A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors.

BACKGROUND: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2 h, starting at 100 mg in the first dose cohort. Nintedanib was administered orally at a dose of 200 mg twice daily. The first treatment cycle comprised 28 days (days 1-7 and days 9-28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2-21. The primary objective was the MTD of volasertib in combination with nintedanib. RESULTS: Thirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300 mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure. CONCLUSIONS: Volasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity.

Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids.

BACKGROUND: Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after radical surgeries. By comparing the gene expression profile of typical (TC) and atypical carcinoids (AC), we intended to find genes specifically expressed in one of the two subtypes that could be used as diagnostic markers. METHODS: Expression profiling, with Affymetrix arrays, was performed on six typical and seven atypical samples. Data were validated on an independent cohort of 29 tumours, by means of quantitative PCR and immunohistochemistry (IHC). RESULTS: High-throughput gene expression profiling was successfully used to identify a gene signature specific for atypical lung carcinoids. Among the 273 upregulated genes in the atypical vs typical subtype, GC (vitamin D-binding protein) and CEACAM1 (carcinoembryonic antigen family member) emerged as potent diagnostic markers. Quantitative PCR and IHC on a validation set of 17 ACs and 12 TCs confirmed their reproducibility and feasibility. CONCLUSIONS: GC and CEACAM1 can distinguish between TC and AC, defining an IHC assay potentially useful for routine cytological and histochemical diagnostic procedures. The high sensitivity and reproducibility of this new diagnostic algorithm strongly support a further validation on a wider sample size.

The choice of whether to participate in a phase I clinical trial: increasing the awareness of patients with cancer. An exploratory study.

OBJECTIVE: In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial. METHODS: After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated. RESULTS: The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as 'guinea pigs' and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice. CONCLUSIONS: Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial.

Safety of mRNA-COVID-19 Vaccines in Patients With Thoracic Cancers.

BACKGROUND: Pivotal trials of COVID-19 vaccines did not include cancer patients with questions remaining in this population. Particularly in patients with thoracic malignancies receiving anticancer treatments, the safety of these vaccines has so far been little investigated. METHODS: This is a prospective trial of patients with thoracic cancer receiving anticancer treatments and COVID-19 vaccines at the Division of Thoracic Oncology of European Institute of Oncology between February and September 2021. RESULTS: A total 207 patients affected by thoracic cancers (199 lung cancers and 8 mesotheliomas) had received Covid-19 vaccines (206 mRNA vaccines and 1 virus-vectored vaccine). The majority of patients had at least one comorbidity (76.3%). They were concomitantly treating with targeted therapy (TT) (45.9%), immunotherapy (IO) (22.7%), and chemotherapy (CT) (14%). A total of 64 AEs (15.6%) were observed after administration of Sars-Cov-2 vaccine. The majority of AEs were grade 1 [G1] (6.3%) and G2 (8.8%), only two events were G3 (0.5%). The median follow-up was 9 months (range 1-22 months), during this follow-up 21 patients (10.1%) had a positive nasal swab, most of the patients were asymptomatic (67%) and the symptomatic ones (33%) had mild symptoms and fewer complications and hospitalizations. CONCLUSIONS: COVID-19 m-RNA vaccines appear to be safe in the cohort of patients with thoracic malignances in active treatment, including those receiving immunotherapy. Considering the high morbidity and mortality associated with COVID-19 in patients with lung cancer receiving active treatments, our study supports the current vaccine prioritization, third and/or fourth dose, of all cancer patients with active treatment.

Optimizing clinical care in patients with advanced soft tissue sarcoma: a phase II study of a new schedule of high-dose continuous infusion ifosfamide and doxorubicin combination.

BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer.

The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA) and ribonucleotide-reductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine-cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.

Gr-MDSC-linked asset as a potential immune biomarker in pretreated NSCLC receiving nivolumab as second-line therapy.

