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CONSORT Diagram (PP = Per Protocol Population).

Related adverse events in the vaccine arm. Number of adverse events.

Overview of all adverse events in the safety evaluable population.

Cervical uterine cancer represents the fourth most common malignant neoplasm worldwide in the female sex in terms of incidence, principally from epithelial origen. The high expression of EGFR in this tumor leads to the search for therapeutic alternatives. An Expanded Access Clinical Program was carried out in parallel groups, randomized, multicenter and prospective study, to evaluate the survival of patients with advanced cervical carcinoma, without therapeutic alternative, who would be treated with the therapeutic vaccine CIMAvax-EGF®, the humanized mAb nimotuzumab or the combination of both products, which targeted EGF and EGFR respectively. The patients were included between 2008 and 2010 with a more than five years follow-up. The results show that the serious adverse events related to the experimental treatments were 0.9%; 1.1% and 2.6% and a median ITT survival of 9.1, 23.5, and 16.3 months for CIMAvax-EGF®, nimotuzumab and the combination of both, respectively. Thus fulfilling the hypothesis of safety and efficacy proposed in the investigation was achieved. The three therapeutic regimens achieved overall survival rates greater than 35% at 60 months, encouraging results for advanced uterine cervical cancer. A phase III clinical trial is proposed to consolidate these results in a greater number of patients with nimotuzumab as study drug.

Bladder cancer is the ninth most common malignancy worldwide and the seventh in male patients. Most of new patients are diagnosed with non-muscle invasive bladder cancer. It usually courses with a favorable prognosis, although there is a high risk of disease recurrence and progression to muscle-invasive disease. The standard treatment for intermediate and high-risk patients is a transurethral resection of bladder tumor, complemented by intravesical therapy with Bacillus Calmette-Guerin. EGFR immunoreactivity is present in about 50% of bladder cancers and correlates with recurrence, time to recurrence, and survival. Here we show the immunological results of an open, randomized, controlled, exploratory clinical trial in patients diagnosed with non-muscle invasive bladder cancer treated with CIMAvax-EGF therapeutic vaccine concomitant with intravesical BCG (n=20) or treated with intravesical BCG alone (n=24). The combination was safe and well tolerated. In vaccinated patients anti-EGF antibody titers increased during the first months of immunization and 80% of patients developed a good anti-EGF antibody response. Anti-EGF response was predominantly against the central region of the EGF molecule (loop B). IgG1 and IgG4 subclasses were the most relevant among the IgG anti-EGF antibodies generated after vaccination. The EGF serum levels were undetectable after six months of treatment. Vaccination with CIMAvax-EGF in combination with intravesical BCG develops a significant inverse correlation between anti-EGF antibody titers and baseline EGF serum concentration suggesting that in this context, the combination allowed the development of CIMAvax-EGF mechanism of action.

Cancer is a leading cause of death in Cuba and the world. Lung cancer is the leading cause of death, breast cancer is the second leading cause of death and colorectal cancer is the third leading cause of death. The 1E10 anti-idiotype vaccine is a new immunotherapeutic agent, registered for lung cancer by the Center for Molecular Immunology (CIM). You want to evaluate the safety of this vaccine in the treatment of various cancer sites. To determine the safety adverse events occurred in six clinical trials (one stage I lung, 3 phase II in breast, colon and lung, 1 phase II-III and program expanded use, both in lung) were evaluated. 656 patients were studied. Demographic variables, the characteristics of the disease and adverse events were measured. The studies were balanced with respect to baseline characteristics. The most common adverse events were local reactions associated with 1E10 anti-idiotype vaccine and systemic reactions of mild or moderate intensity that were not related to the administration of the vaccine under study. The 1E10 anti-idiotype vaccine is safe for the low frequency and intensity of adverse events reported.

Cancer is a leading cause of death in Cuba and the world. Lung cancer is the leading cause of death, breast cancer is the second leading cause of death and colorectal cancer is the third leading cause of death. The 1E10 anti-idiotype vaccine is a new immunotherapeutic agent, registered for lung cancer by the Center for Molecular Immunology (CIM). You want to evaluate the safety of this vaccine in the treatment of various cancer sites. To determine the safety adverse events occurred in six clinical trials (one stage I lung, 3 phase II in breast, colon and lung, 1 phase II-III and program expanded use, both in lung) were evaluated. 656 patients were studied. Demographic variables, the characteristics of the disease and adverse events were measured. The studies were balanced with respect to baseline characteristics. The most common adverse events were local reactions associated with 1E10 anti-idiotype vaccine and systemic reactions of mild or moderate intensity that were not related to the administration of the vaccine under study. The 1E10 anti-idiotype vaccine is safe for the low frequency and intensity of adverse events reported.

