Combination Of Mitoxantrone Research Articles

AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer

Due to low success rates and long cycles of traditional drug development, the clinical tendency is to apply omics techniques to reveal patient-level disease characteristics and individualized responses to treatment. However, the heterogeneous form of data and uneven distribution of targets make drug discovery and precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as a paradigm and uses data mining of a large TNBC cohort and drug databases to establish a biofactor-regulated neural network for rapidly screening and optimizing compound pyroptosis drug pairs. Subsequently, biomimetic nanococrystals are prepared using the preferred combination of mitoxantrone and gambogic acid for rational drug delivery. The unique mechanism of obtained nanococrystals regulating pyroptosis genes through ribosomal stress and triggering pyroptosis cascade immune effects are revealed in TNBC models. In this work, a target omics-based intelligent compound drug discovery framework explores an innovative drug development paradigm, which repurposes existing drugs and enables precise treatment of refractory diseases.

R(h)oad to antitumour therapy.

R(h)oad to antitumour therapy.

Combined mitoxantrone and anti-TGFβ treatment with PD-1 blockade enhances antitumor immunity by remodelling the tumor immune landscape in neuroblastoma

BackgroundPoor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response.Methods975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed.ResultsWe found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8+ T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8+ T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8+ T cells and NK cells.ConclusionsCombined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.

Final Results of Phase I/II Trial of Mitoxantrone in Combination with Clofarabine (MITCL) in Children with Relapsed/Refractory Acute Leukemia

Final Results of Phase I/II Trial of Mitoxantrone in Combination with Clofarabine (MITCL) in Children with Relapsed/Refractory Acute Leukemia

Chitosan IR806 dye-based polyelectrolyte complex nanoparticles with mitoxantrone combination for effective chemo-photothermal therapy of metastatic triple-negative breast cancer

Chemo-photothermal therapy is one of the emerging therapies for treating triple-negative breast cancer. In this study, we have used ionotropic gelation method to fabricate chitosan and IR806 dye-based polyelectrolyte complex (CIR-PEx) nanoparticles. These nano-complexes were in size range of 125 ± 20 nm. The complexation of IR 806 dye with chitosan improved photostability, photothermal transduction, and showed excellent biocompatibility. Cancer cells treated with CIR-PEx NPs enhanced intracellular uptake within 5 h of incubation and also displayed mitochondrial localization. With the combination of CIR-PEx NPs and a chemotherapeutic agent (i.e., mitoxantrone, MTX), a significant decline in cancer cell viability was observed in both 2D and 3D cell culture models. The chemo-photothermal effect of CIR-PEx NPs + MTX augmented apoptosis in cancer cells when irradiated with NIR light. Furthermore, when tested in the 4 T1-tumor model, the chemo-photothermal therapy showed a drastic decline in tumor volume and inhibited metastatic lung nodules. The localized hyperthermia caused by photothermal therapy reduced the primary tumor burden, and the chemotherapeutic activity of mitoxantrone further complemented by inhibiting the spread of cancer cells. The proposed chemo-photothermal therapy combination could be a promising strategy for treating triple-negative metastatic breast cancer.

