ENGAGE- 501: Phase 2 Study Investigating the Role of Epigenetic Therapy with Entinostat (SNDX-275) In Relapsed and Refractory Hodgkin's Lymphoma (HL), Interim Results

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3959-3959 ◽  
Author(s):  
Anas Younes ◽  
Francisco Hernandez ◽  
R. Gregory Bociek ◽  
Yvette L. Kasamon ◽  
Peter Lee ◽  
...  
Keyword(s):  
Demographic Data ◽  
Single Agent ◽  
Dose Intensity ◽  
Epigenetic Therapy ◽  
Dependent Manner ◽  
Phase 2 ◽  
Serum Samples ◽  
Nccn Guidelines ◽  
Phase 2 Study

Abstract Abstract 3959 Background: Entinostat (ENT) is an oral, class 1 isoform selective HDACi. In vitro in HL cell lines, ENT decreases proliferation and induces cell death in a dose dependent manner with an IC50 of 0.4 uM. As an epigenetic agent, ENT modulates immune pathways from a TH2 to a TH1 cytokine/chemokine profile and can upregulate the expression of cancer testis antigens, thus acting as an immunomodulator. This phase 2 study was initiated to define ENT single agent antitumor activity and safety and tolerability. Methods: The trial is a Simon 2-stage design that has completed enrollment in 2 dosing schedules with 24 evaluable patients at 6 sites, 6 patients remain active; enrollment is continuing in an alternate dosing schedule. ENT was administered at a dose of 10 mg every 14 days (d), in a 28 d cycle (C) for the first stage of the study, for the second stage the dose was escalated to 15 mg every 14 d beginning C1d15. Subjects ongoing from the first stage were also allowed to escalate. CT/PET scans are conducted every 2 cycles. Blood samples for correlative study analysis are obtained pre-treatment, C1D8, C1D15, and C3D15. Results: As of August 6, 2010, demographic data are available on 23 evaluable subjects, median age is 28 years (19-53), median prior regimens is 3 (2-10), 13 (56%) had prior autologous transplant, 3 (13%) had prior allogeneic and 3 (13%) had prior autologous and allogeneic transplant. 23 patients have >1 post baseline result available, 65% have disease control (CR+PR+SD), 35% had PD and 2 patients with SD discontinued due to AE (Pericarditis and thrombocytopenia). Two (9%) responses (PR) are reported with time on study 14.7 months and one >6 months. An additional 4 (17%) patients have tumor reduction (25-49%) for at least 4 cycles. Six (26%) patients completed ≥ 6 cycles. Common G1/2 AEs including all causalities were gastrointestinal, fatigue, and pyrexia. Of the 32 patients evaluated for safety, G 3/4 thrombocytopenia occurred in 19 (59.4%) patients, G 3/4 neutropenia in 9 (28.1%) patients, and G 3/4 anemia in 11 (34.4%) patients, including all causalities. Profiling of cytokine, chemokine and growth factor levels in patient serum samples provides support for the biological activity of entinostat as an immunomodulatory agent with ongoing evaluation demonstrating a reduction of IL-13 and TNFα levels within one week of therapy. Conclusions: ENT as a single agent in HL was well tolerated and demonstrated encouraging activity in this heavily pretreated patient population. Further dose intensity is currently being tested; updated results on the immunomodulatory effects will be presented. Disclosures: Off Label Use: Given the CD20 positivity of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) rituximab has been evaluated previously for relapsed NLPHL and was shown to be efficacious. Rituximab however is not FDA approved for NLPHL. This is a retrospective study that evaluates the use of R-CHOP and other therapies for NLPHL. Current NCCN guidelines support consideration of R-CHOP for NLPHL treatment, and given the rarity of the disease there is no one defined preferred chemotherapy regimen. This information will be disclosed to the audience.

