Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.

Background: There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients and methods: Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4-2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Conclusions: Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. Trial registration: ClinicalTrials.gov: NCT02625623.

A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma.

BACKGROUND: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. METHODS: Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS). RESULTS: One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ≥3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%). CONCLUSION: Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.

Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer.

BACKGROUND: We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m(2) weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. RESULTS: Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. CONCLUSIONS: This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291.

First-line bevacizumab-containing therapy for breast cancer: results in patients aged≥70 years treated in the ATHENA study.

BACKGROUND: There are limited data on treatment outcomes in the growing population of elderly patients with locally recurrent/metastatic breast cancer (LR/mBC). To gain information on first-line bevacizumab combined with chemotherapy in the elderly, we analyzed data from the ATHENA trial in routine oncology practice. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor-2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We carried out a subgroup analysis of safety and efficacy in patients aged≥70 years. Possible correlations between tolerability and baseline comorbidities or Eastern Cooperative Oncology Group status were explored. RESULTS: Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older than in younger patients (grade≥3 hypertension: 6.9% versus 4.2%, respectively; grade≥3 proteinuria: 4.0% versus 1.5%, respectively). Grade≥3 arterial/venous thromboembolism occurred in 2.9% versus 3.3%, respectively. Further analysis revealed no relationship between baseline presence and severity of hypertension and risk of developing hypertension during bevacizumab-containing therapy. Median time to progression was 10.4 months in patients aged≥70 years. CONCLUSIONS: These findings suggest that bevacizumab-containing therapy is tolerable and active in patients aged≥70 years. Hypertension was more common than in younger patients but was manageable. We find no evidence precluding the use of bevacizumab in older patients, including those with hypertension, although age may influence chemotherapy choice.

[Effectiveness of DNA repair and expression of MLH1, MSH2 and FASR in lymphocytes of patients with chemotherapy-responsive, disseminated cutaneous melanoma].

Patients with advanced malignant melanoma have poor prognosis as conventional chemotherapy induces complete response in a very small fraction (not more than 20%). One of research strategies aimed at raising its efficiency is the search for markers predicting individual response to chemotherapy. Our study was concerned with evaluation of the potential of DNA damage, repair (BER, MMR), expression of proteins MLH1, MSH2 and FasR as prognosticators of chemotherapy. These parameters were assessed in lymphocytes sampled from the blood of patients with metastatic cutaneous melanoma before and after one cycle of chemotherapy with lomustine, dacarbazine, cisplatin and interferon-gamma (LDCI). Clinical response was evaluated after a full course of therapy. We established that the major DNA damage induced by chemotherapy occurred on the levels of AP sites and single strand (SS) breaks. Despite the individual variations in BER efficacy, complete repair of SS breaks was reported in lymphocytes of all patients 30 days after the first cycle of chemotherapy. As a consequence, this type of damage and relevant BER efficacy did not correlate with clinical response. Conversely, the number of DNA double strand breaks detected in lymphocytes after the first cycle of chemotherapy was in good correlation with positive clinical response (p < 0.001). This parameter does not fully represent MMR function and, if coupled with cytotoxic effect of chemotherapy on lymphocytes, may be used as a predictive marker for clinical response to LDCI chemotherapy regimens for melanoma.

Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.

BACKGROUND: To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). PATIENTS AND METHODS: In this randomised, open-label, phase III study, patients received cisplatin (80 mg/m(2) i.v. day 1) plus oral capecitabine (1000 mg/m(2) b.i.d., days 1-14) (XP) or 5-FU (800 mg/m(2)/day by continuous infusion, days 1-5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). RESULTS: A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63-1.04, P < 0.001 versus noninferiority margin of 1.25]. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64-1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). CONCLUSIONS: XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.

[Influence of molecular-genetic factors on prognosis in patients with oligodendroglial tumors].

