belizatinib (TSR-011) / Amgen, GSK - LARVOL DELTA

[VIRTUAL] Unique NTRK3 Fusion in a Spindle Cell Sarcoma (CAP 2021) - "There are sufficient clinical and preclinical data to indicate that NTRK fusions predict sensitivity to TRK inhibitors such as larotrectinib, entrectinib, belizatinib, and PLX7486. He had a poor response and subsequently died from pulmonary complications related to metastases to the lungs. The fusion partner MEF2A has not previously been reported and may be related to being refractory to therapy and the poor outcome."

Oncology • Sarcoma • Solid Tumor • Spindle Cell Sarcoma • ALK • ETV6 • MYO5A • NTRK • NTRK2 • NTRK3 • ROS1

Q3 2012 Results (Tesaro) - Anticipated initiation of P1/2 trial for NSCLC in H2 2012

Anticipated new P1/2 trial • Non Small Cell Lung Cancer

Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations (ASCO 2014) - Publication only; Abstract #e19005; P1/2, N=23; Sponsor: Tesaro, Inc; NCT02048488; “TSR-011 is a well-tolerated promising second-generation agent for ALK-dependent and crizotinib resistant NSCLC, and is being explored in ALK+ and TRK+ tumors.” 

P1/2 data • Non Small Cell Lung Cancer

Phase (Ph) 1/2a study of TSR-011, a potent inhibitor of ALK and TRK, in advanced solid tumors including crizotinib-resistant ALK positive non-small cell lung cancer (EORTC-NCI-AACR 2014) - Abstract #506; P1/2, N=30; “Four of six (67%) of evaluable ALK+ patients previously treated with crz achieved a response across dose levels evaluated. Two patients with crz naïve ALK+ disease have treatment ongoing with stable disease after 4 cycles. Duration on TSR-011 exceeded that of crz treatment in a majority of responders, up to 10 months longer than treatment with crz for a patient still continuing on study. Twenty six patients with solid tumors have been screened by IHC for expression of TRKA or TRKB and the respective ligand.” 

P1/2 data • Non Small Cell Lung Cancer

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas. (PubMed, Br J Cancer) - P1/2; "At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued."

Clinical • Journal • P1 data

Belizatinib: Novel reactive intermediates and bioactivation pathways characterized by LC-MS/MS. (PubMed, J Pharm Biomed Anal) - "We propose that the tertiary nitrogen in the piperidine ring activates the attached benzyl carbon in addition to the two α carbons inside the ring. To our knowledge, this is the first report on the structural identification of reactive metabolites derived from BZB."

Journal

A Phase I/IIa Open-Label, Dose Escalation and Cohort Expansion Trial of Oral TSR-011 in Patients With Advanced Solid Tumors and Lymphomas (clinicaltrials.gov) - P1/2; N=72; Completed; Sponsor: Tesaro, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Dec 2017 ➔ Jun 2018

Clinical • Trial completion • Trial completion date