Multi-Center Phase II Study of Perifosine (KRX-0401) Alone and in Combination with Dexamethasone (dex) for Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Promising Activity as Combination Therapy with Manageable Toxicity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1164-1164 ◽  
Author(s):  
Paul Richardson ◽  
S. Lonial ◽  
A. Jakubowiak ◽  
A. Krishnan ◽  
J. Wolf ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Single Agent ◽  
Gene Array ◽  
In Vivo Studies ◽  
Significant Activity ◽  
Prior Therapy ◽  
Best Response

Abstract INTRODUCTION: Perifosine (peri) is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt and activation of JNK. In vitro studies showed that peri induces cytotoxicity in both MM cell lines and patient (pt) MM cells resistant to conventional therapies, and augments dexamethasone (dex) and bortezomib-induced MM cell cytotoxicity (Hideshima T. et. al. BLOOD 2006). In vivo studies showed antitumor activity in a human plasmacytoma mouse model. Here we report the results of a phase II trial of peri, alone and + dex, in pts with relapsed or relapsed / refractory MM. METHODS: Pts received 150 mg of peri daily for a 21 day (d) cycle, and were assessed every cycle by serum- and/or urine-electrophoresis. Eligible pts had symptomatic relapsed or relapsed / refractory MM. Pts were permitted to receive bisphosphonate treatment. Concomitant steroids (prednisone > 10 mg/d), creatinine of > 3.0 mg/dL, and hemoglobin < 8.0 g/dL within 14 d of enrollment were exclusion criteria. Progressing pts, documented on 2 occasions at least one week apart, had dex 20 mg twice per week added to peri. Toxicities were assessed by NCI-CTCAE, v3.0. RESULTS: 64 pts (35 M/ 29 F, median age 62, range 38–79) have been treated to date. Median lines of prior treatment was 4 (range 1–11); 32 (50%) pts had relapsed and refractory MM. Prior therapy included dex (95%), thalidomide (89%), bortezomib (73%), lenalidomide (30%) and ASCT (61%). Among 48 pts currently evaluable for response, best response (EBMT criteria) to single agent peri after ≥ 2 cycles was MR in 1 pt, stable disease (< 25% reduction in M-protein) in 22 pts (46%). Dex was added in 37 pts with PD, with 31 pts evaluable for response on the combination as follows: Peri + Dex N (%) Duration (wks) PR 4 (13%) 17, 24, 44+, 46+ MR 8 (25%) 3+, 12+, 19, 21, 25, 30, 32, 55+ Stable Disease 15 (47%) 6+ − 46 (median 12)* *4 pts ongoing at 6, 9, 11 and 24 wks Most common adverse events included nausea (74%, 8% G3); vomiting (61%, 5% G3); diarrhea (65%, 2% G3); fatigue (31%, 2% G3), increased creatinine (51%, 7% G3/4 in the context of PD and light chain nephropathy but reversible) and anemia (63%, 5% G3). 10 pts had G3/4 neutropenia which resolved. Dose reduction was required to 100 mg/d (n=16) or to 50 mg/d (n=4). 9 pts discontinued treatment due to side effects. Attributable toxicities otherwise proved manageable with supportive care and no peripheral neuropathy or DVT seen. CONCLUSION: Perifosine as monotherapy has modest activity, but in combination with dex showed significant activity in pts with relapsed/refractory MM, achieving PR + MR in 38%, and/or stabilization of disease in 47% of evaluable pts to date. It was generally well tolerated, although caution in pts with renal dysfunction is warranted. PK, IHC and gene array studies are ongoing. Other novel studies with peri in combination with bortezomib and with lenalidomide +/−dex are underway.

