Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1'-hydroxymidazolam (1'-HM). Safety was assessed throughout.Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC0-12), respectively; AUC0-t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (Cmax) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC0-12) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased Cmax for paraxanthine and 5-HO by 19% and 7%; Cmax increased by 33% for 1'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3).Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A.GOV: NCT03333824.
The lethal and sub-lethal effects of basic phenylmercuric nitrate, potassium cyanide and mercuric chloride on onion roots and sea urchin embryos can be antagonized by yeast and beef spleen extract. These observations are in agreement with reports that yeast extract can offset the action of respiratory poisons on some enzyme systems.
Abstract: Acquired pure red cell aplasia (PRCA) may be the result of a cellular or humoral autoimmune process. One proposed mechanism is the destruction of erythroid progenitors by self‐reactive, cytotoxic T cells or natural killer (NK) cells. These cells normally express MHC class I receptors (KIR) which inhibit cytotoxicity when the target cell expresses the HLA class I antigen(s) they bind. Therefore, loss of these antigens on maturing erythroid progenitors may render them susceptible to destruction by the pathogenic cells. Interferon‐ α (INF‐ α ) increases HLA class I expression on hematopoietic precursor cells. Therefore, we initiated a trial of INF‐ α in a patient with refractory PRCA. Following treatment, he developed transfusion independence, and a sustained normal hematocrit. Analysis of bone marrow erythroid cells revealed an increase in expression of HLA class I molecules. INF‐ α should be used in a controlled trial in patients with PRCA to determine its activity and mechanism of action.
Summary Sources for allogeneic stem cells for patients with haematological disorders lacking a histocompatible sibling donor include matched unrelated donor (MUD) and umbilical cord blood (UCB). A total of 51 patients with haematological disorders, treated with myeloablation and transplantation with either unrelated human leucocyte antigen (HLA) partially matched UCB (28 patients) or HLA‐matched MUD grafts (23 patients) during 1997–2003, were evaluated for life‐threatening infections, haematological reconstitution, graft versus host disease, relapse and event‐free survival (EFS). The median duration of neutropenia after transplantation was longer (29 d vs. 14 d) in the UCB group. The probability of donor‐derived neutrophil engraftment by day 42 was 0·86 [95% confidence interval (CI) 0·71–1·0] in UCB recipients versus 0·96 (95% CI 0·87–1·0) in MUD recipients surviving >28 d. Overall infection rates were higher in UCB recipients, particularly at the early time points (before day +50) after transplantation. Graft failure occurred in five UCB recipients and two MUD recipients and was associated with the occurrence of bacteraemia during neutropenia. The EFS at 3‐year follow‐up was 0·25 in UCB and 0·35 in MUD recipients. UCB transplantation in adults is associated with delayed neutrophil and lymphocyte recovery compared with MUD grafting, and higher rates of bacteraemia at early time points after transplantation.