A Phase 1/2 Study Of KW-2478, An Hsp 90 Inhibitor, In Combination With Bortezomib (BTZ) In Patients (Pts) With Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1967-1967
Author(s):  
Cavanagh Jamie ◽  
Honorata Giongco Baylon ◽  
Priscilla B. Caguioa ◽  
Faith E. Davies ◽  
Mecide Gharibo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Hsp 90

Abstract Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

A Multicenter Phase 1 Clinical Trial of Tanespimycin (KOS-953) + Bortezomib (BZ): Encouraging Activity and Manageable Toxicity in Heavily Pre-Treated Patients with Relapsed Refractory Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 406-406 ◽  
Author(s):  
Paul Richardson ◽  
Asher Alban Chanan-Khan ◽  
Sagar Lonial ◽  
Amrita Krishnan ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Phase 1 ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Peripheral Neurotoxicity ◽  
Phase 2 Study ◽  
Dose Levels

Abstract Background: Tanespimycin (KOS-953, 17-AAG) disrupts the function of Hsp90, a molecular chaperone of MM client proteins such as IL-6, IGF-1R that are key to growth, survival and drug resistance. In vitro, BZ + KOS-953 show additive cytotoxicity against MM cells. Single-agent KOS-953 produced durable MR and SD (ASH 2005 A#361) in relapsed and refractory MM pts with an MTD ≥ 420 mg/m2. Objectives: Define a phase 2 dose of BZ+KOS-953 in pts with relapsed, refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates. Explore changes in intracellular signaling proteins in PBMCs and CD138+ MM cells. Methods: Pts receive BZ as IVB followed by 1-hr infusion KOS-953 (in a Cremophor formulation) D1,4,8,11 q 21d. Dose escalation occurred in a step-wise manner (KOS-953: 100, 150, 220, 275 and 340 mg/m2; BZ: 0.7, 1.0 and 1.3 mg/m2). Collection of PK and surrogates occurs after D1, 11 dosing. Toxicity is assessed by NCI CTCAE v3.0 and response by EBMT criteria. Results: 40 pts were enrolled in 7 dose levels: 22F/18M; median age/KPS 59y/90; all rel/refy; median # of prior regimens 4 (range 2–16); 97% dex; 73% prior BZ; 87% prior thalidomide; 7% prior lenalidomide; 67% prior SCT. Pts received a median of 4 cycles (range: 1 – 19+). Three episodes of DLT potentially related to KOS-953 were observed (KOS-953/BZ dose): grade (g) 3 pancreatitis (150/1.3); g4 metabolic acidosis with GI hemorrhage secondary to GI amyloidosis (275/1.3); and g3 myalgias/cramps (340/1.3). Other g3–4 toxicity: anemia, back pain and thrombocytopenia (all reversible). Common toxicities (>10%): fatigue, diarrhea, constipation, thrombocytopenia and nausea (predominantly g1-2). Significant cardiotoxicity, peripheral neurotoxicity and DVT were not reported. KOS-953 PK: similar to single-agent trial with no change in clearance on this schedule. Dose (mg) vs exposure to [parent + metabolite] was linear (R2=0.87). 20S proteasome inhibition was similar to published BZ single-agent values. Hsp70 induction was observed in PBMCs prior to D11 infusion, suggesting sustained Hsp90 inhibition on this schedule. Responses (CR+PR+MR) were seen in all dose levels of KOS-953 with BZ ≥ 1.0 mg/m2: BZ-naive pts (5/7 pts; 71%); BZ-refractory pts (defined as PD on BZ-containing regimen prior to study or no response to prior BZ; 2/6 pts; 33%) and BZ-pretreated pts (5/13 pts; 38%); 4 pts were non-evaluable having received ≥ 2 infusions and 10 pts (Cohort 7) are not yet assessable for response. Conclusions: Encouraging anti-MM activity has been observed in all dose groups with KOS-953 with BZ ≥ 1.0 mg/m2. The dose group of 1.3 mg/m2 BZ + 340 mg/m2 KOS-953 is being expanded to assess tolerability; one pt out of 10 experienced DLT at this dose level to date. To date, no additive toxicity or PK interactions are seen. A phase 2 study of the combination in relapsed, refractory MM and a registrational phase 2/3 trial in MM pts in 1st relapse comparing BZ to BZ+KOS-953 are planned.

scholarly journals Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study

2011 ◽  
Vol 17 (21) ◽  
pp. 6905-6913 ◽  
Author(s):  
Richard S. Finn ◽  
Carmelo Bengala ◽  
Nuhad Ibrahim ◽  
Henri Roché ◽  
Joseph Sparano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Study ◽  
Open Label Phase

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

scholarly journals Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused byNeisseria gonorrhoeae

