Phase 1 Study of Weekly Vincristine Sulfate (VCR) Liposomes Injection (VSLI, Marqibo™) Plus Dexamethasone in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2930-2930 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop M Kantarjian ◽  
Wendy Stock ◽  
Leonard Heffner ◽  
Sue Hirabayashi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dose Level ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
Pharmacokinetic Studies ◽  
Cell Transplant ◽  
Motor Neuropathy ◽  
Vincristine Sulfate ◽  
Total N

Abstract Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing. Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status 1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)

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 ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3959-3959 ◽  
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.

Pivotal Phase 2 Study of Weekly Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®) in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Progressing Following Two Anti-leukemia Treatment Lines.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3088-3088 ◽  
Author(s):  
Susan O'Brien ◽  
Gary Schiller ◽  
Lloyd E. Damon ◽  
John Lister ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Study Drug ◽  
Cell Transplant ◽  
Vincristine Sulfate ◽  
Disease Response ◽  
Grade 3

Abstract Abstract 3088 Poster Board III-25 Adult ALL is a disease of primarily young and middle-aged adults that is associated with a high relapse rate following initial remission induction and a short overall survival following relapse. Patients in second relapse must deal with the lingering toxicities of prior therapies, organ dysfunction secondary to extramedullary disease, and the absence of fully approved and standard of care therapies for this advanced disease setting. Realistic goals of treatment in second relapse include eradication of leukemia, bridging to stem cell transplant, and prolongation of survival. Vincristine is active against leukemia and is typically used as part of multi-agent regimens to treat relapsed disease, but the pharmacokinetic profile and dosing cap are suboptimal and contribute to poor disease control and abysmal overall survival. VSLI is a nanoparticle formulation of vincristine sulfate USP encapsulated in sphingomyelin/cholesterol liposomes called Optisomes™. The Optisomal formulation permits dose intensification beyond that attainable with conventional vincristine sulfate injection, USP (VSI). VSLI provides a long circulation time and slow release of encapsulated vincristine sulfate resulting in enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus VSI in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 weekly with no dose cap, while conventional vincristine sulfate is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study involving VSLI in relapsed ALL showed a complete response rate of 19%, suggesting activity in the relapsed setting and prompting further study. This international, multicenter, single-arm study has completed enrollment of its target 56 subjects at 21 centers in 4 countries over 27 months. Major endpoints include response rate (CR/CRi) and overall survival (OS). 56 adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. The highest single dose of VSLI given to date in this study was 5.22 mg contrasted to the 2 mg dose this subject would have received with conventional vincristine. Subjects were monitored for disease response every 4 weeks and could be treated until disease progression. Of the demographic data available for 48 subjects, 24 were female and 24 male with a mean age of 38.7 years (range 19.3-79.6). All subjects received at least one prior vincristine-containing regimen and 21 subjects (44%) received vincristine sulfate in two prior regimens. 18 subjects (37%) had a prior stem cell transplant and 2 subjects (4%) had 2 prior stem cell transplants before receiving single agent VSLI. 71% of subjects had an ECOG Performance Status of 1 or greater, with 21% ECOG 2 or 3. Seven subjects (15%) had evidence of extramedullary disease at study entry. At interim analysis, treatment with single agent VSLI produced morphologic and cytogenetic CR in several of these heavily pretreated subjects, suggesting significant activity of VSLI in second relapsed leukemia. Of investigator-reported responses on 48 subjects with data available to date, 71% have evidence of either disease response or disease stabilization and 29% have reported disease progression. Of the subjects experiencing CR/CRi, at least 5 subjects subsequently underwent allogeneic stem cell transplant after receiving VSLI. At the time of this abstract the median OS is estimated to be 4.7 months (Q1-Q3: 3.4-10.5) using Kaplan-Meier methodology. The 5 most frequently reported adverse event are peripheral neuropathy, 14.6% Grade 3 or 4 (100% attributed to study drug); constipation, 2.4% Grade 3 (100% attributed to study drug); nausea, no Grade 3 or higher; pyrexia, 9.8% Grade 3 (2.4% attributed to study drug); and febrile neutropenia, 34.2% Grade 3 or 4 (7.3% attributed to study drug). VSLI is a promising new agent for the treatment of acute lymphoblastic leukemia in second relapse, a situation where there is high unmet need and no approved therapies exist. VSLI may be used as a single agent as a bridge to transplant in these heavily pretreated, multiply-relapsed subjects, or considered as a substitute for conventional vincristine sulfate. The ability to complete enrollment rapidly internationally with compelling evidence of objective responses in this study underscores the enthusiasm for and importance of developing VSLI for the treatment of this orphan leukemia indication. Efficacy data and preliminary PK results from the target 56 subjects will be presented. Disclosures O'Brien: Hana Biosciences, Inc.: Consultancy. Hagey:Hana Biosciences, Inc.: Employment. Deitcher:Hana Biosciences, Inc.: Employment. Kantarjian:Hana Biosciences, Inc.: Consultancy.