Previous studies demonstrated that patients with oligodendroglial tumors (OT) have longer overall and recurrence free survival than patients with other glial tumors of the same grade. Recent investigations showed high influence of genetic alterations on patients' outcome: overall and recurrence free survival increased in the case of presence 1p19q deletion and decreased in the presence of 9p or 10q deletion and/or EGFR amplification. In the series of 241 cases (107 male, 134 female patients, median age -- 38 years, (16-73)) we analyzed the impact of histology, tumor grade and genetic alterations on time to tumor progression (TTP). All patients underwent surgical resection of tumor or biopsy from 2000 to 2005. 70 patterns (oligodendroglioma (O) -- 13 cases, oligoastrocytoma (OA) -- 13, anaplastic oligodendroglioma (AO) -- 30, anaplastic oligoastrocytoma (AOA) -- 14) were assessed by fluorescent in situ hybridization. Median follow up was 24 months. The type of tumor (pure or mixed) didn't influence survival. TTP of patients with grade II and grade III tumors was 37.7 and 48.2 months, respectively (p = 0.035). Deletion 1p19q was noted in 34 (49%) cases. In pure O codeletion 1p19q was detected more frequently (in O -- 75%, in AO -- 56%) than in mixed tumors (in OA -- 31%, in AOA -- 35%). Deletions 9p, 10q and EGFR amplification were noted in 5, 6 and 4 cases, respectively. None of the tumors with 1pl9q deletion had other genetic alterations. Thus, we generated three prognostic groups: A -- deletion 1p19q; B -- balanced chromosomal profile; C -- deletion 9p. Median TTP in groups A, B and C was 46.6, 25.3 and 6.4 months, respectively (p < 0.001). The percentage of OT with 1p19q codeletion was lower than in previous studies. Pure O more frequently had 1p19q deletion than mixed tumors. Genetic alterations predict outcome stronger than histological criteria.

Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 3. Inhibitory effect of SkQ1 on tumor development from p53-deficient cells.

It was proposed that increased level of mitochondrial reactive oxygen species (ROS), mediating execution of the aging program of an organism, could also be critical for neoplastic transformation and tumorigenesis. This proposal was addressed using new mitochondria-targeted antioxidant SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) that scavenges ROS in mitochondria at nanomolar concentrations. We found that diet supplementation with SkQ1 (5 nmol/kg per day) suppressed spontaneous development of tumors (predominantly lymphomas) in p53(-/-) mice. The same dose of SkQ1 inhibited the growth of human colon carcinoma HCT116/p53(-/-) xenografts in athymic mice. Growth of tumor xenografts of human HPV-16-associated cervical carcinoma SiHa was affected by SkQ1 only slightly, but survival of tumor-bearing animals was increased. It was also shown that SkQ1 inhibited the tumor cell proliferation, which was demonstrated for HCT116 p53(-/-) and SiHa cells in culture. Moreover, SkQ1 induced differentiation of various tumor cells in vitro. Coordinated SkQ1-initiated changes in cell shape, cytoskeleton organization, and E-cadherin-positive intercellular contacts were observed in epithelial tumor cells. In Ras- and SV40-transformed fibroblasts, SkQ1 was found to initiate reversal of morphological transformation of a malignant type, restoring actin stress fibers and focal adhesion contacts. SkQ1 suppressed angiogenesis in Matrigel implants, indicating that mitochondrial ROS could be important for tumor angiogenesis. This effect, however, was less pronounced in HCT116/p53(-/-) tumor xenografts. We have also shown that SkQ1 and related positively charged antioxidants are substrates of the P-glycoprotein multidrug resistance pump. The lower anti-tumor effect and decreased intracellular accumulation of SkQ1, found in the case of HCT116 xenografts bearing mutant forms of p53, could be related to a higher level of P-glycoprotein. The effects of traditional antioxidant N-acetyl-L-cysteine (NAC) on tumor growth and tumor cell phenotype were similar to the effects of SkQ1 but more than 1,000,000 times higher doses of NAC than those of SkQ1 were required. Extremely high efficiency of SkQ1, related to its accumulation in the mitochondrial membrane, indicates that mitochondrial ROS production is critical for tumorigenesis at least in some animal models.

Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised, two-cohort PrefHer study.

AIM: To assess efficacy (event-free survival, EFS) and safety in patients followed up for 3 years in the PrefHer study (NCT01401166). PATIENTS AND METHODS: Post surgery and post chemotherapy in the (neo)adjuvant setting, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomised to receive four cycles of the subcutaneous form of trastuzumab (Herceptin® SC [H SC] via single-use injection device [Cohort 1] or delivery via a hand-held syringe from an SC Vial [Cohort 2]; 600 mg fixed dose) followed by four of the intravenous form of trastuzumab (Herceptin® [H IV]; 8 mg/kg loading, 6 mg/kg maintenance doses) in the adjuvant setting or vice versa every 3 weeks. Patients could have received H before randomisation. H was then continued to complete a total of 18 cycles, including any cycles received before randomisation. RESULTS: A total of 488 patients were randomised across both cohorts. After median follow-up of 36.1 months, 3-year EFS across both groups in the evaluable intention-to-treat population (467 patients) was 90.6% overall, 89.9% in Cohort 1, and 91.1% in Cohort 2. No new safety signals were identified during long-term follow-up, with only one cardiac serious adverse event in the safety population (483 patients). CONCLUSIONS: Three-year EFS data following H SC and H IV treatment are consistent with those reported by previous trials for H in the adjuvant setting. The overall safety profile during adjuvant treatment was as expected.

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

Efficacy of combination chemotherapy including Platidiam in the treatment of malignant testicular tumors.

Thirty-seven patients were treated for advanced malignant testicular tumors with combined chemotherapy including cis-platinum (Platidiam). A complete regression was achieved in 23 patients (62%). No severe side effects were observed. Also in this study the effectivity of cis-platinum in the treatment of testicular tumors was proved.

[Ribamidil as a modulator of the toxic effect of 5-fluorouracil]. / Ribamidil kak moduliator toksicheskogo éffekta 5-ftoruratsila.

The in vitro experiments on CaOv cells demonstrated that ribamidyl (ribavirine) (Rb) enhances the intracellular pool of pyrimidine precursors of DNA. This was the basis for studies of its modifying effect on the antitumour activity of antimetabolites. In experiments with intact hybrid mice F1 (CBA+C57B1) the five times administration of ribavirine increase sharply the toxicity of 5-FU. The data should be taken into consideration when combining Rb with antimetabolites in clinical practice.

[Serological study of a repertoire of human cancer antigens and autoantigens]. / Serologicheskie issledovaniia reperatura rakovykh antgenov i autoanigenov cheloveka.

The spectrum of human antigens allows a monitoring of various pathological processes such as autoimmune disorders and tumorigenesis. Serological analysis of cDNA expression libraries (SEREX) is now used to search for new cancer-associated antigens, which are potential diagnostic markers or targets for immunotherapy of cancer. The results obtained for several solid tumors are reviewed. Groups of antigens detectable by SEREX, causes of immunogenicity of autoantigens, and prospective implication of antigens in diagnostics and monitoring of cancer are discussed.

[Prognostic significance of p53, HER-2/neu, Ki-67 and VEGF expression in chondrosarcomas]. / Prognosticheskoe znachenie ékspressii p53, HER2/neu, Ki-67 i VEGF v khondrosarkomakh.

Expression of the mutant protein-suppressor of tumor growth p53 and the receptor of epidermal growth factor of type II--HER-2/neu may serve as prognostic factors for patients with chondrosarcoma of malignancy grade II. Combined expression of these proteins in the tumor tissue correlates with shorter 5-year survival of recurrence-free patients. The data obtained may be used for prognosis of chondrosarcoma course and choice of adequate therapy.

