Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results from an international study (NHL-003)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8569-8569 ◽  
Author(s):  
C. B. Reeder ◽  
T. E. Witzig ◽  
P. L. Zinzani ◽  
J. M. Vose ◽  
R. Buckstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Single Agent ◽  
International Study ◽  
Response Assessment ◽  
Cell Transplant ◽  
Mantle Cell ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3

8569 Introduction: Relapsed or refractory MCL patients demonstrated a promising overall response rate (ORR) of 53% with a median duration of response (DR) of 13.7 months to single-agent lenalidomide when analyzed as a subset in a recent a phase II study (NHL-002). A supporting international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed or refractory aggressive NHL. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: Fifty-four MCL patients were enrolled and were evaluable for response assessment. Median age was 69 years (33–82) and 40 patients (74%) were male. Median time from diagnosis was 3.2 years (0.4–10.4), patients had received a median of 3 prior treatments (1–8), 17 of the patients (32%) had received prior bortezomib therapy (MCL-bortezomib), and 14 (26%) had received a prior stem cell transplant (MCL-stem cell). Response rates are shown in the Table. The most common grade 3 or 4 adverse events were neutropenia (43%), thrombocytopenia (22%) and anemia (11%). Conclusions: This is the second study to demonstrate that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects. [Table: see text] [Table: see text]

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.

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

scholarly journals Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 354-354 ◽  
Author(s):  
Raajit K. Rampal ◽  
Srdan Verstovsek ◽  
Sean M Devlin ◽  
Eytan M. Stein ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Platelet Count ◽  
Combination Therapy ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
Response Assessment ◽  
Platelet Response ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

scholarly journals Promising Clinical Efficacy and Toxicity Profile of Isatuximab Based Regimens for Treatment of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1949-1949
Author(s):  
Zunairah Shah ◽  
Madeeha Shafqat ◽  
Faiza Jamil ◽  
Mustafa Nadeem Malik ◽  
Abdul Rafae ◽  
...  
Keyword(s):  
Median Time ◽  
Median Duration ◽  
Overall Response Rate ◽  
Single Agent ◽  
Phase Ib ◽  
First Response ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Combination Regimens

