UGT1A1 Status Research Articles

Abstract 3734: Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors

Abstract BACKGROUND: Sacituzumab govitecan (IMMU-132), an ADC targeting Trop-2, an antigen present in many solid tumors, uses SN-38, a topoisomerase I inhibitor that has nanomolar potency derived from irinotecan (IRI), and a pH sensitive linker that releases SN-38 gradually (in vitro, 50% released per 1 day in serum). Clinical studies in patients (pts) with diverse solid tumors have shown manageable toxicity (dose-limiting neutropenia, diarrhea but lower incidence than IRI) and encouraging efficacy. METHODS: Conjugate and IgG were monitored in pts given 8 (N = 24) or 10 mg/kg (N = 29) by ELISA. SN-38 and glucuronidated SN-38 (SN-38G) were measured by reversed-phase HPLC. SN-38 and SN-38G levels are expressed as the amount of drug dissociated from the conjugate (i.e., Free SN-38) and the amount bound to the IgG (Total SN-38). UGT1A1 status was determined in baseline blood sample from 146 pts. RESULTS: IMMU-132 cleared with a half-life of 11.7-18.9 h, depending on the assay, while the IgG half-life was 4-5 days, which agrees with in vitro drug-release data. Levels of Free SN-38 at 30 min or 1 d after injection were <2% and ~ 5% of Total SN-38, respectively, indicating most SN-38 in serum is bound to the conjugate. Free SN-38 clears with a half-life of ~20 h, which is consistent with SN-38 clearance in IRI therapy. No correlation was found between Free SN-38 in serum at 30 min and the incidence of severe neutropenia. Total and Free levels of SN-38G were similar, supporting in vitro results indicating that SN-38 is not glucuronidated while bound to the IgG. Free SN-38G levels were lower than Free SN-38 (SN-38G/SN-38 AUC ratio = 0.52), explaining the lower incidence of severe diarrhea. PK parameters for 8 and 10 mg/kg group were similar; no major differences in toxicity. UGT1A1 status showed 43% and 44% with *1*1 and *1*28 haplotype, respectively, and 13% with *28*28 haplotype, which is associated with higher risk of severe neutropenia and diarrhea for IRI therapy. With IMMU-132, 58% of the *28*28 pts had severe neutropenia compared to ~40% of the *1*1 and *1*28 pts, and 16% of the *28*28 pts had grade 3 diarrhea compared to 5-8% of the *1*1 and *1*28. In 3 of 4 cancer indications, objective response rate and clinical benefit ratio favored the 10 mg/kg group. CONCLUSION: IMMU-132 cleared as predicted from in vitro serum stability data, with no difference between the 8 and 10 mg/kg groups. Current data show neutropenia did not correlate with Free SN-38 levels in serum at 30 min, and low SN-38G levels support the lower incidence of severe diarrhea. While pts with the *28*28 haplotype had a somewhat higher incidence of severe neutropenia or diarrhea than *1*1 and *1*28 pts, the overall incidence of each is small, suggesting toxicity management rather than screening is appropriate. With no major difference in safety and PK, but improved responses with 10 mg/kg, 10 mg/kg is selected for future clinical studies. Citation Format: Robert M. Sharkey, Allyson J. Ocean, Alexander N. Starodub, Aditya Bardia, Michael Guarino, Wells A. Messersmith, Jordan D. Berlin, Vincent J. Picozzi, Rebecca Moroose, William A. Wegener, Pius Maliakal, Serengulam V. Govindan, David M. Goldenberg. Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3734. doi:10.1158/1538-7445.AM2017-3734

Abstract 5480: Effects of UGT1A1 genotype on pharmacokinetics and toxicities of belinostat administered by continuous infusion in two clinical trials