A Multicenter Phase II Study of Perifosine (KRX-0401) Alone and in Combination with Dexamethasone (Dex) for Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3582-3582 ◽  
Author(s):  
Paul Richardson ◽  
S. Lonial ◽  
A. Jakubowiak ◽  
J. Wolf ◽  
A. Krishnan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Single Agent ◽  
Gene Array ◽  
In Vivo Studies ◽  
Cell Transplant ◽  
Prior Therapy ◽  
Grade 3

Abstract Perifosine is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt and activation of JNK. Preclinical in vitro studies showed that perifosine induces significant cytotoxicity in both multiple myeloma(MM) cell lines and patient MM cells resistant to conventional therapies, and augments dexamethasone(dex), doxorubicin, melphalan and bortezomib-induced MM cell cytotoxicity. In vivo studies showed significant antitumor activity in a human plasmacytoma mouse model. PhaseI studies in solid tumors have shown that perifosine is well tolerated at a dose of up to150mg daily, with responses also seen. We report preliminary results of a PhaseII trial of perifosine, alone and in combination with dex, in patients(pts) with relapsed or relapsed/refractory MM. Pts received 150mg of perifosine daily for a 21-day(d) cycle, and were assessed by serum and/or urine electrophoresis. Eligible pts had relapsed or relapsed/refractory MM with measurable disease. Pts were permitted bisphosphonate treatment. Concomitant steroids(prednisone>10 mg/d), serum creatinine of >3.0 mg/dL, and hemoglobin<8.0g/dL within 14 d of enrollment were exclusion criteria. Progressing pts, documented on 2 occasions at least one week apart, had dex 20 mg twice per week added to perifosine. Toxicities were assessed by NCI-CTCAE, v3.0. 40 pts (22 men and 18 women, median age 61 y, range 38–78) have been treated to date. All had relapsed/refractory MM, with a median of 4 lines of prior treatment (range 1–9). Prior therapy included dex(100%), thalidomide(100%), bortezomib(73%), lenalidomide(28%) and stem cell transplant(73%). Among 25 pts currently evaluable for response, best response(EBMT criteria) to single agent perifosine after≥2 cycles was stable disease(<25% reduction in M-protein) in 6 pts(24%). Dex was added in 15 of 25 pts with PD, with 9 pts evaluable for response on the combination: 3 pts(33%) achieved MR and 2(22%) pts achieved SD. The most common adverse events included nausea (45%, 3% grade 3); vomiting (40%); diarrhea(40%); fatigue(24%, 3% grade 3), and increased creatinine(55%, 11% grade 3/4 in the context of PD and light chain nephropathy). 2 pts had G3 neutropenia which resolved. Dose reduction(150 to 100 mgs/d) was required in 11 pts and 4 pts discontinued treatment due to adverse events. Attributable toxicities otherwise proved manageable with appropriate supportive care and perifosine was generally well tolerated, with no peripheral neuropathy or DVT seen. Perifosine as monotherapy and in combination with dex has activity in pts with advanced, relapsed/refractory MM, achieving MR and/or stabilization of disease in 55% of evaluable pts to date. It was generally well tolerated, although caution in pts with renal dysfunction is warranted. PK, IHC and gene array studies are ongoing. Future studies evaluate perifosine at other dosing schedules and in combination with other agents including bortezomib.

A Multicenter Phase II Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2564-2564 ◽  
Author(s):  
James Berenson ◽  
Ralph Boccia ◽  
David Siegel ◽  
Marek Bozdech ◽  
Alberto Bessudo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Vitamin C ◽  
Arsenic Trioxide ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response ◽  
In Vivo Studies

