scholarly journals Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on an Ongoing Phase I/II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3930-3930
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Ulrich Bitz ◽  
Christian Lerchenmueller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Phase Iii ◽  
Mtor Inhibition ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Single Agent Ofatumumab In Patients With Relapsed and/Or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results From a Phase II Open Label Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5131-5131
Author(s):  
Jagoda Jasielec ◽  
David Peace ◽  
Sarah Edwards ◽  
Kathy Tolzien ◽  
Sonali M. Smith ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Open Label ◽  
Open Label Study ◽  
Large B Cell Lymphoma ◽  
Grade 3

Abstract Background Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains a clinical challenge, with no standard options for elderly or transplant-ineligible patients. Ofatumumab is a fully humanized monoclonal antibody with specificity for CD20 that is currently approved for R/R chronic lymphocytic leukemia. Ofatumumab given for 4 weekly doses elicited an overall response rate (ORR) of 11% in a prior French study of R/R DLBCL. However, a maintenance strategy for stable or responding DLBCL has not been tested and could improve the overall clinical benefit. This phase II open label study of single agent ofatumumab tested the efficacy of a combined induction and maintenance schedule. Methods Patients with R/R DLBCL who were transplant-ineligible or who had relapsed after transplantation were included. The treatment schedule was ofatumumab 1000 mg weekly for 8 weeks (induction phase). Patients achieving stable disease (SD) or better continued on a maintenance phase receiving ofatumumab at 1000 mg every other week until objective evidence of disease progression or patient/physician decision to withdraw. The primary end-points were overall response (OR) defined as the sum of partial response (PR) and complete response (CR) (Cheson Criteria), and toxicity using NCI criteria (CTCAE v.4). Secondary end-points included time to disease progression (TTP), overall survival (OS), and the overall clinical benefit defined as the sum of SD, CR, and PR. Results Eleven patients were enrolled in this trial before it was stopped due to slow accrual. Median age was 67 years (range: 41-89) and 4/11 patients were male. All patients had advanced stage III/IV disease and 10/11 had an Eastern Cooperative Oncology Group performance status of 0 or 1. Median LDH was 246 U/l (range: 160-966), one patient had bulky disease, and one patient had B symptoms. Patients were heavily pre-treated with a median of 4 prior therapies (range: 1-7). One patient had relapsed disease, while the other 10 had disease that was rituximab-refractory. Four patients (36%) had prior transplants (2 autologous, 1 allogeneic, and 1 both). All patients were evaluable for response and toxicity. One patient was taken off study without progression due to hemolytic anemia (possibly related) after 6 months of therapy. Best responses achieved were 2 PR and 2 SD, while 7 patients progressed for an OR of 18% and a clinical benefit rate of 36%. Five patients (1 PD patient received maintenance ofatumumab inadvertently) went on to receive ofatumumab maintenance for a median duration of 4 cycles (range: 1-18). Response lasted for 6 and 9 months respectively in the 2 patients with PR. Subsequent therapies for progressing patients were offered (2 received bendamustine and rituximab, 1 received single agent bendamustine, and 3 had investigational therapies). At a median follow-up of 23 months (range: 5-38), 3 patients remain (27%) alive, median event free survival (EFS) was 2 months (range: 1-11), and median overall survival was 7 months (range: 1-31). Ofatumumab was generally well tolerated with 3 patients developing grade 1/2 infusion reactions. Other toxicities included grade 1/2 diarrhea (63%), anorexia (45%), hyponatremia (36%), and fatigue (36%). No grade 3/4 non-hematologic toxicities were observed. Grade 3/4 neutropenia occurred in 3/11 (27%) patients, one of whom was hospitalized for neutropenic fever. In addition, grade 4 thrombocytopenia occurred in 1 pt. Conclusion In this phase II study, we demonstrate modest single agent activity for ofatumumab in heavily pretreated rituximab-refractory DLBCL patients who have failed multiple standard therapies. Ofatumumab was well-tolerated with an acceptable safety profile. Maintenance therapy did not appear to add additional benefit in this small cohort. However, the favorable toxicity profile and modest clinical benefit justify further studies of this antibody in combination with chemotherapy or with other targeted agents. Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau; GSK: Research Funding.

Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on An Ongoing Phase I/II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2697-2697 ◽  
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Christian Buske ◽  
Peter Borchmann ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3 ◽  
Entire Treatment ◽  
Ongoing Phase

Abstract Abstract 2697 Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods: This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results: Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary: In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures: Hess: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

Everolimus Plus RCHOP-21 Is Safe and Highly Effective for New Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of the Phase I Trial NCCTG1085 (Alliance)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 813-813 ◽  
Author(s):  
Patrick B. Johnston ◽  
Betsy R. Laplant ◽  
Ellen D. McPhail ◽  
Thomas M. Habermann ◽  
David J. Inwards ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Assessment ◽  
Newly Diagnosed ◽  
Pet Ct ◽  
Grade 3

Abstract Background: The PI3K/mTORC pathway is upregulated in DLBCL and can be targeted with mTORC1 inhibitors such as everolimus. Everolimus has demonstrated single agent activity in relapsed DLBCL (Leukemia. 2011; 25(2):341-7). These data provide the rationale to combine everolimus with standard RCHOP-21 to improve the effectiveness of upfront therapy for DLBCL. Methods: A phase I study was designed to determine the maximum tolerated dose of everolimus on days 1-10 or 1-14 in combination with RCHOP-21 along with a feasibility cohort to examine response in patients with newly diagnosed CD20+ DLBCL. Response assessment was evaluated using PET/CT and standard criteria. Results: We previously reported (J Clin Oncol 33, 2015 suppl; 8518) that in the phase I portion of trial N1085 that the dose of everolimus recommended for further study was everolimus 10 mg daily days 1-14; RCHOP day 1 and pegfilgrastim 6 mg day two for each of six 21-day cycles. The trial has now completed enrollment with a total of 26 patients. Two phase I patients were replaced during cycle 1 for personal, non-medical issues leaving 24 eligible patients for response assessment. The median age was 59.5 years (23 - 78); 42% were female; 18 (75%) stages III/IV; 12 (50%) had an elevated LDH; 29% had a high IPI score; and 4 (17%) had B-symptoms. Genotype was performed by immunohistochemistry using the Hans algorithm and 54% (13/24) were non-GCB; 13 (5 GCB, 8 non-GCB) had FISH for double hit and all were negative. Twenty-one (88%) patients received everolimus at 10 mg d1-14; the other three patients received 10 mg d1-10. Twenty-two (92%) patients received all 6 cycles. All patients have now completed therapy and the overall response rate was 96% (23/24) with 23 patients attaining functional CR by PET/CT. The remaining patient went off study for refusal in cycle 1, received further RCHOP-21 off study, and attained a CR off study. The median follow-up for the 24 patients is now 16.8 months (7.3 - 35.7) with 20 patients having ≥12 months of follow-up and 8 patients having ≥24 months of follow-up. To date, none of the 24 patients have died and none have experienced relapse with DLBCL. One patient relapsed 16 months from DLBCL diagnosis with a biopsy-proven follicular grade 1 NHL and received off-study Zevalin and achieved a second CR. The most common grade 3/4 toxicity was hematologic with 71% of patients having grade 4. Five (21%) patients had febrile neutropenia. Only 1 patient had grade 3 hyperglycemia and 3 patients had grade 3 hypertriglyceridemia. Reversible rash and pneumonitis were observed in 1 case each. Conclusions: The mTORC1 inhibitoreverolimus at 10 mg daily d1-14 of a standard RCHOP-21 cycle is tolerable with a 96% CR rate in both GCB and non-GCB DLBCL. With a median follow-up of 16.8 months and 8 patients out ≥24 months, the lack of DLBCL relapse is encouraging. Longer follow-up and a larger trial will be necessary to confirm the benefits of this novel combination. Clinical trial information: NCT01334502 Disclosures Off Label Use: Everolimus is an mTOR inhibitor which has activity in B cell lymphomas. It is being investigated in combination with SOC therapy for newly diagnosed DLBCL to examine potential toxicity as well as potential for enhanced disease response.. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8502-8502 ◽  
Author(s):  
B. D. Cheson ◽  
J. M. Vose ◽  
N. L. Bartlett ◽  
A. Lopez ◽  
R. H. Van der Jagt ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Solid Tumors ◽  
Phase Ii ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Vein Thrombosis ◽  
Grade 3 ◽  
Anti Tumor Activity