PB1790: ABCB1 AS A POTENTIAL BENEFICIAL TARGET OF MIDOSTAURIN IN ACUTE MYELOID LEUKEMIA

Background: In AML, therapeutic outcome of anthracycline-based induction therapy often can be compromised by a resistant phenotype associated with overexpression of ABCB1 transporters. Novel anti-AML agent, midostaurin, was designed to aim at multiple targets including FLT3 mutation. Besides, it was also identified as ABCB1 inhibitor. Aims: To evaluate ABCB1 efflux activity and expression in primary AML samples in relation to multiple clinical parameters and investigate ABCB1 regulation by microRNA. Methods: ABCB1 gene expression was absolutely quantified in 28 primary AML samples collected prior to any treatment. Efflux activity was examined using combination of mitoxantrone (ABCB1 substrate) and midostaurin (ABCB1/FLT3 inhibitor). Results were compared in molecular classes defined by CD34 marker, FLT3-ITD and NPM1 mutations, ELN risk classification and (un)achieved complete remission (CR). Enhancement of daunorubicin proapoptotic effect mediated by midostaurin was determined in HL-60 wt and HL-60 overexpressing ABCB1. ABCB1 regulation by microRNAs (miR-9, miR-27a, miR-331) was evaluated by ddPCR and correlated with ABCB1 efflux activity. Results: High ABCB1 expression was associated with unachieved CR, adverse ELN risk and CD34 positivity. ABCB1 efflux activity was observed in a functional study when mitoxantrone accumulation increased as a direct consequence of midostaurin in CD34+ AML and patients with unachieved CR. ABCB1 efflux activity and expression were found to be linked to miR-9 downregulation Summary/Conclusion: We propose therapeutic value of midostaurin for drug-resistant patients beyond the FLT3 inhibition based on ABCB1 expression and CD34 positivity. We also propose miR-9 as a predictive ABCB1-related biomarker that could be helpful in identifying ABCB1-resistant AML phenotype.

Abstract 5207: Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity

Abstract Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we employed a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitise two mouse models of neuroblastoma (NB) sparsely infiltrated by T cells to the host antitumor immune response. Using multiple in vitro, ex vivo, and in vivo approaches, we found that mitoxantrone treatment curbed NB growth and promoted tumor regression when combined with TGFβ and PD-1 blockade in aggressive NB models. This combined immunotherapy strategy resulted in the enrichment of a variety of both innate and adaptive immune cells into the TME, and the concomitant production of inflammatory chemokines involved in remodelling the tumor’s immune landscape. Mitoxantrone in combination with TGFβ and PD-1 blockade could be used to reshape the functional repertoire of intratumoral immune cells, restoring the entire immune cell cycle and overcoming the immunosuppressive microenvironment of aggressive NB. Citation Format: Valeria Lucarini, Ombretta Melaiu, Silvia D'Amico, Fabio Pastorino, Patrizia Tempora, Adele De Ninno, Luca Businaro, Mirco Ponzoni, Franco Locatelli, Doriana Fruci. Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5207.

Phase 1/2 Trial of CLAG-M with Dose-Escalated Mitoxantrone in Combination with Fractionated-Dose Gemtuzumab Ozogamicin for Newly Diagnosed Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms.

Simple SummarySeveral studies have demonstrated that gemtuzumab ozogamicin (GO) improves outcomes with intensive chemotherapy in some adults with acute myeloid leukemia (AML), but it has remained unclear which dosing schedule of GO is best. Here, we conducted a phase 1/2 study in 66 adults with newly diagnosed AML or other high-grade myeloid neoplasm, and found that a fractionated dosing schedule of GO (GO3) can be safely combined with cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M). Fifty-two out of sixty (87%) patients treated with CLAG-M/GO3 achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease. Six- and twelve-month event-free survival were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease. These data indicate that CLAG-M/GO3 is safe and more efficacious than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918). Sixty-six patients with a median age of 65 (range: 19–80) years were enrolled. Cohorts of six and twelve patients were treated in phase 1 with one dose of GO or three doses of GO (GO3) at 3 mg/m2 per dose. Since a maximum-tolerated dose was not reached, the recommended phase 2 dose (RP2D) was declared to be GO3. At RP2D, 52/60 (87%) patients achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease (MRD). Eight-week mortality was 0%. Six- and twelve-month event-free survival (EFS) were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease (EFS: p = 0.007; OS: p = 0.030). These data indicate that CLAG-M/GO3 is safe and leads to superior outcomes than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.

Bortezomib potentiates antitumor activity of mitoxantrone through dampening Wnt/\u03b2-catenin signal pathway in prostate cancer cells

BackgroundBortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown.MethodsAnticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of β-Catenin and its target genes were characterized by western blot and Real-time PCR.ResultsBZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/β-Catenin signaling pathway compared to monotherapy.ConclusionsThis study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/β-Catenin signaling pathway in prostate cancer cells.

