A phase II study of the tolerability and activity of weekly vincristine sulfate liposomes injection (VSLI) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second relapse or progressing following two antileukemia treatment lines

7046 Background: VSLI (Marqibo) is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol liposomes called Optisomes. The optisomal formulation lends itself to an improved pharmacokinetic profile and enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus standard VCR in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 with no dose cap, while conventional VCR is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study in relapsed ALL showed a complete response rate of 19%, warranting further study. Methods: Eligible adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. This international, multicenter, single-arm study will enroll approximately 56 subjects. Major endpoints include response rate and overall survival (OS). An interim analysis was planned following enrollment of 29 evaluable subjects. Results: 29 heavily pretreated subjects received ≥ 1 dose of VSLI. To date, at least 9 of 29 subjects had clearing of leukemic blasts and achievement of an M1 bone marrow. Based on preliminary data, the median OS is estimated to be 7.5 months (95% CI: 4.7–10.5) using the Kaplan-Meier method. The most frequent related adverse event (AE) was peripheral neuropathy (PN) (48%), half of which was grade 3. No grade 4 PN was reported. Six subjects had 8 treatment-associated grade 4 AEs of neutropenia (4), thrombocytopenia (2), anemia (1), and inappropriate antidiuretic hormone secretion (1). Conclusions: These results are encouraging, as VSLI was given as a single agent to a heavily pretreated patient population who nearly universally received prior VCR. This population typically has a very low response rate to anti-leukemia therapies. Early OS data compares favorably to an historical median OS of ∼ 2 months (8.7 weeks) in a second salvage population (data on file, M. D. Anderson). VSLI was well tolerated in these patients in the context of universal prior vincristine treatment. [Table: see text]

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Marqibo® (vincristine sulfate liposomes injection; VSLI) Optimizes the Dosing, Delivery, and Pharmacokinetic (PK) Profile of Vincristine Sulfate (VCR) In Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v116.21.2142.2142 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2142-2142 ◽

Cited By ~ 1

Author(s):

Jeffrey A Silverman ◽

Walter E. Aulitzky ◽

John Lister ◽

Lori Maness ◽

Gary J Schiller ◽

...

Keyword(s):

Plasma Concentration ◽

Specific Activity ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Philadelphia Chromosome ◽