Abstract Background: Despite the recent increase in treatment options for patients with multiple myeloma (MM), the disease remains largely incurable. Both arsenic trioxide (ATO) and melphalan have shown clinical activity in MM. Recent in vitro and in vivo studies in our laboratory have shown that arsenic trioxide sensitizes chemoresistant MM cells to melphalan-induced cytotoxicity; the addition of ascorbic acid (AA) further improves this effect. We conducted a multi-center clinical trial to evaluate the safety and efficacy of this steroid-free combination, melphalan, ATO and vitamin C (MAC), for patients with relapsed/refractory MM. Methods: MM pts who relapsed after responding to 1st-line therapy and/or were refractory to prior treatment were enrolled. During week 1 of each 6-week cycle, pts received ATO, 0.25 mg/kg IV, followed by ascorbic acid (AA), 1 g IV, days 1–4. ATO followed by AA was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Pts received a maximum of 6 cycles followed by weekly maintenance treatment with ATO and AA. The primary objectives of this study were to determine response rate and safety and tolerability of MAC therapy. Results: 65 patients have been enrolled and 51 are currently evaluable for response. 26 (1 CR, 10 PR, 15 MR) of the 51 evaluable patients (51%) had an objective response and an additional 14 patients achieved stable disease, resulting in a total of 40 patients (78%) with disease control. Among patients with elevated serum creatinine levels at baseline, renal function improved for those with responsive or stable disease. 20 of the 26 responding patients had failed ≥ 2 prior therapies: 19 pts had received prior thalidomide or lenalidomide therapy and 8 pts had received prior bortezomib. The regimen was well-tolerated with few significant side effects reported. Mild cytopenias occurred infrequently and were reversible. Conclusions: The results from this large multi-center phase II trial show that the MAC regimen is active in a group of MM patients who had either relapsed or were refractory to standard and/or investigational MM treatments. The regimen was well-tolerated even in this heavily pre-treated patient population. These findings are consistent with preclinical studies that showed the efficacy of this combination from both in vitro and in vivo studies.

scholarly journals HGG-29. VENETOCLAX SYNERGIZES WITH RADIATION THERAPY FOR THE TREATMENT OF DIPG

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i23-i23
Author(s):  
Ilango Balakrishnan ◽  
Senthilnath Lakshmana Chetty ◽  
Krishna Madhavan ◽  
Susan Fosmire ◽  
Angela Pierce ◽  
...  
Keyword(s):  
Single Agent ◽  
Treatment Resistance ◽  
Pediatric Brain Tumors ◽  
Tumor Burden ◽  
Metabolic Reprogramming ◽  
In Vivo Studies ◽  
Significant Activity ◽  
Bcl2 Family

Abstract Background and Rationale Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive pediatric brain tumors. Currently, the main treatment for DIPG is radiation and it’s only a palliative care, as the tumor eventually becomes resistant to radiation. In this study we found that radiation leads to an increase in anti-apoptotic BH3 proteins mainly BCL2 in DIPG. Previous studies in other tumor types have shown that increase in these pro-survival BCL2 family members are associated with treatment resistance and poor prognosis. Therefore, we hypothesize that inhibition of BCL2 using a small-molecule inhibitor, venetoclax that crosses the blood-brain barrier, will represent a possible therapeutic strategy to overcome radiation resistance in DIPG. Approach: For in vitro studies, DIPG cells were exposed to different radiation doses (0–10 Gy) and the magnitude of the sensitizing effect of venetoclax (with IC15) was calculated by clonogenic assay. Evaluated BCL2 family proteins by western and cytotoxicity by cleaved caspase incucyte assays. For in vivo studies, NSG mice orthotopically engrafted with a human H3K27M-DIPG luciferase-expressing cells in the pons were exposed to a focal fractionated radiation of 2Gy/day for 3 days. Mice were randomized into 2 groups based on bioluminescence IVIS signal intensity; each group receiving either venetoclax (15 mg/kg, by i.p) 3 days/week for 10 weeks or vehicle. Decrease in tumor burden was measured by IVIS and survival was evaluated compared to vehicle treated mice. Results Single agent venetoclax showed no significant activity against DIPG tumors in in vitro and in vivo DIPG xenografts. Single-agent radiation cleared the tumor burden but only transiently. Combination of radiation with venetoclax showed considerable synergistic anti-tumor effect in vitro and in vivo leading to a significant increase in animal survival beyond either single agent treatments. The metabolic reprogramming that results in this enhanced cell-killing effect will be discussed.

