Schedule of bortezomib administration may be an important determinant of single-agent activity in patients with relapsed or refractory follicular (FL) lymphoma and mantle cell lymphoma (MCL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8051-8051 ◽  
Author(s):  
O. O'Connor ◽  
P. Hamlin ◽  
C. Moskowitz ◽  
D. Straus ◽  
A. Noy ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Important Determinant ◽  
Single Agent ◽  
Dose Intensity ◽  
Significant Activity ◽  
Weekly Schedule ◽  
Mantle Cell ◽  
Grade 3 ◽  
Multi Center Study

8051 Background: We previously demonstrated the significant activity of bortezomib for the treatment of FL and MCL. The activity in MCL has been confirmed in a multi-center study leading to the recent approval by the FDA. The demonstrated activity was observed on the twice weekly schedule. Recent data using bortezomib in combination with rituximab suggested that weekly bortezomib was less toxic and possibly equally as efficacious as twice weekly bortezomib. This study does not allow a determination of weekly single agent activity alone. We sought to evaluate the single agent activity of bortezomb in FL and MCL administered on a weekly schedule. Methods: Pts with FL and MCL were treated with bortezomib at a dose of 1.8 mg/m2 weekly for 4 of 6 consecutive weeks. To date, 20 pts (12 FL, 8 MCL) have been treated on this schedule, of which 18 are assessable for response. Two pts were inevaluable: 1 pt received steroids for bronchitis (MCL); and 1 pt (FL) with grade 2 diarrhea withdraw consent making her data inaccessible. Results: The range of cycles administered was 1 to 8, with a median of 2. The weekly dosing schedule was well tolerated with 1 pt. developing neuropathy (grade 3). Fourteen pts completed at least two cycles of therapy and underwent restaging. Two pts had a PR (both FL), 8 had SD (5 FL, 3 MCL) and 4 had POD (2 FL, 2 MCL). The other 4 evaluable patients are now being restaged. Conclusions: These data suggest weekly dosing with bortezomib may not be as effective as twice weekly. Typically, bortezomib administered on the twice weekly schedule has an ORR of 30% in MCL and 50% in FL. Additionally, the frequency of pts. experiencing POD appears to be less common on the twice weekly schedule. One difference in the schedules is the dose intensity and dose density. A cycle of twice weekly bortezomib administers 1.7 mg/m2/week, while a weekly schedule administers only 1.2 mg/m2/week, a 30% difference in dose intensity and a 100% difference in dose density (1.33 × per week vs. .67 × per week). What remains unclear from a pharmacologic perspective is the relative importance of high Cmax vs high AUC exposures, and their impact on both toxicity and efficacy. These data suggest that schedule is critical in the activity of bortezomib. No significant financial relationships to disclose.

Flavopiridol in Untreated or Relapsed Mantle-Cell Lymphoma: Results of a Phase II Study of the National Cancer Institute of Canada Clinical Trials Group

2003 ◽  
Vol 21 (9) ◽  
pp. 1740-1745 ◽  
Author(s):  
C. Tom Kouroukis ◽  
Andrew Belch ◽  
Michael Crump ◽  
Elizabeth Eisenhauer ◽  
Randy D. Gascoyne ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Stable Disease ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Biologically Active ◽  
Hematologic Toxicity ◽  
Mantle Cell ◽  
Duration Of Response ◽  
Grade 3

Purpose: To determine the response rate and toxicity of flavopiridol in patients with previously untreated or relapsed mantle-cell lymphoma. Patients and Methods: Adult patients with previously untreated or in first or second relapse of previously responsive mantle-cell lymphoma were given flavopiridol 50 mg/m2/d by intravenous bolus for 3 consecutive days every 21 days with antidiarrheal prophylaxis. Flavopiridol was continued until disease progression, unacceptable toxicity, or stable disease for four cycles. Disease was reassessed every two cycles. Results: From 33 registered patients, 30 were eligible after pathology review, 30 were assessable for toxicity, and 28 were assessable for response. A median of four cycles of treatment was administered; 90% of patients received at least 90% of planned dose-intensity. No complete responses were seen; three patients had a partial response (11%), 20 patients had stable disease (71%), and five patients had progressive disease (18%). The median duration of response was 3.3 months (range, 2.8 to 13.2 months). The most common toxicities were diarrhea (97%), fatigue (73%), nausea (47%), and vomiting (27%). At least one nonhematologic grade 3 or 4 toxicity was seen in 14 patients (47%). Hematologic toxicity was modest. Conclusions: Flavopiridol given as a daily bolus for 3 consecutive days every 3 weeks has modest activity as a single agent for mantle-cell lymphoma. The number of stable and partial responses that was seen indicates that it is biologically active and may delay progression. Future studies in mantle-cell lymphoma should test this agent with other active agents and using different schedules.

