First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE2-receptor E-type 4 (EP4), in patients with advanced cancers.

BACKGROUND: E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046. METHODS: This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment. RESULTS: No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses. CONCLUSIONS: In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting. TRIAL REGISTRATION NUMBER: NCT02540291.

Association between complete response and outcomes in transplant-eligible myeloma patients in the era of novel agents.

OBJECTIVES: Achieving complete response (CR) has been linked to improved progression-free (PFS) and overall (OS) survival in myeloma. A meta-analysis was conducted to investigate whether this holds true in the era of novel agents (bortezomib, lenalidomide, thalidomide). METHODS: A total of 24 studies in newly diagnosed patients undergoing autologous stem cell transplantation (ASCT) that reported associations between responses and long-term outcomes (PFS/OS rates post-ASCT by response, or hazard ratios with 95% confidence intervals from Cox models) were identified and analyzed. RESULTS: Achievement of CR vs.

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.

Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up.

This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma.

Bortezomib-dexamethasone is widely used for relapsed myeloma in routine clinical practice, but comparative data versus single-agent bortezomib are lacking. This retrospective analysis compared second-line treatment with bortezomib-dexamethasone and bortezomib using 109 propensity score-matched pairs of patients treated in three clinical trials: MMY-2045, APEX, and DOXIL-MMY-3001. Propensity scores were estimated using logistic regression analyses incorporating 13 clinical variables related to drug exposure or clinical outcome. Patients received intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, in 21-day cycles, alone or with oral dexamethasone 20 mg on the days of/after bortezomib dosing. Median bortezomib cumulative dose (27.02 and 28.60 mg/m(2)) and treatment duration (19.6 and 17.6 weeks) were similar with bortezomib-dexamethasone and bortezomib, respectively. The overall response rate was higher (75% vs. 41%; odds ratio=3.467; P<0.001), and median time-to-progression (13.6 vs. 7.0 months; hazard ratio [HR]=0.394; P=0.003) and progression-free survival (11.9 vs. 6.4 months; HR=0.595; P=0.051) were longer with bortezomib-dexamethasone versus bortezomib, respectively. Rates of any-grade adverse events, most common grade 3 or higher adverse events, and discontinuations due to adverse events appeared similar between the groups. Two patients per group died of treatment-related adverse events. These data indicate the potential benefit of bortezomib-dexamethasone compared with single-agent bortezomib at first relapse in myeloma. The MMY-2045, APEX, and DOXIL-MMY-3001 clinical trials were registered at, respectively, clinicaltrials.gov identifier: 00908232, 00048230, and 00103506.

Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors.

The purpose of this study was to determine the maximum-tolerated dose (MTD), pharmacokinetics and safety profile for two different dosing regimens of barasertib, a selective inhibitor of Aurora B Kinase. In this Phase I trial, patients with advanced solid malignancies were treated with escalating doses of barasertib, administered as either a 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Thirty-five patients were treated. The MTDs were 150 mg as a 48-h continuous infusion and 220 mg administered as two 2-h infusions (110 mg/day, days 1, 2, 15 and 16), with neutropenia the dose-limiting toxicity (DLT) of each schedule. Common Terminology Criteria of Adverse Events (CTCAE) grade ≥ 3 neutropenia (with or without fever) occurred in 34% of patients overall. Other adverse events, many of hematologic or gastrointestinal etiology, were of mild or moderate intensity. No objective tumor responses were observed, although stable disease was observed in 23% of patients. Systemic exposure to barasertib-hQPA, the more active moiety to which barasertib is converted, was observed by 1 and 6 h into the 2-h and continuous infusion, respectively, and exhibited linear pharmacokinetics. In summary, barasertib was generally well tolerated, with neutropenia the most frequent and dose-limiting toxicity, irrespective of schedule. Future development of barasertib will depend on better definition of its therapeutic index.

The clinical development of molecularly targeted agents in combination with radiation therapy: a pharmaceutical perspective.

This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the clinicaltrials.gov Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with clinicaltrials.gov protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such trials are not given priority by pharmaceutical companies. The potential reasons for this and some challenges and possible solutions are discussed.

Randomized phase II study of gefitinib compared with placebo in chemotherapy-naive patients with advanced non-small-cell lung cancer and poor performance status.

PURPOSE: To compare gefitinib with placebo in chemotherapy naïve patients with advanced non-small-cell lung cancer (NSCLC) and poor performance status. PATIENTS AND METHODS: NSCLC patients (chemotherapy naïve, WHO performance status 2 or 3; unfit for chemotherapy; stage IIIB/IV) were randomly assigned to gefitinib (250 mg/d) plus best supportive care (BSC; n = 100) or placebo plus BSC (n = 101). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and safety. Correlation of gefitinib efficacy with EGFR gene copy number (fluorescent in situ hybridization [FISH]) was explored. RESULTS: Hazard ratios (HRs; gefitinib:placebo) were 0.82 (95% CI, 0.60 to 1.12; P = .217) for PFS and 0.84 (95% CI, 0.62 to 1.15; P = .272) for OS. As expected for this patient population, OS for both arms was poor, at about 3 months. ORRs were 6.0% (gefitinib) and 1.0% (placebo). QOL and PSI rates were 21.1% and 28.3% (gefitinib) and 20.0% and 28.3% (placebo), respectively. In EGFR FISH-positive patients (n = 32), HRs were 0.29 (95% CI, 0.11 to 0.73) for PFS and 0.44 (95% CI, 0.17 to 1.12) for OS. No unexpected adverse events occurred. CONCLUSION: There was no statistically significant difference in PFS, OS, and ORRs after treatment with gefitinib or placebo, in the overall population; improvements in QOL and symptoms were similar in both groups. Tolerability profile of gefitinib was consistent with previous studies. PFS was statistically significantly improved for gefitinib-treated patients with EGFR FISH-positive tumors.