Mitoxantrone in Combination with Clofarabine (MITCL) in Children, Adolescents and Young Adults with Refractory/Relapsed Acute Leukemia

BACKGROUNDDespite excellent outcomes in pediatric ALL, patients who relapse or become refractory to frontline therapies do poorly (Gaynon et al, BJH 2005). In pediatric AML, five-year overall survival remains around 60% among children and adolescents overall with similarly poor prognosis for relapsed or refractory AML (Wells et al, JCO 2003). Novel combinations with improved complete response rates and long term outcomes are required for these high risk patients. Mitoxantrone and clofarabine as single agents, have proven effective in children with relapsed/refractory ALL and AML and offer possible synergistic activity in vivo with less drug resistance. (Wells et al, JCO 2003; Jeha et al, JCO 2009; Chow et al, Leukemia & Lymphoma 2000). We have previously reported our Phase I results using this combination and have shown excellent early results. The MTD of this combination was demonstrated to be Clofarabine 35mg/m2 x 5 days and Mitoxantrone 12mg/m2 x 4 days. Here, we present data on the first 14 patients to be treated at this recommended Phase 2 dose level (RP2D). OBJECTIVESTo determine the overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy in children, adolescents and young adults with refractory/relapsed acute leukemia. To determine the percent of minimal residual disease (MRD) following reinduction with mitoxantrone and clofarabine reinduction therapy. To further characterize the biology of childhood, adolescent and young adult refractory/relapsed acute leukemia. DESIGNProspective, multi-center, treatment-based, non-randomized, open label, uncontrolled, single group assignment, safety and efficacy study (NCT01842672). Patients 0-30.99yr old with ALL or AML with relapse OR primary induction failure were given 1 to 3 cycles of clofarabine (established MTD 35mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6 (MITCL). Dexrazoxane was given prior to Mitoxantrone. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. Patients were allowed subsequent cycles pending response and anthracycline exposure. The majority of patients were planned to undergo allogeneic hematopoietic stem cell transplantation upon achieving CR/MRD negative remission. MRD was defined by flow cytometry (≥ 0.01%) RESULTSTo date 14 patients have been enrolled at the established RP2D of clofarabine (six patients during Phase I, 8 patients during Phase II). Median Age is 6yrs (2-22yrs). Patient characteristics include 9 ALL (5=Induction Failure, 3=Relapse 1, 1=Relapse 2) and 5 AML (3=Induction Failure, 2=Relapse 1). The reinduction regimen was well tolerated. There has been 1 patient with Grade IV prolonged myelosuppression following therapy. For the remaining patients, median time to neutrophil recovery was 24 days. Eleven of 14 (79%) patients achieved a CR after 1 cycle of therapy. Of these patients, 100% achieved MRD negativity (<0.1%). Three patients died of progressive disease after 1 cycle of therapy. All 11 patients achieving CR went on to receive an allogeneic HSCT with no documented transplant associated toxicities attributed to prior MITCL therapy. Baseline and post treatment echocardiograms were compared in patients who achieved CR. No patient had clinical evidence of deterioration of left ventricular systolic function prior to proceeding with AlloHSCT. One patient developed MRD (2.6%) at Day +270 post HSCT. The remaining 10 patients demonstrated continued complete remission with MRD negativity at a median follow up time of 321 days (range 113-1150 days). The overall and event free survival for patients who responded to therapy is 91%. (Figure 1) CONCLUSIONThe combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia has been demonstrated to be safe and well tolerated in children, adolescents and young adults with poor risk acute leukemias. Hematopoietic recovery continues to be rapid and complete. Data from the first 14 patients enrolled at the RP2D of this combination is encouraging with 79% MRD negative CR rate in leukemic patients allowing patients to safely proceed to AlloHSCT. Longer follow up and a larger cohort is planned and ongoing. [Display omitted] DisclosuresOesterheld:Shire Pharmaceuticals: Speakers Bureau. Cairo:Jazz Pharmaceuticals: Speakers Bureau.

Proteasome inhibitors attenuates mitoxantrone-triggered immunogenic cell death in prostate cancer cells.