8502 Background: Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. YM155, a survivin suppressant, has exhibited anti-tumor activity in solid tumors and non-Hodgkins lymphoma (NHL), including DLBCL patients enrolled in Phase I and Phase II monotherapy studies. Methods: Two studies enrolled 43 DLBCL patients; a Phase I study enrolled patients with solid tumors and NHL (n=1 relapsing DLBCL and n=1 refractory DLBCL), and a Phase II study enrolled refractory DLBCL patients (n=41). YM155 was administered at 4.8 mg/m2/day (Phase I) and at 5 mg/m2/day (Phase II) as a 168-hour continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until disease progression or unacceptable toxicity. Results: Data are presented for the first 27 patients (Phase I and Phase II) who have completed therapy. Median age was 61 (23–80) years and 63% were male. Three patients (11%) had partial responses (PR) confirmed by independent review using Cheson criteria (N=2; 1999 criteria and N=1; 2007 updated criteria). All responders received 2 prior regimens. Two responders were refractory to their last regimen and one had relapsed approximately 2 years after stem cell transplant (SCT). One patient responded after 2 cycles, completed 5 total cycles and proceeded to SCT (disease-free > 3.7 years post SCT). A second patient responded after 3 cycles, completed 7 total cycles and proceeded to SCT in OCT08. The third patient responded after 12 cycles and received 26 total cycles (1.5 years) before disease progression. The most common (>4%), treatment-related grade 3/4 adverse events included anemia (16.0%) and neutropenia, fatigue, hemoglobin decrease and deep vein thrombosis (8.0% each). Conclusions: YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients. Because of single-agent activity and preliminary data showing synergism when YM155 is combined with other agents additional clinical studies are being planned. [Table: see text]

Temsirolimus in Combination with Bendamustine and Rituximab (BeRT) for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Final Phase I/II Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2977-2977 ◽  
Author(s):  
Georg Hess ◽  
Wagner Karola ◽  
Paul LaRosee ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Options ◽  
Prospective Trial ◽  
Phase Iii ◽  
Advisory Committees ◽  
Mtor Inhibition ◽  
Entire Cohort ◽  
Grade 3

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas (Smith et al, JCO 2010). Furthermore, in relapsed MCL a phase III trial demonstrated superiority of Temsirolimus to chemotherapy. Although novel treatment options as Ibrutinib have changed the treatment landscape for MCL, no curative potential could be shown for this approach and novel concepts continue to be needed. Several trials provided promising results when Temsirolimus is combined with agents like Rituximab (Ansell et al, Lancet Oncology 2011) or chemoimmunotherapy, as shown in part I (phase I) of the reported trial (Hess, Leukemia, 2015). We now report the final analysis of phase I and II results. Methods: This is a multicenter, national, prospective trial. Inclusion criteria: Patients were eligible with histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall, 39 patients (pts) have been included (15 pts phase I, 24pts phase II): median age was 71 years, with 29 MCL and 10 FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 133 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (17pts, 45%), lymphopenia (14 pts, 37%), neutropenia (12 pts, 32%), and thrombocytopenia (10 pts, 27%). Non-hematologic grade 3 / 4 side effects observed in at least two patients were angioedema, hyperglycaemia and stomatitis. AE's of special interest: pulmonary: rate of cough (4; 10%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (11; 28%), nausea (19, 49%); general: fatigue (18; 46%), mucositis (17, 44%); bleeding: epistaxis (5; 13%), which all were predominantly grade 1 or 2. Response: currently, best responses were 13 CR (38%), 18 PR (53%) and 3 SD (9%) in 34 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 92% in MCL (11 CR, 11 PR, 2 SD) and 90% in FL (2 CR, 7 PR, 1 SD). After a median follow up of 24 months (mean: 26 months) median PFS is 22 months for the entire cohort, with 33 months for MCL and 22 months in FL. Median OS has not been reached for FL and is 3,55 years (95% CI: 2,7-4,4) for MCL. Summary: The BeRT-combination of 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab is a safe and feasible regimen with substantial activity. As mTOR inhibitors display a noticeable side effect profile especially with long term use, combination with chemoimmunotherapy demonstrates a clinically meaningful balance between efficacy and tolerability, thereby widening the therapeutic portfolio. Disclosures Hess: Roche: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria. LaRosee:Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Witzens-Harig:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Engine: Phase III Randomized Study of Enzastaurin/R-CHOP Versus Placebo/R-CHOP in Frontline High Risk Diffuse Large B Cell Lymphoma Patients with Novel Genomic Biomarker DGM1