Full Blood Count ◽

National Study ◽

Vincristine Sulfate ◽

Dose Intensification ◽

The Mean

Abstract Abstract 2142 Background: VCR is an important component of the treatment of ALL, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, and other adult and childhood cancers. In part, because of the cell cycle specific activity of VCR, its anti-cancer activity is believed to be very exposure time and concentration dependent. Standard dosing of conventional VCR (1.4 mg/m2 with a 2 mg cap) is limited because of early onset peripheral neuropathy and fails to achieve sustained VCR delivery. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, prolonged drug delivery and enhanced cancer penetration and concentration. Methods: In a pivotal, Phase 2, multi-national study (RALLY Trial), 65 adults with Philadelphia chromosome negative ALL who were either in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent intravenous VSLI 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. First-dose PK was investigated in a representative subset of 13 study subjects. Blood for analysis was collected at 8 time points ranging from 5 minutes to 48 hours following infusion. Total VCR plasma levels were determined by HPLC-MS/MS. PK parameters were calculated with Phoenix WinNonlin. Results: The PK subject subset had a median body surface area (BSA) of 1.92 m2 (range 1.47 to 2.45 m2) and received a median VSLI dose (VCR component) of 4.32 mg (range 3.3 to 5.51 mg). Based on BSA and the 2 mg dose cap, all subjects in this study group would have been dosed with 2.0 mg of conventional VCR. The median cumulative induction dose of VSLI (VCR component) that was administered in this study was 18.8 mg (range 3.5 to 70.1 mg). Total VCR plasma concentration decreased rapidly from Cmax after the VSLI infusion in 5 subjects (38%); 8 subjects (62%) exhibited a delay of 4 to 10 hours before the total VCR plasma concentration began to decrease. The calculated Tmax was 1.3 ± 0.4 hours (range 1.1 to 2.0 hours). The Cmax was 1214 ± 233 ng/mL (range 919 to 1720 ng/mL). The apparent mean half-life was 7.1 ± 3.2 hours. The mean AUCinf was 13,993 ± 6,588 ng hr/mL with a range from 7,167 to 27,233 ng hr/mL. The mean clearance (CL) was 6.4 ± 2.6 mL/min. The mean volume of distribution (Vd) was 0.051 ± 0.018 L/Kg. There were no significant differences in the PK parameters between the male and female subjects participating in this study. The table below presents VSLI PK parameters in addition to historical PK parameters for conventional VCR dosed at 2 mg. Conclusions: VSLI clearly provides dose intensification and prolonged VCR delivery compared to conventional, non-encapsulated VCR. VSLI, as dosed in this adult ALL clinical trial, delivered individual and cumulative amounts of VCR that exceed those achievable with standard and approved dosing of conventional VCR. This translated into a median dose intensification of 116% (range 65 to 176 percent) calculated as the percent change in VSLI dose from a standard VCR dose. This dose intensification is believed to have contributed to the 35% overall response rate including 20% complete responses (with or without full blood count recovery) reported in this heavily pre-treated, multiply-relapsed/refractory population without apparent enhanced toxicity [J Clin Oncol 28:15s, 2010 (suppl; abst 6507)]. VSLI has a distinctly different PK profile than conventional VCR. The larger VSLI Cmax and AUCinf reflect the dose intensification afforded by a larger mg/m2 dose and lack of dose capping. Even in the absence of dose capping, the 2.25 mg/m2 VSLI dose represents a 61% dose escalation above conventional VCR. While Cmax and AUCinf are dose-dependent PK parameters, the observed differences between VSLI and VCR control cannot be explained by dose alone. The larger AUCinf also reflects prolonged circulation afforded by the sphingomyelin:cholesterol liposome encapsulation. The modest VSLI mean CL and small Vd reflect the retention of encapsulated VCR within the plasma compartment for an extended period of time so that VCR can better penetrate and accumulate in sites of cancer through fenestrated vasculature. The enhanced delivery of encapsulated VCR contributes to maintenance of VCR concentrations above the effective concentration. Disclosures: Silverman: Hana Biosciences: Employment. Deitcher: Hana Biosciences: Employment.

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Marqibo® (vincristine sulfate liposomes injection; VSLI) In the Treatment of Adult Patients with Advanced, Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL): A Combined Analysis of the VSLI-06 and RALLY Studies

Blood ◽

10.1182/blood.v116.21.2143.2143 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2143-2143

Author(s):

Susan O'Brien ◽

Deborah A Thomas ◽

Leonard T Heffner ◽

Wendy Stock ◽

Gerald L. Messerschmidt ◽

...

Keyword(s):

Salvage Therapy ◽

Response Rate ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Complete Response ◽

