scholarly journals Phase II Study of an AKT Inhibitor MK2206 in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3093-3093
Author(s):  
Yasuhiro Oki ◽  
Michelle A. Fanale ◽  
Jorge E. Romaguera ◽  
Luis Fayad ◽  
Nathan Fowler ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Treatment Regimen ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Classical Hodgkin Lymphoma ◽  
Akt Inhibitor ◽  
Refractory Lymphoma ◽  
Grade 3

Abstract Aberrant activation of the PI3K/AKT/mTOR pathway has been implicated in promoting lymphoma cell growth and survival. Several agents targeting this pathway at the PI3K or mTOR levels have demonstrated clinical activity in a variety of lymphoma subtypes. However, there has been no clinical data with AKT inhibitors in lymphoma. MK-2206 is the first oral non-ATP competitive allosteric inhibitor of AKT 1, 2, and 3 which entered clinical development. MK-2206 demonstrated AKT inhibition and antiproliferative activity as single agent and in combination with other agents in multiple human cancer cell lines. MK-2006 synergized antitumor effects of chemotherapeutic agents in vivo and in vitro. To investigate the potential therapeutic value of targeting AKT in lymphoma, we conducted a phase II study of MK2206 in patients with relapsed or refractory lymphoma. Eligible patients were required to have lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma that have relapsed or been refractory after at least one treatment regimen, have no curative option available and have adequate organ functions. MK-2206 (200 mg) was given orally, once per week, in 28-day cycles for a maximum of 12 cycles. In the absences of limiting toxicity, MK2206 dose could be increased to 300 mg. Serum cytokines levels are measured in consenting patients on days 1, 8 and 22 of the first cycle. A total of 59 patients were enrolled including 25 patients with classical Hodgkin lymphoma. The median number of prior treatment regimen was 4 (range, 1-10). Based on intent-to-treat analysis, objective responses were observed in 8 (14%) patients, with 29 (49%) patients demonstrating reduction in their tumor measurements (Figure). The median response duration was 5.8 months. In the 25 patients with classical Hodgkin lymphoma, the response rate was 20%. Treatment was well tolerated, with skin rash being the most common toxicity (Any grade: 53%, Grade 3: 15%). Grade 3 or 4 hyperglycemia was observed in 5%, and neutropenia in 2%. There was no grade 3 or 4 thrombocytopenia. Collectively, the study showed that the AKT inhibitor MK2206 can induce responses in classical Hodgkin lymphoma and indolent lymphoma. The single agent activity, however, seems to be low against large B-cell lymphoma, T-cell lymphoma or mantle cell lymphoma. The possible mechanism of resistance to the treatment with AKT inhibitors may include suboptimal inhibition of AKT phosphorylation at low concentrations or development of alternative survival pathway. Future studies should aim at optimizing the dose and schedule of MK2206, and exploring mechanism-based combination strategies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 55-55 ◽  
Author(s):  
Andrew M. Evens ◽  
Julie M Vose ◽  
Wael Harb ◽  
Leo I. Gordon ◽  
Robert Langdon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Safety Profile ◽  
Tumor Size ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 55 Background: Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods: The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results: A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion: In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures: Off Label Use: PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.