Phase II Trial of Perifosine (KRX-0401) in Relapsed and/or Refractory Waldenström Macroglobulinemia: Preliminary Results.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4493-4493 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Xavier Leleu ◽  
Nancy Rubin ◽  
Marybeth Nelson ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Hemolytic Anemia ◽  
Phase Ii ◽  
Single Agent ◽  
Akt Inhibitor ◽  
Best Response ◽  
M Spike ◽  
Grade 3

Abstract INTRODUCTION: Perifosine is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt. We previously demonstrated that AKT is upregulated in samples of patients with WM and that the AKT inhibitor perifosine induces significant growth inhibition in vitro and in vivo in xenograft models in WM. Phase I trials with perifosine have demonstrated a favorable side effect profile. This phase II study aimed to determine safety and activity of the oral AKT inhibitor perifosine in patients with relapsed/refractory WM. METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 150 mg perifosine daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles. RESULTS: 28 pts (20 men and 8 women, median age 64.8 years, range 51 – 80) have been treated to date. The median number of lines of prior treatment was 2 (range 1 – 5). The median IgM at baseline was 3245 mg/dL (range 972– 8480); median M-spike at baseline was 1.9 g/dL (range 0.5 – 4.85); and median hemoglobin was 11.3 g.dL (7.0–14.0). The median follow up was 5 months (range 1 – 8 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. 21 pts are currently evaluable for response, best response to single agent perifosine after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with perifosine. The median M spike reduction was 20% (0 – 76). Patients tolerated perifosine well without significant toxicities: grade 3 nausea/vomiting in 1 patient resolved with dose reduction to 100 mg; grade 3 anemia in one patient was related to cold-agglutinin hemolytic anemia; and 2 patients had GI bleeding unrelated to therapy. Dose reduction (to 100 mg/d) was required in 4 patients; 2 for nausea and loss of weight, 1 for non-specific bone pain and 1 for an episode of fever and fatigue. Four patients discontinued therapy, one for cold-aggutinin related hemolytic anemia related to WM, one due to corneal ulceration that was possibly related to perifosine and corneal infection, and 2 for patient decision. Attributable toxicities otherwise proved manageable with appropriate supportive care and perifosine was generally well tolerated, with no peripheral neuropathy. CONCLUSIONS: Oral perifosine as monotherapy has been well tolerated and demonstrates encouraging activity achieving PR + MR in 34%, and/or stabilization of disease in 66% of evaluable patients with relapsed WM. Updated data will be presented at the meeting. Table 1 Response N=21; ORR (CR+PR+MR)=34% Median time to best response (months) Partial response 2(10%) 5 Minimal response 5 (24%) 4 (3–6) Stable Disease (SD) 14 (66%) NA Progressive Disease 0

A phase II study of intravenous (IV) wild-type reovirus (Reolysin) in the treatment of patients with bone and soft tissue sarcomas metastatic to the lung

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10524-10524 ◽  
Author(s):  
A. C. Mita ◽  
K. Sankhala ◽  
J. Sarantopoulos ◽  
J. Carmona ◽  
S. Okuno ◽  
...  
Keyword(s):  
Side Effects ◽  
Soft Tissue ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Soft Tissue Sarcomas ◽  
In Vivo Studies ◽  
Open Label