Adult Patients ◽

Cell Transplant ◽

Vincristine Sulfate ◽

Hematopoietic Stem ◽

To Receive

Abstract Abstract 2143 Background: The outcome of adults with relapsed/refractory ALL, and of those whose disease recurs after first salvage, in particular, is extremely poor. Second salvage therapy with single agents has historically produced a complete response (CR) in only 4% of patients. (O'Brien, S, et al. Cancer 2008; 113:3186-3191). Third salvage therapy has not been studied but would be expected to be even less effective. Conventional vincristine sulfate (VCR) is an effective anti-leukemia agent, widely used in the treatment of ALL as part of several intensive regimens. VCR is dosed at 1.4 mg/m2 with a 2 mg cap due to early onset of peripheral neuropathy. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, improve duration of drug exposure, and enhance cancer and bone marrow drug delivery. Methods: Two distinct studies investigated VSLI in adult patients with advanced, relapsed/refractory ALL. Study VSLI-06 was a Phase 1/2, multi-center, 36 patient, dose-escalation study to determine safety, maximum tolerated dose, and anti-leukemia activity. Patients received VSLI intravenously (IV) weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2 with no dose cap plus dexamethasone 40 mg on days 1–4 and 11–14 of each 4 week cycle. The RALLY Study was a Phase 2, multi-national, 65 patient study of single-agent VSLI (2.25 mg/m2 IV weekly without dose cap) in adults with ALL in second relapse or who had progressed following at least two prior lines of anti-leukemia therapy. All subjects had been previously treated with VCR, and all received at least one dose of VSLI. The median age in both studies was 32 years with a combined range of 19 to 83 years. Other than one subject in VSLI-06, all subjects were Philadelphia chromosome negative. Results: The combined overall response rate was 31% (31 of 101). The combined complete response (CR) rate including CR with incomplete platelet (CRp) or hematologic (CRi) recovery was 20% (20/101). This response rate was consistent across the studies (19.4% and 20%, respectively). Hematologic improvement (HI) was achieved in 4 patients (11%) in VSLI-06 and 9 (14%) in RALLY, thus reducing transfusions and hospital visits. Five patients were able to receive a post-VSLI hematopoietic stem cell transplant (HSCT) in VSLI-06, and 10 patients were able to receive a post-VSLI HSCT in RALLY. The table below summarizes key study characteristics. The most commonly reported safety events in the studies were similar and included constipation, neuropathy, fatigue, nausea, pyrexia, febrile neutropenia, and anemia. Conclusion: These two studies totaling 101 patients with similar populations of advanced relapsed/refractory ALL showed a combined 20% CR/CRp/CRi rate, dwarfing the rate in historical studies. This is particularly encouraging, given that 100% of subjects had received prior VCR and that historical control data were largely in a less heavily pre-treated population. Both VSLI alone and combined with pulse dexamethasone appear to be highly active. In total, 15% of combined study patients were able to “bridge” to HSCT. Use of VSLI in the frontline setting and in combination regimens should further improve ALL patient outcomes. Disclosures: Messerschmidt: Hana Biosciences, Inc.: Employment. Hagey: Hana Biosciences, Inc.: Employment. Deitcher: Hana Biosciences: Employment. Kantarjian: Hana Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Early Signs of Tolerability and Activity in a Phase 2 Study of Weekly Vincristine Sulfate Liposomal Injection (VSLI, MarqiboÒ) in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Progressing Following Two Anti-Leukemia Treatment Lines

Blood ◽

10.1182/blood.v112.11.3959.3959 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3959-3959 ◽

Cited By ~ 1

Author(s):

Susan O’Brien ◽

Lloyd E. Damon ◽

Melissa L. Larson ◽

Gary Schiller ◽

Wendy Stock ◽

...

Keyword(s):

Bone Marrow ◽

Patient Population ◽

Stem Cell Transplant ◽

Response Rate ◽

Lymphoblastic Leukemia ◽

Phase 1 ◽

Single Agent ◽

Cell Transplant ◽

Phase 2 ◽

Vincristine Sulfate

Abstract Increased drug delivery through enhanced formulations of standard acute lymphoblastic leukemia (ALL) therapies may improve outcomes while producing less toxicity. Preclinical and Phase 1 and Phase 2 clinical studies of vincristine sulfate encapsulated in liposomes (VSLI, Marqibo®) have shown enhanced efficacy and acceptable tolerability in a variety of solid and hematologic malignancies. A maximum tolerated dose (MTD) of 2.25 mg/m2 with no dose cap has been established for VSLI, which contrasts with the 2 mg dose cap for conventional vincristine (VCR). Pharmacokinetic studies have shown that altered distribution and elimination phases may lead to increased exposure versus traditional VCR and may account for the increased efficacy observed in nonclinical models. The current Phase 2 trial is evaluating VSLI in adult (Ph-) subjects with ALL in second relapse or after progression following two prior ALL therapies. Subjects are receiving intravenous (IV) 2.25 mg/m2 VSLI weekly with no dose cap for up to 12 months. The study will enroll approximately 56 subjects with response rate as the primary endpoint. To date, 23 subjects have received at least one dose of IV VSLI. Preliminary reports indicate that five of these subjects achieved responses (CR/CRi/CRp). While data review is not complete, preliminary signs of efficacy in this underserved patient population warrant discussion: Two subjects had fewer than 5% lymphoblasts; one on Day 28 and the other on Days 28 and 56 after initial VSLI treatment and subsequently underwent stem cell transplant. The latter subject achieved a CR to a single agent (VSLI) in her first relapse (systemic and extramedullary) after a prior allogeneic transplant. One subject achieved a CR with no residual blasts (normocellular bone marrow) and resolution of extramedullary disease including resolution of bilateral pleural effusions without thoracentesis and marked decrease of an anterior mediastinal mass by Day 28. Her chest pain resolved after the first dose of VSLI. This subject subsequently went on to receive a second stem cell transplant. One subject with extramedullary disease of the kidney achieved a CR with no residual blasts detected in the kidney or bone marrow. This subject achieved a true CR (2 confirmed kidney biopsies one month apart) after 11 doses VSLI. One subject with bone marrow disease achieved a CR that was durable for approximately 5 months. Although these data are preliminary in this patient population, these findings are encouraging given that this is a single agent chemotherapy being given to a heavily pretreated leukemic population. The drug appears well tolerated to date with no reports of subjects experiencing Grade 4 toxicity. VSLI appears to have a safety profile similar to conventional VCR. Common AEs include neutropenia, fatigue, constipation, peripheral neuropathy, and nausea. In the previous VSLI (Marqibo) Study VSLI-06, VSLI appeared to be highly effective in second relapsed subjects achieving a CR rate of 29% with a limited sample size (2 out of 7 subjects). The preliminary CR (CR/CRi/CRp) rate from this study further corroborates this result: the CR rate is 28% among patients who completed study treatment and is at least 22% (≥5/23 subjects) among all subjects including those who just started receiving VSLI. The projected rate of activity in this ongoing trial supports these previous Phase 1 study results and confirms the importance of VSLI (Marqibo) in this patient population. These preliminary results are extremely encouraging, as VSLI was given as a single agent to a patient population that typically has a very low response rate to anti-leukemia therapies. Phase 3 combination studies are planned.