Weekly Temsirolimus and Bortezomib For Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma: A Wisconsin Oncology Network Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3035-3035 ◽  
Author(s):  
Timothy S. Fenske ◽  
KyungMann Kim ◽  
Chong Zhang ◽  
John P. Farnen ◽  
Adedayo A. Onitilo ◽  
...  
Keyword(s):  
Partial Response ◽  
Adverse Events ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Mtor Inhibitors ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Background Proteosome inhibitors and mammalian target of rapamycin (mTOR) inhibitors are each known to have activity for various B-cell malignancies, and affect distinct cellular pathways. Preclinical data show synergy between bortezomib and various mTOR inhibitors, supporting this combination in non-Hodgkin lymphoma (NHL). We conducted a phase II trial of temsirolimus and bortezomib in relapsed and refractory B-cell NHL, using a weekly dosing scheme that was previously tested in multiple myeloma (Ghobrial et al, Lancet Oncology, 2011; 263-272). Methods Wisconsin Oncology Network study HO10407 is a single-arm phase II study of IV bortezomib and temsirolimus for patients with relapsed and refractory B-cell NHL. A 35 day cycle was employed with bortezomib given at 1.6 mg/m2 and temsirolimus given at 25 mg IV weekly on days 1, 8, 15, and 22. Initially temsirolimus was also given on day 29 but, due to a high rate of thrombocytopenia, after the first 14 patients were enrolled the protocol was amended and the day 29 temsirolimus dose was removed. Patients were enrolled from 10 sites within the Wisconsin Oncology Network. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS). The secondary endpoints were to determine safety, tolerability, complete response (CR) rate, duration of response (DOR), and overall survival (OS). Results Forty patients were enrolled between February 2011 and May 2013; however one patient withdrew consent immediately after enrollment and was never treated. We are therefore reporting results for 39 patients. The median age was 68, with 72% male. NHL subtypes consisted of diffuse large B-cell lymphoma (DLBCL, n=17), follicular lymphoma (FL, n=10), mantle cell lymphoma (MCL, n=7), small lymphocytic lymphoma (SLL, n=3), and marginal zone lymphoma (MZL, n=2). Patients received a median of 4 prior therapies (range 1 to 11). Three patients were previously treated with bortezomib, one of whom was refractory to a prior bortezomib-containing regimen. As of July, 24, 2013, two patients remained on protocol therapy. The median number of cycles given was 3. Out of 39 patients, CR was achieved in 3 patients (7.7% (95% CI: 1.6% - 21%)), partial response (PR) in 9 patients (23% (95% CI: 11% - 39%)), and stable disease in 9 patients (23% (95% CI: 11% - 39%)). The ORR was therefore 12/39 (31% (95% CI: 17-48%)). Among responders, the DOR ranged from 1.7 to 13.8 months, with a median DOR of 8.5 months (95% CI: 2.9-11.5). The median PFS was 4.7 months (95% CI: 2.1-7.8). The ORR for DLBCL was 18% (3/17, with 2 CR), for FL was 50% (5/10, with no CR), and for MCL was 57% (4/7, with 1 CR). In one patient, protocol therapy led to a partial response which served as a bridge to allogeneic stem cell transplantation. Grade 3/4 adverse events were experienced by 69% of patients. The grade 3/4 adverse events that occurred in at least 10% of patients were anemia (13%), lymphopenia (15%), neutropenia (23%), thrombocytopenia (38%), and gastrointestinal toxicities (15%). Conclusions In this phase II study, the combination of temsirolimus and bortezomib demonstrated activity in a group of heavily pre-treated patients. In some patients dramatic responses were seen, including two DLBCL patients who achieved complete remission after having previously progressed following autologous hematopoietic cell transplantation. Toxicities were manageable and treatment was delivered on an outpatient basis. Further studies with this combination or other proteosome inhibitor + mTOR inhibitor combinations are warranted in specific subtypes of NHL. Disclosures: Fenske: Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy. Off Label Use: Use of the combination of bortezomib and temsirolimus for relpased and refractory B-cell non-Hodgkin lymphoma. Ahuja:Bayer healthcare pharmaceuticals: Consultancy. Kahl:Millennium: Consultancy.

scholarly journals Phase II study of pembrolizumab (MK-3475) for relapsed/refractory classical Hodgkin Lymphoma (r/r cHL): keynote-087

2015 ◽  
Vol 3 (S2) ◽  
Author(s):  
Robert Chen ◽  
Phillippe Armand ◽  
Michelle A Fanale ◽  
Vincent Ribrag ◽  
Pier Luigi Zinzani ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Classical Hodgkin Lymphoma

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

mTOR Inhibition for Relapsed or Refractory Hodgkin Lymphoma: Promising Single Agent Activity with Everolimus (RAD001).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Patrick B. Johnston ◽  
Steven M. Ansell ◽  
Joseph P. Colgan ◽  
Thomas M. Habermann ◽  
David J. Inwards ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Mtor Inhibitors ◽  
Cell Transplant ◽  
Mtor Inhibition ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Background: mTOR inhibition has produced responses in mantle cell lymphoma as well as other non-Hodgkin lymphomas. This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in simultaneous two-stage phase II lymphoma studies, including one arm involving Hodgkin lymphoma. The goals were to learn the toxicity profile and to assess the anti-tumor response. A total of 17 patients with Hodgkin lymphoma were enrolled in the uncommon arm at completion of enrollment. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12, with a possible extension in responders) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. Results: The median age of the 17 pts with Hodgkin lymphoma was 37 yrs (range: 27–68), with a median of 6 (range, 4–14) prior therapies. Fourteen pts (82.4%) had a prior stem cell transplant (SCT). Pts completed a median of 6 (range, 1–13) cycles of therapy. Fifteen of 17 patients were evaluable for response as of this analysis. The overall response rate was 47% (7/15), all partial responses. Ten patients are continuing on study while 6 have gone off due to disease progression and 1 due to other reasons. Common grade 3 adverse events (AEs) include thrombocytopenia (5 pts), anemia (5 pts) and alkaline phosphatase elevation (1 pts). 1 patient was reported to have grade 4 neutropenia. Conclusions: Oral everolimus has promising activity with acceptable toxicity in Hodgkin lymphoma. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens for Hodgkin lymphoma.

