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Aim: This study aimed to evaluate the safety and efficacy of 131I‐rituximab in patients with relapsed or refractory follicular or mantle cell lymphoma. Methods: Twenty‐four patients with relapsed or refractory follicular or mantle cell lymphoma were administered unlabeled rituximab (70 mg) immediately before receiving a therapeutic dose of 131I‐rituximab. Contrast‐enhanced 18F‐fluorodeoxyglucose positron emission tomography/computed tomography was used a month later to assess tumor response. Results: This study enrolled 24 patients between June 2012 and 2022. Depending on how they responded to radioimmunotherapy (RIT), 131I‐rituximab was administered one to five times. Of the 24 patients, 9 achieved complete response after RIT and 8 achieved partial response. The median progression‐free and overall survival was 5.9 and 37.9 months, respectively. During the follow‐up period of 64.2 months, three patients were diagnosed with a secondary malignancy. Among treatment‐related adverse events, hematologic toxicities were common, and grade 3–4 thrombocytopenia and neutropenia were reported in 66.6% of cases. Conclusion: 131I‐rituximab has an effective and favorable safety profile in patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma. This suggests that RIT may also be considered a treatment option for patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma. [ABSTRACT FROM AUTHOR]

Background: Nab‐paclitaxel (nab‐PTX) has better transfer to tumor tissue than cremophor‐based paclitaxel. It suggests that the optimum dose of nab‐PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab‐PTX in patients with previously treated advanced non‐small cell lung cancer (NSCLC). Methods: Patients were randomly allocated (1:1) to receive nab‐PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. Conclusion: Both standard dose and low dose of nab‐PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab‐PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option. [ABSTRACT FROM AUTHOR]

With the rapid development of new anti‐cancer agents which are cytostatic, new endpoints are needed to better measure treatment efficacy in phase II trials. For this purpose, Von Hoff (1998) proposed the growth modulation index (GMI), that is, the ratio between times to progression or progression‐free survival times in two successive treatment lines. An essential task in studies using GMI as an endpoint is to estimate the distribution of GMI. Traditional methods for survival data have been used for estimating the GMI distribution because censoring is common for GMI data. However, we point out that the independent censoring assumption required by traditional survival methods is always violated for GMI, which may lead to severely biased results. In this paper, we construct both nonparametric and parametric estimators for the distribution of GMI, accounting for the dependent censoring of GMI. Extensive simulation studies show that our nonparametric estimators perform well in practical situations and outperform existing estimators, and our parametric estimators perform better than our nonparametric estimators and existing estimators when the parametric model is correctly specified. A phase II clinical trial using GMI as the primary endpoint is provided for illustration. [ABSTRACT FROM AUTHOR]

Background: Anlotinib as a third‐line or beyond therapy for extensive‐stage small‐cell lung cancer (ES‐SCLC) was studied. This single‐arm phase II trial was to investigate the value of anlotinib plus platinum‐etoposide as first‐line treatment in ES SCLC. Methods: The primary endpoint was progression‐free survival (PFS) and objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), time to progression (TTP), duration of remission (DoR), and safety. The subgroups of preset liver metastasis and brain metastasis were analyzed. Results: In 35 ES‐SCLC patients, the median PFS, ORR, DCR, and OS were 8.02 months [95% confidence interval (CI): 6.90–9.66], 85.71% (95% CI: 69.74–95.19), 94.29% (95% CI: 80.84–99.30), and 15.87 months (95% CI: 10.38–18.89), respectively. The median PFS in the liver metastasis and brain metastasis subgroups was 7.33 months (95% CI: 4.76–9.69) and 7.34 months (95% CI: 5.68–9.20), respectively. The most common AEs with grade 3–4 were hand–foot syndrome (17%), granulocytosis (17%), stomatitis (14%), hypertriglyceridemia (11%), hypercholesterolemia (11%), as well as nausea and vomiting (11%), and no grade 5 AEs were recorded. Conclusions: Anlotinib combined with platinum‐etoposide provided an effective and safe therapy for patients with ES‐SCLC. [ABSTRACT FROM AUTHOR]