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Single-Agent Vincristine Sulfate Liposomes Injection (Marqibo®) Compared to Historical Single-Agent Therapy for Adults with Advanced, Relapsed and/or Refractory Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v118.21.2592.2592 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2592-2592 ◽

Cited By ~ 3

Author(s):

Olivia R. Deitcher ◽

Susan O'Brien ◽

Steven R. Deitcher ◽

Deborah A. Thomas ◽

Hagop M. Kantarjian

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Philadelphia Chromosome ◽

Complete Response ◽

Vincristine Sulfate ◽

Study Population ◽

Multi Agent ◽

Equity Ownership

Abstract Abstract 2592 There are no standard of care or approved treatments specifically for advanced, relapsed and/or refractory adult Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL). Pronounced toxicity of multi-agent salvage therapy, residual toxicity in heavily pre-treated subjects, and poor response to prior multi-agent therapy including hematopoietic stem cell transplant (HSCT) may prompt the use of single-agent salvage including investigational agents. We compared the efficacy and early plus induction (30-day) mortality rates for single-agent weekly intravenous vincristine sulfate liposomes injection (VSLI, Marqibo®) 2.25 mg/m2 (no dose cap) in adults with Ph- ALL in second or greater relapse or that had progressed following 2 or more lines of anti-leukemia therapy (RALLY Study, N=65) with those from the not previously described, single-agent (non-VSLI), second salvage, Ph- ALL subpopulation (N=56) from a large published report (O'Brien et al, Cancer 2008; 113:3186–91). Despite inclusion of subjects requiring third and greater salvage therapy in the RALLY Study, the O'Brien single-agent population represents the best historical comparator to the RALLY Study population. The most common of the 28 different agents used in the O'Brien study were vinorelbine (6), clofarabine (5), nelarabine (4), and topotecan (4). No subject in the O'Brien study received single-agent standard vincristine sulfate as second salvage. The table below highlights key characteristics of the two ALL populations as well as key efficacy and toxicity outcomes.RALLY Study VSLI (N=65)O'Brien 2008 Various Agents (N=56)Age (yrs), Median (range)31 (19–83)41 (17–73)Unfavorable Cytogenetics, N (%)33 (50.7)5 (8.9)Prior Lines of Therapy, N (%)Two 32 (49.2) Three 24 (36.9) ≥ Four 9 (13.8)Two 56 (100) Three 0 ≥ Four 0Prior HSCT, N (%)31 (47.7)0Prior Standard Vincristine, N (%)65 (100)56 (100)CR+CRi+PR, N (%)19 (29.2)2 (3.6)CR+CRi, N (%)13 (20.0)2 (3.6)CR+CRi Duration (wks), Median (range)23.1 (4.6–66.1)5 and 14*Overall Survival (wks), Median (range)19.9 (1.9–94.4)7.5 (0–110)Induction (30-day) mortality, N (%)8 (12.3)17 (30.4) Overall, the RALLY Study population was more advanced and heavily pre-treated than the O'Brien population. Despite the poorer prognosis, universal prior standard vincristine exposure, and majority of subjects requiring fourth or greater line therapy, single-agent VSLI 2.25 mg/m2 (no dose cap) resulted in a higher complete response (CR+CRi) rate, complete plus partial response (PR) rate, median complete response duration (* no median was calculated for the O'Brien Population because there were only 2 responders), and overall survival duration than was observed with a variety of third-line single-agent adult Ph- ALL salvage therapies. The median overall survival durations for the RALLY Study subjects achieving CR (7), CRi (6), and PR (6) were comparable. The majority of RALLY Study complete responders had a remission duration sufficient to facilitate a subsequent, and potentially curative HSCT. In fact, 12 (18.5%) of the 65 subjects in the RALLY Study were able to undergo a post-VSLI HSCT and 5 (7.7%) subjects were long-term survivors (post-VSLI survival greater than 1 year). Single-agent VSLI was associated with a more favorable early plus induction (30-day) mortality rate in the RALLY Study than observed in relation to other single-agent therapies. Single-agent weekly VSLI 2.25 mg/m2 has the potential to provide a relatively safe and effective induction treatment and “bridge” to HSCT compared to historical non-VSLI single-agent therapies. Disclosures: Deitcher: Talon Therapeutics: related to an employee with equity ownership. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2012.46.2309 ◽

