Michael Leahy

Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. METHODS We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712. RESULTS From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4-9·2) for regorafenib and 0·9 months (0·9-1·8) for placebo (hazard ratio [HR] 0·27, 95% CI 0·19-0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). INTERPRETATION The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. FUNDING Bayer HealthCare Pharmaceuticals.

Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): A multicentre randomised controlled trial

BACKGROUND The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown. We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas. METHODS In this multicentre randomised trial, patients with macroscopically resected, Trojani grade II-III soft-tissue sarcomas at any site, no metastases, performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery. Patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy (control group). Randomisation was done with a minimisation technique, stratified by hospital, site of primary tumour, tumour size, planned radiotherapy, and isolated limb perfusion therapy. Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2), ifosfamide 5 g/m(2), and lenograstim every 3 weeks. Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent. The primary endpoint was overall survival and analyses were done by intention to treat. The final results are presented. This trial is registered with ClinicalTrials.gov, NCT00002641. FINDINGS Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68-1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67-1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8-73·0) in the chemotherapy group and 67·8% (60·3-74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded. INTERPRETATION Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival. Future studies should focus on patients with larger, grade III, and extremity sarcomas.

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.

Multicenter Phase II Clinical Study of Iodine-131–Rituximab Radioimmunotherapy in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma

PURPOSE To evaluate efficacy and safety of iodine-131 (131I) -rituximab chimeric anti-CD20 antibody radioimmunotherapy in patients with relapsed or refractory indolent non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS After a standard loading dose of rituximab 375 mg/m2, individualized dosimetry was performed by whole-body gamma imaging of a tracer activity of 131I-rituximab followed by administration of a therapeutic activity of 131I-rituximab to deliver an estimated whole-body radiation absorbed dose of 0.75 Gy. RESULTS Ninety-one patients were entered onto the trial: 78 patients (86%) had follicular lymphoma, six patients (7%) had mucosa-associated lymphoid tissue/marginal zone lymphoma, and seven patients (8%) had small lymphocytic lymphoma. The objective overall response rate (ORR) was 76%, with 53% attaining a complete response (CR) or CR unconfirmed (CRu). Median duration of response for patients achieving CR/CRu was 20 v 7 months for those with a partial response (P = .0121). Median progression-free survival for the entire cohort was 13 months, with 14% remaining relapse free beyond 4 years. Median follow-up was 23 months, with a 4-year actuarial survival rate of 59% +/- 10%. Toxicity was principally hematologic; grade 4 thrombocytopenia occurred in 4% and neutropenia occurred in 16% of patients, with nadirs at 6 to 7 weeks after treatment. CONCLUSION 131I-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high ORR and CR rates with minimal toxicity.

Measurement of In Vivo BCR-ABL Kinase Inhibition to Monitor Imatinib-Induced Target Blockade and Predict Response in Chronic Myeloid Leukemia

PURPOSE Intrinsic sensitivity to imatinib, based on measurement of inhibitory concentration 50% for imatinib, is variable in untreated patients with chronic myeloid leukemia (CML). This suggests that patient-tailored dosing may be more rational than a fixed dose for all. Dose optimization potentially could be based on accurate measurement of the level of BCR-ABL kinase inhibition achieved in vivo. PATIENTS AND METHODS In vivo kinase inhibition was measured by calculating the reduction in protein (p)--Crkl level in mononuclear blood cells taken from 49 CML patients at weekly intervals after imatinib therapy was commenced. RESULTS Greater than 50% inhibition (> 50% reduction in p-Crkl from baseline) was achieved by 21% of patients by days 7 to 14 (and maintained in all patients on days 21 to 28) and an additional 24% of patients achieved more than 50% inhibition by days 21 to 28. Thus, overall 45% of patients achieved more than 50% inhibition. All of these patients achieved major molecular responses by 24 months compared with 56% of the patients who failed to achieve 50% kinase inhibition (P < .001). Patients with less than 50% kinase inhibition were also more likely to have suboptimal responses. CONCLUSION In vivo BCR-ABL kinase inhibition can be assessed in the first month of imatinib therapy and may provide a valuable guide to optimization of dosage. The extent of BCR-ABL kinase inhibition is an excellent predictor of cytogenetic and molecular response. These observations suggest that dose adjustment based on in vivo measurements of drug-induced target inhibition could be applied in settings beyond imatinib and may be a more effective approach than using one dose for all patients in targeted anticancer therapy.

Pulmonary embolism associated with tranexamic acid in severe acquired haemophilia

Abstract: Tranexamic acid (an antifibrinolytic agent) is of proven benefit in the treatment of bleeding in patients with congenital and acquired coagulation disorders. We report the case of a patient with an acquired Factor VIII inhibitor, who was on a prophylactic dose of tranexamic acid because of recurrent bleeding episodes and developed a pulmonary embolism. Although studies using tranexamic acid have not shown a definite increased risk for the development of venous thrombosis, this is the likely cause of the pulmonary embolism in this patient.

