Safety Of Ipilimumab Research Articles

Selective activation of IFNγ–ipilimumab enhances the therapeutic effect and safety of ipilimumab

IntroductionImmune checkpoint inhibitor therapy is a highly promising strategy for clinical treatment of cancer. Among these inhibitors, ipilimumab stands out for its ability to induce cytotoxic T cell proliferation and activation by binding to CTLA-4. However, ipilimumab also gives rise to systemic immune-related adverse effects and tumor immune evasion, limiting its effectiveness. ObjectivesWe developed IFNγ–ipilimumab and confirmed that the addition of INF-γ does not alter the fundamental properties of ipilimumab. ResultsIFNγ–ipilimumab can be activated by matrix metalloproteinases, thereby promoting the IFNγ signaling pathway and enhancing the cytotoxicity of T cells. In vivo studies demonstrated that IFNγ–ipilimumab enhances the therapeutic effect of ipilimumab against colorectal cancer by increasing CD8+ and CD4+ lymphocyte infiltration into the tumor area and inducing MHC-I expression in tumor cells. Mice treated with IFNγ–ipilimumab showed higher survival rates and body weight, as well as lower CD4+ and CD8+ lymphocyte activation rates in the blood and reduced organ damage. ConclusionIFNγ–ipilimumab improved the effectiveness of ipilimumab while reducing its side effects. It is likely that future immunotherapies would rely on such antibodies to activate local cancer cells or immune cells, thereby increasing the therapeutic effectiveness of cancer treatments and ensuring their safety.

Evolution: Phase II study of radionuclide 177Lu-PSMA-617 therapy versus 177Lu-PSMA-617 in combination with ipilimumab and nivolumab for men with metastatic castration-resistant prostate cancer (mCRPC; ANZUP 2001).

TPS271 Background: Combination immune checkpoint inhibitors (ICI) with ipilimumab and nivolumab has been shown to induce adaptive immune responses in patients with mCRPC, albeit resulting in modest clinical benefit. There is growing evidence that radiation may enhance the activity of ICI by modulating the tumour immune microenvironment. We hypothesize that the radionuclide 177Lu-PSMA-617 may result in immunogenic cell death and therefore synergise with combination ICI to improve long term clinical outcomes. EVOLUTION aims to determine the activity and safety of ipilimumab and nivolumab in combination with 177Lu-PSMA-617 in patients with mCRPC. Methods: This open label, multicentre, phase 2 study will randomly assign 100 participants with mCRPC in a 2:1 ratio stratified by site and prior exposure to docetaxel to either: the experimental combination of 177Lu-PSMA-617 7.5 GBq every 6 weeks for up to 6 doses plus ipilimumab 3 mg/kg every 6 weeks x 4 doses and nivolumab 1 mg/kg every 3 weeks x 8 doses during induction, followed by nivolumab 480 mg every 4 weeks x 18 doses during maintenance or 177Lu-PSMA-617 alone. Key eligibility criteria include progression on prior androgen receptor pathway inhibitors, no more than one line of prior chemotherapy, significant PSMA avidity on 68GaPSMA-11 PET/CT (SUVmax ≥15 at one disease site and SUVmax ≥10 at measurable sites of disease > 10 mm), no FDG positive/PSMA negative disease and no contraindications to ICI. The primary endpoint is 12-month PSA progression-free survival (PSA-PFS). Secondary endpoints are PSA response rate, adverse events, radiographic-PFS, overall survival, objective response rate, duration of response and health-related quality of life. Correlative studies will evaluate exploratory biomarkers as potential predictive/prognostic factors. Assessments include clinical reviews and blood tests at baseline, then every 3-4 weeks; CT and bone scan at baseline, then every 12 weeks; 68Ga-PSMA-11 and 18F FDG PET/CTs at baseline; 68Ga-PSMA-11 PET/CT at week 24 and 177Lu-PSMA-617 SPECT/CT 24 hours after each 177Lu-PSMA-617 dose. Translational bloods include circulating tumour DNA and peripheral blood mononuclear cells collected at baseline, weeks 13 and 25, and at radiological progression. Optional fresh biopsies will be collected at baseline, weeks 3-5 and at progression. A sample size of 100 provides 90% power at the 10% level of significance to reject the null hypothesis (that 1 year PSA-PFS is 20%) if the alternative hypothesis is true (that 1 year PSA-PFS is 35%). Accrual as of the 11th of October 2022 is 23. Clinical trial information: NCT05150236 .

