First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors.

Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and clinical activity. Methods Forty-seven patients were enrolled in three parts. The primary objective of Parts A and B was safety, whereas Part C evaluated the effect of proton-pump inhibitors on MK-8033 absorption. Dose escalation used an accelerated continual reassessment method, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity (except alopecia or inadequately treated nausea/vomiting/diarrhea), grade 4 hematologic toxicity (except grade 3 neutropenic fever and thrombocytopenia), or toxicity where treatment is held >3 weeks. Results Forty-six patients were treated across nine dose levels, and the MTD was 750 mg twice daily. DLTs were fatigue, nausea, vomiting, transaminitis, and hypokalemia. Most frequent toxicities were fatigue (28.3%), nausea (21.7%), and alopecia (19.6%), predominately grade ≤ 2. One patient with endometriod adenocarcinoma achieved a partial response and eight had stable disease. Median progression-free survival (PFS) was 57 days. Strikingly, the PFS for the one responder was 846 days. PK results showed that proton-pump inhibitors have no effect on MK-8033 absorption. Conclusion MK-8033 was well tolerated with no significant toxicity issues, albeit with limited clinical activity. Unfortunately, the company decided to discontinue further clinical development of MK-8033.

Electrocardiographic Characterization of Ramucirumab on the Corrected QT Interval in a Phase II Study of Patients With Advanced Solid Tumors.

LESSONS LEARNED: Cardiotoxicity can be a serious complication of anticancer therapies. To enable earlier identification of drug-related cardiac effects, the International Conference on Harmonization (ICH) adopted the ICH E14 Guidelines for evaluating the potential for QT/corrected QT (QTc) interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs.The results of the evaluation of ramucirumab on the QT/QTc interval show a lack of effect on QTc prolongation in patients with advanced cancer. BACKGROUND: Ramucirumab is a human immunoglobulin G1 monoclonal antibody that specifically blocks vascular endothelial growth factor receptor-2 and is approved for the treatment of advanced gastric, non-small cell lung, and colorectal cancers. This phase II study was conducted to determine if treatment with ramucirumab causes prolongation of the corrected QT interval using Fridericia's formula (QTcF) in patients with advanced cancer. METHODS: Patients received intravenous ramucirumab (10 mg/kg) every 21 days for 3 cycles. The first 16 patients received moxifloxacin (400 mg orally), an antibiotic associated with mild QT prolongation as a positive control. During cycle 3, determination of QTcF prolongation was made with triplicate electrocardiograms at multiple time points to compare with baseline. RESULTS: Sixty-six patients received therapy; 51 patients completed 9 or more weeks of therapy for the complete QTcF evaluation period. The upper limit of the 90% two-sided confidence intervals for the least square means of change in QTcF from baseline at each time point was less than 10 milliseconds. Concentration-QTcF analysis showed a visible, but not significant, negative association between ramucirumab concentration and QTcF change from baseline. CONCLUSION: Ramucirumab at a dose of 10 mg/kg administered every 21 days for 3 cycles did not produce a statistically or clinically significant prolongation of QTcF.

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

Dual inhibition of the vascular endothelial growth factor pathway: a phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors.