[Molecular-biological markers as prognostic factors in breast cancer of I-IIA stage]. / Molekuliarno-biologicheskie markery kak faktory prognoza pri rake molochnoi zhelezy I-IIA stadii.

The study of molecular-biological markers for prediction of recurrence-free survival in breast cancer stage I-IIA demonstrates that high expression of thymidilate synthetase and high maximal density of microvessels are prognostically effective and that the prognosis is influenced by expression of both Bcl-2 and Bax. Low recurrence-free survival was observed in Bcl-2-/Bax patients (31%, median 44 months) while such survival was high in Bcl-2+/Bax patients (86%, median was not reached). The findings can be used for prognostication of a breast cancer clinical course.

[Methods for clinical study of antineoplastic drugs]. / Metody klinicheskogo izucheniia protivoopukholevykh lekarstv.

Methodologic principles of evaluation of newly-developed antitumor drugs for solid tumors are discussed.

[Clinico-pharmacological study of prospidin]. / Kliniko-farmakologicheskoe izuchenie prospidina.

Different schemes of prospidin administration to 54 patients were evaluated. Stage IV paresthesia or renal derangements are limitations of prospidin treatment due to its toxicity. Rheovasographic studies established that disorders in vascular tension are responsible for paresthesia development. The best results were obtained with the administration of 300-400 mg every other day for 2-3 weeks. Schemes of combined administration of prospidin and cyclophosphamide and bleomycin were worked out (58 cases). Therapeutic effect was recorded in the treatment of melanoma, carcinoma of the lip, tongue, nasopharynx, salivary gland and skin. Prospidin, cyclophosphamide and radiation therapy were successfully used in the management of small cell carcinoma of the lung.

[Management and drug therapy of patients with disseminated testicular tumors]. / Opyt vedeniia i lekarstvennaia terapiia bol'nykh s disseminirovannymi testikuliarnymi opukholiami.

The experience gained in the treatment of 111 cases of testicular tumor is summarized in the paper. Methods of management of testicular cancer in the eighties differ significantly from those employed in the seventies. A set of drugs used is different. The share of cases of monochemotherapy has decreased markedly. PVB and VAB-6 schemes are highly effective inducing complete or partial remission in 80-90% of cases. Issues of treatment of patients with massive metastases in retroperitoneal lymph nodes and lungs remain unresolved. Timely diagnosis of dissemination will improve chemotherapy results.

[4-component chemotherapy and radiation therapy of breast cancer]. / Chetyrekhkomponentnaia khimioterapiia i luchevaia terapiia pri rake molochnoi zhelezy.

The treatment schedule for disseminated breast carcinoma has been developed. It includes the use of adriamycin (30 mg/m2, days 1, 8, 15), methotrexate (30 mg/m2, day 1), 5-FU (600 mg/m2, day 8), and cyclophosphamide (400 mg/m2, day 15 i. v. by jet injection). A complete response was obtained in 50 to 56% of the patients, with remissions lasting for an appreciable period of time. The use of chemotherapy according to the described schedule combined with radiation of the bones of the pelvis and lumbar part of the spine brought about complete or partial reparation of the osteolytic, osteoblastic and mixed metastatic foci in 76.2% of the patients.

[Chemoradiation therapy of inoperable lung cancer]. / Khimioluchevaia terapiia neoperabel'nogo raka legkogo

The results of utilization of different variants of the complex therapy in 416 patients with inoperable lung cancer are reported. 5-fluoruracil, cyclophosphan, methotrexate, chrysomallin were employed as antitumor drugs. Radiotherapy was carried out on a distance gamma machine. The best immediate and early results were gained in patients treated by distance gammatherapy against the background of cyclophosphan injections. The results proved to be most favourable within the terms of 3 years and longer in case of gammatherapy associated with 5-fluoruracil. Application of a fractionated radiation course rendered no positive effect on the results of treatment.