Antineoplastic agents associated with the development of drug-induced pancreatitis

The frequency of drug-induced pancreatitis (LIP) is from 2 to 5% of all cases of acute pancreatitis (OP), but it is much more common in risk groups – among children and HIV-infected patients. The use of a number of drugs (drugs) is associated with the development of lipids, among them a special place is occupied by antitumor drugs due to the great medical and social significance of oncological diseases and the appearance in recent years of a large number of new antitumor drugs. The purpose of this review was to review the literature data on antitumor drugs, the use of which is associated with the development of lipids. LI OP developed in 1.8% of patients treated with nivolumab or pembroluzumab. In total, in 14 phase 1-3 studies on the efficacy and safety of ipilimumab, the development of OP was reported in less than 1% of the subjects. Therapy with molecular-targeted targeted drugs, such as tyrosine kinase inhibitors (TKI) or other representatives of the kinase inhibitor class, is also associated with the development of OP. The HP database of the World Health Organization (WHO, World Health Organization Adverse Drug Reaction database) contains reports of individual clinical cases of OP development during treatment with proteosome inhibitors and antibody-drug conjugates. It is known that the following antitumor drugs are also associated with the development of pancreatitis: 6-mercaptopurine, L-asparaginase, tamoxifen, cisplatin, cytarabine, ifosfamide, paclitaxel, docetaxel, oxaliplatin, capecitabine, periwinkle alkaloids, cytosine, cisplatin, interferon alpha-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, levamizole, methotrexate, 5-fluorouracil, capecitabine, trans-retinoic acid.

Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells’ responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.

Real-world utilization and safety of ipilimumab plus nivolumab (I+N) in metastatic renal cell carcinoma (mRCC) patients: Results from the Canadian Kidney Cancer Information System (CKCis).

633 Background: I+N is now standard of care for first line treatment of intermediate/poor risk mRCC patients (pts). Real world data is vital to understand drug usage, toxicity and outcomes in non-trial pts. This project describes the amount and tolerability of treatment delivered including discontinuation rates, reasons for discontinuation and outcomes from the CKCis database. Methods: Pts in CKCis, a prospective Canadian database from 15 academic centers, who received first line I+N were included. The number of doses of I+N, number of pts who received single-agent nivolumab (N) and duration of single agent N were determined. Reasons for treatment discontinuation, including the rate, type, and grade of toxicities were identified. Efficacy outcomes included time to failure (TTF – time to progression, death, or second line therapy), overall response rate (ORR) and overall survival (OS). Results: The cohort consists of 182 pts. Median age was 63 yrs, 71% had clear cell histology, 11% were on a clinical trial, the IMDC risk distribution was 5% good, 63% intermediate, 32% poor. Median follow up was 8.8 m. All 4 I+N doses were received by 30% of pts of which 78% went on to receive single-agent N. Less than 4 doses of I+N were received by 70% of pts of which 28% went on to receive single-agent N. The median time on single agent N was 5.7 m. In the entire cohort, 21% of patients discontinued therapy due to toxicity. The most common toxicity events were colitis (56% of all events), pneumonitis (19%), and hepatitis (8%). There were no toxicity-related deaths. Median OS has not been reached (22 events to date). Median TTF was 12.4 m. ORR was 32% (5% complete responses). 26% of pts received second line treatment, the most common being sunitinib in 79%. Conclusions: In this real world cohort, the majority of mRCC pts did not receive all 4 doses of I+N, contrasting with clinical trial reporting, yet many of these pts went on to receive single agent N. Discontinuation rates due to toxicity were similar to those reported in CheckMate 214. Further follow up is ongoing and efficacy outcomes analyzed on the basis of treatment quantity/duration will be presented.

