Multicentre study approvals are delayed when submitted to multiple HREC. The three HREC raised similar issues without substantive differences in their recommendations. A process for the mutual acceptance of HREC recommendations could facilitate multicentre research.
A transient deterioration in neurological status following commencement of chemotherapy for high-grade gliomas has not been previously described. We report eight cases of transient deterioration following administration of temozolomide, a relatively new cytotoxic agent used in the treatment of high-grade gliomas. We believe this represents the novel clinical entity of temozolomide-induced tumour flare.
Our (MA) model resulted in clear improvements in HREC processes and timelines. Stakeholder acceptance was high. This model provides a framework for a broader program of MA.
Background: Venetoclax, a potent and selective inhibitor of the survival protein BCL-2 (recently approved in CLL and in development in other hematopoietic malignancies), has yet to be evaluated in pts with solid tumors. BCL-2 is overexpressed in ˜85% of ER+ breast cancer. Pre-clinical findings using patient-derived xenograft breast tumor models suggest that venetoclax synergizes with endocrine therapy by increasing apoptosis. Here we report mBEP, an investigator-initiated phase 1b study of venetoclax with tamoxifen in 33 pts with ER+ (>1%), BCL-2+ (>10%, 2-3+ intensity) and HER2– MBC. Methods: We conducted a 3+3 dose escalation study comprising cohorts receiving venetoclax 200, 400, 600 or 800 mg/d with tamoxifen 20 mg/d (continued until progression). The primary endpoint was to determine the maximum tolerated dose (MTD), define dose-limiting toxicities (DLTs) and identify the recommended phase 2 dose (RP2D). In a dose expansion phase (at the RP2D), secondary endpoints including safety and tolerability, response at 24 wks (RECIST v1.1), clinical benefit rate (CBR) and progression-free survival (PFS) were studied. Results: In the escalation phase (n=15 pts), treatment was well tolerated with no DLTs or high-grade (Gd 3/4) adverse events observed, apart from asymptomatic on-target lymphopenia (Gd 3, 2/15 pts). MTD was not reached. The 800 mg/d dose was selected as the RP2D and the cohort expanded to include 24 pts with ≥24 wks follow up (range 24-105 wks). Fifteen pts had received prior regimens for MBC (median 3, range 1-9) that included tamoxifen in 5/15. For the RP2D cohort (n=24), overall responses (OR) included 1 CR (4%) and 12 PR (50%), with 5 SD (21%), corresponding to a CBR of 75%. The 9 pts treated in the first line setting experienced a 78% OR (7/9 pts) and 11% SD (1/9 pts), equating to an 89% CBR. The data are immature for determining median PFS for the RP2D cohort (currently 40+ wks). Treatment responses were pre-empted by metabolic responses (FDG-PET) at 4 wks (seen in 13/16 (81%) pts studied), and correlated with serial changes in circulating tumor DNA (ctDNA). Intriguingly, responses and clinical benefit were observed in pts with plasma-detected ESR1 mutations (4/10 and 7/10, respectively). The most common treatment-related AEs (CTCAE v4.0) for all pts were lymphopenia in 29/33 (88%; 57% Gd 1-2, 30% Gd 3-4), neutropenia in 24/33 (73%; 67% Gd 1-2, 6% Gd 3), nausea in 22/33 (67%; all ≤Gd 2), anemia in 13/33 (39%; 33% Gd 1-2, 6% G3), thrombocytopenia in 11/33 (33%; all ≤Gd 2), vomiting in 11/33 (33%, all ≤Gd 2), diarrhea in 10/33 (30%; 24% Gd 1-2, 6% Gd 3), infection in 9/33 (27%; 18% Gd 2, 9% Gd 3) and fatigue in 7/33 (21%; all ≤Gd 2). There was one possible treatment-related SAE (infection). Conclusions: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits remarkable activity in ER+ and BCL-2+ MBC. These findings support further investigation of combination therapy for patients with BCL-2-positive breast cancer. Sponsor: The Royal Melbourne Hospital (ACTRN12615000702516) Citation Format: Lindeman GJ, Lok SW, Whittle JR, Siow ZR, Bergin AR, Dawson S-J, Desai J, Gray DH, Liew D, Mann GB, Murugasu A, Roberts AW, Rosenthal MA, Shackleton K, Sherman P, Silva MJ, Teh C, Travers A, Vaillant F, Visvader JE. A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2–positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-06.
14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.
A brave new world of cancer screening he development of colorectal cancer has a clear molecular genetic basis. The last five years has T resulted in an explosion of information emanating from a number of laboratories studying genes involved in the development of this common cancer. Initial data were codified as a paradigm by Fearon and Vogelstein who proposed that colorectal cancer was the end result of cumulative mutations to a restricted set of genes such as p53, DCC (Deleted in Colon Cancer), APC (Adenomatous Polyposis Coli) and Ras.' It is now clear that 75% of colorectal cancers are associated with mutations to the p53 and APC loci and almost half of the cancers also carry a mutated ras gene. It is possible to detect these mutations in small biopsy samples and even stool samples may provide information about the presence of mutations at these loci.Recently a number of exciting new developments have occurred in colorectal cancer genetics. Many additional proto-oncogenes and tumour suppressor genes have been implicated in the genesis of colorectal cancer and in many instances the physiological functions of these genes are beginning to be ~n d e r s t o o d .~-~ These new findings have provided a rational explanation for the biological consequences of the genetic abnormalities and the progression to colorectal cancer. Most importantly during the last year, mutations to genes encoding DNA repair enzymes were linked to Hereditary NonPolyposis Colorectal Cancer (HNPCC).6-10 The hMLH 1 and hMSH2 genes were first identified in yeast as DNA mismatch repair enzymes and the mutations to these genes have been suggested as the cause of the accumulation of other cancerous mutations in HNPCC and sporadic colorectal cancer.In this issue of the Journal, on page 682, Van de Water et al., describe direct mutational analysis in a family with HNPCC." They examined an HNPCC kindred for a germline mutation of the mismatch repair gene hMSH2. Mutations of this gene have been implicated in up to 30% of HNPCC cases. In this kindred the specific C to T transition in codon 622 results in the creation of a new restriction enzyme site which allowed the use of relatively simple laboratory techniques to identifl unequivocally patients carrying the mutation.The study documents that all family members who developed colorectal cancer have the specific hMSH2 gene mutation. In addition, all cancer free elderly family members were mutation negative, while 40% of younger family members were mutation positive. Family members were invited to receive the results of genetic testing and those who were mutation negative were removed from regular colonoscopic surveillance. The non-carriers were also told that they would not pass the defective gene to their children.This report emphasises one possible benefit associated with genetic testing in a high risk setting for colorectal cancer predisposition. That is, current screening strategies for young family members may be enhanced or even superseded by testing for genetic abnormalities. Family members who a...
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