Both mitoxantrone (MTX) and proteasome inhibitors efficiently trigger immunogenic cell death (ICD) in cancer cells. However, whether the combination of MTX and proteasome inhibitors can synergistically enhance ICD remains unknown. In this study, we showed that the proteasome inhibitors bortezomib (BZM) and carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132) impaired MTX-induced ICD in prostate cancer cells, as measured using ICD biomarkers and dendritic cell activation in vitro. Mice vaccinated with RM-1 mouse prostate cancer cell line treated with BZM or MG132 in combination with MTX showed enhanced tumor growth, and shortened tumor-free, and worse overall survival compared with those treated with MTX alone. In conclusion, we demonstrated that proteasome inhibitors (BZM or MG132) attenuated MTX-induced ICD, suggesting that proteasome activation was required for MTX-induced ICD.

Phase II results of mitoxantrone in combination with clofarabine in children with relapsed/refractory acute leukemia.

7036 Background: Despite improved outcomes in pediatric acute leukemia, those who relapse or are refractory do poorly. Mitoxantrone and clofarabine as single agents have proven efficacy in pediatric leukemia. Our previously reported phase I results demonstrated the MTD of this combination to be clofarabine 35 mg/m2 x 5 days and mitoxantrone 12 mg/m2 x 4 days. Here, we present our phase II data utilizing the RP2D. Methods: Prospective, open label safety and efficacy study (NCT01842672). Patients 0-30.99 yr old with ALL or AML with relapse OR induction failure were given 1 to 3 cycles of clofarabine (RP2D 35 mg/m2/day) Day 1-5, in combination with mitoxantrone 12 mg/m2/day on Day 3-6. Dexrazoxane was given prior to mitoxantrone. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. MRD was defined by flow cytometry (≥ 0.01%). Results: Total 21 patients have enrolled at the RP2D clofarabine. Median age 8 yrs (0.5-22 yrs). Patient characteristics include 13 ALL (8=Induction Failure, 4=Relapse 1, 1=Relapse 2) and 8 AML (4=Induction Failure, 4=Relapse 1). Overall regimen was well tolerated. One patient with grade IV prolonged myelosuppression. Median time to neutrophil recovery was 24 days. Eighteen of 21 (85.7%) patients achieved an MRD negative CR. Three patients died of progressive disease. All 18 patients achieving CR went on to receive an allogeneic HSCT with no documented transplant associated toxicities attributed to prior MITCL therapy. One patient developed MRD (2.6%) at Day +270 post HSCT and underwent subsequent therapy. The remaining 17 patients continue to demonstrate MRD negativity. Two patients died of transplant associated complications. The overall and event free survival for patients who responded to therapy are 89% (CI95 0.64-0.98) and 83% (CI95 0.58-0.96), respectively at a median follow up time of 24 months (range 2-58). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35 mg/m2 clofarabine in children with poor risk acute leukemias. Phase II data is encouraging with 85.7% MRD negative CR rate in leukemic patients allowing patients to safely proceed to AlloHSCT with a 2 year survival rate of 89%. Longer follow up and a larger cohort is planned and ongoing. Clinical trial information: NCT01842672.

Evaluation of the Tolerability of Combination Chemotherapy with Mitoxantrone and Dacarbazine in Dogs with Lymphoma.

Combination chemotherapy can be an effective option for treating resistant lymphoma in dogs. This retrospective study examined the tolerability and efficacy of the combination of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (dacarbazine) (DTIC) in a population of dogs with lymphoma resistant to a doxorubicin-containing chemotherapy protocol. Mitoxantrone was administered at 5 mg/m2 IV over 10 min followed by DTIC at 600 mg/m2 IV over 5 hr, every 3 wk. All dogs were treated with prophylactic trimethoprim-sulfadiazine and metoclopramide. The frequency of grade 4 neutropenia was 18%, and 5% of dogs were hospitalized from sepsis. Gastrointestinal toxicity was uncommon. The overall response rate was 34% (15 of 44; 95% confidence interval 20-48%) for a median duration of 97 days (range 24-636 days, 95% confidence interval 44-150 days). Fourteen of 15 dogs who received mitoxantrone and DTIC as first rescue responded to treatment. Dogs who achieved complete remission to their initial L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol were more likely to respond to mitoxantrone and DTIC (23 versus 11%, P = .035). The combination of mitoxantrone and DTIC is a safe treatment option for resistant lymphoma in dogs.

