bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-man phase I study of R306465, a histone deacetylase (HDAC) inhibitor exploring pharmacokinetics (PK) and pharmacodynamics (PD) utilizing an electrochemiluminescent immunoassay in patients (p) with advanced tumours
Authors: Fong P. C. , Settatree S. , Sinha R. , Hardcastle A. , Hellemans P. W. , Arts J. , Brown K. H. , Janicot M. , Aherne W. , De Bono J. S. 
Published: March 2020

3578 Background: R306565 is an aromatic hydroxamic acid with predominant inhibitory effects on Class 1 HDAC enzymes (with IC50 ∼10 nM). HDAC inhibitors (HDACi) affect gene expression at the transcriptional level, leading to cell cycle arrest and induction of apoptosis. Methods: P with solid tumours or lymphoma were given R306465 orally daily for 3 weeks (w) out of 4 in an escalating schedule. Objectives include safety, tolerability, PK (including food effect exploration), PD evaluation and circulating tumour cell (CTC) quantitation. Results: Four dose levels (100, 200, 300 and 400 mg) have been evaluated involving 15 p (7 male), age range 29–72 (median 59 y) and ECOG PS 0–2. A total of 37 cycles have been administered. Most common adverse events (AE) were Grade (G) 1–3 fatigue (87%), G1–2 nausea (66%), G1–2 vomiting (33%), G1–2 diarrhoea (40%), and G1–2 anorexia (40%). Dose limiting toxicity of G3 fatigue was seen in 1/6 p in the 400mg cohort. PK parameters were approximately dose proportional. Plasma concentrations increased in the fed state. PD effect of histone H3 acetylation (AcH3) in peripheral blood mononuclear cells (PBMC) was determined quantitatively with a novel validated electrochemiluminescent immunoassay developed in-house (applying Mesoscale Discovery technology). Although some interpatient variability exists, increased AcH3 was observed in 2/6 p in the 400 mg cohort, while the percentage rise in AcH3 was minimal for cohorts 1–3. Peak AcH3 achieved in 2 p dosed at 400 mg was approximately 5–10 fold increase over baseline. Using CellSearch technology for quantitation of CTCs, 8/14 p had detectable CTCs at baseline; the CTC trend will be presented. 4 p had stable disease (SD) for = 4 months. Conclusions: R306465 could be safely administered on a daily dosing schedule for 3 of 4 w up to 400 mg. Common toxicities seen were gastrointestinal and fatigue. Maximum tolerated dose has not been reached. PK suggests dose proportionality. Promising PD data showing increased acetylation in PBMC at 400 mg, further supports the utilization of the immunoassay platform in HDACi clinical trials. No significant financial relationships to disclose.
Pharmacogenetic prediction for tumor response, toxicity, and survival of NSCLC patients treated with irinotecan and cisplatin chemotherapy
Authors: Han J. , Lee S. , Lee D. , Kim H. , Lee J. 
Published: March 2020

3581 Background: Inherited genetic polymorphisms of the genes involved in the activation and metabolism of irinotecan can affect toxicity and clinical outcome of patients after treatment with irinotecan. We examined 14 polymorphisms within six genes putative influence on irinotecan metabolism to define a pharmacogenetic model for predicting tumor response, toxicity, and survival in NSCLC patients treated with irinotecan/cisplatin chemotherapy. Methods: Blood samples from 81 NSCLC patients treated with irinotecan (80 mg/m2 D1 & D8) and cisplatin (60 mg/m2 D1) chemotherapy were used for genotyping UGT1A1 211G>A (*6), UGT1A1*28, UGT1A9 -118(T)9>10 (*22), ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCC2 -24C>T, 1249G>A, 3972C>T, ABCG2 34G>A, 421C>A, and SLCO1B1 -11187G>A, 388A>G, and 521T>C polymorphisms. Genotypes were correlated with tumor response, toxicity, and survival by multivariate logistic or Cox regression analysis with adjustment for clinical and histopathologic features. Results: The overall response rate was 47% (36/77), the median progression-free survival was 5.1 months, and the median overall survival (OS) was 14.3 months. The most common severe toxicity was NCI-CTC grade 4 neutropenia, which occurred in 22 (27%) patients. Grade 3 diarrhea was developed in 8 (10%) patients. The presence of ABCC2 3972T allele was predictive for tumor response (odds ratio=3.244, 95% CI 1.219–8.629, p=0.018). The UGT1A1 211AA (*6/*6) genotype was a significant risk factor for grade 4 neutropenia (odds ratio=6.111, 95% CI 1.032–36.197, p=0.046). The UGT1A9*22 allele showed a trend for less grade 3 diarrhea (odds ratio=0.205, 95% CI 1.032–36.197, p=0.054). In multivariate Cox regression analysis, the UGT1A1*6/*6, UGT1A9*22/*22, and squamous cell histology were predictive for worse PFS (p=0.015, 0.049, and 0.026, respectively). Whereas, ABCC2 1249A allele, ECOG PS 2, male gender, and stage IV were predictive for worse OS (p=0.017, 0.014, 0.045, and 0.015, respectively). Conclusions: Patients’ selection based on pretreatment genotyping can minimize irinotecan-related severe toxicity and maximize the clinical benefit of irinotecan-based chemotherapy for patients with advanced NSCLC. No significant financial relationships to disclose.
Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers
Authors: Pitot H. C. , Saleh M. , Holmlund J. , Maleski J. , Forero A. 
Published: March 2020