10524 Background: Reolysin is a Dearing strain, naturally occurring, ubiquitous human reovirus. The PKR (double stranded RNA-activated protein kinase) is inhibited and therefore the virus replicates specifically in transformed cells possessing an activated Ras pathway producing lysis. In vitro and in vivo studies with Reolysin in sarcoma cell lines revealed significant antitumor activity. Methods: This phase II open-label, single agent study was designed to characterize the efficacy and safety of Reolysin given IV every 28 days in patients (pts) with bone or soft tissue sarcoma with lung metastasis using a Simon two-stage design. 38 pts were accrued to the first stage. If 1 or more pts experience clinical benefit (prolonged SD > 6 months, partial or complete response) up to 52 pts could be accrued. The agent will be considered active if 3 or more responses or prolonged SD are observed. Results: Since July 2007, 43 pts age 19–76 (median 49) were enrolled (20 female) and received a total of 141 cycles (range 1–18). All pts had performance status 1 (29 pts) or 0 (14 pts). 38 pts received prior chemotherapy, radiotherapy, biological agents or combinations for their metastatic disease, 15 pts received more than 3 chemotherapy regimens. The sarcoma subtypes included: synovial sarcoma (13 pts), osteosarcoma (7 pts), leiomyosarcoma (7 pts), MFH (5 pts), Ewing/PNET (1 pt), chordoma (1 pt), others (9 pts). Side effects were mild to moderate (grade 1–2) and included constitutional symptoms fever, chills, fatigue. Two pts experienced respiratory side effects (cough and dyspnea) and 2 pts had diarrhea. Hematological side effects included grade 2–3 neutropenia (6 pts) and grade 2 thrombocytopenia (2 pts). One patient experienced grade 2 AST elevation. 33 pts are evaluable for response to date: 14 pts (42%) had SD for 2+ months including 5 pts having SD for more than 6 months. Conclusions: Utilization of single agent reovirus for treatment of sarcoma is a novel and unique therapeutic approach to date. Reolysin is well tolerated and shows promise for the treatment of metastatic sarcoma. Primary efficacy goals have been met. Accrual is ongoing to a total of 52 pts. [Table: see text]

A phase I/II clinical trial of intravenous (I.V.) calcitriol with fixed doses of cisplatin and docetaxel in advanced non-small cell lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18118-e18118
Author(s):  
Nithya Ramnath ◽  
Stephanie Daignault-Newton ◽  
Grace K. Dy ◽  
Josephia Muindi ◽  
Araba Adjei ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Normal Liver ◽  
Maximum Tolerated Dose ◽  
In Vivo Studies ◽  
Open Label ◽  
Chi Square

e18118 Background: In vitro and in vivo studies have demonstrated the antiproliferative effects of 1, 25 (OH)2D3 (calcitriol) as single agent and antitumor synergy with cisplatin. The goals of this Phase I/II study were to determine the maximum tolerated dose (MTD) of 1, 25 (OH)2 D3 in combination with cisplatin and docetaxel, and to evaluate the efficacy in patients (pts) with metastatic NSCLC.Methods: The study was a multicenter, open-label study in pts with metastatic NSCLC. Pts were adults 18 yrs., PS 0-1 with normal liver/kidney function. For the phase I study, pts (3–6 per cohort) received 1, 25 (OH)2 D3 I.V. every 21 days prior to docetaxel and cisplatin. The starting dose of 1,25 (OH)2D3 was 15 mcg/m2 at sequential ascending dose levels (DL) (15, 30, 60 and 80 mcg/m2) using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of <33%. Docetaxel was administered at 75 mg/m2 and cisplatin 75mg/m2 following 1, 25 (OH)2 D3 for 4 cycles. We analyzed SNPs in the CYP24A1 gene.Results: 37 pts were enrolled (16 in phase I and 21 in phase II) with a median age of 54 (range 34–79) yrs.; M: F, 12:17. At the 80 mcg/m2 dose level, 2/4 pts had DLT of grade 4 neutropenia. There were no cases of hypercalcemia or azotemia. The MTD and recommended Phase II dose was 60 mcg/m2. Among 6 response-evaluable Phase I pts, and 21 phase II pts, there were: 2 confirmed partial responses (PR), 6 unconfirmed PRs and 10 pts with stable disease. The median time to progression was 6.9 months (95% CI 4.4, 12.9) and the median overall survival was 8.3 months (95% CI 5.8, 14.9). Of the CYP24A1 SNPs, the IVS4-308C>G was associated with progressive disease (Chi-Square=0.0062)Conclusions: The MTD of 1,25 (OH)2D3 in combination with docetaxel and cisplatin was 60 mcg/m2 IV every 21 days. Pre-specified endpoint of a 50% response rate was not met in the phase II study. However, disease control in 66% of patients argues for further study of 1,25 (OH)2D3 as maintenance therapy. The CYP24A1 polymorphism IVS4-308C>G may be associated with resistance to a 1,25 (OH)2D3 based therapeutic regimen