BACKGROUND: The current study was conducted to evaluate the safety and biological activity of dual inhibition of the vascular endothelial growth factor (VEGF) pathway with combined bevacizumab and cediranib (a VEGF receptor tyrosine kinase inhibitor). METHODS: This was a 3 + 3 dose escalation study in patients with advanced solid tumors. Cediranib was given orally daily for 21 days and bevacizumab intravenously every 2 weeks. Pharmacokinetics and correlates (nitric oxide synthase, nitrate oxide, and circulating tumor cells) were assessed. RESULTS: Fifty-one patients were treated. Dose-limiting toxicities (DLTs) (grade 3-4; graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events [version 3.0]) observed included 1 patient with chest pain, 1 patient with fatigue, 2 patients with thrombocytopenia, 3 patients with hypertension (1 with intracranial hemorrhage), and 1 patient with grade 5 hemoptysis. Moreover, 2 patients presented with grade 3 intracranial bleeding beyond the DLT window. Dose level 2 (cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks) was selected as the recommended phase 2 dose (RP2D); 17 patients were treated at dose level 2 with 1 DLT and no intracranial bleeding or severe hypertension reported. Pharmacokinetics of cediranib at dose level 3 demonstrated a 46% to 77% increase in area under the curve (0-24 hours) on cycle 1 day 1 compared with historical controls. Four patients attained partial remissions: inflammatory breast cancer (-54%), basal cell carcinoma (-33%), alveolar soft part sarcoma (-33%), and synovial sarcoma (-32%). Patients with a lower circulating tumor cell count (< 30) at the predose period had a longer time to tumor progression (P = .024, log-rank test). CONCLUSIONS: Cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks was found to be the RP2D. Activity in several tumor types was noted. Central nervous system bleeding and severe hypertension were observed at doses above the RP2D.

Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) in immunocompromised adults.

BACKGROUND: Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) were assessed in immunocompromised adults. METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 4 doses ZVHT or placebo were administered approximately 30 days apart to adults with either solid tumor malignancy (STM); hematologic malignancy (HM); human immunodeficiency virus (HIV) with CD4(+) ≤200; autologous hematopoietic stem-cell transplant (HCT) or allogeneic-HCT recipients. Varicella-zoster virus (VZV) T-cell responses by interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) and VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and approximately 28 days after each dose. RESULTS: No safety signals were found in any group. IFN-γ ELISPOT geometric mean fold rises (GMFR) after dose 4 in STM, HM, HIV, and autologous-HCT patients were 3.00 (P < .0001), 2.23 (P = .004), 1.76 (P = .026), and 9.01 (P = NA), respectively. Similarly, antibody GMFR were 2.35 (P < .0001), 1.28 (P = .003), 1.37 (P = .017), and 0.90 (P = NA), respectively. T-cell and antibody responses were poor after 4 doses of ZVHT in allogeneic-HCT patients. CONCLUSION: ZVHT was generally safe and immunogenic through 28 days post-dose 4 in adults with STM, HM, and HIV. Autologous-HCT but not allogeneic-HCT patients had a rise in T-cell response; antibody responses were not increased in either HCT population. Study identification. V212-002 Clinical Trials Registration. NCT00535236.

Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma.

BACKGROUND: Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing. METHODS: The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity. RESULTS: Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by in vitro immune monitoring assays. CONCLUSIONS: The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma. CLINICAL TRIAL REGISTRATION: NCT00107159.

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

BACKGROUND: In phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZVIN) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZVIN immunogenicity from these studies. METHODS: Patients were randomized to ZVIN or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling. RESULTS: Estimated geometric mean fold rise ratios (ZVIN/placebo) by gpELISA and IFN-y ELISPOT ~28 days post-dose 4 were 2.02 (95% confidence interval [CI], 1.53-2.67) and 5.41 (95% CI, 3.60-8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79-1.98) and 2.10 (95% CI, 1.69-2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81-3.05) in patients with HM. CONCLUSIONS: ZVIN immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZVIN immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations. CLINICAL TRIAL REGISTRATION: NCT01229267, NCT01254630.

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial.

BACKGROUND: Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. METHODS: This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89). FINDINGS: Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3). INTERPRETATION: The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. FUNDING: Merck & Co, Inc.

Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma.

BACKGROUND: CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated. METHODS: Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis. RESULTS: Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup. CONCLUSION: Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood. CLINICAL TRIAL REGISTRATION NUMBER: NCT00086489.

Retinoic acid-induced CD38 antigen promotes leukemia cells attachment and interferon-gamma/interleukin-1beta-dependent apoptosis of endothelial cells: implications in the etiology of retinoic acid syndrome.