The first experience of immunotherapy application of ipilimumab in combination with chemotherapy of small-cell lung cancer in the Russian population. Analysis of the combined data of two centers, participating in the multicenter randomized phase III study СА 184-156

Introduction. Patients with advanced small cell lung cancer (SCLC) have an extremely poor prognosis on the background of standard chemotherapy combination of etoposide and platinum-based drugs. In a randomized, double-blind of СА184-156 phase III study, the efficacy and safety of ipilimumab (immune checkpoint inhibitor) or placebo in combination with etoposide and platinum drugs were evaluated as the first-line therapy of disseminated SCLC. The article deals with the results of treatment of patients with advanced SCLC, who participated in the international multicenter phase III study CA184-156 in two Russian Research Centers: the Department of chemotherapy (33 patients) and the Department of diagnostic (23 patients) N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation. Materials and methods. Randomization of patients was carried out in a ratio of 1:1 in the group of therapy: etoposide + platinum drug (carboplatin or cisplatin) + ipilimumab and etoposide + platinum drug + placebo. Ipilimumab/placebo was administered at a dose of 10 mg/kg every 3 weeks in parallel with the third and fourth cycles of chemotherapy, further two administrations of ipilimumaba/placebo were performed at intervals of 3 weeks. Further, in the absence of progression, the maintenance therapy with ipilimumab/placebo was performed every 12 weeks. The main endpoints of the study were the assessment of progression-free survival (PFS) and overall survival (OS). Results. In the study CA184-156, the median PFS was 4.6 months in the chemotherapy group with ipilimumab (95% CI 4.5-5.0) and 4.4 months in the chemotherapy group with placebo (95% CI 4.4-4.6). There were no statistically significant differences. The analysis of 56 patients in the subgroup in our centers showed similar findings of median PFS: 4.4 and 4.3 months, respectivelyIn the study CA184-156, the median OS was 11 months in the chemotherapy group with ipilimumab (95% CI 10.5-11.3) and 10.9 months in the chemotherapy group with placebo (95% CI 10-11.5). There were no statistically significant differences. The analysis of 56 patients in the subgroup in our centers showed the following results: median OS was 9.7 months (95% CI 7.8-14) and 10.7 months (95% CI 6.5-20.1), respectively. The multifactorial analysis confirmed the significant effect of such factors as: ECOG 1/2 performance status and age on PFS, and ECOG 1/2 performance status and scheme of chemotherapy (etoposide + cisplatin/etoposide + carboplatin) on OS. Unexpected adverse events in the group of chemotherapy with ipilimumab were not noted. Conclusion. The addition of ipilimumab to chemotherapy did not contribute to an increase either in PFS or in OS in comparison with chemotherapy alone for advanced SCLC patients. Unexpected adverse events in the group of chemotherapy with ipilimumab were not noted. The study of the efficacy of ipilimumab in patients with disseminated SCLC in combination with PD1 inhibitors (nivolumab) is ongoing. The results obtained in the analysis of the data in the subgroups of patients, who participated in the study on the basis of the Department of chemotherapy (33 patients) and Department of diagnostic (23 patients) of N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation corresponded to the data received in the entire multicenter study CA184-156.

Real-world use, safety, and survival of ipilimumab in metastatic cutaneous melanoma in The Netherlands

Phase III trials with ipilimumab showed an improved survival in patients with metastatic melanoma. We evaluated the use and safety of ipilimumab, and the survival of all patients with metastatic cutaneous melanoma (N=807) receiving ipilimumab in real-world clinical practice in The Netherlands using data from the Dutch Melanoma Treatment Registry. Patients who were registered between July 2012 and July 2015 were included and analyzed according to their treatment status: treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of treatment-naive patients and 62% of previously-treated patients received all four planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. Median time to first event was 5.4 months [95% confidence interval (CI): 4.7-6.5 months] in treatment-naive patients and 4.4 months (95% CI: 4.0-4.7 months) in previously-treated patients. Median overall survival was 14.3 months (95% CI: 11.6-16.7 months) in treatment-naive patients and 8.7 months (95% CI: 7.6-9.6 months) in previously-treated patients. In both patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. These real-world outcomes of ipilimumab slightly differed from outcomes in phase III trials. Although phase III trials are crucial for establishing efficacy, real-world data are of great added value enhancing the generalizability of outcomes of ipilimumab in clinical practice.