Preliminary Results of a Phase I/II Study of Weekly or Twice Weekly Bortezomib in Combination with Rituximab, in Patients with Follicular Lymphoma, Mantle Cell Lymphoma and Waldenström’s Macroglobulinaemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2559-2559 ◽  
Author(s):  
A. Agathocleous ◽  
S. Rule ◽  
P. Johnson ◽  
J.A. Radford ◽  
N. Lafon ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Haematological Toxicity ◽  
Median Number ◽  
High Dose ◽  
Weekly Schedule ◽  
Mantle Cell ◽  
Grade 3

Abstract Introduction: Rituximab (R) is an integral component of therapy for B-cell lymphoid malignancies; bortezomib (Btz) has shown provocative single agent activity in Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Waldenström’s Macroglobulinaemia (WM), providing the rationale for investigating the combination. Patients+Methods: Forty-five adult patients (pts.) (30 men, 15 women) with histologically confirmed recurrent CD20+ve FL, MCL or WM, median age 60 years (range 45-79), FL: 17, MCL: 18, WM: 10, stage III/IV 40 (93%), bone marrow (BM) infiltration 32 (73%), elevated LDH 22 (49%), performance status ≥1 22 (49%), were enrolled in a randomised trial comparing 2 schedules of Brz+R: Arm A (twice weekly) Btz: 1.3mg/m2 (on days 1, 4, 8, 11 of a 21-day cycle) and R: 375mg/m2 (on day 1) for 8 cycles, or Arm B (weekly) Btz: 1.6mg/m2 (on days 1, 8, 15, 22 of a 35-day cycle) and R: 375mg/m2 (on days 1, 8, 15, 22 of cycles 1 and 4) for 6 cycles (23 arm A, 22 arm B). The median number of previous treatments was 2 (range 1-7). Seventeen pts. had received a R-containing regimen, with response lasting >6 months, and 8 high-dose treatment. Response was evaluated using the IWR criteria (Cheson et al, JCO17: 1244, 1999) and the updated response criteria from the 3rd International Workshop on WM (Treon et al, Blood107: 3442, 2006) Results: Ability to deliver the therapy, toxicity and efficacy were equivalent in both arms. The median number of cycles given in arm A was 4 and 5 in arm B. Haematological toxicity (grade≥3: anaemia 0%, neutropenia 25%, thrombocytopenia 22%) was significantly influenced by the high percentage of pts. with BM infiltration and concomitant cytopenia on entry to the trial. The most common non-haematological adverse events were fatigue (76%), nausea (56%), diarrhoea (56%), lethargy (46%). Neurotoxicity occurred in 19 pts. (46%) (10 pts. grade 1, 7 pts. grade 2, 2 pts. grade 3). Btz dose was reduced in 7 pts.; 5 doses were omitted because of neuro or haematological toxicity. In 16 pts., treatment was delayed by 1-14 days and in 24 pts. treatment was stopped prematurely. The reasons for stopping treatment were: treatment-related toxicity 11 pts., progressive disease 9 pts., patient’s preference 3 pts., myocardial infarction 1 pt. One pt. was excluded having been found ineligible post randomisation. Thirty-nine pts. (21 arm A, 18 arm B) are evaluable for response so far, one having only received 1 cycle of therapy, which had to be discontinued because of excessive toxicity. 15/32 were in remission (CR, CRu, PR) at the completion of therapy, 7/7 at “mid-therapy” assessment, and 5 have yet to be evaluated. Thus the overall response rate (RR) presently is 22/39 (56%) (CR, CRu, PR), FL 44%, MCL 46%, WM 90%. Conclusions: The combination was active in pts. with recurrent NHL especially WM (RR 90%), despite multiple previous treatments, The weekly schedule is preferable being more convenient, as efficacious and no more toxic. Further investigation is warranted, despite not insignificant therapy compromising toxicity.