Despite extensive clinical research in non-small cell lung cancer (NSCLC), overall survival is still poor. Racotumomab-alum is an anti-idiotypic cancer vaccine that targets NeuGcGM3 tumor associated ganglioside. The aim of this study was to evaluate safety and efficacy of racotumomab-alum in advanced NSCLC patients with progressive disease. This expanded access program included 86 histologically confirmed NSCLC patients, 18 years or older age, with advanced disease and without therapeutic option, with ECOG performance status ≤3, adequate organ functions and signed informed consent. The primary endpoint was overall survival and toxicity was measure assessed treatment-related toxicity according CTCAEv3. The study was approved by ethical review boards of participant institutions. Racotumomab-alum treatment consisted in 5 biweekly intradermal doses (1 mg/mL) during the induction phase of treatment (2 months). The maintenance phase consisted in monthly re-immunizations until unacceptable toxicity or PS worsening. The median overall survival time of all patients treated with racotumomab-alum was 8.96 months. The survival rates at 12 and 24 months were 42.8% and 28.0%, respectively. Patients that completed the induction phase of treatment (five doses or more) reached a median OS of 12.1 months. The most common adverse events were injection site reaction, bone pain, cough and asthenia. Racotumomab-alum cancer vaccine could be considered an effective and safe treatment option as second-line therapy for advanced NSCLC. Further clinical studies should be conducted to confirm this result.

Detection of specific-IgG, IgM or IgA immunoglobulin classes at the end of trial vaccinations (week 13). (PDF 100 kb)

Off-trial re-immunizations. (PDF 97 kb)

Reported adverse events which were probably or definitively related to the vaccine during trial period. (PDF 113 kb)

Over-expression of epidermal growth factor receptor in esophageal cancer is associated with poor prognosis. The present study was conducted to evaluate safety and preliminary efficacy of nimotuzumab, a humanized anti-EGFR antibody in combination with radiation and chemotherapy in advanced esophageal tumours.A Phase II clinical trial was conducted, where patients received cisplatin, 5-fluorouracil, and radiotherapy, either alone or combined with six weekly infusions of nimotuzumab at the dose of 200 mg. Safety was the primary endpoint. The antitumoral objective response rate was the secondary endpoint. Epidermal growth factor receptor expression, KRAS mutation status and anti-idiotypic response were also evaluated.Sixty-three patients were included in the study. Thirty patients were entered into the control group, and thirty-three patients received the treatment with nimotuzumab. The antibody was very well tolerated. Objective response rate was 47.8 % (nimotuzumab group) and 15.4 % (control group). Disease control rate was 60.9 % (nimotuzumab group) and 26.9 % (control group). Response and disease control rate were higher in patients with EGFR overexpressing tumors.Nimotuzumab plus chemoradiotherapy was safe and provided statistically significant objective response. A Phase III in patients with similar characteristics will be launched.

Conventional treatment of non-small cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of the patients. For that reason the search for new therapeutic strategies in this type of tumor is justified. 1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to P3 Ab1 MAb, which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some tumors, including those from the lung. We report the treatment with aluminum hydroxide-precipitated 1E10 MAb of 34 stage IIIb and 37 stage IV NSCLC patients. These patients were treated with the anti-idiotype vaccine, after received standard chemotherapy and radiotherapy, in a compassionate-use basis study. Patients received five bi-weekly injections of 1 mg of 1E10/Alum, other 10 doses at 28-day intervals and later the patients who maintained a good performance status continued to be immunized at this same time interval. No evidence of unexpected or serious adverse effects was reported. The median survival time of the 56 patients who entered the study with partial response or disease stabilization and with a PS 1 after the first line of chemo/radiotherapy, was 11.50 months from starting vaccination. In contrast, the median survival time calculated for patients who started vaccination with progressive disease and/or a PS2 was 6.50 months.

Purpose: EGFR is a well-validated target for patients with non–small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF–EGFR interaction. Experimental Design: To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. Results: Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. Conclusions: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782–90. ©2016 AACR.

Purpose: Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of racotumomab as switch maintenance for patients with advanced non–small cell lung cancer (NSCLC). Experimental design: Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS). Results: One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively [HR, 0.63; 95% confidence interval (CI), 0.46–0.87; P = 0.004]. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53–0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill ≥30% L1210 cells showed longer median survival times. Conclusions: Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC. Clin Cancer Res; 20(14); 3660–71. ©2014 AACR.

Background: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic cancer. Around 75% of the patients are in advanced clinical stages at diagnosis. Despite improvements in cytoreductive surgery and primary chemotherapy over 80% of advanced stage patients will relapse. Racotumomab-alum is a therapeutic cancer vaccine composed by a murine monoclonal antibody (racotumomab) and alum as adjuvant. It is able to induce a specific antibody response against N-glycolilGM3 tumor associated antigen. Its antitumoral activity has been demonstrated in melanoma, breast cancer and NSCLC. The aim of this clinical trial is to evaluate the efficacy and safety of racotumomab-alum as maintenance treatment for recurrent platinum-sensitive EOC. Trial design: This phase II/III multicenter, controlled clinical trial will include 88 patients with histologically confirmed EOC, clinical stage II-IV, with two prior platinum-based chemotherapy treatments and objective response after last regimen, with ECOG performance status 0-2, that signed informed consent, with normal renal, haematologic and hepatic functions. Will be excluded patients with prior treatment with racotumomab-alum or any investigational drug, platinum-resistant disease, pregnancy or breast feeding, history of brain metastasis or spinal cord compression, uncontrolled chronic diseases, previous adverse reactions to vaccines, history of immunodeficiency or autoimmune disease. Patients will be randomized with 1:1 ratio to receive racotumomab-alum or best supportive care. The primary endpoint will be progression free survival (PFS) and we will also evaluate OS, Safety, and Immunological response. The NGcGM3 expression in tumor samples and immunophenotype of tumor infiltrating cells will be evaluated to correlate with clinical endpoints. Racotumomab-alum treatment consist in 5 biweekly intradermal doses (induction phase) followed by monthly re-immunization (maintenance phase) until unacceptable toxicity or PS worsening. Treatment will not be stopped at progressive disease; other chemotherapy lines will be given concomitantly. We have hypothesized a 4 months advantage in PFS for vaccinated group. Disclosure: All authors have declared no conflicts of interest.

