Liposomal Vincristine Research Articles

A phase 1 trial of venetoclax in combination with liposomal vincristine in patients with relapsed or refractory B-cell or T-cell acute lymphoblastic leukemia: Results from the ECOG-ACRIN EA9152 protocol.

Relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B- and T-ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for patients with r/r B-or T-cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). In a 3+3 dose escalation design, r/r ALL subjects were given single-agent VEN doses reaching 400, 600, or 800mg for the three respective dose levels. Weekly L-VCR at 2.25mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination. Among the 18 patients in phase I, grade≥3 treatment-related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose-limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600mg). Twenty-two percent of evaluable patients (N=4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD). The combination of VEN and L-VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L-VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

A Multicenter, Prospective Clinical Study of the R-CDOP Regimen in Previously Untreated Non-Hodgkin Lymphoma with High Tumor Burden

Background: The treatment of non-Hodgkin lymphoma (NHL) with high tumor burden is facing severe challenges. The response rate and survival of R-CHOP treatment still need to be further explored in these patients. Pegylated liposomal doxorubicin (PLD) is a promising alternative drug to the current regimen, with a safety and efficacy profile through the enhanced permeability and retention effect and longer circulation1-3, and especially less cardiotoxic compared with traditional anthracyclines4. We conducted this prospective study to evaluate the efficacy and safety of PLD combined with R-COP (R-CDOP) regimen in treatment for previously untreated (TN) NHL with high tumor burden. Methods: This study was a single-arm, multicenter, prospective clinical trial (NCT05040555). TN Patients with CD20+ diffuse large B-cell lymphoma or grade 3b follicular lymphoma with high tumor burden were recruited. Patients are considered to have high tumor burden if they meet at least one of the following criteria: (1) presence of at least three lymph nodes with a diameter of 3 cm or more; (2) presence of any lymph nodes or extranodal masses with a diameter of 7 cm or more; (3) presence of hepatomegaly and splenomegaly confirmed by PET-CT; Spleen: female > 15cm, male > 16cm); (4) presence of pleural and peritoneal effusions determined through cytological examination, flow cytometry, or diagnosed by PET-CT, (5) LDH levels exceeding 3 times the upper limit of normal value, and (6) PET-CT TMTV exceeding 220cm3. The patients received PLD (30-35mg/ m2, d1) plus Rituximab (375mg/m2, d0), Cyclophosphamide (750mg/ m2, d1), Vindesine (3mg/ m2, d1) / Vincristine (1.4mg/m2, d1) and Prednisone (60mg/ m2, d1-5) Q3W for 4 (Limited-stage lymphoma) or 6 (Advanced lymphoma) cycles with an additional 2 cycles of Rituximab therapy. The primary endpoints was objective response rate (ORR). The secondary endpoint were complete response rate (CRR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: At the data cut-off of 5 June 2023, 44 eligible pts were enrolled (Table 1). The ORR and CRR was 84.2% (32/38) [95%CI, 68.8%-94.0%] and 60.5% (23/38) [95%CI, 43.4-76.0%], respectively. The DCR was 89.5% (34/38) [95%CI, 75.2%-97.1%]. The median PFS was 14.4 months [95%CI, 4.7%-24.2%], and the median OS was not reached. The median PFS and OS will be updated after long-term follow-up. The most common grade 3/4 AEs were neutropenia (29.5%), leucopenia (25.0%) and anemia (11.4%). Left ventricular ejection fraction (LVEF) declined in 1(1/44, 2.3%) pt, but did not fall below 50%. Congestive heart failure was not occurred. Dose adjustment and treatment delay due to AE occurred in only one pt, and no treatment termination due to AE occurred except for 1 patient death. Conclusions: The preliminary results of the study indicate that the R-CDOP regimen is safe and shows promising efficacy for treating TN NHL with a high tumor burden. References： 1. Hashizume H, Baluk P, Morikawa S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156 (4):1363-1380 2. Gabizon A, Shmeeda H, Grenader T. Pharmacological basis of pegylated liposomal doxorubicin: impact on cancer therapy. Eur J Pharm Sci. 2012;45(4):388-398. 3. Sadzuka Y, Sugiyama I, Tsuruda T, et al. Characterization and cytotoxicity of mixed polyethyleneglycol modified liposomes containing doxorubicin. Int J Pharm. 2006;312(1-2):83-89. 4. Lu B, Shen L, Ma Y, et al. Cardiovascular adverse events associated with cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone with or without rituximab ((R)-CDOP) in non-Hodgkin's lymphoma: A systematic review and meta-analysis. Front Pharmacol. 2022;13:1060668.

A Comparison of Clinical Prognostic Indices in Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with a Pegylated Liposomal Doxorubicin Combination Regimen in China.