Rituximab, Cyclophosphamide, Bortezomib and Prednisone (R-CBorP): Final Results of a Phase I Trial Evaluating Two Dosing Schedules and the Safety of Overlapping Pegfilgrastim in Patients with Relapsed/Refractory Indolent and Mantle Cell Lymphomas.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3708-3708 ◽  
Author(s):  
John Gerecitano ◽  
Carol S. Portlock ◽  
Paul A. Hamlin ◽  
Craig H Moskowitz ◽  
Ariela Noy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Response Rates ◽  
Neutropenic Fever ◽  
Significant Activity ◽  
Weekly Schedule ◽  
Mantle Cell ◽  
Grade 3 ◽  
Weekly Group

Abstract Abstract 3708 Poster Board III-644 Aim To determine the safety and efficacy of substituting bortezomib (Bor) for vincristine in standard ‘R-CVP’. A separate safety analysis evaluated the safety of pegfilgrastim (PegG) overlapping with Bor administration. Rationale Vincristine has marginal activity in indolent lymphomas, while preclinical and clinical data suggest that single agent Bor has significant activity in indolent and mantle cell (MCL) non-Hodgkin Lymphoma (NHL), and may also be synergistic with rituximab (R) and DNA-damaging agents. Methods In this phase I trial, Bor and cyclophosphamide (C) were alternately escalated. R (375 mg/m2) and C (750 mg/m2 or 1000 mg/m2) were dosed on day one, and prednisone (P) (100 mg daily) on days 2-6. In schedule 1, Bor was given on days 2 and 8, with doses escalated from 1.3 to 1.8 mg/m2. In schedule 2, Bor was given on days 2, 5, 9 and 12 with doses escalated from 1.1 to 1.5 mg/m2. Due to 2 neutropenic fevers in schedule 2 (twice-weekly Bor), the protocol was amended to allow for filgrastim (G) support, administered in between Bor dosing days. This allowed accrual to the highest planned dosing level. A separate cohort of 10 patients was added at the twice-weekly Bor 1.3 mg/m2 + C 1000 mg/m2 level to assess the safety of administering overlapping PegG instead of G. In this cohort, PegG was given with Bor on day 2. Patients with PR or SD after 4 cycles received 4 further cycles, those with CR got 2 further cycles. Toxicity was assessed using NCI-CTC, v. 3.0. No DLT was seen at maximum doses of Bor and C in either schedule. Schedule 1 accrued 15 patients, with one DLT requiring cohort expansion at the second dose level. Schedule 2 accrued 40 patients. Results Demographic variables were similar between the two groups, and both schedules were well tolerated with similar toxicity profiles. Most hematologic toxicities (HTs) and non-HTs across all dose levels and cycles were grade 1-2. Grade 3-4 non-HTs in the weekly treatment cohorts included grade 3 diarrhea (n=1), dehydration (n=1), neutropenic fever (n=1), infection (n=2) and anal incontinence (n=1, likely unrelated). Grade 3 toxicities in the twice-weekly groups included fatigue (n=3), neutropenic fever (n=2), fever (n=1), hypoxia (n=1) and neuropathy (n=2), along with one grade 4 neuropathy. Of the patients who developed neuropathy above baseline, resolution to baseline occurred in 8 of 9 (89%) of patients in the weekly group after a median of 0.7 months, and in 15 of 26 (58%) of patients in the twice-weekly group after a median of 4 months. To evaluate the safety of pegfilgrastim overlapping with 4 doses of Bor, toxicities and CBCs for patients in the PegG group were compared with those of patients treated at identical doses of R-CBorP given non-overlapping G support. All toxicities and CBC trends were similar, with the exception of a significant but mild decline in platelets in the PegG group. Overall response rates in the 13 evaluable weekly and 33 evaluable twice-weekly patients were 46% (23% CR) and 64% (36% CR), respectively. Conclusions R-CBorP is a well-tolerated and promising new regimen in patients with NHL. The safety of administering PegG overlapping with Bor has been established, and simplifies this regimen. Although response rates appeared to be greater in the twice-weekly schedule, a randomized study will be required to determine the true difference. Grade 3-4 neuropathy was seen only in the twice-weekly dosing group, and seemed to be less reversible and longer-lasting than in the weekly group. A randomized phase II study will soon begin enrollment to compare the toxicity and efficacy of these two dosing schedules in a larger group of patients with follicular lymphoma. Disclosures: Gerecitano: Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Off Label Use: bortezomib in combination with other active agents for indolent and mantle cell non-Hodgkin lymphomas. Hamlin:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Zelenetz:Millenium Advisory board: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Anti-Tumor Activity of Single-Agent CCI-779 for Relapsed Mantle Cell Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 129-129 ◽  
Author(s):  
Thomas Witzig ◽  
Susan Geyer ◽  
Irene Ghobrial ◽  
David Inwards ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Median Time ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Pi3k Pathway ◽  
Mantle Cell ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

scholarly journals A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 150-150 ◽  
Author(s):  
Peter Martin ◽  
Kristie Blum ◽  
Nancy L. Bartlett ◽  
Steven I. Park ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