All-trans retinoic acid (RA) treatment of patients with acute promyelocytic leukemia (APL) induces complete remission in more than 90% of the cases. Although RA therapy is well tolerated, about 25% of APL patients develop a potentially fatal condition called retinoic acid syndrome (RAS). Molecular mechanisms underlying the development of RAS pathogenesis, especially those that result in the damage of endothelial cells remain elusive. In the present study, we found that RA treatment induces the expression of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in peripheral blast cells from APL patients. IFN-gamma and IL-1beta also exerted synergistic effect in driving human umbilical cord endothelial cells (HUVECs) and human lung microvascular endothelial cells (HLMVECs) into apoptosis. RA also upregulated the expression of CD38, an ectoenzyme responsible for the generation of the calcium messenger cyclic ADP-ribose. Importantly, RA-induced CD38 expression promoted strong attachment of leukemia cells to endothelial cells, and incubation of endothelial cells with either high concentration (100 ng/ml) of IFN-gamma alone or low concentration of IL-1beta and IFN-gamma (10 ng/ml, each) induced strong apoptotic responses as revealed by caspase-8 activation and DNA fragmentation. Our results suggest that these RA-induced events could contribute to the development of RAS pathogenesis in patients with APL.

Current Status of Biosimilars in Oncology.

Four medicinal cancer biological blockbusters will end their patent lifespan by 2020. It is estimated that the total market for cancer biologicals will reach approximately US$68 billion at that time. Approximately 20 biosimilars have entered the European market since the launch of the original approval guidelines in 2005, and four biosimilars have been approved in the USA since 2015. Data from European countries with the highest market entrance of biosimilars suggest that the incorporation of biosimilars into healthcare systems worldwide may result in a 30-45% cost savings. Initial levels of apprehension expressed by healthcare providers regarding the safety and efficacy of integrating biosimilars into the treatment of cancer patients have gradually decreased through active educational programs. The trust generated by regulatory agencies and drug manufacturers will ultimately make the adoption of biosimilars by healthcare providers and patients a smooth process. Future efforts to improve on the global acceptance and safety of biosimilars must include standardization of naming, regulatory requirements, and pharmacovigilance programs worldwide. High expectations are being placed on the cost savings, safety, and efficacy of these products. The entry costs for biosimilars and the pricing reaction of their originator products will determine the true savings by troubled health systems in dire need of cost cuts. This article discusses basic principles of biosimilars in hematology and oncology, the current status of their clinical development, and trends of acceptance by healthcare providers, and provides insight into potential future challenges.

A Randomized, Open-Label, Safety and Exploratory Efficacy Study of Kanglaite Injection (KLTi) plus Gemcitabine versus Gemcitabine in Patients with Advanced Pancreatic Cancer.

Background: This study was designed to assess the safety and preliminary efficacy of KLTi plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer. Methods: In a randomized, open-label study, patients with locally advanced or metastatic pancreatic cancer were randomized 2:1 to receive KLTi plus gemcitabine or gemcitabine monotherapy. Three sequential cohorts were tested at 30 g/day, 50 g/day, and 30 g/day. Gemcitabine was administered at 1000 mg/m2 on days 1, 8 and 15 of each 28 day cycle. KLTi was administered on days 1-5, 8-12, and 15-19 of each 28 day cycle. Patients received study treatment until disease progression. The primary endpoint was progression-free survival in the ITT population. Safety evaluation was based on patients who received any study treatment. ClinicalTrials.gov identifier NCT00733850. Results: Eighty-five patients were randomized including 41 (28:13) in Cohort 1, 18 (12:6) in Cohort 2, and 26 (17:9) in Cohort 3. Due to a different dose and/or shift in patient populations in Cohort 2 and 3, efficacy data for the 30 gm dose are presented in this manuscript for Cohort 1 alone, and for the combination of Cohort 1+3. The 30 gm KLTi + gemcitabine group had a statistically significant improvement in progression-free survival (PFS) as assessed by blinded independent radiology review in the ITT population, with a median of 112 days, versus 58 days in the gemcitabine group (HR 0.50; 95% CI: 0.27, 0.92), p = 0.0240. The incidence rates of TEAEs, CTCAE Grade 3 or higher TEAEs, and SAEs were similar between the two arms. There were no deaths related to KLTi + gemcitabine treatment. Conclusion: Kanglaite Injection (30 g/day) plus a standard regimen of gemcitabine demonstrated encouraging clinical evidence of anti-neoplastic activity and a well-tolerated safety profile.

Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.

PURPOSE: Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206. PATIENTS AND METHODS: Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose. RESULTS: Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response. CONCLUSION: CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.

Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer.

BACKGROUND: KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF). OBJECTIVE: To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study. MATERIALS AND METHODS: Using a standard 3 + 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment. RESULTS: The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n = 2), at 1 mg/kg in the MTD dose expansion cohort (n = 1), and at 0.1 mg/kg (n = 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9-118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification. CONCLUSIONS: The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291].

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations.

Melanoma remains a critical public health problem worldwide. Patients with stage IV disease have very poor prognosis and their 1-year survival rate is only 25%. Until recently, systemic treatments with a positive impact on overall survival (OS) had remained elusive. In recent years, the United States Food and Drug Administration (FDA) - approved several novel agents targeting the RAS/RAF/MEK/ERK pathway (vemurafenib, dabrafenib, and trametinib) - critical in cell division and proliferation of melanoma, and an immune checkpoint inhibitor (ipilimumab) directed against the cytotoxic T lymphocyte Antigen - (CTLA-4). Moreover, recent reports of clinical trials studying other immune checkpoint modulating agents will most likely result in their FDA approval within the next months. This review focuses on ipilimumab, its safety and efficacy, and future considerations. Ipilimumab has demonstrated a positive OS impact after a several-year follow-up. It is also recognized that due to its mechanism of action, the response patterns to ipilimumab can differ from those observed in patients following treatment with conventional cytotoxic agents and even the most recently approved BRAF inhibitors. Most patients (84.8%) experience drug-related adverse events (AEs) of any grade; most of these are mild to moderate and immune mediated. However, a minority of patients may also experience severe and life-threatening AEs. In clinical studies, AEs were managed according to guidelines that emphasized close clinical monitoring and early use of corticosteroids when appropriate. Preliminary results have taught us the potential greater toxicity when in combination with vemurafenib, and the greater antitumor efficacy when combined with nivolumab, a monoclonal antibody directed against programmed death receptor-1 (PD-1), another immune checkpoint inhibitor. Future challenges include the optimization of dosing and toxicities when used as a single agent, and studying the safety and efficacy of combinations with targeted small molecules and other monoclonal antibodies to treat patients with melanoma and other malignancies.

Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab.

PURPOSE: One of the hallmarks of cancer immunotherapy is the long duration of responses, evident with cytokines like interleukin-2 or a variety of cancer vaccines. However, there is limited information available on very long term outcomes of patients treated with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies. Tremelimumab is an anti-CTLA-4 antibody of immunoglobulin G2 (IgG2) isotype initially tested in patients with advanced melanoma over 12 years ago. METHODS: We reviewed the outcomes of patients with advanced melanoma enrolled in four phase 1 and 2 tremelimumab trials at two sites to determine response rates and long-term survival. RESULTS: A total of 143 patients were enrolled at two institutions from 2002 to 2008. Tremelimumab administration varied between a single dose of 0.01 mg/kg and 15 mg/kg every 3 months. Median overall survival was 13 months (95% confidence interval (CI), 10-16.6), ranging from less than a month to 12+ years. An objective response rate of 15.6% was observed, with median duration of response of 6.5 years, range of 3-136+ months. The Kaplan-Meier estimated 5 year survival rate was 20% (95% CI, 13-26%), with 10 and 12.5 year survival rates of 16% (95% CI, 9-23%). CONCLUSIONS: CTLA-4 blockade with tremelimumab can lead to very long duration of objective anti-tumour responses beyond 12 years.