131I-Anti CD20 Radioimmunotherapy of Relapsed or Refractory Non-Hodgkins Lymphoma: A Phase II Clinical Trial of a Nonmyeloablative Dose Regimen of Chimeric Rituximab Radiolabeled in a Hospital

In order to increase the availability and affordability of radioimmunotherapy of refractory or relapsed non-Hodgkins lymphoma, we developed and evaluated radioiodinated rituximab in an ongoing physician-sponsored Phase II Clinical Trial. The chimeric 1gG(1) anti CD 20 monoclonal antibody rituximab was radiolabeled with iodine-131 using a modified Chloramine T method with high radiochemical purity (98% +/- 0.82) and preservation of immunoreactivity. All patients received therapeutic loading doses of unlabeled rituximab (375 mg/m(2)) immediately prior to administration of tracer (200 MBq (131)I) or therapy (1.7-4.3 GBq (131)I) activities of (131)I-rituximab to provide additive immunotherapy and enhance tumor uptake of the radiolabeled antibody. Objective response rate (ORR) was 71% in 35 patients with a median follow-up of 14 months (range 4-28 months). Complete remission (CR) was achieved in 54% of patients, with median duration 20 months. Toxicity evaluation included an additional 7 patients followed for at least 3 months. Tracer dosimetry studies were performed in each patient and the whole body radiation absorbed dose was limited to a mean prescribed dose (MPD) of 0.75 Gy. Myelosuppression was reversible and in only 2 of 42 patients was grade IV hematological toxicity observed. No hemopoietic support was required in any patient. There was no instance of hemorrhage or infection in this group of patients in each of whom individual prospective dosimetry was performed prior to (131)I rituximab radioimmunotherapy for relapsed or refractory non-Hodgkins lymphoma.

A pragmatic approach to embedding patient blood management in a tertiary hospital

We describe the implementation and impact of a patient blood management program (PBMP) in an Australian teaching hospital.

Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors or Soft-Tissue Sarcoma

Purpose: Cediranib is a potent VEGF signaling inhibitor with activity against all three VEGF receptors and KIT. This phase II study evaluated the antitumor activity of cediranib in patients with metastatic gastrointestinal stromal tumor (GIST) resistant/intolerant to imatinib, or metastatic soft-tissue sarcomas (STS; ClinicalTrials.gov, NCT00385203). Experimental Design: Patients received cediranib 45 mg/day. Primary objective was to determine the antitumor activity of cediranib according to changes in 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) tumor uptake in patients with GIST using maximum standardized uptake values (SUVmax). Secondary objectives included objective tumor response and tolerability in patients with GIST/STS. Results: Thirty-four of 36 enrolled patients were treated (GIST n = 24; STS n = 10). At day 29, five patients had confirmed decreases in SUVmax (≥10% from day 8) and two had confirmed partial metabolic responses (≥25% decrease), but arithmetic mean percentage changes in SUVmax, averaged across the cohort, were not significant at day 8 [6.8%; 95% confidence interval (CI), 19.95–33.54) or day 29 (4.6%; 95% CI, 8.05–17.34). Eleven patients with GIST achieved a best objective tumor response of stable disease; eight achieved stable disease ≥16 weeks. In patients with STS, four of six with alveolar soft-part sarcoma (ASPS) achieved confirmed and durable partial responses. The commonest adverse events were diarrhea (85%), fatigue (74%), and hypertension (68%). Conclusions: In patients progressing on imatinib/sunitinib, cediranib 45 mg/day demonstrated evidence of activity by 18FDG-PET, but did not reduce average SUVmax. Evidence of antitumor activity was seen in ASPS. Clin Cancer Res; 20(13); 3603–12. ©2014 AACR.

Drivers for change: Western Australia Patient Blood Management Program (WA PBMP), World Health Assembly (WHA) and Advisory Committee on Blood Safety and Availability (ACBSA)

Patient blood management is now high on national and international health-system agendas. Serious supply challenges as a result of changing population dynamics, escalating cost of blood, ongoing safety challenges and questions about transfusion efficacy and outcomes are necessitating change in transfusion practice. Numerous initiatives are underway to bring about change, including the institution of comprehensive patient blood management programmes. In 2008, the Western Australia Department of Health initiated a 5-year project to implement a comprehensive health-system-wide Patient Blood Management Program with the aim of improving patient outcomes while reducing costs. Clinically, the Program was structured on the three pillars of patient blood management, namely (1) optimising the patients own red cell mass, (2) minimising blood loss and (3) harnessing and optimising the patient-specific anaemia reserve. It employs multiple strategies to bring about a cultural change from a blood-product focus to a patient focus. This Program was undertaken in a State that already had one of the lowest red blood cell issuance rates per 1000 population in the developed world (30.47 red blood cell units per 1000 population). The Program identified reasons and drivers for practice change. From financial years 2008-09 to 2011-12, issuance has progressively decreased in Western Australia to 27.54 units per 1000. During the same years, despite increasing activity, total issuance of red blood cells to the entire State decreased from 70,103 units to 65,742. Nationally and internationally, other initiatives are underway to bring about change and implement patient blood management. The World Health Assembly in May 2010 adopted resolution WHA63.12 endorsing patient blood management and its three-pillar application. The United States Advisory Committee on Blood Safety and Availability met in 2011 to consider the implications of this resolution and its implementation.