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5330-5330 ◽  
Author(s):  
Jun Zhu ◽  
Grzegorz Nowakowski ◽  
Qingyuan Zhang ◽  
Joshua Brody ◽  
Xiuhua Sun ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Randomized Study ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Assessment ◽  
Phase Iii ◽  
Advisory Committees

Background: Progress in genome technology allows analysis of previously completed trials to identify subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC-β) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) (Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) (Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment (Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Study Design and Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject's treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 57 sites open in the US and China. As of 20 July 2019, 128 patients have been randomized. Clinical trial information: NCT03263026. Disclosures Nowakowski: Genentech, Inc.: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Brody:Acerta Pharma: Research Funding; Merck: Research Funding; Celldex Therapeutics: Research Funding; Genentech: Research Funding; Oncovir, Inc.: Research Funding; BMS: Research Funding; Kite Pharma: Research Funding. Lue:Kymera Therapeutics: Honoraria; Astex Pharmaceuticals: Honoraria. Luo:Denovo Biopharma LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Zhang:Denovo Biopharma LLC: Employment. Han:Denovo Biopharma LLC: Employment. Jivani:TRACON Pharmaceuticals, Inc.: Other: Stock; Denovo Biopharma LLC: Employment. Liu:Denovo Biopharma LLC: Employment. Li:Denovo Biopharma LLC: Employment. Sun:Novartis: Other: Stock; Denovo Biopharma LLC: Employment.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

Preliminary Results of a Phase I/II Trial of BBR-2778 (Pixantrone) in Combination with Fludarabine, Dexamethasone, and Rituximab (FPD-R) in the Treatment of Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1324-1324 ◽  
Author(s):  
Luis Fayad ◽  
James Liebmann ◽  
Manuel Modiano ◽  
Gary I. Cohen ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Outpatient Basis ◽  
Significant Activity ◽  
Cardiac Events

Abstract Background: Fludarabine-mitoxantrone-dexamethasone-rituximab (FND-R) is a combination chemotherapy with significant activity in untreated and relapsed indolent B-cell lymphoma patients (pts). Pixantrone is a novel aza-anthracenedione that has no delayed cardiotoxicity in animal models and has single agent activity in NHL. We conducted an outpatient phase I/II trial, to define the recommended dose (RD) of pixantrone when substituting for mitoxantrone in the FND-R regimen, and the safety and efficacy of this regimen in pts with relapsed or refractory indolent NHL. Methods: Pts received pixantrone with fludarabine (25mg/m2/day, days 1–3), dexamethasone (20mg/day, days 1–5), and rituximab (375mg/m2/day on day 1) in a 28 day regimen (FPD-R). Based on previous single agent clinical studies, the starting dose of pixantrone was defined as 80mg/m². The RD was established to be 120mg/m2 and the protocol was amended to treat patients in the phase II part. Results: 9 pts (6 males) with a median age of 65 years (range 41–78) were included in the dose-finding part of the study. Following the protocol amendment, 23 pts (11 males) of WHO performance status 0–1, median age 61 (range 32–78) have been enrolled in the currently ongoing phase II part. Pathology included SLL/CLL, follicular grade I, follicular grade II, MALT, marginal cell, and other indolent B-cell lymphomas. All pts had received a prior anthracycline-containing regimen (median number 1, range 1–4). The study regimen was well tolerated; median number of courses received was 5 (range 2–8). Grade 4 toxicities were neutropenia in 10 pts, leukopenia in 5 pts, and thrombocytopenia in 1 pt. No clinically significant cardiac events or decreases in LVEF ≥20% were noted. However 4 pts went below 50% LVEF including 1 pt who was below 50% at baseline. Non-hematologic adverse events were primarily grade 1 or 2 in severity. Response rate was 75% for the 20 pts evaluable for response, with 11 (55%) complete remission [7 confirmed (CR), 4 unconfirmed (CRu)], and 4 (20%) partial remission (PR). Two responders went onto bone marrow transplant (BMT): one had a CRu and one a PR. A third patient was pending BMT after CR. At a median follow-up of 345 days, the median duration of response has not been reached, as only two pts have progressed: the first progression occurred at 113 days, and the second pt progressed at 699 days. The remaining pts are still in remission. Conclusions: The RD of pixantrone in the FPD-R regimen is 120mg/m2. The primary toxicity is hematologic. The regimen can be given on an outpatient basis, is associated with major responses, and is very well tolerated in relapsed and refractory indolent NHL pts.

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.

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