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CQS, when given at a dose of 2000 mg/m2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.

CQS, when given at a dose of 2000 mg/m2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.

420 Background: RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by cancer-enriched uridine cytidine kinase 2. Single agent RX-3117 has demonstrated efficacy in a phase III single agent clinical study of RX-3117 in met-PC and bladder cancer. RX-3117 in combination with nab-pac is being evaluated as first line treatment of met-PC cancer. Methods: This is a multicenter, open label phase I/II study (NCT03189914). Eligible subjects (aged ≥ 18 years) have histologically or radiologically proven met-PC with no prior therapies for metastatic disease, ECOG PS 0-1, and normal lab values. phase I identified the MTD dose that is being further evaluated in the phase II: RX-3117 (700 mg administered orally once-daily for 5 consecutive days with 2 days off per week) and nab-pac (125 mg/m2 administered once weekly) for 3 weeks with 1 week off per 4-week cycle. The Safety Committee reviewed data from phase I before moving to phase II. The primary endpoint of phase II (dose expansion) is an adequate number of responders based on PFS at 4 months and/or objective clinical response per RECIST v1.1. Results: As of September 21, 2018, 8 phase I subjects and 13 phase II subjects were enrolled and treated (9 males and 12 females, median age 67 years). The most common (≥ 15%) related adverse events were nausea, diarrhea, fatigue, alopecia, decreased appetite, rash, vomiting, and anemia. Fourteen subjects had at least one on-study scan (after 2 cycles). One subject experienced a complete response (CR) after 6 cycles of therapy with normalization of CA19.9 (-76%). Three subjects exhibited a partial response (PR): two after 2 cycles (39-47%) and one after 4 cycles of therapy (36%). Eight subjects had stable disease for at least 2 months, and 4 subjects had PFS of at least 4 months. The disease control rate (CR+PR+SD) was 86% in evaluable subjects while the overall response rate (CR+PR) was 29%. Conclusions: RX-3117 in combination with nab-pac appears to be safe and well tolerated in subjects with met-PC. Antitumor activity per RECIST was observed in 12 subjects. Phase II of the clinical study is currently ongoing. Clinical trial information: NCT03189914.

BackgroundVerinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for the treatment of gout and asymptomatic hyperuricemia.ObjectivesThis Phase 2a, randomized, open-label, multicenter study investigated the multiple-dose pharmacodynamics (PD), pharmacokinetics (PK), and safety of oral verinurad in combination with allopurinol versus allopurinol alone in adults with gout (NCT02498652).MethodsPatients aged ≥18 and ≤75 years with gout and serum uric acid (sUA) ≥8 mg/dL were randomized to 1 of 2 cohorts to receive allopurinol (300 mg) in combination with verinurad (dose range 2.5 mg to 20 mg) and allopurinol 300 mg or 600 mg alone (each treatment period was 7 days). Medications were administered once daily ∼30 min after breakfast (for allopurinol 300 mg b.i.d. group, the second allopurinol dose was in the evening). Colchicine 0.6 mg for gout flare prophylaxis was initiated at approximately Day -14 (start of urate-lowering therapy [ULT]) washout) or Day -7 if not on ULT. Serial blood and urine samples were measured on Days -1, 1, 7, 14, 21, 28, and 35 for PD and PK endpoints. Safety assessments included adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters.ResultsForty-one patients were randomized (n=20–21 per cohort). Serum PD data pooled across cohorts demonstrated maximal % decrease in sUA from baseline (Emax)at 6–10 h after verinurad and allopurinol combination treatment. Addition of verinurad (2.5 mg to 20 mg) to allopurinol decreased sUA in dose-dependent manner (Figure). Greater sUA reductions were observed for dose combinations of verinurad ≥5 mg with allopurinol 300 mg versus allopurinol 600 mg alone, while allopurinol 600 mg once daily was equivalent to allopurinol 300 b.i.d. Emax was 46.9%, 58.9%, 59.9%, 67.1%, 68.4%, and 74.3% for verinurad at doses of 2.5, 5, 7.5, 10, 15, and 20 mg in combination with allopurinol 300 mg, versus 39.7%, 53.8%, and 54.4% with allopurinol 300 mg, allopurinol 600 mg, and allopurinol 300 mg b.i.d. alone. No drug-drug interaction on verinurad and allopurinol plasma PK parameters was observed.ConclusionsVerinurad coadministered with allopurinol dose-dependently decreased sUA. All dose combinations of verinurad and allopurinol in this study were generally well tolerated with no serious AEs or renal-related events during combination treatment.Disclosure of InterestR. Fleischmann Grant/research support from: Ardea Biosciences, Inc., P. Winkle Employee of: Anaheim Clinical Trials, J. Miner Employee of: Ardea Biosciences, Inc., X. Yan Employee of: Ardea Biosciences, Inc., L. Hicks Employee of: Ardea Biosciences, Inc., S. Valdez Employee of: Ardea Biosciences, Inc., J. Hall Employee of: Ardea Biosciences, Inc., M. Hernandez-Illas: None declared

140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]

Since dose intensity of doxorubicin is correlated with the clinical response of patients with soft tissue sarcomas and since doxorubicin dose intensity may be compromised in combination chemotherapy, we evaluated the use of recombinant granulocytemacrophage colony-stimulating factor (rGM-CSF) to ameliorate myelosuppression and allow doxorubicin dose escalation in a phase I trial utilizing the MAID combination [Mesna 2.5 g/m2/day x 4 days, Adriamycin (doxorubicin) 15 mg/m2/day x 4 days, ifosfamide 2.0 g/m2/day x 3 days, dacarbazine 250 mg/m2/day x 4 days; to be repeated every 21 days]. Thirteen patients were treated. The doxorubicin dose for the first 6 patients was at the standard dose of 15 mg/m2/day x 4 days (level 1), while the doxorubicin dose for the next 7 patients was escalated by 25% to 18.75 mg/m2/day x 4 days (level 2). rGM-CSF was given at 5 micrograms/kg/day, days 5-14. All patients experienced moderate to severe myelosuppression, with all patients at dose level 2 requiring doxorubicin dose reduction to dose level 1 or lower by their third course of treatment. rGM-CSF failed to allow sustained escalation of the doxorubicin dose in the MAID regimen.

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