Acute myeloid leukemia: a classification and treatment update.

Approximately 11,000 Americans will be diagnosed with acute myeloid leukemia (AML) in 2003, and about 75% ultimately will die from the disease. Despite significant advances in understanding biologic, molecular, and cytogenetic aspects of this malignancy, several other areas remain poorly understood. During the 1990s, significant advances in the characterization of this condition have shown that AML affects elderly patients more frequently. Treatment of patients in this age group poses a greater challenge partly because of increased tumor resistance and the presence of multiple medical comorbidities that may contraindicate therapy. New therapeutic approaches are promising and have renewed enthusiasm and optimism among patients and healthcare providers. Future treatment strategies for patients with AML most likely will include combinations of biologic agents with defined molecular targets (e.g., monoclonal antibodies, retinoids, hypomethylating agents, tyrosine kinase inhibitors).

Biosimilars 101: considerations for U.S. oncologists in clinical practice.

Biosimilars of biologics used for cancer treatment and supportive care are expected to enter the U.S. market soon. Biosimilars will be highly similar to their reference products, but unlike generic drugs, not identical. Differences between a biosimilar and its reference product may arise because of the complexity of biologics, and differences in the cell lines and processes used during manufacturing. Biosimilars will be approved in the United States through a regulatory pathway based on comparative analytical and clinical studies for their characterization and demonstration of no clinically meaningful differences from their reference products. Unlike generics, initial approval may not include interchangeability, as additional evidence may be required before a biosimilar could be approved as interchangeable with its reference product; interchangeable designation could allow pharmacy-level substitution without prescriber intervention. In some cases, the U.S. Food and Drug Administration (FDA) may extrapolate an indication that has not been formally investigated for the biosimilar but that is approved for the reference product. Robust safety monitoring of all biologics is important to track and accurately attribute adverse events, particularly because their inherent complexity and manufacturing differences make them susceptible to structural changes that can affect safety (e.g., immunogenicity). Accuracy of postapproval safety reports will partly depend on the biosimilar naming approach. Potential cost savings should be evaluated in the context of differences in manufacturers' patient-assistance programs, copayments, and institutional costs. A manufacturer's ability to ensure reliable supply of high-quality biosimilars should also be considered. Broad understanding of these issues is critical for oncologists preparing for their use in clinical practice.

A randomized phase II study of cilengitide (EMD 121974) in patients with metastatic melanoma.

Cilengitide (EMD 121974) is a selective inhibitor of integrins αvß3 and αvß5. The αvß3 promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells. We conducted a randomized phase II trial in patients with metastatic melanoma to evaluate the clinical efficacy of cilengitide. Patients with stage IV or unresectable stage III melanoma who were either chemonaive or who had previously received one systemic therapy were enrolled. Patients were randomly assigned to either 500 or 2000 mg of cilengitide administered intravenously twice weekly. The primary aim of this study was to determine the progression-free survival rate at 8 weeks. Tumor samples and blood samples were collected for pharmacodynamic and pharmacokinetic studies. Twenty-nine patients were enrolled, of whom 26 were treated (14 at 500 mg and 12 at 2000 mg). Among those treated, only three were progression free at 8 weeks: two in the 500 mg arm and one in the 2000 mg arm. One patient in the 2000 mg arm showed a prolonged partial response after an initial 28% enlargement of her target lesions. The treatment was well tolerated without clinically significant adverse events. The sole responder and one of two patients with stable disease had no αvß3 expression at baseline. Overall, αvß3 expression was decreased by day 8 of the treatment (P=0.05). Cilengitide was well tolerated by patients in both the treatment arms but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma, and the efficacy was not related to baseline αvß3 expression.