Neurological Toxicity Profile of Weekly Vincristine Sulfate Liposomes Injection (Marqibo®) 2.25 mg/m2 Compared to Historical Standard Vincristine Sulfate 1.4 mg/m2, 2 mg, and 4 mg Administered Less Frequently

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4247-4247 ◽  
Author(s):  
Lloyd E. Damon ◽  
Stuart L. Goldberg ◽  
Leonard T. Heffner ◽  
John Lister ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Fixed Dose ◽  
Drug Discontinuation ◽  
Motor Neuropathy ◽  
Toxicity Profile ◽  
Vincristine Sulfate ◽  
Neurological Toxicity ◽  
Multi Agent

Abstract 4247 The accumulated clinical experience with standard vincristine sulfate (VCR) describes a safety profile most notable for the occurrence of a dose-related, symmetrical, sensorimotor and autonomic polyneuropathy. The various manifestations of neuropathy are the usual dose-limiting toxicities associated with standard VCR that limit the extent to which patients can derive clinical benefit from this therapy. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a sphingomyelin-based, liposomal formulation of VCR designed to intensify dose, prolong encapsulated drug circulation time, and target drug to sites of active cancer. We report here the neurological toxicity profile (Graded using CTCAE criteria v3.0) of weekly, single-agent IV VSLI 2.25 mg/m2 in 83 adult subjects with heavily pre-treated, relapsed and/or refractory acute lymphoblastic leukemia (ALL) and 100% past standard VCR exposure. Neuropathy signs and symptoms were rigorously evaluated at baseline and weekly during VSLI treatment in order to maximize adverse event detection. Findings were compared to baseline (post-standard VCR and before VSLI) neuropathy in the same VSLI treated population and to the best available published neurotoxicity data regarding standard VCR administration. In the study by Haim et al ([1] Cancer 1994; 73:2515–9), 104 VCR-naïve patients with lymphoma received multi-agent therapy including standard VCR 1.4 mg/m2 weekly to once every 28 days. In the study by Verstappen et al ([2] Neurology 2005; 64:1076–7), 114 VCR-naïve patients with lymphoma received multi-agent therapy including fixed dose standard VCR 2 mg or 4 mg every 3 weeks. Results are provided in the table below. NR = not reported. The baseline frequency of residual neuropathy in adults with ALL treated with weekly VSLI 2.25 mg/m2 was not unexpected considering that all patients received prior standard VCR. The on-study, incremental neuropathy burden was relatively modest. On-study neuropathy rates during and immediately following weekly VSLI 2.25 mg/m2 were comparable to or less than those reported in lymphoma patients receiving standard VCR at 1.4 mg/m2 every 1 to 3 weeks or at a fixed dose of 2 mg or 4 mg every 3 weeks, despite the dose intensification afforded by VSLI. Constipation, the most commonly reported neurological toxicity associated with standard VCR and VSLI, resulted in standard VCR dose reduction in 22% of patients reported by Haim et al compared to weekly VSLI dose reduction in only 5% of patients due to constipation. Frequent neurological assessments combined with a dose adjustment algorithm facilitated continued VSLI dosing in order to induce remission and minimization of Grade 3 or greater neurotoxicity. One VSLI patient developed peripheral motor neuropathy requiring drug discontinuation after 11 weekly doses. In the VSLI study, neurological toxicity was considered predictable and manageable. Disclosures: Schiller: Talon Therapeutics: Research Funding. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia

Cancer ◽  
2009 ◽  
Vol 115 (23) ◽  
pp. 5490-5498 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Wendy Stock ◽  
Leonard T. Heffner ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Multicenter Study ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Vincristine Sulfate

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 ◽  
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.

Neurotoxicity Profile of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Monotherapy in Adults with Relapsed Acute Lymphoblastic Leukemia and Universal Prior Standard Vincristine Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3568-3568
Author(s):  
Steven R. Deitcher ◽  
Jeffrey A. Silverman
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Dose Intensity ◽  
Vincristine Sulfate ◽  
Pivotal Phase ◽  
Serious Adverse Events