Background: Survival benefit from chemotherapy in advanced hepatocellular carcinoma (HCC) was limited till now. New chemoregimens with cytotoxicity modulators were explored to improve efficacy. Chemotherapy modulated with valproic acid (VA) as a deacetylation inhibitor of histone and DNA damage response proteins, and hydralazine (HZ) as a DNA hypomethylating agent, hypothetically suppressing DNA repair, were used in phase II trial here for advanced HCC. Methods: Between July 2008 and March 2016, patients with chemo‐naive advanced HCC, regardless of previous sorafenib treatment, not amenable to local therapy and with Child Pugh score ≤7, were treated with VA (200 mg thrice per day) and HZ (12.5 mg twice per day) in conjunction with gemcitabine and cisplatin (GCGG): gemcitabine (1000 mg/m2, D1; 800 mg/m2 D8, 15) and cisplatin (70 mg/m2, D1) every 28 days till disease progression and then with Dox‐DTIC: doxorubicin (45 mg/m2) and dacarbazine (450 mg/m2) every 28 days. The primary endpoint was overall survival (OS); the secondary endpoints were safety, progression‐free survival (PFS) and response rate (RR). Results: Thirty‐seven patients with 16 sorafenib‐experienced, underwent GCGG treatment, and 30 of them underwent the following Dox‐DTIC treatment. The median OS was 14.6 months (95% confidence interval: 6.0–23.1). The median PFSs for patients treated with VA‐ and HZ‐combined GCGG and Dox‐DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%. However, there were no chemotherapy‐related deaths. Conclusion: VA‐ and HZ‐combined sequential chemotherapy was effective in advanced HCC with manageable toxicities. [ABSTRACT FROM AUTHOR]

For the cancer clinical trials with immunotherapy and molecularly targeted therapy, time‐to‐event endpoint is often a desired endpoint. In this paper, we present an event‐driven approach for Bayesian one‐stage and two‐stage single‐arm phase II trial designs. Two versions of Bayesian one‐stage designs were proposed with executable algorithms and meanwhile, we also develop theoretical relationships between the frequentist and Bayesian designs. These findings help investigators who want to design a trial using Bayesian approach have an explicit understanding of how the frequentist properties can be achieved. Moreover, the proposed Bayesian designs using the exact posterior distributions accommodate the single‐arm phase II trials with small sample sizes. We also proposed an optimal two‐stage approach, which can be regarded as an extension of Simon's two‐stage design with the time‐to‐event endpoint. Comprehensive simulations were conducted to explore the frequentist properties of the proposed Bayesian designs and an R package BayesDesign can be assessed via R CRAN for convenient use of the proposed methods. [ABSTRACT FROM AUTHOR]

Background: High‐dose chemotherapy (HDCT) with TI‐CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug. Methods: Patients with unfavorable relapsed GCT were treated according to TI‐CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate. Results: Eighty‐nine patients who received HDCT were included in the modified intent‐to‐treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty‐five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow‐up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5–25.9) and OS was 46.3 m (95% CI: 18.6–not reached). For high‐ and very high‐risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2‐year PFS rate was 41.1%. Conclusion: The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug. [ABSTRACT FROM AUTHOR]

Marginal zone lymphomas (MZLs) are indolent yet incurable lymphomas with frequent relapses following therapy. For patients with relapsed/refractory disease, no standard therapies exist. Here we report results of an exploratory phase II study aimed at assessing the efficacy and safety of the alkylator agent bendamustine in combination with the second‐generation anti‐CD20 monoclonal antibody, ofatumumab, in patients with relapsed or refractory MZL. Patients with MZL and previously treated with at least one line of systemic therapy were eligible. Treatment consisted in bendamustine (90 mg/m2 on days 1 and 2) and ofatumumab (1000 mg on day 1) in 28‐day cycles for up to six cycles. Sixteen patients were included in the trial. In one patient, the diagnosis was revised after two cycles of treatment and was excluded from the efficacy analysis. Among 15 patients with MZL, 14 were evaluable for response: the overall and complete response rates were 92.9% and 57.1%, respectively. The median duration of response was 30.4 months (95% confidence interval [CI], 15.5 –not estimable) and 2‐years progression‐free survival 77% (95% CI, 43%–92%). Fifteen patients (94%) experienced grade 3–4 adverse events. Toxicity was mostly hematological. Neutropenia grade ≥3 was recorded in 27% of patients, lymphocytopenia in 93%, and infections and febrile neutropenia each in 13%. One patient discontinued treatment due to myocardial infarction; no treatment‐related deaths occurred. The combination of bendamustine with ofatumumab was active with an acceptable toxicity profile in this small phase II trial and can be considered for further investigation in relapsed/refractory MZL patients. [ABSTRACT FROM AUTHOR]