Abstract Background: Belinostat (B), a histone deacetylase inhibitor recently approved for peripheral T-cell lymphoma, is extensively glucuronidated by UGT1A1. Genotypes with reduced UGT1A1 function could lead to higher B exposure and toxicities (tox). Methods: In a Phase I (BPE) and Phase I/II trial (BPAC), B (400-1000 mg/m2/24 h) was administered as a 48 h continuous infusion in combination with either cisplatin (P) and etoposide (E), or P, doxorubicin (A) and cyclophosphamide (C), respectively. Pts with small cell lung cancer and other cancers of neuroendrocrine origin (n = 25 in BPE) or advanced or unresectable thymic epithelial tumors (n = 26 in BPAC) underwent genotyping for UGT1A1 variants associated with reduced function: UGT1A1*6, *28 and *60. In both trials PK of B was analyzed and during Cycle 1 clinical outcomes were monitored. In 9 pts the Drug Metabolizing Enzymes and Transporter (DMET) genotyping array was carried out to study relationships between drug metabolizing enzymes and transporters with B PK or tox. Results: Pts carrying 1 or 2 UGT1A1*60 variants (n = 18) in BPE, had significantly higher B AUCs than WT pts (n = 5): median 11.4 vs 8.3 ng/mL*h/mg, P = 0.043. Consistent with greater exposure, pts carrying at least 1 variant UGT1A1*60 allele (n = 18) were at significantly higher risk for developing Gr 3-4 thrombocytopenia vs. WT pts (n = 5): OR (95%CI) = 21.2 (1.01-445.30), P = 0.014. A trend towards an increased risk of Gr 3-4 thrombocytopenia (P = 0.038), Gr 3-4 neutropenia (P = 0.045) and QTc prolongation (P = 0.030) was observed for UGT1A1*28. For Gr 3-4 neutropenia a marginal trend was also seen in *60 carriers (P = 0.088). In the BPAC trial UGT1A1*28 and UGT1A1*60 status did not significantly affect B PK (AUC, Cmax and CL, P>0.05) nor the incidence of most tox (P>0.05). Only Gr 3-4 thrombocytopenia occurred more frequently in *28 carriers (n = 11) than in WTs (n = 15): OR (95%CI) = 18.6 (0.88-392.7), P = 0.022. The DMET array revealed significant associations between SNPs in SLC15A1 and CYP24A1 and B PK (P<0.01). SNPs in SLCO1B3, SLCO1B1 and ABCB4 were significantly associated with the incidence of lymphocytopenia (P<0.01). Significant trends were observed between SNPs in UGT1A1, CYP2C19, CHST7, ABCB7 and ATP7A and the incidence of neutropenia. A SNP in XDH significantly trended with the incidence of thrombocytopenia (P<0.01). Conclusion: This is the first report of UGT1A1 polymorphisms effect on the PK and tox of B in combination with PE or PAC. In the BPE trial UGT1A1 status was associated with the extent of systemic exposure to B and the incidence of hematological tox. These associations were less profound in the BPAC trial and possible explanations are still under investigation. The DMET results indicate that besides UGT1A1 other drug transporters or enzymes could affect B PK and tox. Based on these findings, a population PK model accounting for genotype has been developed to titrate B dose based on UGT1A1 genotype. Citation Format: Andrew K.L. Goey, Tristan M. Sissung, Cody J. Peer, Sheryl Ehrlich, Christina Bryla, Arlene W. Berman, Sanjeeve Balasubramaniam, Arun Rajan, Giuseppe Giaccone, Susan E. Bates, William D. Figg. Effects of UGT1A1 genotype on pharmacokinetics and toxicities of belinostat administered by continuous infusion in two clinical trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5480. doi:10.1158/1538-7445.AM2015-5480

527P - A Phase I/II Study of Bi-Weekly Xeliri with Capecitabine 1,000 Mg/M2 Twice Daily and Irinotecan 180 Mg/M2 Plus Bevacizumab(Bv) for Patient with Metastatic Colorectal Cancer As Second-Line Chemotherapy (Bixer Study)

ABSTRACT Aim: Tri-weekly XELIRI is not completely regarded as a valid substitute for FOLFIRI in mCRC because of the potential for greater toxicity. Reduced dose tri-weekly XELIRI is officially recommended recently. This time, we conducted a PI/II study to assess bi-weekly XELIRI plus BV in efficacy and safety as second-line chemotherapy in mCRC. Methods: Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5mg/kg on day 1 every two weeks. PI study was composed of two steps (irinotecan 150 and 180 mg/m2), and dose limiting toxicity was assessed during the first treatment cycle. The primary endpoint of PII study was progression-free survival (PFS). Results: Recommended dose of irinotecan was determined as 180mg/m2 in PI study. Between Nov 2010 and Aug 2013, 44 patients were enrolled in PII study. Characteristics of patients were as follows (N = 44): median age, 60 yrs (range 32-80 yrs); male/female, 21/23; ECOG PS0, 86.4%; colon/rectum, 23/21; UGT1A1 wild/hetero type, 29/15; and 1st chemo regimen FOLFOX/XELOX, 18/26. The median number of treatment cycles was 10.5. Median PFS was 6.8 months (95%CI, 5.3-8.2 months), and the primary endpoint was met. Median overall survival (OS) was 18.3 months (95%CI, 13.4 - 23.1 months). Response rate was 22.7% (95%CI, 9.8-35.6%). No significant differences in PFS or OS occurred in UGT1A1 status and 1st chemo regimen. Grade 3 or greater adverse events observed were: neutropenia in six, diarrhea in five, nausea in four, anorexia in one, vomiting in one, stomatitis in one, fatigue in one, hand-foot skin reaction in one, hypertension in one, and interstitial pneumonia in one. There were no other severe adverse events and treatment related deaths. Conclusions: In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, biweekly XELIRI + BV is effective and feasible as 2nd line chemotherapy. Bi-weekly XELIRI + BV could be a valid substitute for FOLFIRI + BV in mCRC. Disclosure: All authors have declared no conflicts of interest.