BackgroundThere is no consensus regarding the risk stratification scores for elderly patients with diffuse large B-cell lymphoma (DLBCL). We aimed to compare the prognostic predictive ability of the current clinical scoring indices in DLBCL elderly patients treated with the R-CODP regimen (rituximab, cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone).MethodsWe retrospectively collected the data of elderly DLBCL patients who received the R-CODP regimen as the first-line treatment. The efficacy of the regimen was evaluated. The Akaike information criteria (AIC), concordance index (C-index), and integrated discrimination improvement (IDI) were used to assess the fitness and prognostic performance of the current clinical prognostic indices.ResultsIn the total of 158 patients enrolled, the median follow-up time was 6.7 years (95% CI: 6.3–7.9), and the 5-year OS was 52.8% (95% CI: 45.5%–61.2%). The International Prognostic Index (IPI), National Comprehensive Cancer Network-IPI (NCCN-IPI), and Elderly International Prognostic Index (E-IPI) were all significantly associated with OS (P < 0.001 for all). However, no significance was observed in 5-year OS in the low- vs low-intermediate-risk groups for IPI (P = 0.377), NCCN-IPI (P = 0.238), and E-IPI (P = 0.080). Compared with the IPI and NCCN-IPI, the E-IPI had the lowest AIC value of 747.5 and the highest C-index of 0.692. For predicting 5-year mortality, the E-IPI showed better performance (AUC: 0.715 for E-IPI vs 0.676 for IPI, P = 0.036), with the IDI of 6.29% (95% CI: 3.71%-8.88%, P < 0.001) and 4.80% (95% CI: 1.32%-8.28%, P = 0.007) compared to the IPI and NCCN-IPI, respectively.ConclusionThe E-IPI might be a better prognostic prediction model in Chinese DLBCL generics treated with R-CODP for predicting 5-year mortality. However, the IPI, NCCN-IPI, and E-IPI did not seem to be able to distinguish patients with a favorable prognosis well.

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

Trial in Progress: A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE ® Antibody Blinatumomab (Blincyto) and Vincristine Sulfate Liposomal Injection (Marqibo) in Adult Subjects with Relapsed/Refractory Philadelphia Negative CD19+ Acute Lymphoblastic Leukemia

Trial in Progress: A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE ® Antibody Blinatumomab (Blincyto) and Vincristine Sulfate Liposomal Injection (Marqibo) in Adult Subjects with Relapsed/Refractory Philadelphia Negative CD19+ Acute Lymphoblastic Leukemia

Phase II Study of Hyper-Cmad with Liposomal Vincristine (Marqibo) for Patients with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

▪Background: Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy for patients with relapsed / refractory ALL. Replacement of regular vincristine with liposomal vincristine might lead to improve response rate and survival as well as reduced toxicity.Methods: Patients ≥18 years with newly-diagnosed B-cell ALL were eligible for the phase II clinical trial consisting of hyper-CMAD (cyclophosphamide 300 mg/m2 IV every 12 hours on days 1-3; liposomal vincristine 2.0 mg/m2 IV on day 1 and day 8; doxorubicin 50 mg/m2 IV on day 4; dexamethasone 40 mg IV daily on days 1-4 and days 11-14) (odd cycles 1, 3, 5, 7) alternating with high-dose methotrexate 1000 mg/m2 IV on day 1, and cytarabine 3 gm/m2 IV every 12 hours on days 2, 3 (even cycles 2, 4, 6, 8). Rituximab 375 mg/m2 IV on days 1 and 8 for courses 1-4 was administered in CD-20 positive ALL. Imatinib 600 mg PO daily or dasatinib 100 mg PO daily days 1-14 on course 1 and continuously (imatinib 600 mg PO or dasatinib 70 mg PO) daily starting day 1 after the first cycle in Philadelphia chromosome positive (Ph+) ALL.Results: Thirty-one patients (16 men, 15 women) have been treated. Patient characteristic and response are described in Table 1. Median follow-up is 33 months (5-46) with a median cycle of 4 cycles (1-8). Median age is 53 years (range 19-80). Thirteen patients (42%) had CD-20 positive ALL, and 21 (68%) had Ph+ ALL. Thirty (97%) achieved complete remission (CR). Early death was observed in 1 patient (3%) with Ph+ ALL. Of 26 patients evaluable for response, 26 (100%) achieved complete cytogenetic response (3 patients, diploid at start; 1 patient, not performed), and 27 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable patients with Ph+ ALL, major molecular response was achieved in 19 patients (95%); complete molecular response in 14 (70%). Grade 3/4 toxicity ≥10% included infections in 28 (90%); hyperglycemia, 16 (52%); hypokalemia, 15 (48%); hypophosphatemia, 15 (45%); hypocalcemia, 10 (32%); DVT, 7 (23%); hyponatremia, 7 (23%); hypoalbuminemia, 6 (19%); peripheral neuropathy, 5 (16%); elevated ALT, 5 (16%); and acute kidney injury 4 (13%). All grade peripheral neuropathy was observed in 21 (68%). With a median follow-up of 33 months, 21 (68%) patients are alive. Ten (32%) patients died: 1, sepsis on C1D10; 4, unknown; 1, post-transplant complications; 4, relapse. The 2-year CR duration and survival rates were 83% and 68%, respectively (Figure 1).Conclusions: Hyper-CMAD with liposomal vincristine is safe and shows high response and survival rates in patients with newly diagnosed ALL. [Display omitted] DisclosuresJabbour:Bristol-Myers Squibb: Consultancy. Thomas:Amgen: Honoraria; Pfizer: Honoraria. Cortes:BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. O'Brien:Janssen: Consultancy; Sunesis: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; AbbVie: Consultancy; Celgene: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Acerta: Other: Research Support: Honorarium, Research Funding; Aptose Biosciences, Inc.: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Alexion: Consultancy; Astellas: Consultancy; GSK: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding.