PURPOSE: Immunotherapy is a new standard first-line treatment for non-small cell lung cancers (NSCLC) with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%) and second-line treatment regardless of PD-L1 status, though not all patients benefit from this approach. Much effort is ongoing to identify robust prognostic and predictive biomarkers of response to immune checkpoint inhibitors, overcoming PD-L1 that appears limited in its ability to discriminate patient candidates to this new class of anticancer agents. The purpose of this research study is to identify potential new biomarkers for immunotherapy in lung cancer. METHODS: Fifty-three consecutive patients with advanced NSCLC treated with nivolumab were enrolled in the study. All the patients received a blood analysis looking for the relationship between different populations of baseline white blood cells and granulocytic myeloid-derived suppressor cells (Gr-MDSC) detected by flow cytometry, to identify and characterize patients with poor likelihood of benefit from nivolumab in NSCLC second-line setting, regardless of clinical feature and PDL1 expression. RESULTS: Univariate analysis showed that high baseline levels of Gr-MDSC and low baseline CD8/Gr-MDSC ratio are associated with significantly better (P = 0.02) response to immunotherapy treatment. Log-rank tests suggested a significant improvement in OS and PFS with high baseline levels of Gr-MDSC levels (≥ 6 cell/µl), low absolute neutrophil count (< 5840/µl), high eosinophil count (> 90 /µl), and NLR < 3. The multivariate analysis showed a statistically significant improvement for PFS (P = 0.003) and OS (P = 0.05) in favour of the identified good prognostic Gr-MDSC-linked asset group, compared with the poor prognosis group. CONCLUSION: The role of Gr-MDSC appears interesting as a potential biomarker in NSCLC patients receiving immune-checkpoint inhibitors. Further analyses are needed to confirmed and study in deep the role of these particular cells and their role in cancer response and progression during ICI therapy.

Correction to: Gr-MDSC-linked asset as a potential immune biomarker in pretreated NSCLC receiving nivolumab as second-line therapy.

Acknowledgements section was missing.

Phase II trial of estramustine phosphate and oral etoposide in patients with hormone-refractory prostate cancer.

BACKGROUND: There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC. PATIENTS AND METHODS: Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1-21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostate-specific antigen (PSA) levels and lesion assessment. RESULTS: From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week-43 months); median survival was 23 months (range 3 weeks-64+ months). CONCLUSIONS: Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.

Changes in Pulmonary Function in Patients With Advanced Heart Failure Listed for Heart Transplantation.

BACKGROUND: Pulmonary function tests (PFTs) are often impaired in patients with advanced heart failure. There is limited data about their impact on survival after heart transplantation (HT). We sought to assess the prevalence and type of PFT abnormalities in patients on HT waiting list and their impact on outcomes. METHODS: We performed a retrospective analysis of a prospective registry of consecutive patients undergoing HT between 2012 and 2018. Patients were classified into 4 groups according to pre-HT PFT results: 1. normal pattern: forced vital capacity (FVC) ≥ 80% and forced expiratory volume in 1 second (FEV1) to FVC ratio (FEV1/FVC) ≥ 0.7; 2. obstructive: FEV1/FVC < 0.7; 3. nonobstructive: FEV1/FVC ≥ 0.7 and FVC < 80% when total lung capacity value was not available; and 4. restrictive: FEV1/FVC ≥ 0.7 and total lung capacity < 80%. The prevalence of impaired carbon monoxide diffusing capacity corrected for hemoglobin < 80% and FEV1 < 70% was also analyzed. High-urgency HT patients and those referred from other centers without quantitative pulmonary evaluation were excluded. RESULTS: Among 123 patients who underwent HT, 83 patients with complete PFT were included. Median follow-up was 2.7 ± 1.9 years. Of these, 29 (34.9%) had an obstructive pattern, 20 (24.1%) a nonobstructive, 18 (21.7%) a restrictive, and 16 (19.3%) a normal pattern. Fifty-one (61.4%) patients had FEV1 < 70% and 58 (69.9%) a carbon monoxide diffusing capacity corrected for hemoglobin < 80%. There was a tendency to lower survival in all altered PFT groups compared with normal (P = .054) but not within the other groups. Patients with an impaired FEV1 had significantly higher mortality than patients with normal values (P = .008). Area under receiver operating characteristic curve for FEV1 was 0.73 (95% confidence interval [0.60-0.86]). A cutoff value of FEV1 (60.5) predicts mortality with 66% sensitivity and 64% specificity. CONCLUSIONS: PFT alterations have a very high prevalence on HT waiting list patients. Patients with impaired FEV1 had worse outcomes after heart transplantation.

Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients.

Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours.

PURPOSE: L19-TNF is an armed antibody that selectively targets human TNF to extra domain B-fibronectin on tumour blood vessels. We performed a phase I/II first-in-man trial with L19-TNF monotherapy in metastatic solid cancer patients to study safety and signs of clinical activity. METHODS: Six cohorts of patients were treated with increasing (1.3-13 µg/kg) doses of intravenous L19-TNF on day 1, 3, and 5 of repeated 3-weekly cycles, and 12 colorectal cancer patients were treated at 13 µg/kg. PK, antibody formation, changes in lymphocyte subsets, 5-HIAA plasma levels as well as safety and clinical activity were analysed. RESULTS: Thirty-four patients received at least one L19-TNF dose. The serum half-life of L19-TNF at 13 µg/kg was 33.6 min, and maximum peak serum concentration was 73.14 µg/L. Mild chills, nausea and vomiting but no haemato- or unexpected toxicity were observed. Grade 3 lumbar pain in bone metastasis was the only dose-limiting toxicity found in one patient. Objective tumour responses were not detected. Transient stable disease occurred in 19 of 31 evaluable patients. CONCLUSIONS: Intravenous L19-TNF on day 1, 3, and 5 of a 3-weekly schedule was safe up to 13 µg/kg, but did not result in objective tumour responses. The maximally tolerated dose (MTD) was not reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy.

QTc prolongation assessment in anticancer drug development: clinical and methodological issues.

Cardiac safety assessments are commonly employed in the clinical development of investigational oncology medications. In anti-cancer drug development there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can potentially influence decision making at many levels during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Given the potential for serious and irreversible morbidity from cardiac adverse events, it is understandable that cardiac safety results can have broad impact on study conduct and patient management. The methodologies for risk management of QTc prolongation for non cardiac drugs have been developed out of experiences primarily from drugs used to treat non life-threatening illnesses in a chronic setting such as antibiotics or antihistamines. Extrapolating these approaches to drugs for treating cancer over an acute period may not be appropriate. Few specific guidelines are available for risk management of cardiac safety in the development and use of oncology drugs. In this manuscript, clinical and methodological issues related to QTc prolongation assessment will be reviewed. Discussions about limitations in phase-I design and oncology drug development will be highlighted. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. A thoughtful risk management plan generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development programme essential for oncology agents with cardiac safety concerns.

Cisplatin, etoposide and continuous infusion bleomycin in patients with testicular germ cell tumors: efficacy and toxicity data from a retrospective study.

We retrospectively reviewed medical charts of 54 patients who underwent orchidectomy for germ cell tumors (GCT) and received a regimen, given every 3 weeks, consisting of cisplatin 100 mg/m2 day 4 intravenous (i.v.), bleomycin 15 Units (U) day 1 i.v. push; bleomycin 10 U days 1-3 24 h i.v. continuous infusion (c.i.) and etoposide 100 mg/m2 days 1-5/i.v. (PEB). 53 of 54 patients achieved a complete remission without adjunctive surgery. At a median follow-up of 48.2 months (95%CI 41.7 - 54.8 months) all patients but one are alive with no evidence of disease recurrence. Patients receiving PEB experienced no pulmonary toxicity, nephrotoxicity nor neurological adverse events. PEB with c.i.bleomycin is an active regimen with a low rate of acute and late toxicity. The main limitations of our study are related to the retrospective analysis, the limited number of patients and the restricted follow-up time. A prolonged follow-up is necessary to evaluate long term toxicity and outcome.

