Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies

2002 ◽  
Vol 20 (22) ◽  
pp. 4420-4427 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Thomas E. Stinchcombe ◽  
Beverly S. Mitchell ◽  
Thomas C. Shea ◽  
Albert S. Baldwin ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
20S Proteasome ◽  
Dependent Manner ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Systemic Hypersensitivity

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m2, followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m2MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.CONCLUSION: PS-341 was well tolerated at 1.04 mg/m2on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin’s lymphoma in this study, and merits further investigation in these populations.

Clinical Trial of NPI-0052 (2nd generation proteasome inhibitor) in Patients Having Advanced Malignancies with Expanded RP2D Cohorts in Lymphoma and CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4934-4934 ◽  
Author(s):  
Timothy Price ◽  
Peeter Padrik ◽  
Amanda Townsend ◽  
Paul Mainwaring ◽  
Lawrence Catley ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Proteasome Inhibitor ◽  
Standard Of Care ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Preclinical Research ◽  
Novel Structure ◽  
Advanced Malignancies ◽  
Mantle Cell

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of the 20S proteasome. NPI-0052 has a novel structure leading to a unique proteasome inhibition, toxicology and effect profile. Preclinical research suggests an improved therapeutic ratio and activity in hematologic and solid tumor malignancy models. Secondary to these findings, clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Materials and Methods: In this study patients with solid tumor, lymphoma or leukemia diagnoses were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles in a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1 & D15) and pharmacokinetics PK (D1 & D15) were assayed in blood. Once a Recommended Phase 2 Dose (RP2D) is identified, RP2D cohorts of 10 patients in each lymphoma and CLL are enrolled. Results: 25 patients have been treated at doses ranging from 0.1 mg/m2 to 0.7 mg/m2. The AE profile has been very tolerable with fatigue, transient peri-infusion site discomfort and lymphopenia being commonly ascribed to NPI-0052. Whole blood pharmacokinetics were calculated for all patients on study. At the highest dose assessed PK parameters were (mean ± SD) AUCtot =215±129 ng/mL*min; Cmax =22.8 ±14 ng/mL; t1/2 =13.5 ± 9.2 mins; clearance= 7.8 ± 8.2 L/min and Vss = 132 ± 192 L. AUC and Cmax increased linearly with dose and the kinetics are apparently not dose dependant. PI has been assayed in blood, indicating a dose:response relationship with inhibition of chymotrypsin-like activity up to 100% observed and mean Day 1 inhibition of 78%. This level of proteasome inhibition is higher than that reported with standard doses of bortezomib, yet the profile of adverse drug reactions associated with bortezomib has not been observed. A total of 7 patients (33%) have had stable disease for at least 2 cycles (8 weeks; 2months), including one each with mantle cell lymphoma (4 cycles), Hodgkin’s lymphoma (4 cycles), follicular lymphoma (4 cycles) and sarcoma (5 cycles) and prostate adenocarcinoma, and two with melanoma (4 cycles). Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range while producing a toxicity profile that is tolerable and dissimilar to that of the standard of care proteasome inhibitor bortezomib. These data have supported additional studies being initiated in hematologic malignancies and solid tumors.

A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717.

1986 ◽  
Vol 4 (8) ◽  
pp. 1245-1252 ◽  
Author(s):  
A H Calvert ◽  
D L Alison ◽  
S J Harland ◽  
B A Robinson ◽  
A L Jackman ◽  
...  
Keyword(s):  
Phase I ◽  
Thymidylate Synthase ◽  
Renal Toxicity ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Radiation Recall ◽  
Heavily Pretreated ◽  
Recommended Phase Ii Dose ◽  
The One ◽  
Synthase Inhibitor

CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.

scholarly journals Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Jessica Tsalikis ◽  
Mena Abdel-Nour ◽  
Armin Farahvash ◽  
Matthew T. Sorbara ◽  
Stephanie Poon ◽  
...  
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Adaptor Protein ◽  
Proteasome Inhibition ◽  
20S Proteasome ◽  
Protein Homeostasis ◽  
Cancer Cell Death ◽  
Protein Clearance ◽  
Lysosome Biogenesis