3583 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d), and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI_EORTC, 2005; James, ASCO, 2006). Our ongoing Phase 1 study tests different dosing schedules of AT-101 in adults with advanced cancers. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses twice a day for three days every other week (BIDx3dEOW) or once weekly (QW). Adverse events (AEs) were graded by the NCI CTCAE v. 3.0. Results: 24 pts have received pulse dosing; safety data are available for 20 pts (30–70 mg BIDx3dEOW, N=13; 80–160 mg QW, N=7). For comparison, 38 pts received 5–60 mg QD. Median number of cycles (range): BIDx3dEOW_2(1–9); QW_3(1–3), QD_2(1–12). AST/ALT is not yet dose limiting, nor the MTD reached, at 70 mg BIDx3dEOW or 160 mg QW. Ileus occurred in 4/38 pts dosed daily but in no pts on either pulse schedule. Other potentially related Gr 3–4 AEs were: BIDx3dEOW (6 pts)–AST (1 pt), abdominal pain (2 pts), elevated CK/right ventricular dysfunction (1 pt w/history of COPD/doxil therapy), hypokalemia (1 pt);QW: none; QD: AST/ALT (5 pts), nausea/vomiting/diarrhea (3 pts each) fatigue (2 pts), hypocalcemia (2 pts), hypokalaemia/anorexia/dehydration/hypophosphatemia (1 pt), elevated GGT (1 pt). The most common Gr 1–2 AEs_nausea/vomiting/fatigue_occurred in over 50% of QD and BIDx3dEOW pts but only 1/7 QW pts. Plasma Cmax (mean ± SD, μM): 70 mg BIDx3d EOW, 2.4 ± 0.9; 160 mg QW, 3.5 ± 1.3; 40 mg/d (MTD, 21/28 d), 2.6 ± 2.0. T ½ was approx. 3 hours on all schedules. Conclusions: Pulse dosing of AT-101 appears associated with reduced toxicity than more continuous daily dosing, and may be preferable in combination regimens. No significant financial relationships to disclose.
Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors
Authors: Haluska P. , Shaw H. , Batzel G. N. , Molife L. R. , Adjei A. A. , Yap T. A. , Roberts M. L. , Gualberto A. , de Bono J. S. 
Published: March 2020

3586 Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I & -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for > 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types. No significant financial relationships to disclose.
Targeting syk kinase for the treatment of B-cell lymphoma
Authors: Sharman J. P. , Irish J. , Coffey G. , Czerwinski D. , Hitoshi Y. , Levy R. 
Published: March 2020