Comparison of Mitoxantrone in Combination with Intermediate-dose Cytarabine versus High-dose Cytarabine as Consolidation Therapies for Young Non-APL Acute Myeloid Leukemia Patients with Favorable and Intermediate Cytogenetics

In this study, we compared the efficacy of mitoxantrone in combination with intermediate-dose cytarabine (HAM) with that of high-dose cytarabine alone (HiDAC) as consolidation regimens in non-acute promyelocytic leukemia (APL) acute myeloid leukemia patients with favorable and intermediate cytogenetics. A total of 62 patients from Shenzhen People's Hospital were enrolled in this study. All patients enrolled received standard induction chemotherapy and achieved the first complete remission (CR1). In these patients, 24 received HiDAC and 38 received HAM as consolidation. The median relapse free survival (RFS) and overall survival (OS) were similar between these two consolidation regimens. Even in subgroup analysis according to risk stratification, the combination regimen conferred no benefit in longterm outcome in patients with favorable or intermediate cytogenetics. However, in patients receiving HAM regimen, the lowest neutrophil count was lower, neutropenic period longer, neutropenic fever rate higher, and more platelet transfusion support was required. HAM group also tended to have higher rate of sepsis than HiDAC group. According to our results, we suggest that combination treatment with mitoxantrone and intermediate-dose cytarabine has limited value as compared to HiDAC, even in young non-APL AML patients with favorable and intermediate cytogenetics.

Saponins: Current Progress and Perspectives.

Saponins are gaining increasing attention as natural products because of their structural characteristics combining a lipophilic part (triterpene or steroid type) and a hydrophilic part (oligosaccharide moieties) in one molecule. They are thereby able to interact with biological membranes and induce a potential toxic or specific biological response, which is often of pharmacological interest. The wide structural diversity of saponins results in a large variety of biological effects, such as immunoadjuvant, cytotoxic, antitumor, antiinflammatory, antimicrobial properties and so on, just to mention a few. This reflects the increasing number of publications, as indicated in [Fig. 1] showing the numbers of saponin papers over the last 25 years (data from MedLine). Some examples of the current research on saponins can be read in this special edition of Planta Medica. Several articles focus on the isolation, structure elucidation and biological evaluation of previously undescribed saponins in Gledistia sinensis, Maesa argentea, Hernaria hirsuta, Allium fistulosum. As amphiphilic compounds, they possess several properties including foaming and pore forming abilities. The results of one study suggest that the cancer cell death induced by α-hederin mainly depends on its interaction with membrane cholesterol and consequent pore formation. A nice review reports saponin interactions with model membrane systems as a Langmuir monolayer. The pore forming property might represent an interesting mechanism for drug delivery into cells. This opens up promising applications in cancer combined chemotherapy using reduced doses, limiting the systemic toxicity. Another research group has shown the synergy of pro-apoptotic and anti-invasive effects of mitoxantrone in combination with a purified saponin fraction from Lysimachia ciliata in prostate cancer cells. A promising strategy to overcome the limitations of therapeutic antibodies and to improve their therapeutic values in cancer therapy has been investigated with a rituxumab-saporin immunotoxin co-administered with purified saponins from Saponaria officinalis. This combination significantly enhanced cytotoxicity in B-lymphocytes tumor cells originated from Burkittʼs lymphoma. Such beneficial effects of combined therapy were also shown by co-application of glycyrrhizic acid and gentamycin on vancomycin-resistant enterococci. The interest of acetylated saponins from Caryophyllaceae was underlined in a study showing their strong ability to inhibit the efflux of P-glycoprotein in an intestinal barrier model comprised of Caco-2 cells without affecting the cells. Therefore, the use of these surface-active agents in oral dosage forms may represent a promising strategy to enhance the bioavailability of poorly permeable drugs. Finally a nice review provides an overview on the steroid saponins from Ruscus ssp. from a chemical, pharmacological, and quality control point of view.