2013 ◽

Vol 31 (6) ◽

pp. 676-683 ◽

Cited By ~ 114

Author(s):

Susan O'Brien ◽

Gary Schiller ◽

John Lister ◽

Lloyd Damon ◽

Stuart Goldberg ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Chemotherapy Resistance ◽

High Dose ◽

Rapid Progression ◽

Target Tissue ◽

Vincristine Sulfate ◽

Pivotal Phase

Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

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Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.3.575 ◽

1994 ◽

Vol 12 (3) ◽

pp. 575-579 ◽

Cited By ~ 69

Author(s):

P McLaughlin ◽

F B Hagemeister ◽

F Swan ◽

F Cabanillas ◽

O Pate ◽

...

Keyword(s):

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Active Agent ◽

Large Cell ◽

Maximum Tolerated Dose ◽

Low Grade ◽

Overall Response ◽

Nonhematologic Toxicity ◽

High Fraction

PURPOSE Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

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Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia

Blood ◽

10.1182/blood-2003-06-2122 ◽

2004 ◽

Vol 103 (3) ◽

pp. 784-789 ◽

Cited By ~ 176

Author(s):

Sima Jeha ◽

Varsha Gandhi ◽

Ka Wah Chan ◽

Lisa McDonald ◽

Irma Ramirez ◽

...

Keyword(s):

Pediatric Patients ◽

Lymphoblastic Leukemia ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Nucleoside Analog ◽

Dismal Prognosis ◽

Heavily Pretreated ◽

Inhibition Of Dna Synthesis ◽

Dose Levels ◽

Sustained Inhibition

Abstract Despite progress in leukemia therapy, most children who experience relapse have a dismal prognosis. New, effective approaches are needed. We conducted a phase 1 study of a novel nucleoside analog, clofarabine, in pediatric patients with refractory and relapsed leukemia. Clofarabine was infused intravenously over 1 hour each day for 5 days. Six dose levels, between 11.25 and 70 mg/m2 per day for 5 days, were studied in 25 patients. A modified 3 + 3 phase 1 design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. The maximum tolerated dose (MTD) was 52 mg/m2 per day for 5 days. At the end of infusion at MTD, clofarabine triphosphate levels in leukemia blasts varied between 6 μM and 19 μM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m2 per day for 5 days. Twenty-five patients were treated. Five patients achieved complete remission (CR), and 3 achieved partial remission (PR), for an overall response rate of 32%. Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase 2 trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing.

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Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.2.351 ◽

1988 ◽

Vol 6 (2) ◽

pp. 351-379 ◽

Cited By ~ 10

Author(s):

J L Grem ◽

D F Hoth ◽

B Leyland-Jones ◽

S A King ◽

R S Ungerleider ◽

...

Keyword(s):

Individual Component ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Cure Rate ◽

Front Line ◽

Preclinical Models ◽

Investigational Agent ◽

Highly Active ◽

Heavily Pretreated

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.