Efficacy and Safety of Ipilimumab plus Chemotherapy for Advanced Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related deaths worldwide, with poor prognosis in advanced lung cancer patients. Platinum-based chemotherapy has always been a first-line treatment for the majority of advanced lung cancer patients, but its long-term survival benefit is limited. Ipilimumab is an immune drug that targets the CTLA-4 protein in T cells. Therefore, we evaluated the efficacy and safety of adding ipilimumab to simple chemotherapy for patients with advanced lung cancer. We searched literatures in PubMed, Web of Science, EMBASE, the Cochrane Library and cliniclatrials.gov. The primary end points of this assessment were overall survival (OS), progression-free survival (PFS) and immune-related PFS(irPFS) of lung cancer patients. Other end points were objective response rate (ORR), disease control rate (DCR) and safety. The results of this study will be presented by the risk ratio (RR) of the endpoints and the 95% confidence interval (CI) of the various effect sizes. And when the p value is less than 0.05, we think there is a statistical difference. Finally, 6 RCTs and 2,037 patients including 953 with advanced or recurrent non-small cell lung cancer (NSCLC) and 1084 with extensive-disease small-cell lung cancer (ED-SCLC) were identified. Among them, 1089 received immunochemotherapy, and 948 patients received chemotherapy alone. Immunochemotherapy can't improve OS (6months: risk ratio (RR)=0.97 P=0.11; 1year: RR=1.05 P=0.36), ORR (RR=1.00 P=0.95) and DCR (RR=0.92, 95%CI 0.85-1.00, P=0.04) of patients with lung cancer compared to pure chemotherapy, but it can improve the PFS (6months: RR=1.16 P=0.02; 1year: RR=1.39 P=0.02) and 6months-irPFS(RR=1.60 P=0.004). However, due to the addition of ipilimumab, the immune-related toxicities are more apparent in immunochemotherapy group.

Phase I Study of Ipilimumab Combined with Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients with Brain Metastases

Purpose: We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) in patients with brain metastases (BM) from melanoma.

Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma

BackgroundIpilimumab is approved for the treatment of advanced melanoma in adults; however, little information on the efficacy and safety of ipilimumab in younger patients is available. MethodsPatients aged 12 to <18 years with previously treated or untreated, unresectable stage III or IV malignant melanoma received ipilimumab 3 or 10 mg/kg every 3 weeks. Primary end-points were 1-year overall survival and safety. ResultsOver a period of 3.5 years, 12 patients received ipilimumab at either 3 mg/kg (n = 4) or 10 mg/kg (n = 8). The median number of ipilimumab doses was four for 3 mg/kg and three for 10 mg/kg. At 1 year, three of four patients on 3 mg/kg and five of eight patients on 10 mg/kg were alive. Two patients on 10 mg/kg had partial response, and one on 3 mg/kg had stable disease. One patient had durable partial response at 3 years without further treatment, at time of this report. There was one grade 3/4 immune-mediated adverse reaction with 3 mg/kg and five with 10 mg/kg. There were no treatment-related deaths. The study was stopped due to slow accrual. ConclusionsAt >1 year follow-up, ipilimumab demonstrated activity in melanoma patients aged 12 to <18 years, with a similar safety profile as that seen in adults. Our trial highlights the difficulties of enrolling younger patients with rare diseases in clinical trials for treatments that are approved in adults, suggesting adolescents with cancer types occurring predominantly in adults should be considered for inclusion in adult trials of promising new drugs.Clinical trial registration: NCT01696045.

EXPERIENCE OF APPLICATION OF IPILIMUMAB IN COMBINED THERAPY OF SMALL-CELL LUNG CANCER. ANALYSIS OF DATA OF THE MULTICENTER RANDOMIZED RESEARCH CA 184-156, PHASE III