Gemcitabine-induced progressive and sustained tumour response in a patient with multi-drug resistant uterine leiomyosarcoma.

BACKGROUND: despite the fact that the combination of gemcitabine (GCB) and docetaxel shows an increased benefit for disease-free survival and overall survival compared to GCB alone in patients with soft-tissue sarcoma, GCB mono-chemotherapy should be considered as a preferable option with respect to the combination because of its lower toxicity profile and the possibility of it being administered continuously for a long time period. CASE REPORT: we report a clinical case of a woman with advanced high-grade uterine leiomyosarcoma, refractory to ifosfamide, doxorubicin and trabectedin, who experienced a sustained and progressive response to GCB alone. CONCLUSIONS: GCB given as mono-chemotherapy can obtain long-lasting tumour control in patients heavily pre-treated with various chemotherapeutic regimes for uterine LMS and should be considered as a possible option for this subset of patients.

Breast cancer vaccines: a clinical reality or fairy tale?

The characterization of tumor antigens recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. The potential advantages of the vaccines are: (i) the induction of a robust immune response against tumors that are spontaneously weekly immunogenic; (ii) the tumor specificity for some antigens; (iii) the good tolerance and safety profile and (iv) the long-term immune memory, critical to prevent efficiently tumor recurrence. Most trials evaluating breast cancer vaccines have been carried out in patients with extended metastatic breast cancer, characterized by aggressive tumors, resistant to standard cytotoxic treatments, so that clinical efficacy was difficult to achieve. However, some significant immune responses against tumor antigens induced upon vaccinations were recorded. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. Data of clinical activity have been observed by using vaccines targeting HER2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen and carbohydrate antigen given after stem cell rescue. The review discusses possible future directions for vaccine development and applications in the adjuvant setting.

Phase II study of gemcitabine and cisplatin in patients with advanced or metastatic bladder cancer: long-term follow-up of a 3-week regimen.

BACKGROUND: Bladder cancer is the fifth most common cancer among men and the seventh among women. At diagnosis, at least 25% of bladder cancer tumors are locally or systemically advanced. Systemic chemotherapy is the only current modality for advanced or metastatic transitional cell carcinoma of the bladder. Recently, a phase III randomized study has demonstrated that the regimen with gemcitabine (GMC) and cisplatin (CDDP) had a survival advantage similar to the standard M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin), with a better safety profile. AIM: It was the aim of this study to evaluate the tumor response rate, the median time to progression, the median survival and toxicity in a 21-day schedule with GMC and CDDP in patients with advanced/metastatic bladder cancer. PATIENTS AND METHODS: From September 1998 to December 2000, 27 patients with advanced/metastatic transitional cell carcinoma were enrolled. All patients received 1,200 mg/m(2) GMC administered as a 30-min intravenous infusion on days 1 and 8, and 75 mg/m(2) CDDP as a 1-hour infusion on day 2. Cycles were repeated every 21 days. The patients had a median age of 59.8 years (range 39-75) and an Eastern Cooperative Oncology Group performance status of 0-2. RESULTS: Twenty-five patients were valuable for toxic effects, length of survival and tumor response. The statistical analysis was performed in May 2004. Mean and median follow-up were 20.23 and 13.2 months (range 2-68), respectively. The overall remission rate (complete response + partial response) was 48% (95% CI 28.4-67.6%). The median time to progression was 9 months (range 2-56). The median duration of survival for all patients was 13.2 months (range 2-68+), with 1-year and 23-month survival rates of 60 and 20%, respectively. There was no grade 4 toxicity or treatment-related death. Grade 3 anemia was observed in 4 patients (16%) and grade 3 thrombocytopenia occurred in 6 patients (24%). No grade 3-4 nausea/vomiting or neutropenia was observed. CONCLUSION: GMC and CDDP is an active schedule with a good safety profile in a 21-day regimen. It may be a valid alternative to the standard 28-day regimen due to its high tumor response and survival with a low incidence of toxicity, especially in pretreated and metastatic patients.