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Nicole E. Scangarella-Oman ◽  
Mohammad Hossain ◽  
Paula B. Dixon ◽  
Karen Ingraham ◽  
Sharon Min ◽  
...  
Keyword(s):  
Randomized Study ◽  
Microbiological Analysis ◽  
Phase 2 ◽  
Therapeutic Success ◽  
Time Curve ◽  
Content Type ◽  
Phase 2 Study ◽  
Critical Residue ◽  
Oral Doses

ABSTRACTWe evaluated microbiological correlates for the successful treatment ofNeisseria gonorrhoeaeisolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication ofN. gonorrhoeae. Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90= 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) atfAUC/MICs of ≥48 and decreased to 63% (5/8) forfAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, thein vitroFoR to gepotidacin was low (10−9to 10−10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary,fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.)

CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi64
Author(s):  
Zhong-ping Chen ◽  
Cheng-Cheng Guo ◽  
Yang Qun-ying ◽  
Jia-Wei Li ◽  
Shao-xiong Wu ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Radiation Treatment ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Common Adverse Event ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5086-TPS5086
Author(s):  
Neeraj Agarwal ◽  
Stephane Oudard ◽  
Josep M. Piulats ◽  
Michael Thomas Schweizer ◽  
Aude Flechon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Radiographic Progression ◽  
Prostate Cancer Cell ◽  
Response Rate ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 2 Study

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 & 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 & 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material <12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

AMN107 Appears Equipotent and May Synergise with Imatinib at the CML Stem Cell Level through Interaction with ABCG2.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1080-1080 ◽  
Author(s):  
H. Jorgensen ◽  
E. Allan ◽  
N. Jordanides ◽  
A. Hamilton ◽  
J. Mountford ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Single Agent ◽  
Cell Number ◽  
Total Cell ◽  
Dependent Manner ◽  
Cell Level ◽  
Clinical Resistance

Abstract AMN107 (Novartis) is a novel Abl tyrosine kinase inhibitor specifically developed to be more selective for BcrAbl. AMN107 also maintains activity against the most common mutations associated with clinical resistance to imatinib mesylate (IM). In preclinical studies in cell lines and animal models, AMN107 was found to have greater potency than IM. By 3H-thymidine proliferation assays, the IC50 for AMN107 in K562 cells was 30 +/− 10nM compared with 600 +/− 60nM for IM. AMN107 and IM reduced K562 output cell number to 25% of input at 50 and 1000nM respectively, at 72h. These data are in keeping with the reported 20-fold increase in potency of AMN107 over IM. In addition, we have tested AMN107 for in vitro activity against primary CD34+Ph+ CML cells during 72h of culture in 5 growth factors. In CML cells (n=5), AMN107 and IM failed to reduce input cell number although the total cell output was restricted to 50% of PBS treated control at 2 +/− 1μM for AMN107 and to 31 +/− 7% of PBS treated control for 5μM IM suggesting the drugs were equipotent. The ability of the drugs to inhibit BcrAbl activity was then measured indirectly via the phosphorylation status of CrkL using a specific antiphospho-CrkL antibody and flow cytometry. Once again AMN107 and IM appeared equipotent in CML cells with 5μM of each compound leading to equal de-phosphorylation of CrkL. We next tested the efficacy of AMN107 as a single agent and in combination with IM against quiescent CML cells using in vitro dye (CFSE) tracking experiments. We evaluated by flow cytometry the proportion of input cells remaining alive, CD34+ and undivided (CFSEmax) or in first division. Compared to PBS treated control, 1.7, 2.5, 3.8 and 4.7-fold increases were found in the proportion of input CD34+ cells recovered in divisions 0 and 1 after 3 days exposure to 0.005, 0.05, 0.5 and 5μM AMN107, respectively. This was less accumulation than observed in the IM (5μM)-treated cells (11.0-fold). The combination of IM and AMN107, each at 5μM, was more effective in terms of total cell kill (54 and 74% fewer total cells remaining than with IM and AMN107 alone, respectively) and resulted in fewer viable cells recovered in divisions 0 and 1 than with either agent alone (for the combination, 1.9-fold on PBS treated recovery). We finally assessed the role of ABCG2 in modulating AMN107’s access to its intracellular BcrAbl target. We have previously shown ABCG2 to be over-expressed on CML stem cells and to interact with IM (Blood (2004); 104: 205a). We hypothesised that AMN107 and IM may co-operate as ABCG2 substrates or inhibitors to increase the intracellular levels of either or both drugs thus amplifying their efficacy against target protein specifically in CML stem cells. In competition assays with a known fluorescent substrate of ABCG2 (ie BODIPY-prazosin, BP), a specific inhibitor of the ABCG2 pump (fumitremorgin C, FTC) and an ABCG2 stably transfected AML cell line (AML6.2), the sample treated with BP plus FTC is taken to have greatest retention (100%). AMN107 inhibited efflux in a dose dependent manner to a maximum of 88% at 5μM, similarly to IM. Thus, AMN107 was equipotent with IM in primary CML stem cells in terms of restricting cell growth, inhibiting BcrAbl activity and interacting with ABCG2. However, AMN107 alone lead to less accumulation of quiescent CML cells in vitro as compared to IM, with the combination even more effective in this regard. The apparent co-operative effect of AMN107 and IM at the stem cell level would be predicted to improve clinical responses if tolerated in patients.

Phase 2 Study of Oblimersen Sodium (G3139; Bcl-2 Antisense; Genasense®) Plus Gemtuzumab Ozogamcin (Mylotarg®) in Elderly Patients with Relapsed Acute Myeloid Leukemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 865-865 ◽  
Author(s):  
Joseph O. Moore ◽  
Karen Seiter ◽  
Jonathan E. Kolitz ◽  
Wendy Stock ◽  
Richard Yu ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Response Rate ◽  
Apoptotic Cell ◽  
Gemtuzumab Ozogamicin ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Normal Platelet ◽  
Phase 2 Study ◽  
Eligibility Requirements

Abstract Patients with relapsed AML over the age of 60 have a poor prognosis. Gemtuzumab ozogamicin (GO) has been approved for older pts in first relapse, although many pts who attain complete remission (CR) do not fully recover normal platelet count (so-called CRp). In vitro studies have shown that oblimersen down-regulates Bcl-2 in AML cells and enhances apoptotic cell death induced by GO. We conducted a Phase 2 study to evaluate the safety and efficacy of GO combined with oblimersen for older pts with AML. Eligibility requirements included: age ≥ 60 yrs; AML in 1st relapse; ≥ 3 mos 1st CR duration; ≥ 25% CD33-positive AML cells. Pts received oblimersen at a dose of 7 mg/kg/d for 7 days by CIV beginning on days 1 and 15; GO was given at a dose of 9 mg/m2 IV over 2 hrs on days 4 and 18. A total of 48 pts were enrolled (ITT population), all of whom received at least 1 dose of oblimersen; 9 pts failed to receive the required 2 doses of GO (per-protocol population, n=39). The median age was 67 (range, 59 to 88 yrs). Duration of 1st CR: < 6 mos: 7 pts; (15%); 6 to 12 mos: 29 pts (60%); > 12 mos: 12 pts (25%). No. of prior regimens: 1 (17 pts, 35%); 2 or 3 (26 pts, 54%); ≥ 4 (5 pts, 10%). Among treated pts, 79% completed 21 days of protocol therapy. Overall, 12 pts achieved a major response, either CR (n=5) or CRp (n=7), for an ITT response rate of 25% and a per-protocol response rate of 31%. The median time to remission was 52 days. Ten of the 12 responders survived > 6 mos, whereas only 6 non-responders survived ≥ 6 mos. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone and included among other reactions: Grade 3-4 febrile neutropenia (42%) or thrombocytopenia 33%; nausea; fever; rigors, and dyspnea. Treatment-emergent adverse reactions led to discontinuation of protocol therapy in 10 pts (21%). The most common serious adverse event was febrile neutropenia (25%). One pt (2.1%) died during treatment (sepsis) and 16 pts (33%) died within 30 days of last study medication (infection, bleeding, respiratory failure, progressive AML, and other disease-related complications). No episodes of VOD were observed. Oblimersen can be safely combined with GO; however, pts enrolled in this study appear to have had more unfavorable characteristics at entry compared with prior studies using GO alone in pts with relapsed AML. Therefore, assessment of an incremental benefit from the addition of oblimersen will require a randomized trial.

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