3600 Background: B-Cells require constitutive signaling from the B-Cell Receptor (BCR). Elimination of the BCR induces cell death. Since the BCR lacks enzymatic activity and relies upon the non-receptor tyrosine kinase Syk to initiate a signal transduction cascade, we hypothesized that R406; a small molecule Syk kinase inhibitor might eliminate the constitutive BCR signal and therefore have selective cytotoxicity for B-cells. Methods: Signal transduction changes were evaluated in cell lines and primary normal B-Cells via western blotting and phosphoflow cytometry. Effects on B-Cell, T-Cell, and Myeloid lineage cell lines were evaluated by 3H-thymidine proliferation assays, BRDU cell cycle analysis, and Annexin-V staining. Primary tumor samples were evaluated for B-Cell selective toxicity by evaluation of active caspase activity. Results: In cell culture R406 significantly alters the basal phosphorylation status of multiple proteins. Proliferation of B-Cell lines is reduced with an IC50 range of 625nM to 2.5uM without effect on T-Cell or Myeloid lineage cell lines. Cell cycle analysis reveals a reduction in B-Cell S-Phase with increase in G1/G0. Apoptosis is also increased in the B-cell lines without significant increase in the non-B cell lines. Primary normal B-Cells show reduced phosphorylation of BTK, Erk, and p38 in response to BCR cross linking. Primary tumor samples reveal activity against B-Cell neoplasms. In samples containing both malignant B-Cells and normal T-Cells, the induction of active caspase-3 is restricted to the malignant B-Cell population. Conclusions: 1) R406 alters signal transduction in B-Cells. 2) R406 demonstrates selective anti-B-Cell activity among cell lines. 3) Primary tumor samples reveal cytotoxic activity against malignant B-Cells without toxicity to T-Cells within the same specimen. 4) This compound has been safely tested in humans for non-malignant diseases with an appropriate pharmacokinetic profile; therefore these results support the initiation of an upcoming multicenter phase I/II clinical trial in patients with lymphoma. No significant financial relationships to disclose.
Two phase 1 studies of MPC-6827, a novel vascular disrupting agent (VDA), in patients with advanced solid tumors and CNS metastases
Authors: Kurzrock R. , Akerley W. , Hong D. , Ng C. , Warren T. , Zavitz K. , McCage C. , Laughlin M. , Camacho L. 
Published: March 2020

3604 Background: MPC-6827 is a novel competitive inhibitor of tubulin polymerization via the colchicine binding site and functions as a highly potent (1–10nM) cytotoxic agent and as a VDA. MPC-6827 inhibits tumor cell growth and survival in vitro and in vivo, with activity in xenograft models of mouse melanoma and human cancers of the ovary, breast, prostate, colon and pancreas. The compound is not a substrate for multidrug resistance pumps and reaches high CSF concentrations. Methods: Two 3+3 designed dose-escalating Phase 1 studies were conducted to define the safety, tolerability, maximum tolerated dose (MTD) and PK of weekly IV administrations of MPC-6827 for pts with advanced solid malignancies (trial 1; N=46 pts) and measurable CNS involvement (trial 2; N=17 pts). In trial 2, there was intrasubject dose escalation for the first cycle and subsequent cycles were dosed at the highest dose achieved in Cycle 1. Antitumor activity was evaluated by RECIST guidelines in both studies. Results: Dose escalation proceeded until MTD was determined at 3.3 mg/m2. The dose limiting toxicity was acute coronary syndrome. Common mild to moderate toxicities included fatigue, headache, flushing, diarrhea, nausea, vomiting and arthralgias. There were no neurological deficits observed and no evidence of myelosuppression. No objective responses were observed. Radiographic changes consistent with vascular disruption in tumors were documented in a number of subjects at higher doses. Conclusions: MPC-6827 is safe and overall well tolerated. MTD is 3.3 mg/m2. Vascular flow modulation analyses are ongoing. MPC-6827 is currently in Phase 2 development. No significant financial relationships to disclose.
Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years
Authors: de Gramont A. , Boni C. , Navarro M. , Tabernero J. , Hickish T. , Topham C. , Bonetti A. , Clingan P. , Lorenzato C. , André T. 
Published: March 2020

4007 Background: The MOSAIC study was designed to evaluate the effects of the FOLFOX4 regimen (5-FU/LV + oxaliplatin) on 3- year disease free survival (DFS) probability in patients with stage II and III colon cancer. Methods: Patients (n=2246) with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive 5-FU/LV (LV5FU2) or FOLFOX4 every 2 weeks for 12 cycles. Results: Results for the primary endpoint of the study (for the overall population, with a median follow-up [FU] of 3 years), showed a significant benefit in DFS for the FOLFOX4-treated patients (78.2% vs 72.9%; HR: 0.77, p=0.002) (André et al, NEJM, 2004). Patients were followed beyond the 3-year cut-off for DFS and overall survival (OS) updates. Final DFS, at 5 years FU, are consistent with earlier results (HR: 0.80, p = 0.003). In addition, at a median FU of 6 years, the study demonstrates a significant benefit in OS for the stage III patients. Summary of OS results (median FU 6 years) Long-term safety update shows no increase in the rate of secondary cancer (5.0% in both treatment arms). Conclusions: These results confirm the benefit of the FOLFOX4 regimen in adjuvant colon cancer patients. [Table: see text] No significant financial relationships to disclose.
Sequential compared to combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (ACC): A Dutch Colorectal Cancer Group (DCCG) phase III study
Authors: Punt C. J. , Koopman M. , Douma J. , Wals J. , Honkoop A. H. , Erdkamp F. L. , de Jong R. S. , Rodenburg C. J. , Mol L. , Antonini N. F. 
Published: March 2020

