Functional integrity of lacrimal drainage apparatus by radionuclide dacryocystography

30 patients with epiphora and related complaints were investigated by Radionuclide Dacrocystography. It was possible to do this procedure easily in all age groups. The site of block in the lacrimal system could be accurately determined by this non-invasive technique

StrateGIST 1: A first-in-human (FIH), phase 1 study of IDRX-42 in patients with metastatic gastrointestinal stromal tumors resistant to prior treatment with tyrosine kinase inhibitors (TKIs)

11501 Background: Resistance to kinase inhibitors in gastrointestinal stromal tumors (GIST) is mainly driven by secondary mutations in KIT, and currently available TKIs fail to inhibit the full spectrum of secondary KIT mutations.IDRX-42 is an oral, potent, and highly selective inhibitor of the KIT tyrosine kinase, active against multiple primary and secondary resistance mutations in KIT-driven GIST. We present data from the ongoing FIH phase (ph) 1 study evaluating IDRX-42 in patients (pts) with metastatic GIST in 2 nd or later lines of therapy after failure of imatinib and other drugs. Methods: This ph 1 study evaluates the safety, tolerability, pharmacokinetics, and antitumor activity of oral IDRX-42 in adult pts with KIT-mutant GIST in dose escalation (ph1a) and defines the recommended dose for continued development (ph 1b). Ph 1b comprises 4 cohorts including pts without prior exposure to TKIs (1 st line), pts treated with prior imatinib only (2 nd line) and later line treatment cohorts. Correlative studies include sequential circulating tumor DNA (ctDNA) analyses and metabolic imaging using 18FDG-PET. Results: As of January 2, 2024, 42 pts received IDRX-42 in the ph 1a portion of the study with median treatment duration of 19+ (range 2-73+) weeks, with 30 pts remaining on treatment as of data cutoff. The median number of prior TKI therapy lines was 4 (range 1-6). Primary driver mutations were in KIT exon (ex) 11 (n = 27), ex 9 (n = 13) and ex 8 (n = 2). To date, five dose levels (120, 240, 400 and 600 mg QD; 400 mg BID) have been deemed safe to continue escalation. MTD has not been reached. A total of 39/42 pts are evaluable for efficacy; 9 achieved objective partial response (PR) per mRECIST (5 confirmed, 4 pending) across all doses studied. Three of 6 patients receiving IDRX-42 as 2 nd line therapy have confirmed PRs at 120 mg QD, 400 mg QD, and 400 mg BID respectively. The clinical benefit rate (mRECIST PR or stable disease ≥16 weeks) is 71% overall and 100% in 2 nd line. Sequential analyses of ctDNA show reductions across all primary and secondary KITmutations. Treatment-related adverse events (TRAE, CTCAE v5.0) were mainly low grade. The most frequently reported TRAE (≥25%) were gastrointestinal symptoms (diarrhea, nausea, vomiting, decreased appetite, dysgeusia) and fatigue. Eight of 42 pts reported Grade 3/4 TRAEs including gastrointestinal symptoms, fatigue and anemia. Two events qualified as DLT, 1 at 600 mg QD (syncope) and 1 at 400 mg BID (vomiting); after dose reduction both pts continued IDRX-42 for more than 8 and 5 months, respectively. Only two patients discontinued treatment due to TRAEs. Conclusions: IDRX-42 demonstrates promising clinical activity and a favorable safety profile in patients with advanced GIST following resistance to prior TKIs. Dose finding continues, and additional cohorts are ongoing. Clinical trial information: NCT05489237

Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma

Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation

MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (<b>8</b>) and alisertib (MLN8237, <b>10</b>) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (<b>10</b>) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors