Search

Simple Summary: Patients with MESCC and favorable survival prognoses assigned to radiotherapy alone may benefit from increased doses. In a multi-center phase 2 trial, patients receiving 15 × 2.633 Gy or 18 × 2.333 Gy were evaluated and subsequently compared to a historical control group receiving 10 × 3.0 Gy. The phase 2 cohort, including 50 (of 62 planned) evaluable patients, showed promising results regarding 12-month local progression-free survival (LPFS), 12-month overall survival (OS), improvement of motor and sensory functions, post-radiotherapy ambulatory status, and relief of pain and distress. Radiotherapy with 15 × 2.633 Gy or 18 × 2.333 Gy was well tolerated and appeared more effective than 10 × 3.0 Gy with respect to LPFS and improvement of motor function. Patients with metastatic epidural spinal cord compression (MESCC) and favorable survival prognoses may benefit from radiation doses exceeding 10 × 3.0 Gy. In a multi-center phase 2 trial, patients receiving 15 × 2.633 Gy (41.6 Gy10) or 18 × 2.333 Gy (43.2 Gy10) were evaluated for local progression-free survival (LPFS), motor/sensory functions, ambulatory status, pain, distress, toxicity, and overall survival (OS). They were compared (propensity score-adjusted Cox regression) to a historical control group (n = 266) receiving 10 × 3.0 Gy (32.5 Gy10). In the phase 2 cohort, 50 (of 62 planned) patients were evaluated for LPFS. Twelve-month rates of LPFS and OS were 96.8% and 69.9%, respectively. Motor and sensory functions improved in 56% and 57.1% of patients, and 94.0% were ambulatory following radiotherapy. Pain and distress decreased in 84.4% and 78.0% of patients. Ten and two patients experienced grade 2 and 3 toxicities, respectively. Phase 2 patients showed significantly better LPFS than the control group (p = 0.039) and a trend for improved motor function (p = 0.057). Ambulatory and OS rates were not significantly different. Radiotherapy with 15 × 2.633 Gy or 18 × 2.333 Gy was well tolerated and appeared superior to 10 × 3.0 Gy. [ABSTRACT FROM AUTHOR]

Purpose: Equitable inclusion of racial and ethnic participation in clinical trials is crucial to improving disparities in health care, especially for historically marginalized populations. Our study aims to describe the racial and ethnic demographics of patients enrolled in published phase 2 clinical trials involving proton therapy in the United States. Materials and Methods: Published manuscripts were identified in PubMed, Embase, World of Science, and Cochrane. Phase 2 trials evaluating proton therapy for US patients were included. For each article in the study, data were collected comprising authors, title, and publication year, and clinical trial numbers were verified. Additional data included tumor site, primary institution, sample size, reported race/ethnicity, and raw number/percentile of race/ethnicity. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used. Results: Overall, 970 titles were identified; 636 remained after duplicate screening, and 75 full-text articles were assessed. We identified 38 eligible manuscripts for inclusion comprising 2648 patients. Only 15 (39%) of the publications reported race/ethnicity. Of these, 8 (21%) and 10 (26%) documented Hispanic or Black trial participants, respectively; however, only 6 (16%) documented trial participation for both Hispanic and Black patients. Of the 1409 patients with a documented race/ethnicity, 89.0% (n = 1254) were non-Hispanic white, 5.3% (n = 75) were Black, and 2.2% (n = 31) were Hispanic. Other and unknown race/ethnicity comprised the remaining patients (3.5%; n = 49). Conclusion: We identified underreporting of demographic data in published phase 2 proton therapy trials, which unfortunately mirrored underreporting for cancer drug clinical trials. We also noted dramatic Black and Hispanic patient underrepresentation across the trials in which race and ethnicity are reported. Findings highlight the urgent need to identify and address barriers to proton therapy trials for Black and Hispanic patients ensuring clinical trials in radiation oncology are representative of the patients seen in clinical practice.

Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design, setting, and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients). Outcome measurements and statistical analysis: The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests. Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42–1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy. Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.

Summary: Background: BGB-DXP593, a neutralising monoclonal antibody against SARS-CoV-2, has demonstrated strong activity in reducing viral RNA copy number in SARS-CoV-2-infected animal models. We aimed to examine the efficacy and safety of BGB-DXP593 in ambulatory patients with mild-to-moderate COVID-19. Methods: This global, randomised, double-blind, phase 2 study (ClinicalTrials.gov NCT04551898) screened patients from 20 sites in Australia, Brazil, Mexico, South Africa, and the USA from December 2, 2020, through January 25, 2021. Patients with a first-positive SARS-CoV-2 test (positive reverse transcription–polymerase chain reaction test or authorised antigen test) ≤3 days before screening and mild-to-moderate COVID-19 symptoms for ≤7 days before treatment were randomised 1:1:1:1 to receive a single intravenous infusion of BGB-DXP593 5, 15, or 30 mg/kg, or placebo. The primary endpoint was change from baseline to Day 8 in viral RNA copies/mL as measured in nasopharyngeal swabs. Secondary endpoints were hospitalisation rate due to worsening COVID-19 and treatment-emergent adverse events (TEAEs). A prespecified exploratory endpoint was change in viral RNA copy number in saliva. Findings: Relative to the natural rate of clearance as assessed in placebo-exposed patients (−3.12 log10 copies/mL), no significant differences in nasopharygneal viral RNA copy number changes were observed (−2.93 to −3.63 log10 copies/mL) by Day 8 in BGB-DXP593-treated patients. Reductions from baseline to Day 8 in saliva viral RNA copy number were larger with BGB-DXP593 5 mg/kg (−1.37 log10 copies/mL [90% confidence interval −2.14, −0.61]; nominal p = 0.003) and 15 mg/kg (−1.26 [−2.06, −0.46]; nominal p = 0.01) vs placebo, and differences favoring BGB-DXP593 were observed by Day 3, although not statistically significant; no difference from placebo was observed for BGB-DXP593 30 mg/kg (−0.71 [−1.45, 0.04]; nominal p = 0.12). Hospitalisation rate due to COVID-19 was numerically lower with BGB-DXP593 (pooled: 2/134 patients; 1.5%) vs placebo (2/47 patients; 4.3%), although not statistically significant. Incidence of TEAEs was similar across treatment groups. No TEAE led to treatment discontinuation. Five serious TEAEs occurred, all attributed to COVID-19 pneumonia. Interpretation: BGB-DXP593 was well tolerated. Although nasopharyngeal swab SARS-CoV-2 viral RNA copy number was not significantly decreased compared with placebo, viral RNA copy number was inconsistently reduced by Day 8 in saliva at some doses as low as 5 mg/kg. Funding: BeiGene, Ltd.

ProCAID tested the benefit of using the AKT inhibitor capivasertib with chemotherapy to treat advanced castration-resistant prostate cancer. This updated analysis provides evidence that capivasertib addition extends overall survival in patients who have previously received abiraterone and/or enzalutamide. The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47–1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36–0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63–3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor–targeted agents, which should be evaluated in prospective trials. The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor. [ABSTRACT FROM AUTHOR]

Introduction: Intra-arterial hepatic (IAH) treatment has shown promising results in the management of patients with unresectable colorectal liver metastases (CRLM) the prognosis of which is poor. Bevacizumab adjunction to standard chemotherapy has been shown to improve survival of this patient population. This prospective study was conducted to assess the efficacy and safety of IAH bevacizumab combined to systemic chemotherapy after first-line treatment failure in patients with CRLM. Methods: Included patients had dominant or isolated unresectable CRLM progressing after standard first-line treatment for metastases of colorectal cancer. Three patients had less than 30% liver invasion, three patients between 30 and 50%, two more than 50% and data was missing in two patients. An intra-hepatic catheter was implanted surgically or percutaneously. Bevacizumab 7.5 mg/kg was administered once every 3 weeks in combination with capecitabine 2000 mg/m² per day for 2 weeks and oxaliplatin 130 mg/m² or irinotecan 200 mg/m² once every 3 weeks. The primary end-point was the objective response rate. Results: Between June 2013 and February 2015, 10 patients were included. The trial was prematurely closed because of the lack of financial support and poor accrual. The patients had a median of 6 [1–9] cycles of treatment. Partial response was achieved in 2 patients (20%) and a R0 liver metastases resection in one another. All patients died of disease progression. The median overall and progression-free survival rates were respectively 14.0 (95% IC [4.8 – 25.8] and 5.4 months (95% IC [1.6 – 6.2]). Four patients had severe side effects but no toxic death occurred. Conclusion: IAH bevacizumab combined to systemic chemotherapy is feasible and safe in patients with unresectable isolated or dominant CRLM progressing after a first-line systemic treatment. Based on the low number of patients included in our study, our results suggest that this treatment does not increase dramatically the response rate versus an adapted systemic treatment. However, considering the safety data provided in this study, arterial infusion of bevacizumab in adjunction to chemotherapeutic agents could be evaluated in the future.

IntroductionThis study aims to evaluate the efficacy and safety of the novel combination of Aza and HIA as the frontline induction therapy in newly diagnosed AML patients eligible for intensive chemotherapy (IC) (registered on ClinicalTrials.gov, number NCT04248595).MethodsAza (75mg/m2/d on days1-5 subcutaneous) is administered in combination with HIA [HHT 2mg/m2/d on days 4-8 intravenous over 3 hours, idarubicin 6mg/m2/d on days 4-6 intravenous, and cytarabine 100mg/m2/d on days 4-10 intravenous]. The primary endpoint was complete remission (CR) or CR with incomplete blood count recovery (CRi). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), and adverse events (AEs).ResultsA total of 20 AML patients (aged 18-70 years) were enrolled between Jan 2020 and Sep 2022. 95% (19/20) of patients achieved CR/CRi, and 89.5% (17/19) had undetectable MRD, in which 94.7% (18/19) reached CR/CRi, and 88.9% (16/18) obtained MRD negative after the 1st cycle of induction therapy. Median OS and RFS were both not reached during the follow-up. The estimated 2-year OS and RFS were 87.5% (95%CI, 58.6% to 96.7%) and 87.1% (95%CI, 57.3% to 96.6%), respectively. No patient discontinued the treatment for AEs.DiscussionThis study provides preliminary evidence for this novel combination therapy as the first-line induction therapy for young or older AML patients fit for IC.

The analysis demonstrated that the starting dose of lenvatinib 14 mg is not noninferior to that of lenvatinib 18 mg (both with everolimus). Safety profiles were similar in both arms. Findings support lenvatinib 18 mg + everolimus 5 mg for patients with advanced renal cell carcinoma. Lenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. To assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. A randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor–targeted therapy (prior anti–programmed death-1/programmed death ligand-1 therapy permitted). Patients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. The primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORR wk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. The ORR wk24 for the 14-mg arm (32% [95% confidence interval {CI} 25–39]) was not noninferior to the ORR wk24 in the 18-mg arm (35% [95% CI 27–42]; odds ratio: 0.88; 90% CI 0.59–1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. The study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. In this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used. [ABSTRACT FROM AUTHOR]

Purpose: We previously demonstrated that real-time monitoring of plasma Epstein-Barr virus DNA (EBV DNA) during chemoradiation therapy defined 4 distinct phenotypic clusters of nasopharyngeal carcinoma. In particular, the treatment-resistant group, defined as detectable EBV DNA at the end of radiation therapy, had the worst prognosis and is thought to have minimal residual disease.Methods and Materials: This is the first phase 2 trial to use a targeted agent, apatinib (an inhibitor of vascular endothelial growth factor receptor 2 tyrosine kinase), in the treatment-resistant group. Eligible patients had plasma EBV DNA > 0 copies/mL at the end of radiation therapy (±1 week). Patients received apatinib (500 mg, once daily) until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was disease-free survival (DFS).Results: Twenty-five patients were enrolled and 23 patients who received apatinib were included in the analyses. Three-year DFS was 47.8% and overall survival was 73.9%. Patients with plasma vascular endothelial growth factor-A ≤150 pg/mL at 28 days after the initiation of treatment had significantly better 3-year DFS (66.7% vs 14.3%; P = .041) and overall survival (88.9% vs 42.9%; P = .033). The most common adverse event of grade ≥3 was nasopharyngeal necrosis (26%), oral/pharyngeal pain (22%), and hand-foot syndrome (22%). Nineteen patients had serial EBV DNA data. Fourteen patients had plasma EBV DNA clearance (turn to 0), and 5 (36%) of these 14 patients had disease recurrence or death, whereas all 5 patients without EBV DNA clearance had disease recurrence or death (3-year DFS: 64.3% vs 0%; P = .001).Conclusions: The use of antiangiogenic agents shortly after radiation therapy might increase the risk of necrosis. This approach needs to be avoided until translational and preclinical studies reveal the underlying mechanism of interaction between radiation therapy and antiangiogenic agents. [ABSTRACT FROM AUTHOR]

Background: Prophylactic granulocyte-colony stimulating factor (G-CSF) has been shown to effectively prevent febrile neutropenia (FN) and grade 3/4 neutropenia during myelosuppressive treatment. The present study reports the clinical efficacy and safety of the prophylactic use of G-CSF with a half dose for cancer patients with an intermediate risk of FN combined with ≥1 patient-specific risk during multiple chemotherapy. Methods: This multicenter, one-arm, and open-label clinical study involved 151 patients [median age, 54 years old (range, 46.0–62.5); 38.4% female] with malignant tumors, including >20 different cancers. These patients underwent a total of 604 cycles of chemotherapy and received a half dose of PEG-rhG-CSF administration prior to each cycle. Results: The incidence rate of FN was 3.3% for this cohort during chemotherapy. Chemotherapy delay occurred in 6 (4.0%) patients for 12 (2.0%) cycles. Early termination of cancer treatment occurred in 14 (9.3%) patients. In this cohort, 23 (15.2%) patients required antibiotic use during courses of chemotherapy. A total of 28 (18.5%) patients experienced clear adverse effects during cancer treatment. Conclusion: The prophylactic PEG-rhG-CSF with a half dose can both efficaciously and safely prevent neutropenia for patients of diverse cancers with an intermediate risk of FN combined with ≥1 patient-specific risk during chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet‐derived growth factor receptor β (PDGFR‐β), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2‐B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum‐containing chemotherapy. Methods: A Fleming single‐arm, single‐stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8‐week progression‐free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8‐week PFS rate of ≥50% (≥8 of 19 evaluable patients progression‐free at 2 months). Results: From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi‐criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8‐week PFS rate was 78.9% (15 of 19 patients). Grade 3‐4 treatment‐related adverse events were observed in 10 patients (52.6%). Conclusions: The primary end point of this study was reached. The high rate of PR (Choi‐criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies. The results of the activity and toxicity profile of regorafenib observed in this small series of thymic epithelial tumors are encouraging and should be better evaluated in subsequent larger and specific study phases. [ABSTRACT FROM AUTHOR]

BackgroundProphylactic granulocyte-colony stimulating factor (G-CSF) has been shown to effectively prevent febrile neutropenia (FN) and grade 3/4 neutropenia during myelosuppressive treatment. The present study reports the clinical efficacy and safety of the prophylactic use of G-CSF with a half dose for cancer patients with an intermediate risk of FN combined with ≥1 patient-specific risk during multiple chemotherapy.MethodsThis multicenter, one-arm, and open-label clinical study involved 151 patients [median age, 54 years old (range, 46.0–62.5); 38.4% female] with malignant tumors, including >20 different cancers. These patients underwent a total of 604 cycles of chemotherapy and received a half dose of PEG-rhG-CSF administration prior to each cycle.ResultsThe incidence rate of FN was 3.3% for this cohort during chemotherapy. Chemotherapy delay occurred in 6 (4.0%) patients for 12 (2.0%) cycles. Early termination of cancer treatment occurred in 14 (9.3%) patients. In this cohort, 23 (15.2%) patients required antibiotic use during courses of chemotherapy. A total of 28 (18.5%) patients experienced clear adverse effects during cancer treatment.ConclusionThe prophylactic PEG-rhG-CSF with a half dose can both efficaciously and safely prevent neutropenia for patients of diverse cancers with an intermediate risk of FN combined with ≥1 patient-specific risk during chemotherapy.

Background We evaluated an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for immunogenicity and safety in adults aged 18–59 years. Methods In this randomized, double-blinded, controlled trial, healthy adults received a medium dose (MD) or a high dose (HD) of the vaccine at an interval of either 14 days or 28 days. Neutralizing antibody (NAb) and anti-S and anti-N antibodies were detected at different times, and adverse reactions were monitored for 28 days after full immunization. Results A total of 742 adults were enrolled in the immunogenicity and safety analysis. Among subjects in the 0, 14 procedure, the seroconversion rates of NAb in MD and HD groups were 89% and 96% with geometric mean titers (GMTs) of 23 and 30, respectively, at day 14 and 92% and 96% with GMTs of 19 and 21, respectively, at day 28 after immunization. Anti-S antibodies had GMTs of 1883 and 2370 in the MD group and 2295 and 2432 in the HD group. Anti-N antibodies had GMTs of 387 and 434 in the MD group and 342 and 380 in the HD group. Among subjects in the 0, 28 procedure, seroconversion rates for NAb at both doses were both 95% with GMTs of 19 at day 28 after immunization. Anti-S antibodies had GMTs of 937 and 929 for the MD and HD groups, and anti-N antibodies had GMTs of 570 and 494 for the MD and HD groups, respectively. No serious adverse events were observed during the study period. Conclusions Adults vaccinated with inactivated SARS-CoV-2 vaccine had NAb as well as anti-S/N antibody and had a low rate of adverse reactions. Clinical Trials Registration NCT04412538. [ABSTRACT FROM AUTHOR]

Stopping for futility is a useful tool in a clinical trial. It is widely used in single-arm trials in oncology and in many two-arm trials. We review three stopping rules for futility. We give recommendations for the optimal timing of futility looks in two-stage trials in terms of the information fraction and the probability of stopping under the alternative hypothesis. We discuss futility stopping in trials with substantial uncertainty about the variability of the outcome and in crossover trials. [ABSTRACT FROM AUTHOR]

Background: Available essential tremor (ET) therapies have limitations. Objectives: The objective of this study was to evaluate CX‐8998, a selective T‐type calcium channel modulator, in essential tremor. Methods: Patients 18–75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX‐8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in‐person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. Results: The video‐rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX‐8998 (n = 39) versus placebo (n = 44; P = 0.696). CX‐8998 improved investigator‐rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX‐8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). Conclusions: The primary efficacy end point was not met; however, CX‐8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Abstract Background Symptom assessment requires psychometrically validated questionnaires that are easy to use, relevant to the disease, and quick to administer. The MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM) was adapted from the general (core) MDASI to assess the severity of cancer-related and treatment-related symptoms specific to patients with this condition. The MDASI-MPM includes the 13 core MDASI symptoms, which are experienced by most cancer patients, and 6 MPM-specific items developed via qualitative interviewing, a method favored by the US Food and Drug Administration for instrument item generation and development. Qualitative interviewing that summarizes the item generation and development for the MDASI-MPM is detailed in a separate report. The psychometric study reported here was the next step in developing the validation dossier for the MDASI-MPM. Results In this secondary analysis of data from a Phase II trial, 248 patients provided MDASI-MPM data at multiple timepoints during therapy. Over time, fatigue, pain, shortness of breath, feeling of malaise, and muscle weakness were consistently the worst symptoms reported; symptoms interfered most with work and general activity and least with relations with others. Cronbach coefficient alpha values for all MDASI-MPM subscales were at least 0.88 at baseline and 0.91 during treatment, indicating good internal consistency reliability. Intraclass correlations of at least 0.86 for all MDASI-MPM subscales administered a cycle apart (n = 82) were indicative of good test-retest reliability. Correlations between MDASI-MPM subscales and LCSS-Meso scores were at least 0.70 (P

Background: Tocilizumab, an IL-6 receptor antagonist, was suggested as a possible treatment of severe or critical COVID-19 pneumonia in a small Chinese study. The TOCIVID-19 trial evaluates efficacy and tolerability of tocilizumab in the treatment of patients with severe or critical COVID-19 pneumonia. Methods: TOCIVID-19 is an academic multicenter, single-arm, open-label, phase 2 study. All the patients are being offered a single shot of 8 mg/kg of Tocilizumab (up to a maximum of 800 mg), with an eventual second administration at the discretion of the Investigator. A companion prospective cohort, added to corroborate internal validity, includes either patients not eligible for phase 2 or subjects eligible for phase 2 but exceeding the planned sample size. 14- and 30-days lethality rates are the two co-primary endpoints in the intention-to-treat (ITT) population. Secondary objectives are to evaluate mortality and clinical improvement in the modified-ITT population of subjects who received the drug. Details of the methodological and statistical approaches are reported here reflecting the amendments impelled by the continuously increasing knowledge on COVID-19 progression and challenges in data collection. Conclusion: This paper provides details of planned statistical analyses for TOCIVID19 trial to reduce the risk of reporting bias and increase validity of the study findings.TOCIVID-19 trial is registered in the EudraCT database with number 2020-001110-38 and in clinicaltrials.gov with ID NCT04317092.

The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9–28–112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease is a rare, severe, inherited neurodegenerative disease in which we assessed the safety and efficacy of grafting human fetal ganglionic eminence intrastriatally.Methods: Patients at the early stage of the disease were enrolled in the Multicentric Intracerebral Grafting in Huntington's Disease trial, a delayed-start phase II randomized study. After a run-in period of 12 months, patients were randomized at month 12 to either the treatment group (transplanted at month 13-month 14) or the control group and secondarily treated 20 months later (month 33-month 34). The primary outcome was total motor score compared between both groups 20 months postrandomization (month 32). Secondary outcomes included clinical, imaging, and electrophysiological findings and a comparison of pregraft and postgraft total motor score slopes during the entire study period (month 0-month 52) regardless of the time of transplant.Results: Of 54 randomized patients, 45 were transplanted; 26 immediately (treatment) and 19 delayed (control). Mean total motor score at month 32 did not differ between groups (treated controls difference in means adjusted for M12: +2.9 [95% confidence interval, -2.8 to 8.6]; P = 0.31). Its rate of decline after transplantation was similar to that before transplantation. A total of 27 severe adverse events were recorded in the randomized patients, 10 of which were related to the transplant procedure. Improvement of procedures during the trial significantly decreased the frequency of surgical events.We found antihuman leucocytes antigen antibodies in 40% of the patients.Conclusion: No clinical benefit was found in this trial. This may have been related to graft rejection. Ectopia and high track number negatively influence the graft outcome. Procedural adjustments substantially improved surgical safety. (ClinicalTrials.gov NCT00190450.) © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM.Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6).Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome.Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone. [ABSTRACT FROM AUTHOR]

Objective: A phase 2, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of erenumab for the prevention of episodic migraine in Japanese patients was conducted. Background: Previous global clinical studies have demonstrated the efficacy of erenumab in the prevention of migraine. Methods: Patients were randomized to placebo or erenumab 28, 70, or 140 mg administered subcutaneously once per month for 6 months. The primary endpoint was change from baseline in mean monthly migraine days over months 4‐6 of the double‐blind treatment phase. Secondary endpoints included the proportion of patients achieving ≥50% reduction from baseline in mean monthly migraine days (≥50% response) and change from baseline in mean monthly acute migraine‐specific medication treatment days (MSMD) and mean Headache Impact Test (HIT‐6™) scores. Efficacy outcomes were also determined at months 1, 2, and 3. Results: Four hundred and seventy five patients were randomized 2:1:2:2 to placebo and erenumab 28, 70, and 140 mg, respectively. Greater reductions in monthly migraine days were observed for erenumab vs placebo with differences of –1.25 (95% CI: –2.10 to –0.41; P = .004), –2.31 (95% CI: –3.00 to –1.62; P < .001), and –1.89 (95% CI: –2.58 to –1.20; P < .001) days for erenumab 28, 70, and 140 mg. The odds of having a ≥50% response were 3.2, 5.6, and 4.7 times greater for erenumab 28 mg (95% CI: 1.30‐7.88; P = .009), 70 mg (95% CI: 2.60‐12.06; P < .001), and 140 mg (95% CI: 2.24‐9.99; P < .001) than for placebo. Greater reductions from baseline in mean acute monthly MSMD were observed for erenumab vs placebo with differences of –1.07 (95% CI: –1.80 to –0.35; P = .004), –2.07 (95% CI: –2.66 to –1.49; P < .001), and –2.04 (95% CI: –2.63 to –1.45; P < .001) days for erenumab 28, 70, and 140 mg. Erenumab 70 and 140 mg also resulted in greater improvements in HIT‐6™ scores. The safety profile was similar across treatment groups. The most common adverse event was nasopharyngitis, which occurred in 29.4% of patients in the placebo group and 28.9%‐33.3% of patients in the erenumab groups. Conclusion: Monthly subcutaneous injections of erenumab 70 mg demonstrated statistically significant and numerically maximal efficacy with a favorable safety profile, suggesting that erenumab is a potential new therapy for migraine prevention in Japan. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the pCR rate and toxicity of the addition of weekly carboplatin (Cp) to paclitaxel (wP) and dose-dense (dd) epirubicin/cyclophosphamide (EC) in an open-label phase II study in TNBC patients. Methods: Patients were included if they had stage II and III TNBC and received wP (80 mg/m2/week) concurrent with weekly Cp (AUC = 2) for 12 weeks, followed by bi-weekly epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) plus granulocyte colony-stimulating factor (G-CSF) for four cycles, followed by surgery. The primary endpoint was the rate of pCR [(ypT0/isypN0)]. Secondary endpoints included safety and drug delivery. Results: Sixty-three eligible patients were included. Median age was 51 years (range 29–74); 88.9% had stage II disease, 46% were clinically node positive, and 77.8% had grade 3 tumors. Fifty-four percent achieved a pCR. Twelve percent missed two or more doses of wP, whereas at least two cycles of EC were missed in 9.5%. The rate of tolerance without delays or dose reductions is very low (16%). Sixty-two percent had G3/4 neutropenia. Febrile neutropenia occurred in 18 patients of which more than eighty percent occurred during EC despite primary prophylaxis with G-CSF. Thrombocytopenia grade 3/4 was noticed in 11 pts. Three patients developed grade 3 peripheral neuropathy. Conclusion: The addition of weekly carboplatin to neoadjuvant paclitaxel and dd EC leads to a pCR rate comparable to prior studies (54%). However, hematological toxicity and febrile neutropenia rate was unexpectedly high. Future investigations could focus on reversing the sequence, which may lead to better hematological tolerability. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a phase II trial to evaluate the efficacy and safety of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for advanced non-squamous non-small-cell lung cancer (NSCLC).Methods: Patients with advanced or recurrent untreated non-squamous NSCLC received split-dose cisplatin (40 mg/m2, days 1 and 8) plus pemetrexed (500 mg/m2, day 1) tri-weekly. After four cycles of induction, patients without disease progression received pemetrexed maintenance until disease progression or unacceptable toxicity. The primary endpoint was the 1-year survival rate. The secondary endpoints were progression-free survival (PFS), overall survival (OS), response in induction phase, and safety.Results: From February 2012 to September 2014, 53 assessable patients were enrolled in this study. Thirty-eight (71.7%) patients completed induction therapy, while 35 (66.0%) received maintenance therapy. The 1-year survival rate was 67.7%. The median PFS and OS were 5.3 and 18.6 months, respectively. The response rate and disease control rate (DCR) during the induction phase were 37.7 and 86.8%, respectively. Eight patients (15.1%) discontinued the therapy due to adverse events (AEs) during the induction phase, but both hematological and non-hematological AEs were infrequent.Conclusions: Treatment with induction chemotherapy of pemetrexed plus split-dose cisplatin showed a promising 1-year survival rate, DCR, and transition rate into maintenance phase. This regimen is feasible and well-tolerated. A phase III study comparing this regimen with conventional tri-weekly regimen is warranted. [ABSTRACT FROM AUTHOR]