Patients with advanced small cell lung cancer (SCLC) have an extremely poor prognosis against a background of standard therapy with a combination of etoposide with platinum drugs. In a randomized, double-blind of the CA184-156 phase 3, the efficacy and safety of ipilimumab or placebo in combination with etoposide and platinum preparations was evaluated as the first line treatment for disseminated SCLC. Material and methods. Randomization of patients was carried out in a ratio of 1:1 in the group of therapy: etoposide + platinum drug (carboplatin or cisplatin) + ipilimumab and etoposide + platinum preparation + placebo. Ipilimumab/placebo was administered at a dose of 10 mg/kg every 3 weeks, starting from the 3rd course of chemotherapy to the 6th course of chemotherapy. Further, in the absence of progression, maintenance therapy with ipilimumab/placebo was performed every 12 weeks. The main end point of the study was the assessment of overall survival (OS). Results. Out of 1,132 randomized patients, 954 received at least 1 administration of ipilimumab/placebo in combination with chemotherapy: ipilimumab, n = 478; placebo, n = 476. Median OS was 11.0 months in the chemotherapy group with ipilimumab and 10.9 months, in the chemotherapy group with placebo (RR, 0.94, 95% CI, 0.81-1.09, p =0,3775). The median progression-free survival was 4.6 months in the chemotherapy group with ipilimumab and 4.4 months in the chemotherapy group with placebo. (RR, 0.85, 95% CI, 0.75-0.97). The frequency and severity of side effects in the compared groups was similar, with the exception of diarrhea, rash, and colitis, which occurred significantly more frequent in the chemotherapy group with ipilimumab. The frequency of the discontinuation of therapy due to toxicity was higher in the chemotherapy group with ipilimumab (18% vs. 2%). Treatment-related deaths accounted for 5 in the chemotherapy group with ipilimumab and 2 - in the chemotherapy group with placebo. Conclusion. The addition of ipilimumab to chemotherapy did not contribute to an increase in OS in comparison with only chemotherapy in advanced SCLC patients. Unexpected adverse events in the chemotherapy group with ipilimumab were not noted. The study of the efficacy of ipilimumab in patients with disseminated SCLC in combination with PD1 inhibitors is ongoing. The results obtained in the analysis of data in a subset of 33 patients who participated in this study on the basis of the Department chemotherapy of N.N. Blokhin Russian Cancer Research Center, correspond to data obtained in the entire multicenter study CA184-156.

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases

We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3mg/kg every 3weeks, starting on day 3 of WBRT or 2days after SRS. The ipilimumab dose was escalated to 10mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3mg/kg (n=7) or 10mg/kg (n=9). The median follow-up was 8months (arm A) and 10.5months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5months and 8months and in arm B was 2.1months and not reached, respectively. Concurrent ipilimumab 10mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

Phase II study of ipilimumab (IPI) in children and adolescents with unresectable stage III or IV malignant melanoma (MEL).

e21006 Background: IPI (anti-CTLA4) is approved for treatment of advanced MEL in adults, and more information on efficacy and safety of IPI in younger patients (pts) is needed. Methods: Pts from study CA184-178 (NCT01696045) age 12 to &lt;18 yrs with previously treated or untreated, unresectable stage III or IV malignant MEL received up to 4 doses of IPI at 3 or 10 mg/kg Q3W. Key exclusion criteria were ocular MEL, active brain metastases, or autoimmune disease. Primary endpoints were 1-yr overall survival (OS) and safety. Results: From April 2013 to June 2016, 12 pts received either IPI 3 mg/kg (n=4) or 10 mg/kg (n=8); 2 did not meet study criteria and were not treated. For the 3 and 10 mg/kg groups, median age was 13 yrs and 15 yrs, 50% and 63% were male, 25% and 13% had elevated baseline lactate dehydrogenase, and 75% and 50% had prior systemic therapy, respectively. Median number of IPI doses received was 4.0 (range: 2–4) for 3 mg/kg and 3.0 (range: 1–4) for 10 mg/kg. At 1 yr, 3/4 pts on 3 mg/kg and 5/8 pts on 10 mg/kg were alive (Table). Two pts on 10 mg/kg had partial response and 1 pt from each group had stable disease (Table). One pt had ongoing partial response &gt;2 yrs without further treatment. Treatment-related grade 1-4 adverse events were reported in 2/4 and 7/8 pts in 3 and 10 mg/kg groups, respectively. There was 1 grade 3-4 immune-mediated adverse reaction with 3 mg/kg (hepatitis) and 5 with 10 mg/kg (hepatitis [2] and pyrexia [2] were most common). The study was stopped early due to slow accrual. Conclusions: At &gt;1 yr of follow-up, IPI demonstrated activity in MEL pts aged 12 to &lt;18 yrs, with a safety profile consistent with that observed in adults. Our trial highlights the difficulties of enrolling children with rare diseases in clinical trials for drugs that are approved in adults, suggesting adolescents should be included earlier in adult trials of promising new drugs. Clinical trial information: NCT01696045. [Table: see text]

EURO-VOYAGE: Effectiveness and safety of ipilimumab (IPI) administered during a European Expanded Access Programme (EAP) in patients with advanced melanoma (MEL)

EURO-VOYAGE: Effectiveness and safety of ipilimumab (IPI) administered during a European Expanded Access Programme (EAP) in patients with advanced melanoma (MEL)

Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort.

PurposeIpilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes.Materials and MethodsAdvanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes.ResultsA total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (≥ 5) were independent poor prognostic factors by multivariate analysis.ConclusionIn the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR.

Abstract B72: Long-term survival and outcome update on patients (pts) with recurrent ovarian cancer who received Ipilimumab post GVAX vaccine.

Abstract Immunotherapeutic approaches are amongst the most exciting new therapies for cancer, and trials of immunotherapy agents to treat ovarian cancer are underway. We report on long-term outcomes of patients with advanced and recurrent ovarian cancer treated with single agent ipilimumab, a fully humanized IgG1 monoclonal antibody against CTLA-4, following receipt of GVAX vaccine, which was a lethally irradiated, autologous ovarian cancer cells engineered by adenoviral gene transfer to secrete granulocyte macrophage colony stimulating factor (GM-CSF). The objectives of this study were to determine the safety of ipilimumab, identify preliminary evidence of biologic activity and efficacy of ipilimumab post GVAX, and, as an exploratory objective, to correlate clinical benefit with the presence of antibodies to NY-ESO and p53. Results: Eleven pts who initially were treated with GVAX received ipilimumab (3 mg/kg) IV every 2 months on this study. These 11 patients had a median age of 61 years (range 38-82 years of age) at the time on enrollment and all had measureable cancer by RECIST 1.0. Eight pts had platinum resistant cancer and 3 had platinum sensitive cancer. Histologies enrolled were high grade serous (8 pts), clear cell (1pt), poorly differentiated (1 pt), and low grade serous that had evolved to high grade (1 pt). Patients were allowed to have had intervening treatment between initial GVAX vaccine and start of ipilimumab. Of the 11 pts, the median interval between GVAX and ipilimumab was 3 months, ranging from 1 month to 38 months. Overall, ipilimumab at 3 mg/kg was well tolerated; rash was grade 1 (63%), grade 2 (9%), grade 3 (9%). Diarrhea was 18% grade 2 and 18% grade 3. Other constitutional symptoms such as fatigue were 18% grade 1 and 9% grade 3. Of the 11 pts, 6 pts had disease progression by RECIST after 1 infusion of ipilimumab with overall survival post-ipilimumab ranging from 3 to 35 months; 2 of these pts had platinum sensitive recurrence. Of the 5 pts who either experienced SD (4 pts) and PR (1 pt), the number of ipilimumab infusions were 1, 2 (2 pts), 4, and 25 infusions with survival ranging from 23 to 104 months post-ipilimumab. One patient (OV65) who received 25 ipilimumab infusions from 2003 through 2011 lived for 104 months post-initiation of ipilimumab and had a PR to ipilimumab at 95 months; she had high grade serous platinum resistant cancer with spread to liver/omentum/lymph nodes, had present NY-ESO Ab's, and had a 1 month interval between GVAX and the initiation of ipilimumab infusions. OV65 received no further chemotherapy treatment after ipilimumab was started though she had evidence of cancer present during her ipilimumab treatment course; her eventual death was not cancer related. Conclusions: CTLA-4 blockade with ipilimumab can induce long-term disease control and has evidence of activity in ovarian cancer. The role of prior GVAX vaccination is not clear. Citation Format: Ursula Anne Matulonis, Stephen Hodi, Glenn Dranoff, Susana Campos, Richard Penson, Robert Soiffer, Marcus Butler. Long-term survival and outcome update on patients (pts) with recurrent ovarian cancer who received Ipilimumab post GVAX vaccine. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B72.