ABSTRACTProtein degradation pathways are critical for maintaining proper protein dynamics within the cell, and considerable efforts have been made toward the development of therapeutics targeting these catabolic processes. We report here that isoginkgetin, a naturally derived biflavonoid, sensitized cells undergoing nutrient starvation to apoptosis, induced lysosomal stress, and activated the lysosome biogenesis geneTFEB. Isoginkgetin treatment led to the accumulation of aggregates of polyubiquitinated proteins that colocalized strongly with the adaptor protein p62, the 20S proteasome, and the endoplasmic reticulum-associated degradation (ERAD) protein UFD1L. Isoginkgetin directly inhibited the chymotrypsin-like, trypsin-like, and caspase-like activities of the 20S proteasome and impaired NF-κB signaling, suggesting that the molecule may display its biological activity in part through proteasome inhibition. Importantly, isoginkgetin was effective at killing multiple myeloma (MM) cell linesin vitroand displayed a higher rate of cell death induction than the clinically approved proteasome inhibitor bortezomib. We propose that isoginkgetin disturbs protein homeostasis, leading to an excess of protein cargo that places a burden on the lysosomes/autophagic machinery, eventually leading to cancer cell death.

Initial Results of PX-171-003, An Open-Label, Single-Arm, Phase II Studyof Carfilzomib (CFZ) in Patients with Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 864-864 ◽  
Author(s):  
Sundar Jagannath ◽  
Ravi Vij ◽  
A. Keith Stewart ◽  
George Somlo ◽  
Andrzej Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Complete Response ◽  
Open Label ◽  
Upper Respiratory Infection ◽  
Heavily Pretreated ◽  
Clinical Benefit Response ◽  
High Level

Abstract Background: Carfilzomib (CFZ) is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteasome and has been shown in a phase 1 study to result in greater than 80% proteasome inhibition on a QDx2 consecutive day schedule. We piloted this agent in MM patients with relapsed and refractory disease, who had failed bortezomib (BTZ) and at least one immunomodulatory (IMiD) agent, e.g., thalidomide (THAL) and/or lenalidomide (LEN). Methods: PX-171-003 is an open-label, multicenter study enrolling pts with MM who have relapsed from at least 2 prior therapies and who are refractory; defined as progressing on or within 60 days of last therapy or<25% response to the last therapy. Pts received CFZ 20 mg/m2 IV Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. Responses were evaluated by the International Uniform Response Criteria for Multiple Myeloma. Clinical benefit response (CBR) was defined as complete response (CR) + partial/very good partial response (PR/VGPR) + minimal response (MR, as defined by EBMT criteria). Responses were adjudicated by an independent review committee. Results: 46 pts were enrolled, including 78% with progression on or within 60days of last therapy and 22% with no response to last therapy. 39 pts initiated treatment, completed at least one cycle of CFZ, had measurable M-protein, and were evaluable (eval) for response. The mean number of prior therapies (excluding transplant) was 6.4(range 1 to 18). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplantation (SCT). To date, pts received a median of 3 cycles(range 1–9) of CFZ; 22 started at least 4 cycles. The CBR was 26% (10/39 eval pts), including 5 pts achieving PR, 5 pts achieving MR, and 16 additional patients achieving stable disease (SD). Time to response was rapid, frequently occurring in the 1st cycle. CFZ was generally well tolerated; the most common adverse events (AEs) were fatigue(65%), nausea (37%), upper respiratory infection (37%), and diarrhea (33%). Worsening of hematologic parameters: anemia (65%); thrombocytopenia (46%) and neutropenia(20%) were predominantly Grades 1 and 2. Increased creatinine, both drug and non-drug related, was seen in 15/46 pts (33%), but treatment was discontinued in only 3 patients due to a renal adverse event. Acute renal failure was documented in 4 pts (9%), 2 (4%) of whom also had possible tumor lysis. 78% of pts had Grade 1 or 2 peripheral neuropathy (PN) at baseline. Exacerbation of PN was rare, and there were no study discontinuations or dose reductions due to PN. Conclusions: In the context of this heavily pre-treated MM population, single agent CFZ was able to induce CBR in 26% of MM patients, the majority of whom had failed BTZ, LEN, THAL, and SCT. CFZ was generally well-tolerated, and toxicities were manageable. Importantly, exacerbation of pre-existing PN was rare and did not result in dose reduction or discontinuation of therapy. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment is proceeding at an escalated dose (based on tolerability) in this trial. Additional studies of CFZ in patients who are less heavily pretreated and in combination with other chemotherapy agents are ongoing.

