Clinical trial in progress: BCC020 a dose escalation study using difluoromethylornithine (DFMO) and AMXT-1501 followed by a randomized controlled trial of DFMO with or without AMXT-1501 for neuroblastoma, CNS tumors, and sarcomas

Background: Aggressive pediatric tumors such as neuroblastoma (NB), brain tumors, and sarcomas respond poorly to standard therapies, creating an urgent need for novel treatments. Elevated polyamines promote tumor growth through LIN28 up-regulation and Let-7 microRNA suppression, promoting cell proliferation, metastasis, and retention of a stem cell phenotype. Eflornithine (DFMO) reduces intracellular polyamine synthesis and in NB models decreases LIN28B and MYCN expression and neurosphere formation. However, cancer cells can compensate by increasing polyamine uptake via transporters like SLC3A2 or ATP13A3. Combining DFMO with AMXT 1501, an oral small molecule polyamine uptake inhibitor, achieves deeper polyamine depletion and in DIPG models demonstrates significant antitumor activity. This combination offers a promising metabolic approach for polyamine-dependent high-risk pediatric cancers. Methods: AMXT 1501 will be combined with DFMO in an open label multicenter study (NCT06465199) for subjects with NB, high-risk CNS tumors [Diffuse Intrinsic Pontine Glioma (DIPG), Atypical Teratoid Rhabdoid Tumor (ATRT), Embryonal Tumor with Multilayered Rosettes (ETMR)], Ewing sarcoma and Osteosarcoma. The Phase I portion uses a standard 3+3 design in which groups of 3 subjects will receive 28-day cycles of oral AMXT 1501 combined with oral DFMO for up to 24 cycles. In phase II, all cohorts besides NB will receive AMXT 1501 and DFMO at the maximally tolerated dose identified in Phase I. NB subjects will be randomized to receive either the combination of AMXT 1501 plus DFMO or DFMO alone (with the option to cross over to combination therapy for disease progression). The primary objective of Phase II is to evaluate the efficacy of the combination based upon progression free survival. Eligibility criteria include: age <21 years at initial diagnosis, pathologically confirmed disease that was relapsed or refractory following standard multiagent induction therapy (except for DIPG, where newly diagnosed patients can enroll without pathologic confirmation following standard upfront radiation), disease staging prior to enrollment showing no evidence for disease or stable disease, and ability to swallow capsules. For safety reasons phase I will initially enroll only patients ≥ 12 years of age, before adding patients < 12 years of age. A projected total of 6-30 subjects will be enrolled in Phase 1 and 229 subjects in Phase II to ensure that there will be 206 evaluable subjects (131 NB, 25 ETMR/ATRT, 30 DIPG, and 20 with sarcoma). Enrollment will occur at up to 50 Beat Childhood Cancer (BCC) Research Consortium hospitals. The study is currently open to enrollment at 3 centers, with additional centers pursuing activation.