Anti-Tumor Phagocytic Cell Activation in Multiple Myeloma By the IAP Antagonist LCL161: Results of a Phase II Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3039-3039
Author(s):  
P. Leif Bergsagel ◽  
Martha Q. Lacy ◽  
David Dingli ◽  
Shaji K. Kumar ◽  
Sikander Ailawadhi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stable Disease ◽  
Immune Cells ◽  
Research Funding ◽  
Single Agent ◽  
Best Response ◽  
Iap Antagonist ◽  
Nfkb Pathway

Abstract Dexamethasone is a powerful anti-inflammatory, immunosuppressive agent widely used in the treatment of MM with pleiotropic effects on both the tumor, and host immune cells. We report on a completely novel approach to immune modulation using an agent with almost directly opposite effects to glucocorticoids on innate immune cells. LCL161 is an IAP antagonist targeting the cellular inhibitor of apoptosis proteins cIAP1 and -2 (cIAP1/2) that in a phase I study in solid tumors was well tolerated with a cytokine release syndrome as the dose limiting toxicity. We previously reported that loss of cIAP1/2 in MM cells results in the stabilization of NIK and activation of the non-canonical NFkB pathway, a pathway we found frequently activated by a promiscuous array of mutations in multiple myeloma (MM). As expected, we found that LCL161 has no direct anti-tumor activity against MM cells in vitro and ex vivo. However, the non-canonical NFkB pathway is also a key activator of the innate immune response. Remarkably, we found that in vivo LCL161 has dramatic, apoptosis-independent activity associated with marked phagocytosisagainst MM that develops spontaneously in an immunocompetent genetically engineered mouse model of MM (Vk*MYC). Cyclophosphamide (Cy), which has been shown to induce an acute secretory activating phenotype in tumor-associated macrophages, markedly potentiated the anti-tumor effects of LCL161. We show that phagocytes (depleted by liposomal clodronate), but not adaptive immune cells, are required for the anti-tumor effect. Consistently we show that LCL161 activates dendritic cells and macrophages in vitro, and in vivo, and upregulates production of inflammatory cytokines. A phase 2 clinical trial of LCL161 was conducted in 24 patients with relapsed MM previously exposed to both IMiDs and PIs, but less than 5 prior lines of therapy. Patients received LCL161 1200mg po weekly, with Cy 500mg po weekly added for progressive disease or lack of response. Single agent LCL161 was well-tolerated, with grade 3 or 4 non-hematologic toxicity in four patients, and following the addition of cyclophosphamide in 9 patients. No patients responded to single agent LCL161, and the best response was stable disease in 6/24. In 21 patients, Cy was added after a median of 2 cycles, in whom the best response was stable disease or better in 18/21 (p<0.001 compared to LCL161 alone), and a PR or better (including 1 VGPR and 1 CR) in 5/21 (p<0.001 compared to LCL161 alone). Six months following the initiation of Cy, 35% of patients remain event-free. Two patients had stable disease for more than nine months after stopping treatment. One, relapsing after VDT-PACE, HDM200, RVd x 3 years with t(11;14) and del17p, received only three months of LCL161, the last month in combination with Cy. He then achieved a PR, reconstitution of his uninvolved IgG to normal levels for the first time in more than 3 years and still has not progressed one year after stopping therapy. Similar changes in serum and bone marrow inflammatory cytokines and gene expression were observed in patients following treatment with LCL161 to those observed in the mice. We conclude that LCL161 is able to modulate the tumor microenvironment to exert long-term disease control in combination with Cy, and deserves further study in combination with agents that more directly depend on phagocytic cell activity (e.g., monoclonal antibodies, inhibitors of "Don't eat me" signals). Disclosures Bergsagel: Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Incyte: Consultancy; Jannsen: Consultancy; Mundipharma: Consultancy. Off Label Use: Use of LCL161 to treat multiple myeloma. Kumar:Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Stewart:Oncospire Genomics: Research Funding.