TPS3111 Background: Despite extensive research in NSCLC treatment, overall survival remains insufficient. Immunotherapy has become a viable treatment to help the immune system to control or elimina...

3086 Background: Racotumomab is a therapeutic vaccine that induces a cellular and humoral immune response against NeuGc-containing gangliosides expressed in several tumors but not in normal human tissues. A previous randomized, double blinded, placebo-controlled trial has demonstrated low toxicity of racotumomab and a statistically significant benefit in overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) who had achieved partial or complete response or disease stabilization after first line therapy. Methods: An open, non-randomized study was performed to evaluate if racotumomab could also be beneficial in patients with progressive disease. Patients with recurrent and advanced stages (IIIB/IV) of NSCLC, in progression after completion of first-line onco-specific treatment as per the NCCN Oncology Therapeutic Guidelines (surgery, chemotherapy and/or radiotherapy) were included in the study. Most of them had received 4 to 6 cycles of cisplatin/vinblastin. Vaccination consisted of 5 intradermic doses of racotumomab (1 every 14 days), followed by 1 dose every 28 days until patient refusal or worsening of ECOG status. The patients did not receive second-line therapy. Results: 180 patients were included in an intent to treat (ITT) survival analysis (Kaplan Meier estimate), after at least 10 months of follow-up. Median survival was 8.06 months. OS rate (%) at 24 months was 21%. A control group of 85 consecutive patients treated at the same institution by the same investigators, who did not receive second-line therapy or racotumomab showed a median survival of 6.26 months (log rank test p= 0.011). OS rate (%) at 24 months was only 7%. A per protocol survival analysis including only the 124 patients (68.8%) who received ≥ 5 doses of racotumomab showed a median survival of 12 months. OS rate (%) at 24 months was 30%. Conclusions: Patients with PD after first-line treatment show favorable results in survival when vaccinated with racotumomab. This result is similar to previous clinical trials where racotumomab was administered to patients with objective response (partial or complete) or stable disease after first line therapy.

Background Gangliosides, especially NeuGc-GM3, are an attractive target for cancer immunotherapy. They do not express in normal human cells but are overexpressed in several solid tumors including NSCLC and are involved in tumor development and growth. Racotumomab is therapeutic vaccine which induces a cellular and humoral immune response against NeuGc-GM3 expressed in tumors. Phase I and II trials in melanoma, breast and lung cancer have shown the low toxicity and high immunogenicity of racotumomab. Methods Multicenter, randomized, placebo controlled, double blind clinical trial in patients with advanced (IIIB and IV) NSCLC who had an ECOG status ≤ 2 and had achieved partial or complete response or disease stabilization after completion of onco-specific treatment. 176 patients were randomized 1:1 to placebo or racotumomab. Initially 1 dose was administered every 14 days (induction period, 5 doses in total), followed by 1 dose every 28 days (maintenance period) until patient refusal or worsening of ECOG status. Results Safety: The most common adverse events were expected mild reactions at the injection site (pain and itching). No differences were observed between both groups. Overall Survival (OS): Intent to Treat Analysis (ITT): Survival since inclusion was 15.7 months (mean) and 8.3 months (median) in the racotumomab arm and 10.6 months (mean) and 6.3 months (median) in the placebo arm (log rank test, p= 0.02). OS rate (%) at 12 and 24 months was 38 % and 17 % in the racotumomab arm and 24 % and 7 % in the placebo arm. Per Protocol Population Analysis (PPP): Includes patients who received ≥ 5 doses of racotumomab/ placebo (135/174 patients, 77% of the patient population). Survival since inclusion was 18.9 months (mean) and 10.9 (median) in the racotumomab arm and 11.4 months (mean) and 6.9 months (median) in the placebo arm (log rank test, p= 0.002). OS rate (%) at 12 and 24 months: 48 % and 22 % in the racotumomab arm and 28 % and 8 % in the lacebo arm. Conclusions Immunization with racotumomab is safe. There is an OS benefit for racotumomab, both in the ITT and PPP analyses. Survival benefit appears to be increased when the patient's clinical condition allows completion of the induction period of vaccination. Disclosure R.E. Gomez: Is a full time employee at Elea Laboratories. M.L. Ardigo: Is a full time employee at Elea Laboratories. All other authors have declared no conflicts of interest.