Abstract Background: Adavosertib (AD), a selective WEE1 inhibitor, may alter exposure to compounds metabolized by cytochromes P450 (CYP); this two-period open-label study (NCT03333824) assessed the effect of AD on pharmacokinetics (PK) of probe substrates for CYP1A2 (caffeine; C), CYP2C19 (omeprazole; O) and CYP3A4 (midazolam; M). Methods: In period 1, patients (pts) with locally advanced or metastatic solid tumors received a cocktail (CKT) of C 200 mg, O 20 mg, M 2 mg (single dose); in period 2, after a 7–14-day washout, pts received AD 225 mg bid on days 1–3 (5 doses), and with CKT on day 3. After CKT and AD administration, 24-hour PK sampling took place for C, O, M and their respective metabolites paraxanthine (P), 5-hydroxyomeprazole (5-HO), and 1′-hydroxymidazolam (1′-HM). Safety was assessed throughout. Results: Of 33 pts (median age, 60.0 years, range 41–83; F:M, 18:15) receiving CKT, 30 pts were given AD. AD co-administration increased C, O and M exposure by 49%, 80% and 55% (AUC), respectively; AUC0–t increased by 61%, 98% and 55%; Cmax increased by 4%, 46% and 39% (Table 1). AD addition increased 5-HO and 1′-HM exposure by 43% and 54% (AUC), respectively, and by 49% and 58% (AUC0–t) respectively; P exposure was unchanged. AD co-administration decreased Cmax for P and 5-HO by 19% and 7%, respectively, whereas Cmax increased by 33% for 1′-HM. AD addition decreased CL/F and Vz/F for all substrates and increased t1/2 and tmax for most substrates and metabolites; tmax for M and 1′-HM were unchanged. A trend of decreasing metabolite/substrate ratios for AUC, AUC0–t and Cmax was seen with AD co-administration. After receiving AD, 24 (80%) pts reported adverse events (AEs), most commonly diarrhea (16 [53%]), vomiting (9 [30%]) and nausea (8 [27%]). Nineteen (63%) pts had treatment-related AEs (6 [20%] pts with grade ≥3). Table 1Point estimates of the geometric least-square mean ratios S+AD/S (90% CI), %Median (range) tmax, hMean (SD) t½, hMean (SD) CL/F, L/hMean (SD) Vz/F, LMean MRAUCAUC0–tCmaxAUCAUC0–tCmax−AD+AD−AD+AD−AD+AD−AD+AD−AD+AD−AD+AD−AD+ADCaffeine*149.1 (131.3, 169.3)160.8 (143.3, 180.5)103.8 (92.2, 116.9)0.5 (0.3–3.0)0.7 (0.3–3.0)6.4 (3.8)13.5 (6.8)5.7 (2.5)3.8 (1.9)39.3 (15.0)37.9 (12.1)NAOmeprazole180.2 (145.7, 222.9)198.1 (160.3, 244.7)145.5 (114.0, 185.7)3.0 (0.7–6.0)3.9 (0.5–8.0)2.0 (1.0)2.5 (1.3)13.3 (10.5)7.6 (7.3)28.3 (16.6)19.8 (10.1)NAMidazolam155.3 (138.6, 173.9)155.2 (140.5, 171.5)138.5 (118.9, 161.3)0.5 (0.2–1.0)0.5 (0.2–1.0)5.5 (2.6)6.6 (3.0)59.0 (34.3)39.7 (14.5)409.9 (211.5)364.1 (182.7)NAParaxanthine†NCNC81.2 (74.6, 88.5)8.0 (4.0–11.8)9.9 (6.0–24.9)7.0 (2.7)12.2 (5.4)NA0.65NC0.540.320.230.165-HO143.0 (123.8, 165.0)148.8 (129.6, 170.8)92.9 (78.6, 109.8)3.0 (0.7–6.0)4.0 (1.8–7.8)2.7 (1.7)4.5 (4.7NA0.500.460.730.500.530.301′-HM153.5 (131.0, 179.8)158.2 (139.1, 180.0)133.4 (106.5, 167.1)0.5 (0.3–2.1)0.5 (0.2–1.0)7.2 (6.1)7.6 (7.1)NA0.410.450.430.440.470.43Patient numbers for cocktail without AD (period 1) were: caffeine (AUC: 22; AUC0–t, Cmax, tmax and t½: 25), omeprazole (AUC and t½: 21; AUC0–t, Cmax and tmax: 27), midazolam (AUC and t½: 22; AUC0–t, Cmax and tmax: 23), paraxanthine (AUC: 10; t½: 14; AUC0–t, Cmax and tmax: 19), 5-HO (AUC: 22; t½: 24; AUC0–t, Cmax and tmax: 28) and 1''-HM (AUC: 20; t½: 22; AUC0–t, Cmax and tmax: 24). Patient numbers for cocktail with AD (period 2) were: caffeine (AUC: 8; AUC0–t and t½: 18; Cmax and tmax: 19), omeprazole (AUC and t½: 15; AUC0–t: 18; Cmax and tmax: 20), midazolam (AUC and t½: 18; AUC0–t, Cmax and tmax: 19), paraxanthine (AUC: 1; t½: 5; AUC0–t: 15; Cmax and tmax: 16), 5-HO (AUC: 13; t½: 17; AUC0–t: 18; Cmax and tmax: 20) and 1''-HM (AUC: 17; t½: 18; AUC0–t, Cmax and tmax: 19). *Caffeine AUC was only reliably characterized in eight patients receiving cocktail with AD in period 2. Caffeine AUC increased in all patients with paired data for both periods for seven patients; results were considered representative of the data; †Paraxanthine AUC was only reliably characterized in 10 patients in period 1 (only cocktail) and one patient in period 2 (cocktail with AD); thus, the treatment comparison for AUC was not considered scientifically meaningful. 