4012 Background: Overall survival (OS) in phase III studies with 1st line combination therapy in ACC may be influenced by imbalances in salvage treatments. This is the first study that prospectively investigates the sequential vs the combined use of all available effective cytotoxic drugs. Methods: Previously untreated patients (pts), WHO PS 0–2 were randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) (Arm A, sequential) vs 1st line CapIri and 2nd line CapOx (Arm B, combination). The dose of Cap was 1250 mg/m2 (mono) or 1,000 mg/m2 (combination) b.i.d. day 1–14, Iri 350 mg/m2 (mono) or 250 mg/m2 (combination), and Ox 130 mg/m2. All cycles were q 3 weeks with Iri/Ox given i.v. on day 1. Response was assessed q 3 cycles. Primary endpoint was OS. The study was designed to detect a 20% reduction in the hazard of death (HR=0.80) for an increase in median OS from 14 to 17.5 months (a=0.05, 2-tailed test). Results: 820 pts were randomized between Jan ‘03 and Dec ‘04 in 74 Dutch hospitals. Of 804 eligible pts, 796 received = 1 cycle. Median age was 63 (27–84) yrs, median WHO PS 0 (0–2), median follow-up 32 months. Pts (n) in arm A: 398 (1st line), 248 (2nd line), 141 (3rd line); arm B: 398 (1st line), 210 (2nd line). Median OS in arm A was 16.3 months (95%CI 14.3–18.2) and in arm B 17.7 months (95%CI 15.2–19.4), logrank p=0.2. Overall gr 3–4 toxicity over all lines did not differ significantly except for gr 3 hand-foot syndrome (HFS) (13% in A and 6% in B, p=0.0009). Death was probably related to treatment in 11 pts (neutropenic sepsis and/or diarrhea, 8 arm A, 3 arm B) and involved protocol violations in some. In 1st line significant differences in gr 3–4 toxicity in arm A vs arm B were diarrhea (10% vs 25%, p<0.0001), febrile neutropenia (1% vs 6%, p=0.0001) and HFS (12% vs 5%, p=0.0004). All-cause 60-day mortality was 3.0% (n=12) in arm A and 4.5% (n=18) in arm B. Updated results will be presented at the meeting, including data on QoL (EORTC QLQ C30). Conclusions: Combination therapy does not significantly improve OS compared with sequential therapy. Both treatment strategies are valid options for pts with ACC. No significant financial relationships to disclose.
Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study
Authors: Maindrault-Goebel F. , Lledo G. , Chibaudel B. , Mineur L. , Andre T. , Bennamoun M. , Mabro M. , Artru P. , Louvet C. , de Gramont A. 
Published: March 2020

4013 Background: The OPTIMOX2 study was designed to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: OPTIMOX2 is a large phase II study performed before the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU2 until progression then reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 202 pts were included between Feb 2004 and Apr 2006. Response rates were (OPTIMOX1/OPTIMOX2): CR+PR 63%/61%. Median PFS were OPTIMOX1/OPTIMOX2) 8.3/6.7 months (p=.04). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 10.8m in the OPTIMOX1 arm and 9.0m in the OPTIMOX2 arm, p=.32. Median duration of chemotherapy-free interval (CFI) in the OPTIMOX2 arm was 4.6 months. Patients with poor prognostic factors had a shorter CFI, p=.01. Median overall survival was 24.6m in the OPTIMOX1 arm and 18.9m in the OPTIMOX2 arm, p=.05. Median survivals (OPTIMOX1/OPTIMOX2) were not reached/28.7m in patients with good prognostic and 20.9/14.5m in patients with poor prognostic. Conclusions: Maintenance LV5FU therapy prolongs PFS and OS, especially in patients with poor prognosis. CFI can be recommended only in selected patients without adverse prognostic factors. Our next study, DREAM, is evaluating maintenance therapy with targeted agents alone. No significant financial relationships to disclose.
Endpoints in adjuvant trials: A systematic review of the literature in colon cancer and proposed definitions for future trials
Authors: Buyse M. E. , Punt K. J. , Köhne C. H. , Hohenberger P. , Labianca R. , Schmoll H. J. , Pahlman L. , Sobrero A. F. , Douillard J. Y. 
Published: March 2020

4018 Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors. [Table: see text] No significant financial relationships to disclose.