Aim: Right‐half dissection of the superior mesenteric artery (SMA) nerve plexus in pancreatoduodenectomy for pancreatic cancer was initiated to accomplish R0 resection; however, subsequent refractory diarrhea was a major concern. This study aimed to evaluate the necessity of this technique. Methods: From April 2014 to June 2018, 74 patients with pancreatic head cancer were randomly allocated to either Group A, in which right‐half dissection of the SMA nerve plexus was performed (n = 37), or Group B, in which total preservation of the nerve plexus was performed (n = 37). Short‐term, long‐term, and survival outcomes were prospectively compared between the groups. Results: The patient demographics, including the R0 resection rate, were not significantly different between the groups. Postoperative diarrhea occurred in 26 (70.3%) patients in Group A and 18 (48.6%) patients in Group B. There was a tendency for the development of severe diarrhea in Group A within 1 year postoperatively, and the frequency of diarrhea gradually decreased within 2 years, although that did not affect tolerance to adjuvant chemotherapy. There was no difference in either locoregional recurrence (27.0% vs 32.4%) or systemic recurrence (46.0% vs 46.0%). The median overall survival time in Groups A and B was 37.9 and 34.6 months, respectively (P = 0.77). Conclusion: We did not demonstrate a clinical impact of right‐half dissection of the SMA nerve plexus on locoregional recurrence or survival. Therefore, the prophylactic dissection of the SMA nerve plexus is unnecessary given that refractory diarrhea could be induced by this technique (UMIN000012241). [ABSTRACT FROM AUTHOR]

Phase II clinical trials make a critical decision of go or no‐go to a subsequent phase III studies. A considerable proportion of promising drugs identified in phase II trials fail the confirmative efficacy test in phase III. Recognizing the low posterior probabilities of H1 when accepting the drug under Simon's two‐stage design, the Bayesian enhancement two‐stage (BET) design is proposed to strengthen the passing criterion. Under the BET design, the lengths of highest posterior density (HPD) intervals, posterior probabilities of H0 and H1 are computed to calibrate the design parameters, aiming to improve the stability of the trial characteristics and strengthen the evidence for proceeding the drug development forward. However, from a practical perspective, the HPD interval length lacks transparency and interpretability. To circumvent this problem, we propose the BET design with error control (BETEC) by replacing the HPD interval length with the posterior error rate. The BETEC design can achieve a balance between the posterior false positive rate and false negative rate and, more importantly, it has an intuitive and clear interpretation. We compare our method with the BET design and Simon's design through extensive simulation studies. As an illustration, we further apply BETEC to two recent clinical trials, and investigate its performance in comparison with other competitive designs. Being both efficient and intuitive, the BETEC design can serve as an alternative toolbox for implementing phase II single‐arm trials. [ABSTRACT FROM AUTHOR]

Rituximab‐containing induction followed by autologous stem cell transplantation (ASCT) is the standard first‐line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo‐immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high‐dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow‐up of 77·5 months for patients still alive, 5‐year event‐free survival (EFS) was 51% (95% CI 42–59%); 5‐year overall survival (OS) was 73% (95% CI 65–80%). The median follow‐up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5‐year EFS of 63% (95% CI 44–78%) and 5‐year OS of 90% (95% CI 72–97%). The patients randomised to observation had 5‐year PFS of 60% (95% CI, 40–75%) and OS of 90% (95% CI 72–97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT. [ABSTRACT FROM AUTHOR]

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome. [ABSTRACT FROM AUTHOR]