1′-HM, 1′-hydroxymidazolam; 5-HO, 5-hydroxyomeprazole; AD, adavosertib; AUC, area under the plasma concentration–time curve from time zero to infinity; AUC0–t, area under the plasma concentration–time curve from time zero to time of last quantifiable concentration; CI, confidence interval; CL/F, apparent clearance; Cmax, maximum plasma drug concentration; MR, metabolic ratio in relation to parent compound; NA, not available; NC, not calculable; S+AD/S, substrate (or compound) + AD compared with substrate or compound alone; SD, standard deviation; tmax, time to reach maximum plasma concentration; t½, terminal half-life; Vz/F, apparent volume of distribution Conclusions: AD (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19 and CYP3A4. No new AD-related safety concerns were identified. Citation Format: Mats Någård, Mei-Lin Ah-See, Karen So, James Strauss, Trisha Wise-Draper, Howard Safran, Ding Wang, Laura Nadeau, William Edenfield, Lionel D. Lewis, Lone Ottesen, Yan Li, Ganesh Mugundu. Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19 and CYP3A4 in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3035.
Abstract Purpose: To determine the impact of estrogen receptor (ER) negativity on clinical outcomes for patients treated with Accelerated Partial Breast Irradiation (APBI). Materials/Methods(s): We evaluated 506 consecutive patients treated with interstitial brachytherapy (n= 199), balloon-based brachytherapy (n=203), and 3D-CRT (n=104). ER negative (ERN) status was assigned using the traditional definition of an ER nuclear IHC stain < 10%, which corresponds to an Allred/NSABP staining score of < 2. 63 patients (12.5%) were ER negative and 443 (87.5%) were ER positive (ERP). Patient demographics and clinical outcomes (IBTR, RNF, DM, DFS, CSS, OS) were analyzed for each group. Results: The two groups had similar patient characteristics. Tumor sizes were slightly larger for the ERN group at 11.9mm vs. 10.7mm, although this was not statistically significant (p=0.14). No differences were seen in median age (63 vs. 64 years, p=0.36), rate of HER-2/neu overexpression (83% vs. 91%, p=0.11), or lymph node positivity (6% vs. 9%, p=0.55) between the ERN vs. ERP groups, respectively. There were an equal distribution of invasive ductal carcinoma (ERN n=55, 87%; ERP n=387, 87%) and DCIS (ERN n=8, 13%; ERP n=56, 13%) patients within each group. The use of chemotherapy (55% vs. 15%, p<0.001) and nuclear grade (71% vs. 12%, p<0.001) were higher in the ERN vs. ERP cohort. With a mean follow up of 6.1 years, the 5-year actuarial rates of ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the entire cohort were 1.8%, 0.6%, and 3.2%. Although this was not statistically significant, ERN patients appear to have an increased rate of local failure than patients with ERP histology (4.0% vs. 1.5%, p=0.13). Rates of RNF and DM were, however, significantly higher for the ERN group (RNF: 4.9% ERN vs. 0% ERP, p<0.001; DM: 12.1% ERN vs. 2.0% ERP, p<0.001). Although there was no difference in overall survival at six years (86% vs. 90%, p=0.67), we observed a shorter disease-free survival (86.4% vs. 96.5%, p= 0.01) and cause-specific survival (90% vs. 98%, p=0.01) for the ERN vs. ERP groups. Conclusion: The ER negative phenotype of early-stage breast cancer may have a decreased rate of locoregional control. We observed a higher rate of DM with reduced disease-free and cause-specific survival in ER negative cases, emphasizing the importance of systemic therapy and careful, long-term follow up for these patients. Prospective study of this histologic subtype with a larger cohort of patients is needed to substantiate these findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-09.