Abstract 3203: Phase I results of mitoxantrone in combination with clofarabine in children with refractory/relapsed acute leukemia

Abstract BACKGROUND: Despite excellent outcomes in pediatric ALL, multiply relapsed patients have response rates ∼40%, with &amp;lt;10% OS in CR3.(Gaynon, BJH 2005) The prognosis for relapsed or refractory AML is ∼20% OS.(Wells, JCO 2003) Novel combinations with improved outcomes are needed. Clofarabine and Mitoxantrone have proven efficacy in children with leukemia and offer possible synergistic activity in vivo with less drug resistance.(Chow, Leukemia &amp; Lymphoma 2000) OBJECTIVES: To determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. To determine the percent of minimal residual disease (MRD) following reinduction. DESIGN: Prospective, open label, uncontrolled, safety and efficacy study. Patients 0-30.99yr old with ALL, AML or NHL in 1st, 2nd or 3rd relapse OR primary induction failure were given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. Dexrazoxane was given prior to Mitoxantrone. Dose escalation was planned every 3 patients pending dose limiting toxicities. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. Patients were allowed subsequent cycles pending response and anthracycline exposure. RESULTS: To date 17 patients have been enrolled on the Phase I safety portion of this study. Median Age is 13yrs (8months-23yrs); 11 ALL (3 = Induction Failure, 6 = Relapse1, 2 = Relapse2), 5 AML (4 = Induction Failure, 1 = Relapse2), 1 NHL ( = Progressive Disease). There have been 2 prolonged Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence additional patients were enrolled at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery was 24 days. Fourteen of 16 (88%) evaluable leukemia patients achieved a CR after 1 cycle of therapy. Of these patients, 94% achieved MRD negativity (&amp;lt;0.1%). Two patients with relapsed ALL had no response. One patient with relapsed/refractory NHL had progressive disease after 2 cycles. Thirteen of 14 patients achieving CR went on to receive an allogeneic HSCT with continued remission at a median follow up time of 275 days (range 40-634). Overall 1 year survival for leukemia patients is 78.7% (CI95: 47.2-92.5). CONCLUSION: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia appears to be safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The Phase I MTD of this combination was found to be 35mg/m2 Clofarabine. Hematopoietic recovery appears to be rapid and complete. Initial data from the first 17 patients enrolled is encouraging with an 88% CR rate in leukemic patients. An extended multicenter Phase II Study is ongoing. Citation Format: Jessica Hochberg, Javier Oesterheld, Olga Militano, Liana Klejmont, Lauren Harrison, Berkley Nickerson, Mitchell S. Cairo. Phase I results of mitoxantrone in combination with clofarabine in children with refractory/relapsed acute leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3203.

Phase I results of mitoxantrone in combination with clofarabine in children, adolescents and young adults with refractory/relapsed acute leukemia.

10533Background: Despite excellent outcomes in pediatric ALL, multiply relapsed patients have low response rates and low OS. The prognosis for relapsed/refractory AML is also poor. Clofarabine and ...

Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

ABSTRACTTumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.

A Pilot Study of Mitoxantrone in Combination with Clofarabine (MITCL) in Children, Adolescents and Young Adults (CAYA) with Refractory/Relapsed Acute Leukemia