This study investigated the applicability of personalized peptide vaccination ( PPV) for patients with metastatic upper tract urothelial cancer (m UTUC) after failure of platinum-based chemotherapy. In this single arm, open-label, phase II clinical trial, patients with mUTUC received PPV at a single institution. Personalized peptide vaccination treatment used a maximum of four peptides chosen from 27 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for six s.c. injections weekly as one cycle. The safety of PPV, as well as its influence on host immunity and effect on overall survival were assessed. Forty-eight patients were enrolled in this study. Personalized peptide vaccinations were well tolerated without severe adverse events. Median survival time was 7.3 months (95% confidence interval [ CI], 5.3-13.1) with 13.0 months for patients receiving combined salvage chemotherapy (95% CI, 5.7-17.5) and 4.5 months for patients receiving PPV alone (95% CI, 1.7-10.1) ( P = 0.080). Patients with positive CTL responses showed a significantly longer survival than patients with negative CTL responses (hazard ratio, 0.37; 95% CI, 0.16-0.85; P = 0.019). Multivariate Cox regression analysis showed that lower numbers of Bellmunt risk factors and lower levels of B-cell activating factor were significantly associated with favorable overall survival for patients under PPV treatment. This study indicated that PPV for patients with m UTUC after failure of platinum-based chemotherapy induced substantial peptide-specific CTL responses without severe adverse events and has the potential to prolong survival when combined with salvage chemotherapy. UMIN Clinical Trials Registry ID: 000001854. [ABSTRACT FROM AUTHOR]

Background: Patellofemoral joint osteoarthritis is a common condition, yet information regarding conservative management is lacking. Foot orthoses are an effective intervention for improving pain and function in younger individuals with patellofemoral pain and may be effective in those with patellofemoral osteoarthritis. This pilot study will seek to establish the feasibility of a phase III randomised controlled trial to investigate whether foot orthoses worn in prescribed motion controlled footwear are superior to prescribed motion control footwear alone in the management of patellofemoral osteoarthritis. Methods/design: This phase II pilot clinical trial is designed as a randomized, single-blind, parallel group, two arm, superiority trial. The trial will recruit 44 participants from Queensland and Tasmania, Australia. Volunteers aged 40 years and over must have clinical symptoms and radiographic evidence of patellofemoral osteoarthritis to be eligible for inclusion. Those eligible will be randomized to receive either foot orthoses and prescribed motion control shoes, or prescribed motion control shoes alone, to be worn for a period of 4 months. The feasibility of a phase III clinical trial will be evaluated by assessing factors such as recruitment rate, number of eligible participants, participant compliance with the study protocol, adverse events, and drop-out rate. A secondary aim of the study will be to determine completion rates and calculate effect sizes for patient reported outcome measures such as knee-related symptoms, function, quality of life, kinesiophobia, self-efficacy, general and mental health, and physical activity at 2 and 4 months. Primary outcomes will be reported descriptively while effect sizes and 95% confidence intervals will be calculated for the secondary outcome measures. Data will be analysed using an intention-to-treat principle. Discussion: The results of this pilot trial will help determine the feasibility of a phase III clinical trial investigating whether foot orthoses plus motion control footwear are superior to motion control footwear alone in individuals with patellofemoral osteoarthritis. A Phase III clinical trial will help guide footwear and foot orthoses recommendations in the clinical management of this disorder. [ABSTRACT FROM AUTHOR]