Excellent Outcome of Elderly Patients with Favourable-Prognosis DLBCL Treated with 4 Cycles CHOP/Chlip-14 Plus 8 Applications of Rituximab and a PET-Based Intensification Strategy That Includes Involved-Site Radiotherapy (IS-RT): Results of the First 120 Patients of the OPTIMAL>60 Trial of the Dshnhl

Background: The RICOVER-60 trial established 6 cycles CHOP-14 plus 8 2-week applications of rituximab (8xR) as the optimal treatment for elderly patients with DLBCL [Pfreundschuh et al., Lancet Oncol 2008; 9: 105-116]. With a 2-year PFS of 90% and OS of 91% for patients with favourable prognosis (defined as IPI=1 [age >60 years], no bulky disease) a controlled reduction of treatment intensity appeared to be justified for this population. We hypothesized that patients with a negative PET (metabolic complete remission = mCR) after 4xR-CHOP-14 might be spared further chemotherapy (ChT), while patients not in mCR might benefit from the addition of RT. To ensure that this strategy does not put patients at risk, an interim analysis was planned after 40% of the expected events for a comparison with RICOVER-60.Patients and Methods: 61 to 80 year-old IPI=1 pts. without bulky (≥7.5 cm) disease were randomized to 4xCHOP-14 or 4x-CHLIP-14 (liposomal instead of conventional vincristine) in combination with 8 2-week applications of rituximab. Primary endpoint was the comparison of the neurotoxicity of conventional and liposomal vincristine. Patients with a negative PET after 4x-R-CHOP/R-CHLIP-14 completed the remaining 4xR, while PET-positive (Deauville 3-5 as by central review) patients in addition received 2 additional CHOP/CHLIP-14 + plus IS-RT (39.6 Gy) to the originally involved sites.Results: This planned interim analysis was performed to compare patient outcome with the old (fixed) and the new PET-adapted (flexible) treatment strategy. Compared to 74 RICOVER-60 pts. who had received 6xCHOP-14 plus 8xR, OPTIMAL>60 pts. were older (median: 71 vs. 68 years; p=0.009), with a larger proportion of patients >70 and >75 years. Despite the unfavourable demographics, outcome of the OPTIMAL>60 pts. receiving R-CHOP/CHLIP-14 was non-inferior to RICOVER-60 (2-y-PFS: 94% vs. 90% ; 2-y-OS 98% vs. 91%). In a multivariable analysis adjusting for strata (age >75 years and male sex), the hazard ratio of the OPTIMAL>60 compared to the RICOVER-60 was 0.5 (95% CI: 0.2-1.5; p=0.208) for PFS and 0.2 (95% CI: 0.1-0.9; p=0.036) for OS. 82% pts. were in mCR after 4xR-CHOP/CHLIP-14 and received no further ChT; 18% were PET-positive and thus to receive 2 additional CHOP/CHLIP-14 plus IS-RT, and their outcome was as good as that of mCR patients.Conclusion: A PET-based treatment strategy allows sparing 2 cycles ChT in 82% of patients without compromising their outcome. 4xCHOP/CHLIP-14 plus 8xR for patients with a negative PET after 4 cycles of immunochemotherapy in OPTIMAL>60 is at least as good as 6xCHOP-14 plus 8xR in RICOVER-60 and appears to provide a normal life expectancy for this elderly population with a median age of 71 years. 2 additional ChT cycles plus IS-RT appear to compensate for the assumed worse prognosis of PET-positive patients, which might be in part due to the early start of RT made possible by the 2-week ChT regimens. The 98% 2y-OS is the best reported to date for this elderly population and should be the reference to which alternative strategies should be compared. Updated 3-year results will be reported. S upported by Amgen, Roche, Spectrum DisclosuresChristofyllakis:medac: Other: travel expenses, event fees; Gilead: Other: travel expenses, event fees. Haenel:Roche, Novartis: Honoraria. Schmidt:Janssen: Other: Travel grants; Amgen: Membership on an entity's Board of Directors or advisory committees. Huebel:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hellwig:Employment at University Hospital Regensburg, Germany: Employment; Research Funding by Saarland University, Saarbruecken, Germany: Research Funding.

Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia in Real-World US Practices

BACKGROUNDAcute Lymphoblastic Leukemia (ALL) in adults is a rare malignancy associated with high rates of relapse and poor outcomes. Despite the availability of multi-agent chemotherapies and the recently-approved novel targeted therapy blinatumomab (BLINA), most adults with relapsed or refractory (R/R) ALL are unlikely to achieve remission, undergo hematopoietic cell transplant (HCT), and experience long-term survival. The objective of this study was to determine current real-world standard of care, patient characteristics, healthcare resource utilization, and outcomes for adult R/R ALL after first relapse. Here we report patient characteristics, treatment patterns, and outcomes for this population.METHODSWe conducted a retrospective study using Symphony Health Solutions' Integrated Dataverse, a longitudinal transactional database that includes prescription, medical and hospital claims across > 4,900 US payers. Eligible patients were >15 yr, and had at least 1 ICD-9 or ICD-10 diagnosis code for ALL between Jan 1, 2009 and Aug 31, 2016. Adolescent and young adults were defined as age 15-39, adults > 40, induction therapies, and salvage regimens were based on NCCN ALL guidelines Ver 2, 2016. To identify patients receiving their 1st salvage regimen (S1), the following criteria were applied: patients had at least 1 medical or 1 hospital claim 12 months prior to first ALL diagnosis, and either one prior induction or an ALL diagnosis of relapse or remission on or before the start of first identified induction. Those with prescriptions for a tyrosine kinase inhibitor were excluded to focus analyses on Philadelphia chromosome negative ALL only. Index date was the start of S1. A minimum of 90 days follow-up to study end was required. Patients who died prior to the end of minimum follow up were also included. Baseline comorbidities and the Charlson Age-adjusted Comorbidity Index (CCI) were analyzed for up to 6 months prior to index date. We categorized the most frequently-used S1 regimens, with regimens representing <10% of the sample grouped as “other”. Summary statistics were reported.RESULTS588 R/R ALL patients receiving a S1 regimen met the inclusion/exclusion criteria. Median duration of follow-up was 415 days (range 7-700). Median age was 37 (range 15-87), with 54% aged 15-39, 46% aged >40, and a slight male predominance (57% vs 43%). The 4 most commonly used S1 regimens were BLINA 33%, liposomal vincristine (LV 19%), nelarabine (NEL 12%), and hyper-CVAD (HCVAD 10%). BLINA was commonly used among patients >40 (41%; 113 patients/273 Total), although LV was most frequently used in patients > 65 (41%; 32 patients/78 Total). Patients receiving LV and BLINA were the oldest (median 49 and 47 yr, respectively). Patients on HCVAD were the youngest (median 30 yr).HCT use pre-S1 (23%) and post-S1 (22%) was highest in NEL patients. Overall, post-S1 HCT use was low (11%), and was lowest after BLINA (7%) (Table 1).At baseline, CCI was highest (mean 4.5) for patients receiving LV (mean 3.9, 3.8, and 4.0 for BLINA, HCVAD, and NEL, respectively). As expected, most patients suffered from bone marrow insufficiency, including anemia, neutropenia, and thrombocytopenia, with patients on HCVAD having the highest prevalence. Corresponding constitutional and gastrointestinal (GI) problems were also prevalent, including fever, nausea, fatigue, headache, cough, pain (back, abdominal, extremities), constipation, diarrhea, dehydration, and infections (pneumonia, sepsis, bacteremia). Anxiety and depression were frequent. Comorbidities associated with advanced age, such as hypertension, diabetes, and congestive heart failure (CHF) were the lowest among patients on HCVAD and higher for patients on LV and NEL (Table 2).CONCLUSIONSThe burden of illness for adults with R/R ALL is high. This real-world study suggests that age and comorbidities may be associated with choice of S1 therapy. Overall, BLINA was the most common S1 choice. Patients treated with HCVAD were younger, had higher hematological burden, and lower age-related comorbidities. Patients receiving LV were older, had lower hematological disease burden, but a higher overall CCI. HCT rates were low after all S1 therapies, with BLINA having the lowest rate despite being the newest, most commonly used option. It would be important to determine resource utilization, cost and outcomes of various treatment choices. [Display omitted] DisclosuresLeBlanc:Celgene: Honoraria; Cambia Health Foundation: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria; Janssen: Honoraria; AstraZeneca: Research Funding; American Cancer Society: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Flatiron Health: Consultancy; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Borham:Pfizer Inc.: Employment, Equity Ownership. Su:Pfizer Inc.: Employment, Equity Ownership. Chun Hayes:Symphony Health Solutions: Consultancy, Employment. Fielding:Principled Strategies Inc.: Employment. Benigno:Pfizer Inc.: Employment, Equity Ownership. Cappelleri:Pfizer Inc: Employment, Equity Ownership.