Importance of patient, tumour and treatment related factors on quality of life in head and neck cancer patients after definitive treatment.

The purpose of this study is to assess patient, tumour and treatment related factors on quality of life (QoL) outcomes of patients who received definitive or postoperative radiotherapy +/- chemotherapy for head and neck (H&N) cancer. In this cross-sectional study, 110 H&N cancer patients were evaluated in follow-up visit and were asked to fill out the European Organisation for Research and Treatment of Cancer QoL Core Questionnaire (QLQ-C-30) and H&N Module (QLQ-H&N35). Patients were also graded for their late side effects using EORTC/RTOG scoring system. The QLQ C-30 and QLQ-H&N35 mean scores were compared using ANOVA analysis for these variables: age, gender, occupation, educational status, social security status, place of residence, tumour localization, clinical stage, comorbidity, Karnofsky performance score, treatment modality and side effects. Median follow-up was 29 (4-155) months. Tumour localization was significant factor affecting physical (P = 0.03), social (P = 0.01), cognitive (P = 0.002) functioning. Treatment modality had significant impact on the physical (P = 0.02) and cognitive scores (P = 0.008). Global QoL was affected significantly by disease stage (P = 0.01) and occupation (P = 0.01). The QLQ-H&N35 scores were found significantly higher in patients with moderate/severe late morbidity. Tumour localization and the treatment modality are the most important factors affecting the QoL of H&N cancer patients treated definitively.

The impact of treatment center on the outcome of patients with laryngeal cancer treated with surgery and radiotherapy.

For laryngeal cancer, surgical excision of the primary tumor should be undertaken with the aim of achieving tumor-free margins. Adequate pathological assessment of the specimen and the competency of the treatment center play a crucial role in achieving cure. The present study aimed to analyze the significance of place of surgery on the outcome of patients with laryngeal cancer who underwent surgical operation in other centers and were subsequently referred to Doküz Eylul University Head and Neck Tumour Group (DEHNTG) for postoperative irradiation. Patients were divided into three groups according to their place of surgery. The first group (Group I) consisted of patients who had their surgical operation at DEUH. Patients in the second group (Group II) were referred from centers with oncological surgical experience. The third group (Group III) consisted of patients referred from hospitals with no surgical teams experienced in head and neck cancer treatment. The clinical and pathological features of patients in these three groups were analyzed to assess the impact of place of surgery on clinical outcome as well as the prognostic factors for survival. The study population consisted of 253 patients who were treated between 1991 and 2006 with locally advanced laryngeal cancer according to the protocol of DEHNTG. The median follow-up was 48 (3-181) months. The 5 years overall, loco-regional disease-free and distant disease-free survivals were 66, 88 and 91%, respectively. When patients' clinical and histopathological features were analyzed for the impact of place of surgery, surgical margin positivity rates were found to be higher in Group III (P = 0.032), although the other two groups had more advanced clinical and pathological N stage disease (P = 0.012, P = 0.001). In multivariate analysis, older age (P < 0.0001), presence of perinodal invasion (P = 0.012), time interval between surgery and radiotherapy longer than 6 weeks (P = 0.003) and tumor grade (P = 0.049) were the most significant factors. For loco-regional failure-free survival, advanced clinical stage (P = 0.002), place of surgery (P = 0.031) and presence of clinical subglottic invasion (P = 0.029) were shown to be important prognostic factors. For distant metastasis-free survival, only pathological (+) lymph node status (P = 0.046) was a significant factor in multivariate analysis. The significance of place of surgery as well as other well-known prognostic factors underlines the importance of an experienced multidisciplinary treatment team if best results are to be obtained for the patient.

Improving the capture of adverse event data in clinical trials: the role of the International Atomic Energy Agency.