BACKGROUNDDespite excellent outcomes in pediatric ALL, 20-30% of patients relapse or become refractory to frontline therapies with subsequent CR2 rates of only 60%. For multiply relapsed patients, response rates remain around 40%, with <10% overall survival in third complete response.(Gaynon, BJH 2005) In pediatric AML, five-year overall survival remains around 60% among children and adolescents but with a very poor prognosis for relapsed or refractory AML (<20% three-year OS).(Wells, JCO 2003) Clearly, novel combinations with improved complete response rates and long term outcomes are needed for these high risk patients. Several studies have supported the rationale for using either Clofarabine or Mitoxantrone in patients with refractory/relapsed acute leukemia.(Wells, JCO 2003; Jeha, JCO 2009) Mitoxantrone and clofarabine as single agents, have proven effective in children with relapsed/refractory ALL and AML and offer possible synergistic activity in vivo with less drug resistance. (Chow, Leukemia & Lymphoma 2000) OBJECTIVESTo determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. To determine the percent of minimal residual disease (MRD) following reinduction with mitoxantrone and clofarabine reinduction therapy.To further characterize the biology of childhood, adolescent and young adult refractory/relapsed acute leukemia. DESIGNProspective, multi-center, treatment-based, non-randomized, open label, uncontrolled, single group assignment, safety and efficacy study (phase I/II). Patients 0-30.99yr old with ALL, AML or NHL in 1st, 2nd or 3rd relapse OR primary induction failure were given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. Dexrazoxane was given prior to Mitoxantrone. Dose escalation was planned every 3 patients pending dose limiting toxicities. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. (Figure 1) Patients were allowed subsequent cycles pending response and anthracycline exposure. RESULTSTo date 15 patients have been enrolled on the safety portion of this study. Median Age is 16yrs (8months-23yrs); 9 ALL (3=Induction Failure, 4=Relapse1, 2=Relapse2), 5 AML (4=Induction Failure, 1=Relapse2), 1 NHL (=Progressive Disease). There have been 2 prolonged Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence we are currently enrolling at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery is 24 days. Twelve of 14 (86%) evaluable leukemia patients achieved a CR after 1 cycle of therapy. Of these patients, 92% achieved MRD negativity (<0.1%). Two patients with relapsed ALL had no response. One patient with relapsed/refractory NHL had progressive disease after 2 cycles. Eleven of 12 patients achieving CR went on to receive an allogeneic HSCT with continued remission at a median follow up time of 224 days (range 31-593). CONCLUSIONThe combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia appears to be safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The MTD or tolerable dose of this combination has yet to be reached. Hematopoietic recovery appears to be rapid and complete. Initial data from the first 15 patients enrolled is encouraging with an 86% CR rate in leukemic patients. Once the MTD or tolerable dose is reached, an extended multicenter Phase II Study will be initiated.Table 1Treatment SchemaDAY1234567821CLOFARABINE●●●●●DEXRAZOXANE●●●●MITOXANTRONE●●●●DEXAMETHASONE●●●●●IT LIPOSOMAL ARAC●FILGASTRIM (…continued until ANC > 1500/mm3 x 2 consecutive days)●→→ DisclosuresNo relevant conflicts of interest to declare.

Abstract B73: Screen among 1200 FDA-approved drug library reveals mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme

Abstract Glioblastoma multiforme (GBM) is the most aggressive and frequent type of primary brain tumor with dismal survival rates. As GBM cells suppress apoptosis and evade death, re-activating dormant apoptotic programs with pro-apoptotic ligands or small molecules might be a promising approach to direct tumor cells to self-destruct. As such, the tumor-selective killing capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) makes it a potential treatment option in GBM. However, many tumor cells are intrinsically resistant and/or acquire resistance to TRAIL. While the mechanisms of TRAIL resistance is still not completely solved, several studies suggest that TRAIL resistance can be overcome by combination therapies. Therefore, combination of TRAIL with secondary chemotherapeutics, radiation or other novel therapeutic drugs might be a favorable therapeutic strategy. In this study, we aimed to identify TRAIL sensitizing agents and utilized a chemical library consisting of 1200 Food and Drug Administration (FDA)-approved compounds in a high-throughput screen that assessed GBM cell viability. In the screen that was conducted in TRAIL-midsensitive and TRAIL-resistant isogenic cell pairs in parallel, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective in reducing cell viability as single agents. Cardiac glycosides constituted a large group among our hits. While cardiac glycosides were potent TRAIL-sensitizers and also singly effective on GBM cells, they caused cell death in non-malignant cells, such as GBM-patient derived fibroblasts. Therefore, the future use of these agents might be challenging due to toxicity problems. We then explored the second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA damaging agent, did not cause any toxicity to non-malignant cells at the doses that were able to synergize with TRAIL on tumor cells. We then investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptor (DR4 and DR5) expression was upregulated markedly, as revealed by qRT-PCR and Western blotting. In addition, we observed significant changes in pro-apoptotic and anti-apoptotic gene expression. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients. Citation Format: Filiz Senbabaoglu, Ahmet Cingöz, Ezgi Kaya, Selena Kazancioglu, Nathan Alan Lack, Ceyda Acilan, Tugba Bagci-Onder. Screen among 1200 FDA-approved drug library reveals mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B73.