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

scholarly journals HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Sekar Natesampillai ◽  
Nathan W. Cummins ◽  
Zilin Nie ◽  
Rahul Sampath ◽  
Jason V. Baker ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Hiv Protease ◽  
Dependent Manner ◽  
Clinical Use ◽  
Protease Cleavage ◽  
Infected Cells ◽  
Memory Cd4 T Cells

ABSTRACTHIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner.IMPORTANCEThe Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

Phase II Evaluation of Vindesine in Mycosis Fungoides, Extraosseous Plasmacytoma and other Hematologic Malignancies

1982 ◽  
Vol 68 (4) ◽  
pp. 321-324
Author(s):  
Eros Ferrazzi ◽  
Giovanni L. Pappagallo ◽  
Romana Segati ◽  
Orazio Vinante ◽  
Enzo Galligioni ◽  
...  
Keyword(s):  
Mycosis Fungoides ◽  
Phase Ii ◽  
Vinca Alkaloid ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Phase Ii Trials ◽  
Minor Response ◽  
Apparent Lack ◽  
Starting Dose ◽  
Heavily Pretreated

We conducted a phase II trial of Vindesine in 24 patients, mostly pretreated (23/24 fully evaluable for therapeutic response) with advanced hematologic malignancies. The drug was administered at weekly bolus doses of 3 mg/m2 i.v. Overall, objective tumor regressions were seen in 9 of 23 patients. The drug appeared effective in extraosseous plasmacytoma (1 complete response and 1 minor response in 3 patients) and in mycosis fungoides (1 complete response, 1 partial response and 1 minor response in 6 patients). Further phase II trials in these 2 diseases are justified. In addition, 3 partial responses in 7 patients with advanced lymphoma were also obtained. Previous vinca-alkaloid exposure did not adversely affect the response rate: 8 of 9 responsive patients had previously received vincristine and/or vinblastine. Drug-related toxic effects were mainly represented by manageable and reversible neurotoxicity and by moderate leukopenia with apparent lack of thrombocytopenia. In heavily pretreated patients, leukopenia may be occasionally severe: in these conditions a starting dose of 2 mg/m2 seems more appropriate.

A phase Ib/II study of eribulin with cyclophosphamide (EC) in patients (pts) with advanced breast cancer (ABC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13079-e13079
Author(s):  
Ozge Gumusay ◽  
Jonathan R. Renslo ◽  
Chiara A. Wabl ◽  
Amy Jo Chien ◽  
Michelle E. Melisko ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Cycle Phase ◽  
Microtubule Inhibitor ◽  
Phase Ib ◽  
Duration Of Response ◽  
Heavily Pretreated