A phase II study of second-line S-1/CPT-11+bev for advanced colon cancer (NCCSG04): Subset analysis by K-ras, EGFR, UGT1A1, and previous bevacizumab.

564 Background: We planned a phase II trial to evaluate the efficacy and safety of irinotecan, S-1, and bevacizumab (IRIS/Bev) as second-line therapy for patients with metastatic colorectal cancer (mCRC). The result of this study was reported an active and generally well-tolerated 2nd-line treatment for mCRC (Takii et al. ASCO-GI 2013 #496). We analyzed subset of EGFR, K-ras, UGT1A1, and previous Bev. Methods: The study design was multicenter, single-arm, open-label phase II study. Eligible patients had to have mCRC with confirmed diagnosis of adenocarcinoma, history of oxaliplatin containing regimen as first-line therapy, an age from 20 to 80 years, ECOG performance status (PS) of 0-1. S-1 65 mg/m2 daily p.o. was given on days 1-14 and Irinotecan 75mg/m2and bevacizumab 10mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. We retrospectively examined progression-free survival (PFS), overall response rate (OR), overall survival (OS), time to treatment failure (TTF) and safety by K-ras, EGFR, UGT1A1, and previous Bev status. Results: Thirty-four patients were investigated. The OR was 21.1% (7/33) and disease control rate was 84.8% (28/33). Median PFS was 8.9 months, median TTF was 8.2 months and median OS was 23.4 months. Median PFS was 9.9 months on K-ras wild group and 6.6 months on K-ras mutant group (p = 0.517). Median OS was not reached on K-ras wild group and 16.4 months on K-ras mutant group (p = 0.097). The EGFR-negative case was three cases, and it did not become a data to compare because of small number. Median PFS was 8.5 months on previous Bev group and 9.9 months on previous no-Bev group (p = 0.637). Median OS was not reached on previous Bev group and 23.1 months on previous no-Bev group (p = 0.701). Median PFS, TTF and OS was no different between UGT1A1 wild group and mutant group. On safety analysis, there were no different between the two groups, respectively. Conclusions: IRIS/Bev is an active and well-tolerated second-line treatment for patients with mCRC. Only K-ras status influendced OS. Clinical trial information: UMIN000001631.

Irinogenetics: How Many Stars Are There in the Sky?

Irinogenetics: How Many Stars Are There in the Sky?

Individualisation des prescriptions dans le cancer colorectal Le point de vue du clinicien

Regarding the evolution of the treatments of colorectal cancer during the last five years, it appears that numerous questions have to be considered with a strategic point of view. In order to avoid inclusion of a lot of patients in clinical patients, we urgently need the help of biology to give us arguments to choose one treatment or another. The fact that ten years after their approval, we are not able to select responders to oxaliplatin or irinotecan, confirm that this is difficult problem to solve. The contribution of biology to the prescription of drugs commonly used in colorectal cancer is discussed in this paper. There are already situations where the contribution of biology to clinical practice and prescription is not debatable : this is the case for the use of UGT1A1 status determination when using irinotecan and the determination of KRAS status for the prescription of panitumumab (and cetuximab in a few months). This individual adaptation is a dream that becomes reasonable when we look on the recent results concerning EGFR inhibitors, but a lot of work has to be done and it is not sure that biological assessment of the tumour will be able to solve all the problems. For instance, to determine predictive factors of response to angiogenesis inhibitors, it is likely that solutions will come from new techniques of imaging rather than from biology. However, new tools such as proteomics or metabolomics, as well as a better dialogue between clinician and biologist, will allow fast improvements. It must be emphasised that, for the first time in 2008, it is possible to prescribe targeted therapies to a specific "targeted" group of patients with metastatic colorectal cancer.