Abstract Abstract 3568 Background: VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) is a nanoparticle formulation of vincristine sulfate (VCR) that encapsulates the drug in long-circulating sphingomyelin and cholesterol liposomes. The unique pharmacologic properties of VSLI impart superior nonclinical efficacy and pharmacokinetic properties versus standard VCR. Decades of clinical experience with standard VCR has established peripheral neuropathy as the most notable toxicity and one that underpins the common practice of individual dose capping which limits cumulative dosing. We recently conducted clinical trials to support VSLI accelerated approval for the treatment of adults with relapsed and refractory Philadelphia chromosome negative acute lymphoblastic leukemia (ALL). Here we present data on the neurotoxicity profile of weekly VSLI at the approved dose. Methods: Eighty-three subjects received weekly VSLI 2.25 mg/m2as a 1-hour infusion, with no dose cap, for treatment of advanced, relapsed and/or refractory ALL; Sixty-five patients were enrolled in a pivotal, Phase 2 study and 18 patients were enrolled in an expanded cohort in a Phase 1 study. Signs and symptoms of peripheral neuropathy were proactively assessed using a detailed 15-point evaluation. The pooled data from these studies are the primary safety population for VSLI. Neurotoxicity data are presented here in comparison to two published studies that prospectively evaluated standard VCR induced peripheral neuropathy in patients with Hodgkin disease, non-Hodgkin lymphoma or acute lymphoblastic leukemia (Haim et al, Cancer 1994; 73:2515–2519 and Verstappen et al Neurology 2005; 64:1076–1077. Results: The median individual VSLI dose per infusion was 4.1 mg (range 3.1–5.5) and the median cumulative dose was 18.4 mg (range 3.5–70.1). All patients had prior exposure to VCR containing regimens that resulted in 80% of patients entering the studies with Grade 1 or Grade 2 residual neuropathy. The most common neurological adverse events were constipation (56.6%) and peripheral neuropathy (37.3%). Serious adverse events (SAEs) were reported in 76% of patients and were consistent with advanced ALL. The most frequently reported neuropathy-associated SAEs in patients treated with VSLI were peripheral neuropathy (4.8%) and constipation (3.6%). Incidence of paraesthesia, the only neuropathy uniformly reported across VSLI and VCR studies, was greater in the VCR studies than following much higher dosages and dose density (based on BSA of 1.8) of VSLI. Conclusions: Experience with VCR has established a clear relationship between dose intensity and symptoms of peripheral neuropathy. Administration of VSLI at a dose of 2.25 mg/m2with no dose cap did not result in any new or unexpected toxicity. Although neuropathy remains a significant toxicity associated with VSLI, the frequency and severity of neuropathic AEs was no greater than what would be expected from a standard VCR regimen. Despite administration of higher doses and dose density, incidence of peripheral neuropathy following exposure to VSLI was lower than previously reported with standard VCR. This is significant given that the individual and cumulative doses of VSLI were 2–3 fold greater than what is generally achieved with standard VCR. VSLI facilitates increasing the tolerable dose and dose density and may result in improved clinical response with similar or less toxicity than VCR. *On behalf of the RALLY trial investigators Disclosures: Deitcher: Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Temsirolimus combined with etoposide and cyclophosphamide for relapsed/refractory acute lymphoblastic leukemia: Therapeutic advances in Childhood Leukemia Consortium (TACL 2014-001) trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10512-10512
Author(s):  
Susan R. Rheingold ◽  
Lewis B. Silverman ◽  
James A. Whitlock ◽  
Richard Sposto ◽  
Eric S. Schafer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dose Level ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Complete Response ◽  
Pi3k Pathway ◽  
Critical Pathway ◽  
Pathway Inhibition

10512 Background: PI3K/mTOR signaling, a critical pathway in cell proliferation, metabolism, and apoptosis, is often dysregulated in acute lymphoblastic leukemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus combined with etoposide and cyclophosphamide was performed in children with relapsed/refractory (r/r) ALL. Methods: Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily days 1-5. The starting dose level (DL) of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). MRD was performed centrally. PI3K pathway inhibition was measured by phosphoflow cytometry (PFC) analysis of peripheral blood (PB) from treated patients (pts). Results: Sixteen heavily pretreated r/r ALL pts ages 2-19 years with marrow blasts > 25% were enrolled; 15 were evaluable [10 B-ALL/5 T-ALL]. One dose-limiting toxicity (DLT) of grade (Gr) 4 pleural and pericardial effusions with pneumonitis/lung infection leading to Gr 5 cardiorespiratory arrest occurred in a pt treated at DL3. No further DLTs were seen in the DL3 expansion and DL4 cohorts. Gr 3/4 non-hematologic toxicities occurring in ≥ 3 pts included febrile neutropenia, elevated ALT, hypokalemia, mucositis, and tumor lysis syndrome and were independent of dose. Of 15 evaluable pts, 4 (27%; 2 B-ALL/2 T-ALL) had a complete response (CR) after cycle 1, comprised of 1 pt at each DL. Three had MRD < 0.01%. Three pts (20%; 2 B-ALL/1 T-ALL) had partial response (PR). Overall response rate (CR+PR = ORR) was 47%. Pharmacodynamic PFC studies compared phosphoprotein levels pre (day 0) and post treatment (days 3-5) in 9 consenting pts with available PB. All tested pts showed basal activation of PI3K pathway signaling. Dose-dependent inhibition of mTOR targets phosphorylated (p) S6 and/or p4EBP1 was observed in 9/9 and 6/9 pts, respectively, following temsirolimus and chemotherapy treatment. Various patterns of compensatory upregulation of pPI3K, pmTOR, pAkt, and/or pERK was observed. Conclusions: Temsirolimus at 25 mg/m2 combined with salvage etoposide and cyclophosphamide has an acceptable safety profile in high-risk pediatric patients with r/r ALL. Responses were observed at all DLs. mTOR target inhibition was achieved and appeared to correlate with dose level. Future testing of other PI3K/mTOR pathway inhibitors in combination with chemotherapy may be warranted with a goal of further increasing response in r/r ALL. Clinical trial information: NCT01614197.

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 ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2592-2592 ◽  
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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