In this paper, a Bayesian approach is developed for simultaneously comparing multiple experimental treatments with a common control treatment in an exploratory clinical trial. The sample size is set to ensure that, at the end of the study, there will be at least one treatment for which the investigators have a strong belief that it is better than control, or else they have a strong belief that none of the experimental treatments are substantially better than control. This criterion bears a direct relationship with conventional frequentist power requirements, while allowing prior opinion to feature in the analysis with a consequent reduction in sample size. If it is concluded that at least one of the experimental treatments shows promise, then it is envisaged that one or more of these promising treatments will be developed further in a definitive phase III trial. The approach is developed in the context of normally distributed responses sharing a common standard deviation regardless of treatment. To begin with, the standard deviation will be assumed known when the sample size is calculated. The final analysis will not rely upon this assumption, although the intended properties of the design may not be achieved if the anticipated standard deviation turns out to be inappropriate. Methods that formally allow for uncertainty about the standard deviation, expressed in the form of a Bayesian prior, are then explored. Illustrations of the sample sizes computed from the new method are presented, and comparisons are made with frequentist methods devised for the same situation. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Conventional phase II trials using binary endpoints as early indicators of a time-to-event outcome are not always feasible. Uveal melanoma has no reliable intermediate marker of efficacy. In pancreatic cancer and viral clearance, the time to the event of interest is short, making an early indicator unnecessary. In the latter application, Weibull models have been used to analyse corresponding time-to-event data. Bayesian sample size calculations are presented for single-arm and randomised phase II trials assuming proportional hazards models for time-to-event endpoints. Special consideration is given to the case where survival times follow the Weibull distribution. The proposed methods are demonstrated through an illustrative trial based on uveal melanoma patient data. A procedure for prior specification based on knowledge or predictions of survival patterns is described. This enables investigation into the choice of allocation ratio in the randomised setting to assess whether a control arm is indeed required. The Bayesian framework enables sample sizes consistent with those used in practice to be obtained. When a confirmatory phase III trial will follow if suitable evidence of efficacy is identified, Bayesian approaches are less controversial than for definitive trials. In the randomised setting, a compromise for obtaining feasible sample sizes is a loss in certainty in the specified hypotheses: the Bayesian counterpart of power. However, this approach may still be preferable to running a single-arm trial where no data is collected on the control treatment. This dilemma is present inmost phase II trials, where resources are not sufficient to conduct a definitive trial. [ABSTRACT FROM AUTHOR]

BACKGROUND Second-line treatment options in advanced hepatocellular carcinoma (HCC) are limited. Axitinib, a selective potent tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor VEGF) receptors 1, 2, and 3, merits exploration in HCC. METHODS This was a single-arm phase II trial of axitinib in advanced HCC. Eligible patients were Child-Pugh A/B7, with measurable progressive disease after TKIs/antiangiogenic drugs. Axitinib was started at 5 mg twice daily orally, titrated from 2 to 10 mg twice daily as tolerated. The primary end point was tumor control at 16 weeks by RECIST1.1; secondary end points were response rate, comparing response by RECIST1.1 to Choi and modified RECIST, exploring dynamic contrast-enhanced imaging models, safety, progression-free (PFS), and overall survival (OS). RESULTS Thirty patients were treated. Of 26 patients evaluable for response, there were 3 partial responses (PR) per RECIST1.1; 13 PR by Choi, 6 PR and 1 complete response by modified RECIST. Tumor control rate at 16 weeks was 42.3%. Two-week perfusion changes were noted on functional imaging. Of 21 patients with evaluable α-fetoprotein response, 43% had >50% decrease from baseline. Most common axitinib-related grade 3/4 adverse events (AEs) were hypertension, thrombocytopenia and diarrhea. Of 11 patients with any grade hypertension, 7 had disease control >36wks. Four patients discontinued treatment due to AEs. Median PFS was 3.6months. Median OS was 7.1months. CONCLUSIONS With 42.3% tumor control at 16weeks, primary endpoint was met. Axitinib has shown encouraging tolerable clinical activity in VEGF-pretreated HCC patients but further study should be in a selected population incorporating potential biomarkers of response. Cancer 2015;121:1620-1627. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

This work is motivated by trials in rapidly lethal cancers or cancers for which measuring shrinkage of tumours is infeasible. In either case, traditional phase II designs focussing on tumour response are unsuitable. Usually, tumour response is considered as a substitute for the more relevant but longer-term endpoint of death. In rapidly lethal cancers such as pancreatic cancer, there is no need to use a surrogate, as the definitive endpoint is (sadly) available so soon. In uveal cancer, there is no counterpart to tumour response, and so, mortality is the only realistic response available. Cytostatic cancer treatments do not seek to kill tumours, but to mitigate their effects. Trials of such therapy might also be based on survival times to death or progression, rather than on tumour shrinkage. Phase II oncology trials are often conducted with all study patients receiving the experimental therapy, and this approach is considered here. Simple extensions of one-stage and two-stage designs based on binary responses are presented. Outcomes based on survival past a small number of landmark times are considered: here, the case of three such times is explored in examples. This approach allows exact calculations to be made for both design and analysis purposes. Simulations presented here show that calculations based on normal approximations can lead to loss of power when sample sizes are small. Two-stage versions of the procedure are also suggested. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B- NHL), such as follicular lymphoma ( FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B- NHL and mantle cell lymphoma ( MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate ( ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival ( PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B- NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval ( CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted. [ABSTRACT FROM AUTHOR]

