Quadriga Biosciences (United States)

Abstract BACKGROUND QBS10072S, is a L-type amino acid transporter 1 (LAT-1) targeted alkylating agent that utilizes LAT1 as both a transport and targeting mechanism. QBS10072S can cross the blood-brain barrier, exhibits potential for cytotoxicity with a mechanism distinct from temozolomide and has low off-target effects. QBS10072S is being evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial (NCT02977780), a randomized phase 2 adaptive multi-arm platform trial. METHODS Adult patients with newly diagnosed MGMT-unmethylated glioblastoma are eligible for INSIGhT. Since there is no safety data available for QBS10072S in combination with radiotherapy, a safety lead-in evaluation was conducted utilizing a 3 + 3 design. Starting dose for QBS10072S was 12mg/m2 in combination with radiation therapy and adjuvantly as monotherapy in 28 day cycles. Patients were monitored for dose-limiting toxicities (DLTs) to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). RESULTS Nine patients were enrolled December 2022 to October 2023 for safety lead-in testing, and median age was 57 years (41-67) with 6 (66%) males, 6 (66%) patients with gross total resection, and median KPS 90 (range 80-100). Pharmacokinetic studies indicated that drug exposure was lower than prior studies, and three patients received 12mg/m2, 15mg/m2, and 18mg/m2, respectively, per dose escalation protocol. No DLTs nor adverse events leading to study drug discontinuation were reported during the evaluation period. Four patients had possible treatment-related CTCAE grade ≥ 3 toxicity including lymphopenia (n=3) and fatigue (n=1). The RP2D was determined to be 18mg/m2. Seven patients were discontinued from study treatment due to progressive disease and two patients remain on treatment. CONCLUSION QBS10072S, concurrent and adjuvant to radiation therapy, was well-tolerated in patients with newly diagnosed unmethylated MGMT glioblastoma. QBS10072S 18mg/m2 is being evaluated as a treatment arm in phase 2 testing in the ongoing INSIGhT trial.

Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43