A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7116-7116 ◽  
Author(s):  
Selina M. Luger ◽  
Casey Lee O'Connell ◽  
Virginia Klimek ◽  
Maureen A. Cooper ◽  
Emmanuel C. Besa ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Single Agent ◽  
Risk Category ◽  
Open Label ◽  
Prior Therapy ◽  
Hodgkin's Lymphomas

7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.

scholarly journals Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2423-2440 ◽  
Author(s):  
Canyu Yang ◽  
Bing He ◽  
Qiang Zheng ◽  
Dakuan Wang ◽  
Mengmeng Qin ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Tumor Burden ◽  
Antitumor Efficacy ◽  
In Vivo Studies ◽  
Immunogenic Cell Death ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tumor Tissues

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

Inhibition of Human Lymphoma Cell Growth by the PKC-Beta Selective Inhibitor Enzastaurin (LY317615) in Combination with Multiple Therapeutic Agents.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1595-1595
Author(s):  
Randall M Rossi ◽  
Marlene Balys ◽  
Dean Franklin ◽  
Valerie Grose ◽  
Richard I Fisher ◽  
...  
Keyword(s):  
Single Agent ◽  
Large Cell ◽  
Therapeutic Agents ◽  
In Vivo Studies ◽  
Therapeutic Drugs ◽  
Potential Synergy ◽  
Size Growth ◽  
Reduce Tumor Growth

Abstract Previous studies in our lab have shown that the PKC-beta inhibitor, enzastaurin (LY317615), when used to treat a panel of human diffuse large cell lymphoma (DLCL) lines, was able to induce cell death in vitro and substantially reduce tumor growth in xenograft assays. These findings support the hypothesis that activation of PKC contributes to tumor cell survival and proliferation, which has been implicated in the pathogenesis of human B cell lymphomas. Specifically, PKC-beta activation is increased in tumor cells from patients with poor prognosis DLCL, suggesting that PKC-beta may be a target for therapeutic intervention. In the present study, we have explored the interaction of enzastaurin with a panel of well characterized therapeutic agents to evaluate whether its anti-tumor activity can potentially be enhanced. Drugs were chosen for analysis based either on known single agent activity in lymphoma, or by preclinical evaluation indicating potential synergy with enzastaurin. For in vitro culture assays (48–72 hr treatment), the addition of gemcitabine, rapamycin, or bortezomib, increased the cytotoxicity of enzastaurin from 2 to 7 fold. This effect was evident with multiple human DLCL cell lines, (OCI-Ly3, 7, 10, 19, and SUDHL-4, and 6), as well as two independent primary DLCL cultures. For in vivo studies, subcutaneous transplantation of the DLCL cell line OCI-Ly19, (previously engineered to express luciferase which allows for real time in vivo imaging), or a primary DLCL isolate, into immune deficient NOD/SCID mice formed reproducible tumors. Recipient animals were separated into uniform cohorts when the tumors were of &lt;=500 cubic mm in size. The animals were then simultaneously or sequentially treated with enzastaurin, (150 mg/kg b.i.d. via oral gavage) and a secondary drug, either gemcitabine, (2.5 or 5.0 mg/kg 1x/3 days IP), bortezomib, (0.4 mg/kg twice weekly IP), rapamycin, (1.0 mg/kg, daily IP), or rituxan, (5 mg/kg, weekly IP). Imaging and analysis of tumor volumes showed that addition of either rituxan or rapamycin provided no additional benefit in comparison to enzastaurin alone during the course of treatment. In contrast, the combination of either gemcitabine or bortezomib with enzastaurin demonstrated significantly reduced tumor volumes in comparison to enzastaurin alone (17% to 38% greater decrease with enzastaurin + gemcitabine, and 50% greater decrease in tumor volume with enzastaurin + bortezomib). These data suggest that the use of enzastaurin in combination with existing therapeutic drugs (gemcitabine or bortezomib) has the potential to limit tumor size/growth while lowering dose levels and thereby reducing potential side effects associated with traditional treatments.

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