Abstract 2883: A transformable delivery system for the effective treatment of pediatric central nervous system tumors

Abstract Malignancies of the central nervous system (CNS) are the most common type of solid tumor affecting children and a leading cause of cancer-related death in children. With the deterioration of brain tumors, blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB) with poor permeability, and relatively weak enhanced permeability and retention effect become major obstacles in delivering therapeutics to brain tumors. Vincristine (VCR) is a mainstay of treatment of a variety of cancers including brain tumors due to its well-defined mechanism of action and demonstrated anticancer activity. However, the clinical application of VCR in brain tumors was limited by its neurotoxicity and inability to penetrate BBB/BBTB resulting in unsatisfactory anti-cancer efficacy. In this project, we developed a transformable nanoparticle, named Ninja-nanoparticle, which is capable overcoming several important barriers for drug delivery to CNS tumors resulting in better efficacy and toxicity profile. Ninja-NP was stable during circulation due to crosslinking and could transpass BBB/BBTB through glucose receptor-mediated transcytosis. Ninja-NP could further transform into smaller nanoparticle upon encountering acidic microenvironment and revealed hidden moiety to target tumor surface overexpressed sialic acid. Ninja-NP employed a unique strategy which could sequentially target BBB/BBTB and brain tumor cells. Our study confirmed that VCR loaded Ninja-NP significantly accumulated at the orthotopic brain tumor sites, and exhibited superior anti-cancer efficacy in orthotopic diffuse intrinsic pontine glioma (DIPG), the most deadly pediatric CNS tumor, then free VCR or Liposomal VCR with limited systemic toxicity. Ninja-NP addresses multiple challenges for CNS tumor treatment and exhibits great potential to be translated into an effective theranostic nano-platform which could be seamlessly integrated into standard human brain tumor management (imaging-guided drug delivery) with reduced long term toxicity. Citation Format: Tzu-yin Lin. A transformable delivery system for the effective treatment of pediatric central nervous system tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2883.

Abstract 3116: Targeting fibroblast growth factor receptors in rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma and is classified into two main histopathological subtypes: embryonal RMS (eRMS), characterized by different genomic changes or alveolar RMS (aRMS), driven by the oncogenic fusion protein PAX3-FOXO1. The significant toxicity associated with conventional chemotherapies represents a major complication in pediatric oncology. To improve current therapies, we adopted two different strategies targeting fibroblast growth factor receptors (FGFR) in RMS. FGFR1-4 are a family of transmembrane receptor tyrosine kinases. Their activation upon binding of fibroblast growth factors (FGF) triggers pro-survival and proliferative signals. Our goal is to deliver drugs specifically to the tumor site by taking advantage of FGFR4 overexpression in RMS. To this end, we will covalently link FGFR4 specific nanobodies to the surface of liposomal vincristine in order to actively target RMS cells. We have established the optimal conditions to formulate liposomes loaded with vincristine. Following nanobody phage display selection on recombinant FGFR4 we focused on the top scoring candidates. Flow cytometry analysis on FGFR4-expressing versus FGFR4 knock-out RMS cell lines showed receptor-specific binding of three nanobodies. In activation assays with the FGFR4 specific growth factor FGF19, we demonstrated that the three binding candidates also blocked downstream ERK activation in RMS cells. We will now assess their theranostic potential on drug-loaded and fluorescently labeled nanovesicles on RMS tumor cells in vitro and in xenografts in vivo. Surprisingly, we observed change in cell morphology followed by cell death upon exposure to FGF2 in a subset of cultured cells established from eRMS patient-derived xenografts. Inappropriate expression of FGFRs and FGF signaling is implicated in tumor progression and therefore our findings appear contradictory. Dose-response experiments have shown that FGFR inhibition with small molecule inhibitors completely rescued FGF2 toxicity. In contrast, however, we detected high expression levels of FGFR1, 2 and 4 as well as activating mutations of FGFR4 in FGF2-sensitive eRMS cells. Therefore, our results are of upmost clinical relevance since genetically-based drug selection could lead to an inappropriate treatment inducing tumor promoting conditions. Hence, our second goal is to further unravel the molecular mechanism underlying the toxic effect of FGF-2 in a subset of eRMS tumors to avoid potentially harmful treatments. In summary, we have identified FGFR4 specific nanobodies that bind to the receptor and block downstream signaling in RMS cells. Active drug delivery of liposomal vincristine to the tumor site has the potential to enhance the therapeutic impact and decrease side effects. Moreover, we discovered a toxic effect of FGF2 in a subgroup of eRMS patient derived xenograft cells which might open new avenues for treatment. Citation Format: Nagjie Alijaj, Sandrine Moutel, Maxim Gray, Maurizio Roveri, Gabriele Manzella, Marco Wachtel, Franck Perez, Beat Schäfer, Michele Bernasconi. Targeting fibroblast growth factor receptors in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3116.

