A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results.

BACKGROUND: The equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment. PATIENTS AND METHODS: Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period. RESULTS: Of 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59-1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ. CONCLUSIONS: Final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).

A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy.

BACKGROUND: Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, which targets dual antiemetic pathways. PATIENTS AND METHODS: This multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline-cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25-120 h) phase in cycle 1. RESULTS: The percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0-120 h) (74.3% versus 66.6%; P = 0.001) and acute (0-24 h) (88.4% versus 85.0%; P = 0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO. CONCLUSIONS: NEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.

Palifermin for prevention of oral mucositis after haematopoietic stem cell transplantation- single centre experience.

PURPOSE: Oral mucositis (OM) is one of the most debilitating and common side effects in patients treated with high-dose chemotherapy supported by haematopoietic stem cell transplantation (HSCT). We tested the effectiveness of palifermin to avoid oral mucosal injury induced by the conditioning regimen. PATIENTS AND METHODS: Twenty patients with haematological malignancies were treated with palifermin for prevention of OM during HSCT procedures. Nine patients received allogeneic haematopoietic stem cells, and in 11 autologous HSCT was performed. The control group was composed of patients who had been treated with HSCT previously, before the palifermin era. The source of graft was peripheral blood. RESULTS: Among patients treated with palifermin no grade 2-4 OM was observed. No patient had to receive opioid analgesics or total parenteral nutrition. 30% of the patients developed grade 1 OM of 4-5 days' duration. In the control group OM was observed in all cases, with 50% of the patients developing grade 3-4 OM. Median duration of OM was 10 and 12 days for auto- and allogeneic patients, respectively. In comparison with the control group, treatment with palifermin was associated with significant reduction of grade 2-4 OM, shorter duration of OM, less analgesics intake, and reduced number of days with antibiotic treatment. Additionally, allogeneic patients treated with palifermin had shorter time to platelet engraftment. CONCLUSION: Palifermin reduces incidence, severity and duration of OM, and decreases the number of days with analgesics and antibiotics. For allogeneic patients it can shorten the time to platelet engraftment, but this observation needs further studies.

Which parameters of nutritional status should we choose for nutritional assessment during hematopoietic stem cell transplantation?

Since changes in nutritional indices after hematopoietic stem cell transplantation (HSCT) have not been well studied, there is no definition of risk factors for the development of malnutrition, and the inception of total parenteral nutrition (TPN). We sought to analyze changes in nutritional status parameters and acute phase protein levels as qualifications for TPN. Nutritional status was assessed in 54 patients during autologous (n = 30) on allogeneic (n = 24) transplantations. Eight of 15 patients who had to be treated with TPN, needed prolonged hospitalization (>5 weeks). We assessed biochemical and anthropometric indices of nutritional status, body fat and resting energy expenditure, and acute phase protein levels on the day before starting a conditioning regimen, after chemotherapy completion, and every 7 days until engraftment, which was at least three times after stem cell infusion. Wilcoxon test and canonical analysis were used for statistical analyses. The measurement of body weight and retinol binding protein or transferrin may be useful for nutritional assessment during autologous or allogeneic HSCT, respectively. Prealbumin level, measured 8 days after the end of the conditioning regimen was helpful to make a decision about starting TPN.

Multimodality treatment of germ cell cancer patients who had progression or relapse after high dose chemotherapy and autologous bone marrow transplantation.

PURPOSE: When a patient with germ cell tumor (GCT) fails to be cured with high dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (auto- BMT) the overall prognosis is very poor and any further treatment has only palliative character. A question requiring answer is how intense should this kind of treatment be, and what can be expected from it. PATIENTS AND METHODS: Of 44 patients with GCT who were transplanted after HDC in our centre between 1999- 2005, 17 experienced treatment failure. Amongst them 14 had marker-positive relapse or confirmed germ cell histology. Another 3 had second primary neoplasms. Of the 17 patients 14 received further treatment that consisted of surgery alone in 2, chemotherapy in 2, radiotherapy in 1, combined surgery + chemotherapy in 5, chemotherapy +surgery + radiotherapy in 3 and chemotherapy + radiotherapy in 1 patient. RESULTS: The median survival from the time of relapse was 3 months in all patients, and 6 months in the 14 patients who received further treatment. In 6 patients with relapse confined to a single site the median survival was 11 months. Three patients in this group are alive with overall survival (OS) of 37.4+, 24.3+ and 6.2+ months (all had multimodal treatment: chemotherapy + surgery or radiotherapy, and all achieved durable complete response/CR). CONCLUSION: Our results suggest that GCT patients who have relapsed/ progressed after HDC may benefit from further treatment. Best chances for long term survival have those who experience relapse confined to one metastatic site and receive combined treatment (surgery or radiotherapy plus systemic therapy).

How can we help patients with refractory chronic graft versus host disease- single centre experience.

Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic haematopoietic stem cell transplantation (alloHSCT). Ocular involvement as well as dermal sclerosis, joint contractures and pathological changes in oral cavity are often refractory to treatment. This kind of patients require complex aggressive immunosuppressive therapy. We are still waiting for drugs against cGVHD, characterized by decreased infectious complications, encouraging efficacy and rare and reversible side effects. We describe eight patients who developed extensive chronic graft versus host disease with eye involvement after alloHSCT. All had ocular manifestations, which were refractory to the first and second line of systemic immunosuppressive therapy. All patients responded to the topical cyclosporine therapy, but clinical improvement was seen only since the fifth month of starting treatment. Topical cyclosporine was well tolerated. Other four patients with sclerodermoid type of skin changes, refractory to second line systemic immunosuppressive therapy, were treated with clofazimine. Clofazimine is a drug used to treat leprosy. Because of its anti-inflammatory effects, clofazimine is used also as a second or third line therapy for various skin disorders including: pyoderma gangrenosum, lupus erythematosus, palmoplantar pustulosis and chronic graft versus host disease. All patients,who received clofazimine due to dermal sclerosis, joint contractures and oral manifestations, achieved partial or complete responses and were able to reduce other immunosuppressive drugs. Clofazimine was generally well tolerated.

Biochemical indices for the assessment of nutritional status during hematopoietic stem cell transplantation: are they worth using? A single center experience.

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders, solid tumors and autoimmune diseases. One of the major challenges in the post-transplant period is nutrition. The purpose of this investigation was to assess changes in the biochemical indices of nutritional status during HSCT and compare them with acute-phase protein levels to find the best parameters for nutritional support qualification. Nutritional status was assessed in 54 patients during autologous (30 cases) and allogeneic (24 cases) transplantation. Fifteen patients had to be treated with total parenteral nutrition (TPN), eight of them needing prolonged hospitalization. All nutritional indices and acute-phase protein levels were evaluated during the day before the beginning of conditioning regimen, after chemotherapy completion and every 7 days until engraftment, at least three times after stem cells infusion. Wilcoxon test and canonical analysis were used for statistical analyses. The measurement of retinol-binding protein and transferrin can be useful for nutritional assessment during autologous and allogeneic HSCT, respectively. Prealbumin level, measured 8 days after the end of conditioning regimen, is helpful in making a decision about starting TPN.

Nutritional assessment during allogeneic hematopoietic stem cell transplantation: single centre experience.

PURPOSE: The aim of this study was to analyse the changes in several parameters of nutritional status, acute phase proteins' levels and evaluation of the usefulness of the investigated parameters for qualification for total parenteral nutrition (TPN) during allogeneic hematopoietic stem cell transplantations (HSCT). PATIENTS AND METHODS: The nutritional status was assessed in 24 patients. Biochemical and anthropometric indices of nutritional status as well as body fat and resting energy expenditure were assessed. The levels of acute phase proteins were estimated at the same time. All parameters were evaluated during the day before starting a conditioning regimen, after chemotherapy completion and every 7 days until engraftment, at least 3 times after stem cells infusion. Wilcoxon test and canonical analysis were used for statistical analyses. RESULTS: The measurement of body weight and estimation of transferrin levels can be useful for the nutritional assessment during allogeneic HSCT from sibling donors. Prealbumin level, measured 8 days after the conditioning regimen, can be helpful to make a decision for TPN. Statistically significant differences were found in the levels of biochemical indices of nutritional status and in resting energy expenditure (REE) between patients who received stem cells from the bone marrow and from peripheral blood. Values were lower and decreased earlier after transplantation when bone marrow was the source of HSCT. CONCLUSION: These findings may indicate that the influence of transplantation procedures over patients' nutritional status is bigger when bone marrow is used as a source of hematopoietic stem cells.

Allogeneic non-myeloablative hematopoietic stem cell transplantation for treatment of metastatic renal cell carcinoma -- single center experience.

We evaluated the efficacy of allogeneic non-myeloablative stem cell transplantation (NST) in patients with metastatic renal cell carcinoma (RCC). A total of 5 patients received blood stem cells from HLA identical siblings. Conditioning consisted of: cyclophosphamide 60 mg/kg/d, days -7 to -6 and fludarabine 25 mg/m2/d for consecutive days [days -5, -4, -3, -2, -1]. The median CD34+ cell dose was 3.34 million/kg. Immunosuppression consisted of cyclosporine A and methotrexate. Among all, four patients achieved full donor chimerism with a median of 89 days. One patient rejected the graft and received the second transplantation. Grade II-III acute GVHD occured in 3 patients. None of patients achieved complete or partial response and there were only two mixed responses. All patients died due to cancer progression. There were no transplant-related deaths. Summarising, NST regimen allows allogeneic engraftment with low treatment related mortality in this high-risk population of patients. Acute and chronic GVHD are the major morbidities. Progression is common after NST in unselected patients with advanced RCC. However, regression of some metastases suggests that the graft versus tumor effect may occur after this type of treatment. At present such a procedure should be considered as an experimental approach.

Antisense therapy in cancer.

This review discusses laboratory and clinical studies of antisense oligodeoxynucleotides as potential treatments for haematological malignancies and solid tumours. Mechanisms of action, pharmacokinetics, toxicities and potential clinical applications of these agents are described.