Pathologic complete response (pCR) is a predictor for favorable outcome after neoadjuvant treatment in early breast cancer. Modulation of gene expression may also provide early readouts of biological activity and prognosis, offering the possibility for timely response-guided treatment adjustment. The role of early transcriptional changes in predicting response to neoadjuvant chemotherapy plus bevacizumab was investigated. One-hundred-and-fifty patients with large, operable and locally advanced HER2-negative breast cancer received epirubicin and docetaxel, with the addition of bevacizumab. Patients underwent tumor biopsies at baseline, after Cycle 2 and at the time of surgery. The primary end point, pCR, and its relation with the secondary endpoints event-free survival (EFS), overall survival (OS) and gene expression profiles, are reported. The pCR rate was 13% (95% CI 8.6-20.2), with significantly more pCRs among triple-negative [28% (95% CI 14.8-45.4)] than among hormone receptor positive (HR+) tumors [9% (95% CI 4.6-16.3); (OR = 3.9 [CI = 1.5-10.3])]. pCR rates were not associated with EFS or OS. PAM50 subtypes significantly changed after Cycle 2 ( p = 0.03) and an index of absolute changes in PAM50 correlations between these time-points was associated with EFS [HR = 0.62 (CI = 0.3-1.1)]. In univariable analyses, signatures for angiogenesis, proliferation, estrogen receptor signaling, invasion and metastasis, and immune response, measured after Cycle 2, were associated with pCR in HR+ tumors. Evaluation of changes in molecular subtypes and other signatures early in the course of neoadjuvant treatment may be predictive of pCR and EFS. These factors may help guide further treatment and should be considered when designing neoadjuvant trials. [ABSTRACT FROM AUTHOR]

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m, 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m. Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors. [ABSTRACT FROM AUTHOR]

Background Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation. Objective Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC. Design, setting, and participants This was a nonrandomized expansion (NRE) cohort ( n = 144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals. Intervention Open-label cabozantinib (100 mg or 40 mg). Outcome measurements and statistical analysis The following stringent response definition was used: clinically meaningful pain reduction (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed. Results and limitations Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant ( p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design. Conclusions Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients’ narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies. Patient summary We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well-controlled trials are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Background The addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC. Methods In this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m 2 intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m 2 IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m 2 orally twice daily on days 1–14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end-points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83. Findings Median PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41–0.67; p < 0.0001). The ORR in ATX patients with measurable disease ( n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT ( p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT ( p = 0.53). The increased rate of grade 3–4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that 1) patients receiving capecitabine at some line for treatment have significantly improved OS and 2) a prognostic model can classify patients into three risk groups associated with OS. Interpretation In patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease. Funding F. Hoffmann-La Roche Ltd, the Netherlands. [ABSTRACT FROM AUTHOR]

BACKGROUND Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. METHODS Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. RESULTS Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed ≤2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. CONCLUSIONS Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy. Cancer 2014;120:976-982. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