Liposomal Vincristine as a Bridge Therapy Prior to CAR-T Therapy in Relapsed and Refractory Diffuse Large B-Cell Lymphoma?

We report a case of a 76-year-old male with a history of relapsed and refractory diffuse large B-cell lymphoma (DLBCL).Our patient was initially treated with front line chemotherapy along with central nervous system (CNS) prophylaxis with complete response. He subsequently relapsed, was sensitive to second-line chemotherapy, and underwent autologous stem cell transplantation achieving a complete remission. Only a few months after transplant, the patient suffered his second relapse and was deemed a candidate for Chimeric Antigen Receptor T-Cell Therapy (CAR-T). Given his aggressive disease, combined with the time needed to generate CAR-T cells, a multidisciplinary team recommended to treat our patient with liposomal vincristine in combination with rituximab as a bridge therapy. Durable responses have been seen using liposomal vincristine based on results from a recent phase II trial in heavily pretreated patients with DLBCL1. This therapy was effective in stabilizing and reducing active disease in our patient. This case looks to illustrate the use of liposomal vincristine in combination with immunotherapy in a novel setting bridging highly selected patients with active and refractory lymphoma prior to CAR-T. Moreover, we expanded an additional therapeutic point, highlighting the importance of optimal disease control prior to CAR-T cell harvesting, as recent literature has shown that residual malignant cells in the pheresis product may be inadvertently be transfected with the CAR gene, resulting in resistance and further relapse2.

Dynamic Personalized Assessment of Outcome in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Dynamic Personalized Assessment of Outcome in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future.

Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future.

Phase II study of hyper-CMAD with Liposomal Vincristine (Marqibo) for Patients with Newly Diagnosed Acute Lymphoblastic Leukemia

Abstract Background: Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy for patients with relapsed / refractory ALL. Replacement of regular vincristine with liposomal vincristine might lead to improve response rate and survival as well as reduced toxicity. Methods: Patients ≥18 years with newly-diagnosed B-cell ALL were eligible for the phase II clinical trial consisting of hyper-CMAD (cyclophosphamide 300 mg/m2 IV every 12 hours on days 1-3; liposomal vincristine 2.0 mg/m2 IV on day 1 and day 8; doxorubicin 50 mg/m2 IV on day 4; dexamethasone 40 mg IV daily on days 1-4 and days 11-14) (odd cycles 1, 3, 5, 7) alternating with high-dose methotrexate 1000 mg/m2 IV on day 1, and cytarabine 3 gm/m2 IV every 12 hours on days 2, 3 (even cycles 2, 4, 6, 8). Rituximab 375 mg/m2 IV on days 1 and 8 for courses 1-4 was administered in CD-20 positive ALL. Imatinib 600 mg PO daily or dasatinib 100 mg PO daily days 1-14 on course 1 and continuously (imatinib 600 mg PO or dasatinib 70 mg PO) daily starting day 1 after the first cycle in Philadelphia chromosome positive (Ph+) ALL. Results: Thirty-one patients (16 men, 15 women) have been treated. Patient characteristic and response are described in Table 1. Median follow-up is 33 months (5-46) with a median cycle of 4 cycles (1-8). Median age is 53 years (range 19-80). Thirteen patients (42%) had CD-20 positive ALL, and 21 (68%) had Ph+ ALL. Thirty (97%) achieved complete remission (CR). Early death was observed in 1 patient (3%) with Ph+ ALL. Of 26 patients evaluable for response, 26 (100%) achieved complete cytogenetic response (3 patients, diploid at start; 1 patient, not performed), and 27 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable patients with Ph+ ALL, major molecular response was achieved in 19 patients (95%); complete molecular response in 14 (70%). Grade 3/4 toxicity ≥10% included infections in 28 (90%); hyperglycemia, 16 (52%); hypokalemia, 15 (48%); hypophosphatemia, 15 (45%); hypocalcemia, 10 (32%); DVT, 7 (23%); hyponatremia, 7 (23%); hypoalbuminemia, 6 (19%); peripheral neuropathy, 5 (16%); elevated ALT, 5 (16%); and acute kidney injury 4 (13%). All grade peripheral neuropathy was observed in 21 (68%). With a median follow-up of 33 months, 21 (68%) patients are alive. Ten (32%) patients died: 1, sepsis on C1D10; 4, unknown; 1, post-transplant complications; 4, relapse. The 2-year CR duration and survival rates were 83% and 68%, respectively (Figure 1). Conclusions: Hyper-CMAD with liposomal vincristine is safe and shows high response and survival rates in patients with newly diagnosed ALL. Download : Download high-res image (147KB) Download : Download full-size image Disclosures Jabbour: Bristol-Myers Squibb: Consultancy. Thomas: Amgen: Honoraria; Pfizer: Honoraria. Cortes: BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. O'Brien: Janssen: Consultancy; Sunesis: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; AbbVie: Consultancy; Celgene: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Acerta: Other: Research Support: Honorarium, Research Funding; Aptose Biosciences, Inc.: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Alexion: Consultancy; Astellas: Consultancy; GSK: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding. Kantarjian: Amgen: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding.