e13079 Background: Eribulin is an effective microtubule inhibitor for the treatment of ABC. Based on encouraging efficacy with docetaxel/cyclophosphamide, we hypothesized that eribulin combined with cyclophosphamide (EC) would be effective with tolerable toxicity. The aim of the study was to determine the maximum tolerated dose (MTD) of EC, followed by a dose expansion study to estimate the clinical benefit rate (CBR) of EC in pts with ABC. Methods: Study eligibility included pts with histologically confirmed ABC with any number of prior lines of therapy. Pts were treated using a dose escalation strategy with cohort expansion once MTD was determined. Dose level 0 (DL0): E 1.1 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. DL1: E 1.4 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. Phase II expanded enrollment at DL1. The primary objective of the phase II study was CBR [(complete response (CR), partial response (PR), and stable disease (SD)]. Secondary objectives were response rate (RR), duration of response (DOR), time to progression (TTP), and safety. Using a 2-stage design, responses in 3 of the first 22 pts allowed continued enrollment to a planned 40. Results: No dose limiting toxicities (DLT) were identified in phase Ib (n = 6). 3 pts were treated at DL0 and 3 at DL1, the MTD. 44 pts with ABC were enrolled at the MTD and are included in the analysis. 31 pts had HR+/HER2- disease, 12 pts had triple negative disease (TNBC), 1 pt had HR+/HER2+ disease. Median age was 56 yrs, prior treatment (rx) for ABC included a median of 1 line of hormone rx (range 0-6) and 2 lines of prior chemorx (range 0-7). CBR was 79.5% (35/44; 7 PR, 28 SD) and median PFS 16.4 wks (95%CI:13.8-21.1 wks). Longer PFS was observed in those with HR+ disease vs TNBC (18.1 vs 10.8 wks; P = 0.067). Adverse events (AE) of any grade included fatigue (68.2%, n = 30), neutropenia (ntp) (59.1%, n = 26), nausea (56.8%, n = 25), constipation (50%, n = 22), peripheral neuropathy (47.7%, n = 21), dyspnea (40.9%, n = 18), headache (36.4%, n = 16), and anorexia (36.4%, n = 16). The most common grade 3/4 AE ntp (47.7%, n = 21); 3 pts had febrile ntp. Dose reductions due to ntp were required to 500 mg/m2 C (n = 17) and to 1.1 mg/m2 in eribulin (n = 12). Conclusions: EC in heavily pretreated ABC resulted in an encouraging CBR of 79.5% and PFS of 16.4 wks, comparing favorably to single agent E (PFS 14.8 wks). Dose reduction and delays were due primarily to ntp. EC is an effective combination therapy with manageable toxicity in ABC. Clinical trial information: NCT01554371 .

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3058-3065 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Peter M. Voorhees ◽  
Reynaldo A. Garcia ◽  
Melissa D. Hall ◽  
Fred J. Kudrik ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Chemotherapeutic Agents

Abstract Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

A Phase I Study of the Proteasome Inhibitor Bortezomib in Patients with Myelofibrosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3540-3540
Author(s):  
Giovanni Barosi ◽  
Elisabetta Gattoni ◽  
Tiziano Barbui ◽  
Alessandro M. Vannucchi ◽  
Alessandro Rambaldi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Proteasome Inhibitor ◽  
Distress Syndrome ◽  
Phase 1 ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Minor Response ◽  
Cutaneous Rash

Abstract Myelofibrosis (MF) is the most serious myeloproliferative disorder, characterized by clonal myeloproliferation associated with cytokine-mediated bone marrow stromal reaction including fibrosis and osteosclerosis. Because the NF-κB pathway is implicated in the abnormal release of cytokines in MF, the proteasome inhibitor bortezomib might be a potential therapy. We conducted a phase 1 trial of intravenously administered bortezomib (Velcade®) in 12 adults with advanced primary MF (11 patients) or post-PV/post-ET MF (1 patient). Eligibility was defined as refractory or not suitable to first line chemotherapy. Median age was 57 years (range, 22 to 69 years). Three cohorts of patients were treated with bortezomib at day 1, 4, 8, and 11 from 0.8 to 1.3 mg/m2, every 21 days x 6 cycles. Three patients received less than 5 cycles and are not considered evaluable for response (cutaneous vasculitis, respiratory distress syndrome and peripheral neuropathy). Dose-limiting toxicity (DLT) occurred in 1 patient treated with bortezomib in the 1.3 mg/m2 cohort, consisting on respiratory distress syndrome. The patient was hospitalised and improved with corticosteroid therapy. The maximum-tolerated dose was 1.3 mg/m2 for 4 days every 3 weeks. Other frequent non-DLTs were thrombocytopenia (2/12), fatigue (3/12), oedema (1/12), cutaneous rash (2/12). No complete, major or moderate responses according EUMNET response criteria were documented. One minor response was documented due to complete response in platelet count (platelet count 150–400 x 109/L at the end of the sixth cycle of therapy). Our results show that bortezomib in MF is clinically tolerable at the 1.3 mg/m2 every 21 days x 6 cycles. The efficacy of the drug is under examination in a phase II study.

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