We previously conducted a phase 1 study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy and determined the optimal dose of bortezomib to be 1.0 mg/m. We then conducted a multicenter phase 2 study in patients with relapsed or refractory myeloma. Bortezomib 1.0 mg/m was administered intravenously on days 1, 4, 8 and 11, in combination with intravenous doxorubicin 9 mg/m on days 1-4, and dexamethasone 20 mg orally on days 1-2, 4-5, 8-9 and 11-12 at a 3-week interval for six cycles. The primary endpoint of this study was the complete remission (CR) rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Twenty-seven patients, median age of 63, were enrolled. An overall response rate was 89 % with CR rate of 30 %. The median PFS time was 12.1 months, and the median OS time was not reached. One patient died of pneumonia. Although the incidence of hematological toxicities was high, these were transient and manageable. The most common non-hematological toxicity was sensory neuropathy; grade 3 toxicity was observed in six patients (22 %) and treatment was discontinued in four. We conclude that iPAD therapy is feasible, and shows efficacy by inducing high response rates and long response duration. [ABSTRACT FROM AUTHOR]

BACKGROUND There is no standard treatment for progressive epithelioid hemangioendothelioma (EHE). To investigate the significant vascularization of EHE, the activity/toxicity of sorafenib in patients with progressive EHE was explored. METHODS In this multicenter, 1-stage, phase 2 trial of sorafenib (800 mg daily), the primary endpoint, which was chosen by default, was the 9-month progression-free rate. All patients had documented progressive disease at the time of study entry. RESULTS Fifteen patients were enrolled between June 2009 and February 2011. The median age was 57 years (range, 31-76 years), and the ratio of men to women was 9:6. The performance status was zero in 10 patients and 1 in 5 patients. Twelve patients had metastases, mainly in the lung (12 patients), liver (5 patients), and bone (3 patients). Five patients had received prior chemotherapy (doxorubicin in 5 patients and taxane in 3 patients). The median sorafenib treatment duration was 124 days (range, from 27 to >271 days). Seven patients required dose reductions or transient treatment discontinuation. The 9-month progression-free rate was 30.7% (4 of 13 patients). The 2-month, 4-month, and 6-month progression-free rate was 84.6% (11 of 13 patients), 46.4% (6 of 13 patients), and 38.4% (5 of 13 patients), respectively. Two partial responses were observed that lasted 2 months and 9 months. CONCLUSIONS Further clinical trials exploring sorafenib as treatment of progressive EHE are needed. Cancer 2013;119:2639-2644. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) as a local salvage treatment after incomplete transarterial chemoembolization (TACE) for inoperable hepatocellular carcinoma (HCC). METHODS: The main eligibility criteria were a greatest tumor dimension (LD sum) <10 cm, inoperable HCC, and incomplete response after TACE. Prescribed SBRT doses were up to 60 gray (Gy) in 3 fractions, but doses were reduced until normal tissue constraints were allowed. RESULTS: Between May 2008 and February 2011, 50 patients were enrolled in this phase 2 trial, of which 47 patients were evaluable. Forty-one patients had Child-Pugh class A disease (A5/A6 were 32/9), 6 patients had class B7 disease, and 5 patients had portal vein tumor thrombosis. All patients underwent TACE 1 to 5 times before SBRT. SBRT doses ranged from 42 to 60 Gy in 3 fractions (median dose, 57 Gy), and the median LD sum was 29 mm (range, 13-78 mm). Eighteen patients (38.3%) achieved complete remission within 6 months of completing of SBRT, and 18 patients (38.3%) had a partial response. The 2-year local control rate was 94.6%, the overall survival rate was 68.7%, and the progression-free survival rate was 33.8%. Three patients (6.4%) experienced grade 3 gastrointestinal toxicity, and 2 patients (4.3%) experienced grade 4 gastric ulcer perforation. CONCLUSIONS: This trial demonstrated that SBRT after incomplete TACE for inoperable HCC achieves promising rates of response and local control. On the basis of these study results, a modified, multi-institutional, phase 2 trial to reduce gastrointestinal toxicity is recommended. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. Patients and methods Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41–70) in the ganitumab arm, 59% (42–73) in the conatumumab arm, and 50% (33–64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). Conclusions Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate. [ABSTRACT FROM AUTHOR]

The mature results of the neoadjuvant and adjuvant chemotherapy arms of the nonrandomized, phase 2 Yale University cisplatin, bleomycin, methotrexate, and 5-FU protocol are presented.Sixty-seven patients were prospectively accrued with a median follow-up of 5.4 years, and standard parameters of toxicity and efficacy were studied. Both univariate and multivariate analyses were applied.The 5-year disease-free survival of 78% for the 25 patients in the adjuvant group, of which 80% had high-risk features including positive margins, parametria, and lymph nodes and 28% had adenocarcinomas, was comparable to recent relevant literature. Only 64% of patients in this group received consolidation radiation therapy, which did not impact on survival. Only 12% of patients recurred distantly. Notably, those who received 4 months or more of chemotherapy had prolonged survival (P = 0.012). In the neoadjuvant group, chemotherapy response rate among 42 patients (with stages 1B-IIIB cancer) was 79% (50% partial response, 29% complete response), and no patient progressed. In the subgroup of 22 patients who underwent surgery after chemotherapy, 59% had nonsquamous histology. Forty-five percent of patients with stage IIB cancer were deemed operable after chemotherapy. Ninety-five percent received postoperative radiation therapy. There was a 9% pathologic complete response rate, with positive lymph nodes found in 27%. Notably, those who received 3 months or less of chemotherapy had improved overall survival (P = 0.030). Survival rates of these 22 patients at 3 and 5 years were 73% and 63%, respectively. Although not randomized, these survival rates were similar to those achieved with chemoradiation.Although there are several logistical/design features of the cisplatin, bleomycin, methotrexate, and 5-FU regimen that are not in line with the current chemotherapy era, our experience with this well-tolerated regimen can serve as a proof of principle. Our data suggests that both neoadjuvant and adjuvant cisplatin-based neoadjuvant chemotherapy may have their place. It also raises the possibility that the optimal duration of chemotherapy in adjuvant cases should be longer than in neoadjuvant cases. [ABSTRACT FROM AUTHOR]