ANTI‐INFECTIVE PROPHYLAXIS WITH ACICLOVIR AND COTRIMOXAZOLE SIGNIFICANTLY REDUCES THE RATE OF INFECTIONS AND THERAPY‐ASSOCIATED DEATHS IN ELDERLY PATIENTS WITH DLBCL UNDERGOING R‐CHOP IMMUNOCHEMOTHERAPY

Background: To study if anti-infective prophylaxis with aciclovir and cotrimoxazole is effective in preventing infections in pts. receiving R-CHOP, we compared infections and treatment-related deaths in two prospective DSHNHL trials with different anti-infective strategies. Methods: 61- to 80-year-old pts. in RICOVER-60 study [Pfreundschuh et al; Lancet Oncol 2008; 9:105-116] received 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab. Anti-infective prophylaxis consisted of ciprofloxazine (500 mg/d) during days of severe leukocytopenia (<1000/mm3). In OPTIMAL > 60, pts. were randomized to 6xCHOP-14 or 6xCHLIP-14 (conventional substituted by liposomal vincristine [2 m/m2, uncapped]) in combination with rituximab, 8 applications q 2 weeks or 12 applications between days -4 and 238 in a 2 × 2 factorial design. In OPTIMAL > 60, anti-infective prophylaxis consisted of cotrimoxazole (2 double-strength doses twice every week p.o.) and aciclovir (4 × 400 mg/d p.o.) in addition to ciprofloxazine. Results: In RICOVER-60, grade 3&4 infections in 232 patients (IPI = 1 and bulky disease or IPI > 1) receiving 6xCHOP-14 + 8R were 6% (76/1200) per cycle and 28% (60/218) per patient. OPTIMAL > 60 pts. were older (70 vs 68 years) and had more IPI = 3 (33% vs 29%) and IPI = 4.5 (34% vs 23%) compared to RICOVER-60. With intensified anti-infective prophylaxis in OPTIMAL > 60, there were no differences with respect to infections between the 4 treatment arms. Despite the considerably less favourable demographics of the OPTIMAL > 60 study, grade 3&4 infections were 4% (83/1987) per cycle and 18% (64/365 pts. with toxicity documentation) per patient, significantly less than in RICOVER-60 (per cycle: p = 0.007; per patient: p = 0.004). Even more importantly, treatment-related deaths (defined as all non-lymphoma associated deaths during and within 2 months after the end of chemotherapy) went down from 15/232 (7%) in RICOVER-60 to 7/385 (2%) in OPTIMAL > 60 (p = 0.003). Conclusion: Anti-infective prophylaxis with cotrimoxazole and aciclovir in addition to ciprofloxazine significantly reduced the rates of severe infections and treatment-related deaths in elderly patients receiving R-CHOP supporting the use of this anti-infective strategy in all DLBCL patients receiving R-CHOP. Keywords: diffuse large B-cell lymphoma (DLBCL); immunochemotherapy; R-CHOP

Anti-infective prophylaxis with aciclovir and cotrimoxazole to reduce the rate of infections and therapy-associated deaths in elderly patients with DLBCL undergoing R-CHOP immunochemotherapy.