PURPOSE: To report meetings of the Applied Radiation Biology and Radiotherapy section of the International Atomic Energy Agency (IAEA), organized to discuss issues surrounding, and develop initiatives to improve, the recording of adverse events (AE) in clinical trials. METHODS AND MATERIALS: A first meeting was held in Atlanta, GA (October 2004). A second meeting was held in Denver, CO (October 2005) and focused on AE data capture. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 (CTCAE) was suggested during the first meeting as the preferred common platform for the collection and reporting of AE data in its clinical trials. The second meeting identified and reviewed the current weaknesses and variations in the capture of AE data, and proposals to improve the quality and consistency of data capture were discussed. RESULTS: There is heterogeneity in the collection of AE data between both institutions and individual clinicians. The use of multiple scoring systems hampers comparisons of treatment outcomes between centers and trials. There is often insufficient detail on normal tissue treatment effects, which leads to an underestimate of toxicity. Implementation of improved data capture was suggested for one of the ongoing IAEA clinical trials. CONCLUSIONS: There is a need to compare the quality and completeness of data between institutions and the efficacy of structured/directed vs. traditional passive data collection. Data collection using the CTCAE (with or without a questionnaire) will be investigated in an IAEA multinational trial of radiochemotherapy and high-dose-rate brachytherapy in cervical cancer.

Optimization of follow-up timing from study of patterns of first failure after primary treatment. An example from patients with NSCLC: a study of the REACT working group of ESTRO.

BACKGROUND AND PURPOSE: The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on Recording providing Education, and Ameliorating the Consequences of Treatment (REACT). An important aim of follow-up (FU) after treatment for cancer is to detect various events associated with disease recurrence or metastatic spread or severe treatment-related complications as early as possible. Each tumour type may show a specific pattern and timing of these events related to different prognostic factors. The aim of this study was to propose a way of defining an optimal timing schedule for follow-up after treatment based on the analysis of failure patterns determined from follow-up data from prospective clinical trials. MATERIAL AND METHODS: Cox proportional hazards model was used to identify prognostic factors associated with each failure type (loco-regional recurrence (LR), distant metastasis (DM) or side effects (SE)). Competing risks methods were applied to estimate the cumulative incidence functions (CIF), adjusted on the significant prognostic factors. Equally spaced quantiles of the CIF were then used to estimate the corresponding optimised follow-up times depending on a pre-specified total number of visits. Follow-up data from the CHART bronchus clinical trial were used to analyse the pattern of time to first failure. RESULTS: A significantly higher risk of failure was observed for males (SE), stage III (DM) and conventional treatment (LR). Overall, patients treated with CHART needed 1 fewer visit in each category of patients compared to the Conventional group. For example, stage III male patients treated with CHART would need 8 visits during the first two years at 7, 11, 16, 24, 37, 52, 64 and 104 weeks rather than the 9 follow-up visits planned in the protocol. Similar patients treated with Conventional radiotherapy would need 8 visits at 3, 5, 7, 11, 15, 24, 52 and 104 weeks. CONCLUSIONS: Use of these methods would allow timing of follow-up visits to be adapted according to tumour site and prognostic factors determined previously from audit or clinical trials. Application of this approach could optimize the timing of follow-up visits by placing them closer to the times when failures are expected to occur. It does not address the wider issues of follow-up such as who should do it or what should be done for which further studies are required.

Molecular biomarkers and site of first recurrence after radiotherapy for head and neck cancer.

The prognostic significance of a panel of molecular biomarkers in head and neck squamous cell carcinoma (HNSCC) for first failure site (primary (T), nodal (N) or distant (M)) was analysed in 309 patients randomised to continuous hyperfractionated accelerated radiotherapy (CHART) vs. conventionally fractionated radiotherapy. Multivariate competing risks analysis was performed using an accelerated failure-time model. First-order interactions between each marker and trial arm were also tested. Bcl2-positivity increased the time to T- and N-failures, increasing cyclin D1 score decreased the time to N-failures. A random proliferative pattern and low Ki-67 decreased the time to M-failures. A high CD31 score was associated with a significantly longer time to T-failure after CHART, but not after conventional fractionation. Risks of T-, N- and M-failures could be estimated for individual patients. Competing risks analysis of failure sites allows the rational selection of patients for more aggressive loco-regional or systemic therapy.

Audit of effectiveness of routine follow-up clinics after radiotherapy for cancer: a report of the REACT working group of ESTRO.

BACKGROUND AND PURPOSE: The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on recording providing education, and ameliorating the consequences of treatment (REACT). An European audit was carried out as part of which to assess the usefulness of current follow-up practices. PATIENTS AND METHODS: Over a 4-month period in 15 cancer centres in 10 countries, patients attending for routine follow-up completed a questionnaire covering their expectations of and satisfaction with the visit. This was matched with a questionnaire completed by the physician about the content and usefulness of the consultation. The feasibility of a short toxicity scale developed by Dische and Saunders was also investigated. RESULTS: In total, 2303 matched questionnaires were analysed. Forty percent of the patients had symptoms or medical problems related to their disease. In 18% there was a positive finding on clinical examination. In 28% investigations were undertaken part of departmental routine practice. Ten percent of the investigations showed an abnormal result. Ninety nine percent of physicians and 85% of the patients expressed satisfaction. Using the short toxicity scale rates of recording toxicity could be increased from 28 to 93%. CONCLUSIONS: There is wide variation in follow-up practices among European centres. There was a low incidence of positive findings clinically or with routine investigations. A simple scale for recording morbidity has proved easy to use by departments, which have not routinely used one of the standard measures. Further work will attempt to produce an European guideline for effective routine follow-up after radiotherapy.