We investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with advanced lymphoid malignancies undergoing autologous SCT. Bu 130 mg/m2 was infused daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 uMol-min, determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen, followed by a rest day, followed by two daily doses of Mel at 70mg/m2. Stem cells were infused the following day. 80 patients had i.v. Bu delivered per test dose guidance. The median daily systemic Bu exposure was 4867 uMol-min. 102 patients [Hodgkin's Lymphoma (HL) n=49, Non Hodgkin's Lymphoma (NHL) n=12, Multiple Myeloma (MM) =41] with median age 44 years (range 19 to 65 years) were treated. 2-year overall survival (OS) and progression-free survival (PFS) rates were 85% and 57%, respectively, for patients with HL, 67% and 64%, respectively, for patients with NHL, and 82% and 42%, respectively, for patients with MM. The regimen was very well-tolerated with treatment-related mortality at 100 days, 1 year, and 2 years of 1%, 3%, and 3%, respectively. Intravenous Bu-Mel is well-tolerated. Disease control is encouraging, and should be explored in larger phase II studies.

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2045 Background: Preclinical studies demonstrated that RTA 744, a 4’-O benzyl anthracycline designed to circumvent P-gp and MRP1-mediated efflux, effectively crosses the BBB, is retained in brain & brain tumor tissue for >24 hrs, and has demonstrated in vivo activity against glioblastoma multiforme (GBM) in an orthotopic model. Methods: We designed a multicenter, phase I dose- escalation study of RTA 744 administered as a short intravenous infusion for 3 consecutive days, every 3 weeks. Patients enrolled in the study were adult patients with recurrent or refractory GBM, anaplastic astrocytoma, or other primary brain tumors. Peripheral blood samples for PK analysis were collected prior to and at selected timepoints from 5 min to 96 hrs after drug administration, and quantified by LC/MS/MS. PK parameters describing RTA 744 disposition were determined by fitting compartmental models to individual patient plasma concentration-time data. Results: Twenty patients have been enrolled at daily doses ranging from 1.2 to 9.6 mg/m2. Mean (range) population terminal half-life was 34.6 (20.5–89.2) hrs, plasma drug clearance was 45.0 (27.4–86.9) L/hr/m2, and Vss was 1942 (684.9–4721.7) L/m2; population PK values reported for doxorubicin are 20–32 hrs, 24–35 L/hr/m2, and 700–1100 L/m2, respectively. Regimen related toxicity has been minimal with the most common adverse event being myelosuppression. Percentage of unchanged parent drug renally eliminated was 2.4% (0.42–6.03%). Several partial responses and one complete response have been noted, even at dose levels below the observed MTD of 7.5 mg/m2/day. Conclusions: These results are similar to what we have observed in our preclinical studies, demonstrating increased lipophillicity and enhanced biodistribution of RTA 744 when compared to doxorubicin. Direct confirmation of drug penetration into the CNS has not been determined in this study, however this is the focus of an ongoing trial in patients with leptomenigeal malignancies. No significant financial relationships to disclose.

440 Background: Futibatinib, an irreversible FGFR1–4 inhibitor, is being investigated for the treatment of advanced intrahepatic cholangiocarcinoma (iCC) with FGFR2 fusions/rearrangements. We conducted an indirect treatment comparison to evaluate efficacy outcomes with futibatinib for advanced iCC patients from the FOENIX-CCA2 trial (NCT02052778) relative to published data for chemotherapy and FGFR inhibitors. Methods: A systematic literature review was conducted to identify clinical trials for FGFR inhibitors published 01/2015-02/2021, with additional targeted searches for chemotherapy data. A simulated treatment comparison was conducted using individual-level patient data from FOENIX-CCA2 and published aggregate data from comparator trials, applying regression models to adjust for between-trial differences in baseline characteristics. Population-adjusted Cox regression models were used for base case time-to-event outcomes (progression-free survival [PFS], overall survival [OS], duration of response [DOR]) and binomial-logistic regressions for binary outcomes (objective response rate [ORR]). Results: Two studies of FGFR inhibitors among previously treated patients with FGFR2 fusions/rearrangements were identified with sufficient data for analysis: FOENIX-CCA2 (n=103) and FIGHT-202 (n=107, pemigatinib). Two studies were identified for chemotherapy in this setting (an analysis of prior systemic therapy in the FIGHT-202 cohort [n=53] and a natural history study using a clinicogenomic database [n=71]). Comparisons of futibatinib with chemotherapy showed significantly lower risk of progression or death with futibatinib (table). Comparisons of futibatinib with pemigatinib showed similar outcomes between treatments (table), however, there was a numerical advantage for futibatinib in all efficacy parameters. Conclusions: Data suggest that futibatinib provides longer survival vs chemotherapy among previously treated advanced iCC patients with FGFR2 fusions/rearrangements. No statistically significant differences were observed in efficacy outcomes between futibatinib and pemigatinib, although numerical trends favored futibatinib. Molecular detail such as improved activity against co-mutated tumours and resistance mutations may explain such trends. [Table: see text]

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