The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1661-1661 ◽  
Author(s):  
Brad S Kahl ◽  
Hailun Li ◽  
Mitchell R Smith ◽  
Randy D. Gascoyne ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Complete Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

Results of a Feasibility and Phase II Study on Bortezomib (BTZ) in Pediatric Multiply Relapsed or Refractory Acute Lymphoblastic Leukemia: Complete Hematological Responses with a Modestly Intensive Regimen Including BTZ

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2290-2290
Author(s):  
Gertjan Kaspers ◽  
Denise Niewerth ◽  
Satianand Ramnarain ◽  
Andishe Attarbaschi ◽  
André Baruchel ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Clinical Research ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Research Support ◽  
Grade 3 ◽  
Intensive Regimen

Abstract Prognosis of refractory and relapsed ALL is poor and its improvement requires the introduction of novel agents with a new mechanism of action. Bortezomib (BTZ) as proteasome inhibitor is such an agent, and has been shown to be safe as single agent in phase I studies in children with either solid tumors (Blaney 2004) or leukemias (Horton 2007). Recently, Messinger (2012) reported in a single-arm study that BTZ can be combined safely with vincristine (VCR), dexamethasone (DXM), pegylated asparaginase (PEG-ASP) and doxorubicin and that the combination was remarkably effective in B-cell precursor ALL. BTZ has been reported to sensitise malignant cells to other agents, both in vitro for leukemias as well as for multiple myeloma patients in vivo. In patients with ALL, the sensitizing effect of BTZ regarding the efficacy of glucocorticoids (GC) has not been addressed yet. Considering the lack of any clinical experience with BTZ in children, we developed a European multicenter feasibility and phase II study in refractory or relapsed ALL, in which all patients receive BTZ, with day 8 peripheral blast count as primary endpoint. The study is performed in compliance with the Declaration of Helsinki. Patients are randomised for BTZ to be administered “early”, or “late”. Bortezomib is then given as iv push for 4 doses at 1.3 mg/m2/dose, thus in group “early” on days 1, 4, 8 and 11 and in group “late” on days 8, 11, 15 and 18. In addition, all patients receive DXM (10 mg/m2/day in 3 doses for 2 weeks, orally or iv) and VCR (1.5 mg/m2/dose with a maximum of 2 mg as 1-hour infusion on days 8 and 15), as well as one intrathecal administration of methotrexate (MTX, dose age-adjusted) on day 1. No ASP and no anthracycline is given. Cycles can be repeated in case of a good response. Eligible patients have 2nd or greater relapsed ALL, 1strelapsed ALL after allogeneic stem cell transplantation (allo-SCT) in CR1, or refractory first relapsed ALL, and bone marrow (BM) involvement and at least 100 leukemic cells per µl blood. Exclusion criteria include symptomatic CNS leukemia. It is planned to evaluate 24 fully evaluable randomised patients. This analysis, not being an official interim-analysis and not evaluating the primary endpoint of the study, focusses on haematological responses with this modestly intensive regimen. BM M1 indicates <5% blasts, M2 5-15% and M3>15% blasts. Between October 2010 and March 2014, a total of 21 eligible patients with information on response and/or toxicity after cycle 1 has been enrolled, 11 boys and 10 girls, median 9.8 years of age (range, 1.2 – 17.5). Most had second relapsed ALL (n=11), others first relapsed ALL following allo-SCT in CR1 (n=8) or refractory first relapsed ALL (n=2). Regarding efficacy, 17 patients were evaluable (1 patient no material received, 2 patients discontinued treatment due to toxicity, and 1 patient had early progression which led to treatment discontinuation). Day 22 BM showed M1 in 5, M2 in 6, and M3 in 6 patients. There was no relation between day 22 BM status and the administration of BTZ being early or late. There was no association between response and disease status, being either refractory or relapsed, although numbers are small. Two patients with a relapse after allo-SCT achieved BM M1, as well as 3 patients with a second or subsequent relapse. Four patients (23.5%) achieved hematological remission after cycle 1, while 11 out of 17 patients (65%) had a good initial response (day 22 BM M1 or M2). A total of 10 patients received a 2ndcycle and 5 out of them achieved a complete remission, 4 of whom already had a day 22 BM M1. Eight out of 21 (38%) patients suffered from grade 3 and/or 4 toxicity during cycle 1, and most frequently reported were pain (n=4), peripheral neuropathy and fatigue (n=2 each). After 2 cycles, grade 3/4 toxicity was reported in 3 out of 10 patients: one with peripheral neuropathy, one with peripheral neuropathy, haemorrhage and hematuria, and one with raised ALAT. Future analyses will focus on sensitisation to GC by BTZ and on the efficacy of BTZ in relation to PK and PD. Meanwhile, BTZ in combination with VCR, DXM and intrathecal MTX is effective in a significant subset of pediatric relapsed and refractory ALL, and repetitive cycles could be given in several children without undue toxicity. This research is financially supported by the Dutch Foundation Children Cancer-free (clinical research support) and by Janssen Pharmaceuticals (clinical research support and free drug). Disclosures Baruchel: Janssen-Cilag: Consultancy.

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