Abstract: Clinical development of malaria vaccines progresses from trials in malaria naïve adults to malaria exposed adults followed by malaria exposed children. It is not well known whether immune responses in non-target populations are predictive of those in target populations, particularly in African children. Therefore humoral responses in three different populations (U.S. adults, Malian adults and Malian children) were compared in this study. They were immunized with 80μg of Apical Membrane Antigen 1 (AMA1)/alhydrogel on days 0 and 28. Sera were collected on days 0 and 42; antibody levels were determined by ELISA and the functionality of antibodies was evaluated by Growth Inhibition Assay. After immunization, there was no significant difference in antibody levels between the Malian children and the Malian adults, but U.S. adults showed lower antibody levels. Vaccination did not significantly change growth-inhibitory activity in Malian adults, but inhibition increased significantly in both U.S. adults and Malian children. Vaccine-induced inhibitory activity was reversed by pre-incubation with AMA1 protein, but pre-existing infection-induced inhibition was not. This study shows that humoral responses elicited by the AMA1 vaccine varied depending on the population, most likely reflecting different levels of previous malaria exposure. Thus predicting immune responses from non-target populations is not desirable. [Copyright &y& Elsevier]

This article discusses a study which assessed the efficacy and toxicity of sorafenib as front-line therapy in patients with stage IIIB or IV nonsmall cell lung cancer (NSCLC). The patients were given sorafenib continuously and were evaluated every two weeks during the first eight weeks. Only one partial response (PR) was observed in the first 20 patients. Of the 25 patients, there were three PR and six cases with stable disease observed. The study concluded that sorafenib is not effective as front-line therapy in the general unselected NSCLC population.

The International Harmonization Project defined complete response (CR) after treatment for Hodgkin disease (HD) by absence of fluorodeoxyglucose avidity, regardless of the size of residual masses. Residual avidity after initial treatment is known to predict inferior survival. In the setting of retrieval therapy, early positron emission tomography (PET) scans may improve assessment of treatment efficacy. Retrospective analysis after 2 cycles of gemcitabine and vinorelbine for refractory HD revealed 6 CR among 13 patients by PET and 1 CR in 13 by computed tomography (CT). No relationship between PET response and event-free or overall survival could be discerned, presumably because of the heterogeneity of subsequent therapies. [ABSTRACT FROM AUTHOR]

The article presents the study on the use of capecitabine and oxaliplatin in treating patients with refractory and recurrent carcinoma of unknown primary site (CUP). It states that CUP patients who undergo at least one preceded chemotherapy session were given capecitabine and oxaliplatin with treatment cycles every 21 days. The results show that out of the 48 patients, nine had objective responses to treatment and that capecitabine and oxaliplatin combination is tolerable for CUP patients.

The article presents a study which examines the response rate and toxicity of intravenous (iv) calcitriol oral dexamethasone to castration-resistant prostate cancer (CRPC) patients. The study, phase 2 trial, used 4 milligram dexamethasone given on days 1 and 2 weekly and calcitriol on day 2 to18 patients. Results show that no patient had a response to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria or prostate-specific antigen (PSA) while toxicity was seen in 7 patients.

The article reports on the result of the study conducted to determine the efficacy and toxicity the combination between of bortezomib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with B-cell lymphoma. The study includes 49 patients having B-cell lymphoma. Result shows that the combination was an effective regimen and produced an 84 percent complete response rate.

Background: Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC).Methods: Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival.Results: TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months.Conclusions: TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational. [ABSTRACT FROM AUTHOR]

Thalidomide is an immunomodulatory agent with demonstrated activity in multiple myeloma, mantle cell lymphoma and lymphoplasmacytic lymphoma. Its activity is believed to be due modulation of the tumour milieu, including downregulation of angiogenesis and inflammatory cytokines. Between July 2001 and April 2004, 24 patients with relapsed/refractory indolent lymphomas received thalidomide 200 mg daily with escalation by 100 mg daily every 1–2 weeks as tolerated, up to a maximum of 800 mg daily. Patients had received a median of 2 (range, 1–4) prior regimens. Of 24 evaluable patients, two achieved a complete remission and one achieved a partial remission for an overall response rate of 12·5% (95% confidence interval: 2·6–32·4%). Eleven patients progressed during therapy. Grade 3–4 adverse effects included myelosuppression, fatigue, somnolence/depressed mood, neuropathy and dyspnea. Of concern was the occurrence of four thromboembolic events. Our results failed to demonstrate an important response rate to single agent thalidomide in indolent lymphomas and contrast with the higher activity level reported with the second generation immunomodulatory agent, lenalidomide. [ABSTRACT FROM AUTHOR]

The article presents a study which aimed to determine response rates among women who were treated for recurrent ovarian cancer using topotecan with or without thalidomide. Women were enrolled in this phase two randomized trial between April 2001 and July 2005. The study concluded that the addition of thalidomide to topotecan for the treatment of recurrent ovarian cancer appears to improve response rates.