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Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v108.11.4528.4528 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4528-4528

Author(s):

Richard Sposto ◽

Elizabeth A. Raetz ◽

Charles P. Reynolds ◽

Paul S. Gaynon

Keyword(s):

Phase I ◽

Phase I Trial ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Cell Transplant ◽

Phase I Trials ◽

Hematopoietic Stem ◽

The Impact

Abstract Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a > 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia. Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity. Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time. Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.

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Final Report of a Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v120.21.3567.3567 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3567-3567

Author(s):

Yanis Boumber ◽

Deborah A. Thomas ◽

Farhad Ravandi ◽

Michael E. Rytting ◽

Marian R Love ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Phase I ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Philadelphia Chromosome ◽

Mtor Inhibitors ◽

Median Number ◽

Mtor Signaling ◽

Final Report ◽

Grade 3

Abstract Abstract 3567 Background: Acute lymphoblastic leukemia (ALL) is an aggressive lymphoproliferative disorder, responsive to frontline standard induction and consolidation chemotherapy. However, the prognosis of patients (pts) with relapsed/refractory ALL is extremely poor. Deregulation of the PI3K/Akt/mTOR signal transduction pathway is central to leukemic cell growth, proliferation and survival, and has been implicated in ALL pathogenesis. In a recent phase II study of pts with relapsed/refractory non-Hodgkin lymphoma, single agent mTOR inhibitor everolimus showed ORR 30% and acceptable toxicity in 77 heavily pretreated pts (Witzig TE et al, Leukemia 2011; 25,341–7). The purpose of this study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD in pts with relapsed/refractory ALL, and to study effects of everolimus on AKT/mTOR signaling in ALL blasts. Methods: In this single center phase I/II study, pts aged 10 years or older with relapsed/refractory ALL or lymphoblastic lymphoma were treated with oral everolimus at a daily dose of 5 mg or 10 mg in combination with the standard hyper-CVAD regimen (Kantarjian HM et al, J Clin Oncol. 2000 Feb;18(3):547–61) until disease progression or unacceptable toxicity. Primary endpoints were to establish safety (after 2 cycles) and efficacy. Secondary endpoints included assessments of pharmacodynamics and pharmacokinetics. Results: Twelve pts have been enrolled and are evaluable for response. Median was age 24 years (range, 11–59). Five pts had T-ALL and 7 had Philadelphia chromosome negative precursor-B-ALL. Median number of prior treatments was 2 (range, 1–4); 5 pts were 1st salvage attempts. Three pts received everolimus 5 mg/day and 9 were treated with 10 mg/day continuously in combination with hyper-CVAD. Median number of cycles given was 2 (range, 1–4). Median follow-up was 12 months (range, 7–23). Three pts achieved CR (all were 1st salvage attempts) and 1 patient had CRi (second salvage); 2 pts achieved PR. No responses were seen beyond second salvage. Of the 9 pts completing 2 cycles, both EFS and OS were not reached for 3 pts in the 1st salvage, and were 8.5 weeks and 18.5 weeks respectively for pts in second salvage and beyond (P=.01 and P=0.04). Of the 12 pts (including 3 only treated with one cycle), both EFS and OS were not reached for 3 pts in the 1st salvage, and were 10 weeks and 18 weeks respectively for pts in second salvage and beyond (P=0.17 and P=0.05). Treatment-related toxicities in the 9 pts evaluable for MTD (completed 2 cycles) included 3 episodes of grade 3 mucositis, which was a dose-limiting toxicity, 3 episodes of grade 4 infections (sepsis) and 9 episodes of grade 3 infections (neutropenic fever, pneumonia, bacteremia). There was no deaths on-study. Inhibition of mTOR signaling (p-pS6K) was observed in 5 of 8 (62%) patient samples tested, at both the 5 and 10 mg dose levels, suggesting that 5 mg is sufficient to block the pathway. Lack of inhibition of p-pEBP1 and pAKT argues for potential benefit of second generation mTOR inhibitors or dual PI3K/mTOR inhibitors. Conclusions: We conclude that administration of hyper-CVAD plus everolimus is well-tolerated. The study warrants further investigation of next generation mTOR inhibitors in combination with hyper-CVAD for ALL in relapsed and frontline settings. Disclosures: Cortes: Novartis: Consultancy, Research Funding.

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