Abstract Introduction: Despite the recent advancements in the treatment of multiple myeloma (MM), there is a constant need of newer therapies in order to treat the complex issue of the disease relapse and refractory disease. Isatuximab (ISA) is a non-Food and Drug Administration (FDA) anti-CD38 monoclonal antibody that acts through immune cell engagement and direct tumor targeting. We report efficacy & toxicity of ISA in newly diagnosed MM ((NDMM) as well as relapsed, refractory MM (RRMM) patients (pts). Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after January 2012 using PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. On initial search, 246 articles were found and after a detailed screening, 6 completed and 11 ongoing phase I/II/III studies were included. Results: A total of 249 pts were included. Two hundred thirty-four pts had RRMM while 15 pts had NDMM, overall response rate (ORR) was 37.60% and 87% respectively. In a phase I trial involving 34 pts with RRMM, single-agent ISA (1-20 mg/kg) was given. The median age of pts was 64 years (y) [range (r) = 38-85]. The overall response rate (ORR) was 24% with a partial response (PR) in 18% pts. The most common adverse events (AEs) were nausea (34%), fatigue (49%), fever (29%) and headache (26%) and upper respiratory infection (23%). In a phase II trial, 97 pts with RRMM were stratified into 4 groups. Single-agent ISA [3mg/kg, every 2 week,(Q2W); 10 mg/kg, Q2W - every 4 weeks (Q4W); 10 mg/kg (Q2W), 20 mg/kg (QW-Q2W)] was given. The median age of pts was 62.5 y (r = 38-85). The ORR was 9%, 20%, 29% and 24% respectively. The cumulative ORR was 20.6%. The median time to first response was 1.4 months (M) while the median duration of response was 6.6 M. The most common AEs were nausea (33%), fatigue (30%), diarrhea (26%) and cough (24%). In a phase Ib trial, 57 pts with RRMM were stratified into 5 groups. ISA [3 mg/kg (Q2W); 5 mg/kg (Q2W); 10 mg/kg (Q2W); 10 mg/kg (QW-Q2W); 20 mg/kg (QW-Q2W)] in combination with lenalidomide (R) (25mg), and dexamethasone (D) (40 mg) was given. The median age of pts was 61 y (r = 42-76). The median time since the initial diagnosis was 4 y. The ORR was 33%, 67%, 63%, 50%, and 50% respectively. The cumulative ORR was 56% with complete response (CR) in 3.8 % pts, very good partial response (VGPR) in 32.7 % pts and PR in 19.2 % pts. The progression-free survival (PFS) was 8.5 M (r=4.73-16.59). The most common grade 3 and 4 AEs were neutropenia (60%), lymphopenia (58%), leukopenia (53%), anemia (25%), thrombocytopenia (38%), pneumonia (9%), fatigue (7%), and dyspnea (4%). In another phase Ib trial, 36 pts with RRMM were stratified into 3 groups. ISA (5 mg/kg; 10 mg/kg, 20 mg/kg) in combination with pomalidomide (P) (4 mg), and D (40 mg) was given. The ORR was 63%, 55%, and 50% respectively. The cumulative ORR was 55.5%. The median time to first response was 4.1 weeks (W) while the median duration of response was 33.1 W. The most common grade 3 AEs were neutropenia (81%), lymphopenia (75%), and leukopenia (75%). In another phase Ib trial involving 10 pts with RRMM, ISA (10-20 mg/kg) in combination with carfilzomib (CFZ) (27 mg) was given. The median number of prior lines of therapy was 4.5 (2-8). The ORR was 80% with VGPR in 20% pts and PR in 60% pts. The most common grade 3 and 4 AEs were lymphopenia (64%), anemia (9%), and neutropenia (9%). In a phase Ib trial involving 15 pts with NDMM, ISA (10 mg) in combination with bortezomib (V) (1.3 mg/m2) and cyclophosphamide (CY) (300 mg/m2) was given. The median age of pts was 71 y (r= 68-80). The ORR was 87% with CR in 33% pts, VGPR in 27% pts, and PR in 27% pts. The median time to first response was 1.5 M while the median duration of response was 11 M. The most common grade 3 and 4 AEs were lymphopenia (50%), leucopenia (18%), neutropenia (8%), anemia (6%) and thrombocytopenia (6%). Conclusion: In RRMM pts, ISA as a single agent has shown weaker efficacy when compared to combination regimens i.e. ORR 21% vs. 58%. The best result was seen when ISA was used in combination with CFZ demonstrating an ORR of 80%. In NDMM pts, combination regimens have shown excellent efficacy with an ORR of 87%. Nausea and fatigue were the major AEs reported with the monotherapy while neutropenia, leucopenia, and lymphopenia were the major AEs reported with the combination regimens. Further studies involving a larger population are required to gather evidence in favor of the improved efficacy and to evaluate AEs. Disclosures No relevant conflicts of interest to declare.

Long median survival with capecitabine (X) single-agent therapy for patients (pts) with anthracycline- and taxane-pretreated metastatic breast cancer (MBC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10710-10710
Author(s):  
R. Largillier ◽  
P. Fumoleau ◽  
C. Clippe ◽  
V. Dieras ◽  
H. Orfeuvre ◽  
...  
Keyword(s):  
Median Survival ◽  
Single Agent ◽  
Survival Rates ◽  
Metastatic Breast ◽  
Highly Active ◽  
Randomized Phase Ii ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3