7539 Background: To study if anti-infective prophylaxis with aciclovir and cotrimoxazole is effective in preventing infections in pts. receiving R-CHOP, we compared infections and treatment-related deaths in two prospective DSHNHL trials with different anti-infective strategies. Methods: 61-80-yo. pts. in RICOVER-60 study [Lancet Oncol 2008; 9:105-116] received 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab. Anti-infective prophylaxis consisted of ciprofloxazine (500 mg/d) during days of severe leukocytopenia ( &lt; 1000 / mm3). In OPTIMAL &gt; 60, pts. were randomized to 6xCHOP-14 or 6xCHLIP-14 (conventional substituted by liposomal vincristine) in combination with rituximab, 8 applications q 2 wks. or 12 applications between days -4 and 238 /2x2 factorial design). In OPTIMAL &gt; 60, anti-infective prophylaxis consisted of cotrimoxazole (2 double strength doses twice every week p. o.) and aciclovir (4 x 400 mg/d p.o.) in addition to ciprofloxazine. Results: In RICOVER-60, grade 3&amp;4 infections in 232 patients (IPI = 1 and bulky disease or IPI &gt; 1) receiving 6xCHOP-14+8R were 6% (76/1200) per cycle and 28% (60/218) per patient. With intensified anti-infective prophylaxis in OPTIMAL &gt; 60 there were no differences with respect to infections between the 4 treatment arms. Grade 3&amp;4 infections were 4% (83/1987) per cycle (p = 0.007) and 18% (64/365 pts. with toxicity documentation) per patient (p = 0.004). Treatment-related deaths (defined as all non-lymphoma associated deaths during and within 2 months after the end of chemotherapy) went down from 15/232 (7%) in RICOVER-60 to 7/385 (2%; p = 0.003) in OPTIMAL &gt; 60. Conclusions: Anti-infective prophylaxis with cotrimoxazole and aciclovir in addition to ciprofloxazine significantly reduced the rates of severe infections and treatment-related deaths in elderly patients receiving R-CHOP supporting the use of this anti-infective strategy in all DLBCL patients receiving R-CHOP. Clinical trial information: NCT01478542.

Prolonged circulation and increased tumor accumulation of liposomal vincristine in a mouse model of rhabdomyosarcoma.

Our goal was to improve vincristine (VCR) based rhabdomyosarcoma (RMS) therapy by encapsulating the drug into liposomes. A targeting strategy was attempted to enhance tumor accumulation. VCR was loaded in control and peptide-decorated liposomes via an active method. The interaction of an RMS-specific peptide with the presumed target furin and the cellular uptake of both liposomal groups were studied in vitro. Pharmacokinetics and biodistribution of VCR-containing liposomes were assessed in an RMS xenograft mouse model. Liposomes ensured high VCR concentration in plasma and in the tumor. Peptide-decorated liposomes showed modest uptake in RMS cells. The investigated peptide-modified liposomal formulation may not be optimal for furin-mediated RMS targeting. Nevertheless, VCR-loaded liposomes could serve as a delivery platform for experimental RMS.

Biodegradable Self-Assembled Micelles Based on MPEG-PTMC Copolymers: An Ideal Drug Delivery System for Vincristine.

Despite advantageous properties, micelles using methoxy poly(ethylene glycol)-poly(trimethylene carbonate) (MPEGPTMC) have not been widely studied. In this work, we aim to develop a novel vehicle for vincristine (VCR) based on a MPEG-PTMC micelle system. MPEG-PTMC with a series of molecular weights were synthesized and screened for the appropriate range for forming stable VCR micelles. The prepared micelles were then characterized in vitro and in vivo . VCR micelles presented high stability and ideal sustained release profile. The passive targeting effect was also enhanced compared with liposomal VCR. These results provide critical data to give the first clues regarding novel VCR micelles which exhibit potential for clinical application.

Update Results of Frontline Therapy with Combination of Hyper-CMAD with Liposomal Vincristine (M) in Patients (Pts) with ALL (ALL)

Update Results of Frontline Therapy with Combination of Hyper-CMAD with Liposomal Vincristine (M) in Patients (Pts) with ALL (ALL)

Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14)

BackgroundChemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity. Patients and methodsPatients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment. ResultsThe mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Thirty-six of 40 (90%) patients in the R-COMP arm, but only 24/36 (66.7%) in the R-CHOP arm had all NT-proBNP levels below 400 pg/ml during and at the end of treatment (P = 0.013). There were more serious adverse events in the R-CHOP arm (26 versus 40, P = 0.029). Infections were more common (15 versus 28) in the R-CHOP arm. InterpretationIn patients with normal cardiac function, six cycles of R-CHOP resulted in a low rate of early cardiotoxicity. NPL-doxorubicin did not reduce cardiotoxicity, although cardiac safety signals were elevated in R-CHOP compared to R-COMP. FundingCephalon provided the Arbeitsgemeinschaft Medikamentöse Tumortherapie with NPL-doxorubicin and an unrestricted grant, but was not involved in the study protocol, data acquisition, data analysis or the writing of the paper.