Abstract 246: Phase 1 study: Ipilimumab (anti CTLA-4) in combination with Lenalidomide in patients with advanced cancers

Abstract Background: Ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody potentiates an antitumor T-cell response. Lenalidomide, a derivative of thalidomide possesses immunomodulatory, antiangiogenic, and antineoplastic properties and thereby inhibits the growth of blood vessels and exhibits an anti-inflammatory effect. The potential synergistic effect of stimulating one's own immune system to attack cancer in combination with depriving further tumor growth provides rationale for combining Ipilimumab and Lenalidomide. Methods: We designed a phase I study (3+3 design) to determine the safety of Ipilimumab (1.5-3mg/kg IV q 28 days x 4) and Lenalidomide (10-25mg PO daily x 21 q 28 days) until disease progression or unacceptable toxicity in advanced cancers. Endpoints included maximum tolerated (MTD), dose limiting toxicities (DLT), safety, and response per immune response criteria (iRC). Results: To date, 21 patients (men, n = 8; women, n = 13), median age 56 (19-75) years, median of 3 (0-6) prior therapies (including 3 patients with prior ipilimumab) were enrolled in 3 of 5 dose levels ranging from 1.5-3mg of Ipilimumab and Lenalidomide 10-15 mg. The MTD has not been reached yet. DLT included grade (G) 3 macular rash in 2 patients (dose levels 2 and 3) and G3 pancreatitis (dose level 2). Other G3/4 drug related toxicities included G4 hypopituitarism (n = 1) and G3 pulmonary embolism (n = 1). Of 21 treated patients, 11 (52%) patients had stable disease. The median change in size of target lesions per iRC was 13% (-44% to +86%) with 5 (24%) of patients with at least -10% shrinkage (Hodgkin lymphoma, n = 2; melanoma, n = 1; follicular thyroid carcinoma, n = 1; teratoma, n = 1) lasting for 0.9 to 12.3+ months. The median time-to-treatment failure was 2.1 months (95% CI 1.4-2.8). Conclusion: Ipilimumab and Lenalidomide have manageable side effect profile and demonstrate possible activity in patients with refractory Hodgkin lymphoma, melanoma, follicular thyroid cancer and teratoma. Citation Format: Divya Sakamuri, Sonia L. Betancourt Cuellar, Isabella C. Glitza, Siqing Fu, Jennifer J. Wheler, Gerald S. Falchook, Apostolia M. Tsimberidou, David S. Hong, Vivek Subbiah, Michelle A. Fanale, Maria E. Cabanillas, Funda Meric-Bernstam, Filip Janku. Phase 1 study: Ipilimumab (anti CTLA-4) in combination with Lenalidomide in patients with advanced cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 246. doi:10.1158/1538-7445.AM2015-246

Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups.

9031 Background: Ipilimumab is a recently approved immunotherapy that has shown an overall survival benefit in previously treated and treatment-naive patients with metastatic melanoma in two phase ...

Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme

BackgroundElderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. Data from clinical trials and expanded access programmes (EAPs) suggest ipilimumab confers a consistent survival benefit and has a similar safety profile across different age groups of patients with metastatic melanoma. Here we report the efficacy and safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy.MethodsPatients aged > 70 years with pretreated melanoma received ipilimumab 3 mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated at baseline and after completion of induction therapy using immune-related response criteria and patients were monitored throughout the treatment period for adverse events (AEs), including immune-related AEs.ResultsThe immune-related disease control rate among 188 evaluable patients was 38%, including four patients with an immune-related complete response, 24 with an immune-related partial response and 44 with immune-related stable disease. Median progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1- and 2-year OS rates were 38% and 22%, respectively. The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines.ConclusionsThese results suggest ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.

Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases.

Patients with melanoma brain metastases have a poor prognosis and historically have been excluded from clinical trials. The Expanded Access Program (EAP) provided an opportunity to evaluate the feasibility of ipilimumab (3 mg/kg every 3 weeks for four doses) in patients with stage 3 (unresectable) or 4 melanoma and asymptomatic brain metastases, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Tumor assessments were conducted at baseline and week 12 using immune-related response criteria and patients were monitored for adverse events (AEs). Of 855 patients participating in the EAP in Italy, 146 had asymptomatic brain metastases. With a median follow-up of 4 months, the global disease control rate was 27 %, including 4 patients with a complete response and 13 with a partial response. Median progression-free survival and overall survival were 2.8 and 4.3 months, respectively and approximately one-fifth of patients were alive 1 year after starting ipilimumab. In total, 29 % of patients reported a treatment-related AE of any grade, which were grade 3/4 in 6 % of patients. AEs were generally reversible with treatment as per protocol-specific guidelines. Ipilimumab shows durable benefits in some patients with advanced melanoma metastatic to the brain, with safety results consistent with those previously reported in clinical trials.