10710 Background: X (Xeloda) is an oral fluoropyrmidine with consistently high activity in MBC, a good safety profile with little myelosuppression and no alopecia, and the convenience of oral administration. The addition of X to docetaxel in anthracycline-pretreated pts also increases survival. This non-randomized phase II study was conducted to evaluate the efficacy, safety and impact on quality of life (QoL) of X in pts with MBC pretreated with anthracyclines and taxanes. Main findings from this trial have been published previously [Fumoleau et al. Eur J Cancer 2004;40:536–42]. Here we present mature data after a follow-up of 48 months. Methods: Pts with anthracycline- and taxane-pretreated MBC received X 1250 mg/m2 twice daily on days 1–14 every 3 weeks for a median of 6 cycles (range 1–15). Results: Baseline characteristics of the 126 pts enrolled were typical of a pretreated MBC population. X achieved complete/partial response or stable disease in 63% of patients (overall response rate, 28%). Median time to progression was 4.9 months (95% CI: 4.0–6.4).Median duration of response was 5.9 months (95% CI: 4.5–12.7). The only grade 3/4 events occurring in ≥ 10% of patients were diarrhea (10%) and HFS (21%). The most common grade 3/4 laboratory abnormality was granulocytopenia (14%). After a follow-up of 48 months, 8 patients are still alive. Updated median overall survival is 15.9 months (95% CI: 13.5–21.3). 1-, 2- and 3-year survival rates are 63%, 37% and 17%, respectively. QoL assessment showed that X treatment was associated with an increase in mean Global Health Score up to cycle 6, with the increase maintained at subsequent evaluations. Conclusions: X is highly active in patients with anthracycline- and taxane-pretreated MBC, leading to a long median survival of 15.9 months. X is also well tolerated and improves QoL. [Table: see text]

The Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Mantle Cell Lymphoma Previously Treated with Bortezomib: Pooled Data from Two Phase II Studies (NHL-002 and NHL-003).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1560-1560 ◽  
Author(s):  
Craig B. Reeder ◽  
T.E. Witzig ◽  
Julie M. Vose ◽  
Pier Luigi Zinzani ◽  
Rena Buckstein ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Prior Treatment ◽  
Cell Transplant ◽  
Phase Ii Trials ◽  
Phase Ii Studies ◽  
Mantle Cell

Abstract Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma that if not cured with aggressive chemoimmunotherapy and stem cell transplant is usually fatal. The intravenous proteasome inhibitor bortezomib produces an overall response rate (ORR) of 33% in patients with relapsed MCL (J Clin Oncol2006;24(30):4867–74). Unfortunately, most patients eventually relapse and new agents are needed for this disease. Two recently conducted phase II trials (NHL-002 and NHL-003) tested single-agent lenalidomide for patients with relapsed MCL. Fifty-four patients with MCL were enrolled into the two studies; 26% (14/54) had received prior bortezomib and they are the subject of this report. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least one prior treatment regimen including prior bortezomib were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Therapy was continued as tolerated or until disease progression. The 1999 IWLRC methodology was used to assess response and progression. Results: The 14 patients in this study were heavily pretreated with a median of 4 (2–6) prior treatments (including bortezomib) and 50% were bortezomib-refractory. Median age was 66 (45–84) years and 6 (43%) patients were female. Median time from diagnosis to lenalidomide treatment was 3.3 (0.7–7.6) years. The ORR with lenalidomide was 57% (8/14), including 21% (3/14) complete response (CR)/unconfirmed CR and 36% (5/14) partial responses. One (7%) patient had stable disease. The most common grade 3 or 4 adverse events were neutropenia (50%), thrombocytopenia (43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenic fever occurred in 7% of patients. Conclusion: These results demonstrate that lenalidomide oral monotherapy is very effective with manageable side effects in patients with relapsed or refractory MCL who had received prior treatment with bortezomib.

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.

Bendamustine Is Highly Active in Heavily Pre-Treated Relapsed and Refractory Hodgkin Lymphoma and Serves as a Bridge to Allogeneic Stem Cell Transplant.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 720-720 ◽  
Author(s):  
Alison J. Moskowitz ◽  
Paul A. Hamlin ◽  
John Gerecitano ◽  
Steven M. Horwitz ◽  
Matthew Matasar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Maximal Response ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Treatment Delays ◽  
Highly Active ◽  
Grade 3

Abstract Abstract 720 Introduction: No standard treatment exists for relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) failure and prognosis is poor. Nonmyeloablative allogeneic stem cell transplant (NMT) offers a chance of cure in a subset of these patients; therefore the goal of treatment should be to ultimately refer patients to NMT. Bendamustine is a bifunctional alkylating agent, recently FDA approved for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Limited data supports the use of bendamustine in HL (Borchmann, et al. Ann Oncol 1998). Methods: This is a phase II clinical trial evaluating the activity of single-agent bendamustine in rel/ref HL for ASCT failures, NMT failures, or patients (pts) who are ineligible for transplant. Our primary outcomes are response rate and, for eligible pts, referral to NMT. Pts receive bendamustine 120mg/m2, for two consecutive days, every 28 days. Pegfilgrastim is administered with each cycle and treatment is delayed until absolute neutrophil count is > 1000/ul and the platelet count is > 75,000/ul. Dose is reduced to 100mg/m2 in cases of treatment delays > 5 days due to neutropenia or thrombocytopenia or for grade 3 non-hematologic toxicities. Pts are evaluated for response by CT and PET after 2, 4, and 6 cycles. Pts deemed eligible for NMT at initiation of bendamustine are referred when they have had maximal response to bendamustine. Others receive a maximum of 6 cycles. Results: To date, 18 out of a planned 37 pts have been enrolled. Twelve of the 18 pts previously failed ASCT, 2 failed NMT. Of 16 evaluable pts, 2 progressed prior to the first re-evaluation and died rapidly from HL. Of the remaining 14 pts, 12 pts responded. There were 6 CRs (38%), 6 PRs (38%), 1 SD; ORR was 75%. All responding pts showed evidence of improvement at first restaging. One pt withdrew consent after 1 cycle. This pt achieved a CR and has been monitored off therapy for 10 months. At time of enrollment, 12 of the 16 evaluable pts were deemed eligible for NMT. Reasons for NMT ineligibility were additional comorbidities (3) and previous NMT (1). Of the 12 NMT eligible pts, 3 have completed NMT and 3 were referred but ultimately refused. The three completed NMTs were performed following 4 cycles of bendamustine. Bendamustine was very well tolerated. Three SAEs have occurred: grade 3 nausea following cycle 1, fungal pneumonia following cycle 2, and pyelonephritis following cycle 6. There have been 6 treatment delays due to thrombocytopenia (3), neutropenia (1), pneumonia (2). There have been 4 treatment reductions due to neutropenia (2), nausea (1), and thrombocytopenia (1). Conclusion: Interim results from this ongoing trial indicate that bendamustine is highly active in heavily pre-treated rel/ref HL and enables referral to NMT in a significant portion of eligible pts. Future studies will combine bendamustine with novel agents in rel/ref HL. Disclosures: No relevant conflicts of interest to declare.

Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

2006 ◽  
Vol 24 (33) ◽  
pp. 5259-5264 ◽  
Author(s):  
Hervé Rubie ◽  
Julia Chisholm ◽  
Anne Sophie Defachelles ◽  
Bruce Morland ◽  
Caroline Munzer ◽  
...  
Keyword(s):  
High Risk ◽  
Partial Response ◽  
Phase Ii ◽  
Response Assessment ◽  
Complete Response ◽  
Lesion Size ◽  
Mixed Response ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

Purpose To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. Patients and Methods A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2/d × 5 days every 28 days) was undertaken in children with refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine (MIBG) score. Activity was defined by a reduction in lesion size or isotope uptake at anytime. Methodology included a two-step design using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort. All data was centrally reviewed by a panel. Results Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy. Twenty-three patients had metastatic NB either refractory (n = 9) or in relapse (n = 14). Grade 3 or 4 thrombocytopenia was the most frequent toxicity (16% of cycles). Myelosuppression resulted in treatment delays and dose reductions (24% and 21% of cycles, respectively). Response (complete response, very good partial response, or partial response) was observed in five patients (RR = 20% ± 8%) with a median duration of 6 months and an objective or mixed response in five additional patients. Conclusion Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

scholarly journals Safety and Activity of Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Initial Results of a Phase I/II Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1834-1834 ◽  
Author(s):  
Ryan D Cassaday ◽  
Jonathan Fromm ◽  
Andrew J. Cowan ◽  
Edward N. Libby ◽  
Mary Philip ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dose Escalation ◽  
Limit Of Detection ◽  
Single Agent ◽  
Initial Therapy ◽  
Salvage Chemotherapy ◽  
Cell Transplant ◽  
Antibody Drug Conjugate ◽  
Sequential Approach ◽  
Grade 3

Abstract Background: When initial therapy for cHL fails, the standard approach is multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). The success of ASCT can be predicted by achievement of complete remission (CR) by fluorodeoxyglucose positron emission tomography (PET) following salvage chemotherapy (Moskowitz, et al. Blood 2012;119:1665-70). Unfortunately, about half of patients (pts) are unable to achieve CR with first salvage. The anti-CD30 antibody-drug conjugate BV is effective as a single agent in rel/ref cHL (Younes, et al. JCO 2012;30:2183-9). Pre-ASCT salvage chemotherapy combinations with BV have been explored (LaCasce, et al. ASH 2015, #293; Garcia-Sanz, et al. ASH 2015, #582), as has a PET-adapted sequential approach with BV then ICE (Moskowitz, et al. Lancet Oncol 2015;16:284-92). We hypothesized that concurrent therapy with BV and ICE would be safe and produce high CR rates. We also sought to explore inflammatory microenvironment prognostic factors. (ClinicalTrials.gov #NCT02227199) Methods: Pts ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible. Key inclusion criteria were ≥ 1 FDG-avid site of disease ≥ 1 cm; adequate marrow, hepatic, and renal function; and HIV-. Key exclusions were any prior BV; chemotherapy ≤ 3 weeks of enrollment; and pre-existing neuropathy > NCI-CTCAE Grade 1. All pts signed IRB-approved informed consent forms. Treatment included BV on Days 1 and 8, ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2daily on Days 1-3. A 3+3 dose-escalation schema for BV was used to determine the maximum tolerated dose (MTD) with ICE: starting dose was 1.2 mg/kg on Days 1 and 8, escalated to 1.5 mg/kg on Days 1 and 8 or de-escalated to 1.2 mg/kg on Day 1 only, based on rate of dose-limiting toxicity (DLT). Once MTD of BV was established, subsequent pts received this dose. 2 21-day cycles were given with G-CSF support. PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue from presentation and relapse were collected for correlative studies. Pre-treatment PB PD-L1 levels were measured by ELISA. Results: To date, 16 pts have enrolled and completed study treatment. Median age was 32 (range, 23-60). All received ABVD-based initial chemotherapy, and 5 (31%) received radiation. 11 (69%) did not obtain CR with initial therapy. Grade 3-4 neutropenia, lymphopenia, and anemia was seen in 2 (12%) pts each; thrombocytopenia in 4 (25%) pts. 6 (38%) pts experienced Grade 3-4 non-heme toxicity, but no single toxicity occurred in > 1 pt. Neuropathy was seen in 5 (31%) pts: 4 Grade 1, and 1 Grade 3. 1 DLT (sepsis) was observed in the 9 pts treated in the dose-escalation phase, defining 1.5 mg/kg on Days 1 and 8 as the MTD of BV with ICE. Overall response rate for all enrolled patients was 94% (n=14), with 88% (n=14) and 69% (n=11) achieving CR by investigator and central independent radiographic review, respectively. 15 (94%) pts underwent PBSC collection, all of which were successful. 12 (75%) pts proceeded to ASCT immediately following this treatment. With a median follow-up of 6.5 (range, 2-20) months, there have been 3 (19%) relapses (2 were in CR after BV-ICE) and no deaths. Counts of CD68+ macrophages (15%, 14%), granzyme+ cytotoxic cells (6.2%, 8.7%), and CD20+ B cells (24%, 14%) by immunohistochemistry were not significantly different between presentation and relapse (respectively). Levels of PD-L1 were below the limit of detection (500 pg/mL) in all pts. Conclusions: Pts with rel/ref cHL can safely receive BV up to 1.5mg/kg on Days 1 and 8 per cycle of ICE. Apart from generally-mild neuropathy, adding BV does not appreciably change the toxicity profile of ICE. Observed response rates by PET are very encouraging. Inflammatory cell composition appears similar at presentation and relapse. Without more sensitive testing, circulating levels of PD-L1 are unlikely to be of use in this setting. Enrollment is ongoing, and updated clinical and correlative data, including the use of next-generation sequencing-based detection of lymphoma-specific DNA sequence as a novel method of response assessment, will be presented at the meeting. Disclosures Gopal: Seattle Genetics: Research Funding.

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