bone loss in a ligature‐induced model of periodontitis

Article

Author: Ngala, Bidii ; Ho, Anny ; Nusbaum, Amilia ; Duarte, Carolina ; Yamada, Chiaki ; John, Vanchit ; Akkaoui, Juliet ; Birsa, Maxim ; Movila, Alexandru ; Garcia, Christopher ; AlQallaf, Hawra

AbstractMacrophage colony‐stimulating factor (M‐CSF) and interleukin‐34 (IL‐34) are ligands for the colony‐stimulating factor‐1 receptor (CSF‐1r) expressed on the surface of monocyte/macrophage lineage cells. The importance of coordinated signaling between M‐CSF/receptor activator of the nuclear factor kappa‐Β ligand (RANKL) in physiological and pathological bone remodeling and alveolar bone loss in response to oral bacterial colonization is well established. However, our knowledge about the IL‐34/RANKL signaling in periodontal bone loss remains limited. Recently published cohort studies have demonstrated that the expression patterns of IL‐34 are dramatically elevated in gingival crevicular fluid collected from patients with periodontitis. Therefore, the present study aims to evaluate the effects of IL‐34 on osteoclastogenesis in vitro and in experimental ligature‐mediated model of periodontitis using male mice. Our initial in vitro study demonstrated increased RANKL‐induced osteoclastogenesis of IL‐34‐primed osteoclast precursors (OCPs) compared to M‐CSF‐primed OCPs. Using an experimental model of ligature‐mediated periodontitis, we further demonstrated elevated expression of IL‐34 in periodontal lesions. In contrast, M‐CSF levels were dramatically reduced in these periodontal lesions. Furthermore, local injections of mouse recombinant IL‐34 protein significantly elevated cathepsin K activity, increased the number of tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts and promoted alveolar bone loss in periodontitis lesions. In contrast, anti‐IL‐34 neutralizing monoclonal antibody significantly reduced the level of alveolar bone loss and the number of TRAP‐positive osteoclasts in periodontitis lesions. No beneficial effects of locally injected anti‐M‐CSF neutralizing antibody were observed in periodontal lesions. This study illustrates the role of IL‐34 in promoting alveolar bone loss in periodontal lesions and proposes the potential of anti‐IL34 monoclonal antibody (mAb)‐based therapeutic regimens to suppress alveolar bone loss in periodontitis lesions.

01 May 2024·Journal of Immunotherapy and Precision Oncology

Phase Ib/II Study of Lacnotuzumab in Combination with Spartalizumab in Patients with Advanced Malignancies

Article

Author: Stephen, Bettzy ; Pant, Shubham ; Ahmed, Jibran ; Kwiatkowski, Evan ; Yang, Yali ; Ejezie, Chinenye Lynette

ABSTRACTIntroductionBlocking the colony-stimulating factor 1 (CSF-1) signal on tumor-associated macrophages can lead to an upregulation of checkpoint molecules, such as programmed cell death ligand 1 (PD-L1), thus causing resistance to this blockade. Combining spartalizumab (PDR001), a high-affinity, ligand-blocking, humanized anti–PD-1 immunoglobulin G4 antibody, with lacnotuzumab (MCS110), a high-affinity, humanized monoclonal antibody directed against human CSF-1 can potentially overcome this resistance.MethodsThis was a multicenter, phase Ib/II trial using a combination of spartalizumab with lacnotuzumab in patients with advanced cancers, including anti–PD-1/PD-L1 treatment-resistant melanoma, and anti–PD-1/PD-L1 treatment-naïve triple-negative breast cancer, pancreatic cancer, and endometrial cancer (ClinicalTrials.gov identifier: NCT02807844). The primary objective of dose escalation phase Ib was to assess safety, tolerability, and recommended phase II dose. The primary objective of the phase II expansion study was to assess the combination’s antitumor activity, including objective response rate and clinical benefit rate.ResultsA total of eight patients (five in phase Ib and three in phase II) were evaluable for adverse events (AEs) at our study site. All eight patients experienced at least grade 1 AE. The most common treatment-related AEs were increased serum aspartate aminotransferase (38%), fatigue (38%), anemia (25%), increased alkaline phosphatase (25%), hyperbilirubinemia (25%), hypocalcemia (25%), and hypoalbuminemia (25%). Most of these AEs were grade 1 or 2. None of the patients experienced grade 4 AEs and no drug-related fatal AEs were reported among the eight patients treated in the study. One (13%) patient had stable disease (SD) (captured as unknown by the study sponsor because the evaluation criteria set per protocol was not met) and three (38%) patients had progressive disease. Four (50%) patients developed clinical disease progression based on investigator evaluation. One patient with pancreatic cancer achieved immune-related SD for 26 months while on the study treatments.ConclusionThe study completed phase Ib dose escalation and phase II. However, gating criteria for efficacy were not met for expansion beyond 80 patients in phase II and the sponsor did not continue development of the combination of spartalizumab and lacnotuzumab for oncology indications. The potential signal of activity in pancreatic cancer should be further explored.

01 Jun 2023·Investigational new drugs

A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition.

Article

Author: Ott, Patrick A ; Buchbinder, Elizabeth I ; Giobbie-Hurder, Anita

BACKGROUNDPrognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy.METHODSWe performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110.RESULTSBetween September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26-71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached).CONCLUSIONMCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

100 Deals associated with Lacnotuzumab

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Triple-Negative Breast Carcinoma	Phase 3	TW	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	HK	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	AU	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	KR	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	ES	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	FR	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	DE	Novartis Pharmaceuticals Corp.	10 Aug 2015
Advanced Triple-Negative Breast Carcinoma	Phase 3	AT	Novartis Pharmaceuticals Corp.	10 Aug 2015
Bone metastases	Phase 2	US	Novartis Pharmaceuticals Corp.	01 Sep 2008
Prostatic Cancer	Preclinical	US	Novartis Pharmaceuticals Corp.	01 Sep 2008

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