Aim: Hepatocellular carcinoma (HCC) is one of the most commonly fatal malignancies in Asia but treatment options are limited. Methods: This multinational, nonrandomized phase II trial using the combination of irinotecan (Campto or CPT-11) and capecitabine (Xeloda) was conducted to determine efficacy and safety of this combination in Asian patients with advanced inoperable HCC. The starting dose was irinotecan 200 mg/m2 every 3 weeks followed by capecitabine 1000 mg/m2 orally twice daily for 14 days followed by a 7-day rest. The primary endpoint was tumor response rate, based on response evaluation criteria in solid tumors criteria. Secondary objectives included the safety and tolerability of the treatment combination, time to progression, duration of overall response, tumor growth control rate (complete response, partial response plus stable disease) and overall survival. Results: Of the 63 recruited patients, 47 were evaluable. Of these, three (6.4%) achieved a partial response (lasting 2.2, 3.4 and 8.0 months, respectively). The median overall survival was 4.5 months. Grade 4 diarrhea was reported in four patients. Hematologic grade 4 laboratory abnormalities observed in patients while on study treatment included neutropenia (5.2%) and anemia (1.7%). Seven patients (12.1%) had grade 4 elevations in their total bilirubin. Both irinotecan and capecitabine were generally well tolerated, with manageable and reversible toxicities. Conclusion: Combination therapy with irinotecan and capecitabine has limited efficacy in the treatment of advanced-stage HCC. Further investigation of this combination is not warranted. [ABSTRACT FROM AUTHOR]

Background: An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG).Methods: Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m2 per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata.Results: Ninety-seven patients with a median age of 11.2 years (range, 3.2-21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for >or=4 courses (range, 4-25 courses). The median number of courses received was 2 (range, 1-25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (+/-standard deviation) was 14%+/-6% for HGG, 6%+/-6% for MB/PNET and 3%+/-3% for BSG.Conclusions: Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies. [ABSTRACT FROM AUTHOR]

Anaemia is a common complication in the treatment of patients with aggressive non-Hodgkin lymphoma (NHL), but there are no published data on the effect of erythropoiesis-stimulating agents in such patients. This is the first open-label, phase II, dose-finding study to evaluate the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.). Ninety-three anaemic patients with aggressive NHL who were receiving chemotherapy (including many advanced NHL, heavily pretreated patients) were randomised to receive 2·1, 4·2 or 6·3 μg/kg C.E.R.A. subcutaneously once every 3 weeks for 12 weeks. Haematopoietic response was achieved in 45%, 57% and 65% of patients at the respective dose level. During weeks 5–13, the mean haemoglobin changes from baseline in the intent-to-treat population were increases of 0·2, 2·4, and 5·7 g/l in the 2·1, 4·2, and 6·3 μg/kg treatment groups, respectively, and 4·4, 5·7 and 6·8 g/l in the per-protocol population at the respective dose levels. C.E.R.A. was generally well tolerated in all three groups. C.E.R.A. appeared to have dose-dependent clinical activity in most anaemic patients with aggressive NHL who were receiving chemotherapy. [ABSTRACT FROM AUTHOR]

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0·1 mg/kg p.o.), ATO (0·25 mg/kg i.v.) and AA (1 g i.v) on days 1–4 of week 1, ATO and AA twice weekly during weeks 2–5 and no treatment during week 6 of cycle 1; during cycles 2–6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM. [ABSTRACT FROM AUTHOR]

The ability to identify non-responders to cytotoxic chemotherapy has significant clinical and economic benefits. Differential staining cytotoxicity (DiSC) assays were performed in 34 previously treated patients with chronic lymphocytic leukaemia prior to treatment with cladribine. Of the 28 identified as ex vivo sensitive, 26 achieved a complete (CR) or partial response (PR) (median length of response 1.5 years, median survival 3.37 years) and two had a >70% fall in lymphocytes: six identified as ex vivo resistant failed to respond. The DiSC assay can accurately identify a subgroup of patients resistant to cladribine. [ABSTRACT FROM AUTHOR]