Flavopiridol, Fludarabine and Rituximab Is a Highly Active Regimen in Indolent B-Cell Lymphoproliferative Disorders Including Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 944-944 ◽  
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Mollie E. Moran ◽  
Maureen M. Buckner ◽  
Roshini Shank ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Stage Iii ◽  
Clinical Activity ◽  
Mantle Cell ◽  
Grade 3

Abstract The cyclin-dependent kinase inhibitor flavopiridol was inactive when given by 24–72-hr infusion, but 1-hr IV bolus dosing demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis independent of p53 and may be able to eliminate tumor cells resistant to fludarabine and rituximab. We performed a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with MCL, CLL and indolent B-cell non-Hodgkin’s lymphoma (NHL). Pts had ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), day 1–2 (cohort 2), or day 1–3 (cohort 3) of each cycle. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was prohibited. Twenty-one pts were enrolled and are evaluable for toxicity and response. Median age was 62 years (range, 43–81), and 10 pts were male. Pts had the following diagnoses: CLL (8), MCL (5), follicular lymphoma (FL; 4), small lymphocytic lymphoma (SLL; 3), and lymphoplasmacytic lymphoma (1). Nine pts had received 1-2 prior therapies; 12 pts were previously untreated. CLL pts were Rai stage III/IV (5) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. NHL pts were stage III/IV (10) or had progressive stage II disease (3). Three pts were treated in cohort 1, and dose limiting toxicity (DLT) was not observed. Six pts were treated in cohort 2. Two pts developed DLT; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Three pts in cohort 2 did not receive flavopiridol after cycles 2, 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Twelve additional pts were enrolled at the cohort 1 dose level, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 9 of 21 pts completed all 6 planned cycles. Therapy was stopped early due to cytopenias (7), infection (2), DLT (2) or progressive disease (1). One patient who received only 2 cycles of FFR due to cytopenias subsequently received 4 cycles of fludarabine and rituximab from his local oncologist. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 90%; 15 pts achieved CR (71%), and 4 pts achieved PR (19%). Six pts relapsed a median of 7.5 months (range 4–18) after completing therapy; 13 pts remain in remission a median of 11 months (range 4–23) after completing therapy. Of note, all 9 MCL/FL pts responded (8 CR, 1 PR), and 8 pts remain in remission a median of 15 months (6–23) after finishing therapy. In conclusion, FFR exhibited significant clinical activity in a small group of pts, but cytopenias limited the administration of therapy. We are currently studying a modified FFR regimen administering a more active flavopiridol schedule (30-min IV bolus followed by 4-hr IV infusion) and allowing the use of prophylactic filgrastim, prior to phase II clinical study.

Flavopiridol, Fludarabine and Rituximab (FFR): An Active Regimen in Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1571-1571 ◽  
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Kristie A. Blum ◽  
Pierluigi Porcu ◽  
Eric H. Kraut ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) induces p53-independent apoptosis and may be able to eliminate tumor cells resistant to fludarabine and rituximab. Study Design and Treatment: We report final results of a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with mantle cell lymphoma (MCL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL). Pts had ANC 3 1500, hemoglobin 3 9.0, platelets 3 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. Flavopiridol was administered 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1, n=15) or day 1 and 2 (cohort 2, n=6) of each cycle. Based on promising results with a novel single agent dosing schedule in CLL, the study was amended to give flavopiridol by 30-min IV bolus followed by 4-hr IV infusion at a dose of 20 mg/m2 + 20 mg/m2 (cohort 3, n=3) or 30 mg/m2 + 30 mg/m2 (cohort 4, n=14) beginning with cycle 2. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was allowed in cohorts 3 and 4. Results: Thirty-eight pts were enrolled. Median age was 62 years (range, 38–81), and 22 pts were male (58%). Pts had CLL (11), MCL (10), follicular (FL, 9), small lymphocytic (3), marginal zone (4) or lymphoplasmacytic lymphoma (1). Sixteen pts had received 1 or 2 prior therapies; 22 pts were previously untreated. Two of 6 pts in cohort 2 developed dose limiting toxicity; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Fifteen pts were enrolled in cohort 1 and 14 pts were enrolled in cohort 4, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 16 of 38 pts completed all 6 planned cycles. Cytopenias (10), fatigue (3), fever (2) and progression (2) were the most common reasons for early discontinuation of therapy. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 82% (CR 50%, CRu 5%, PR 26%). Median progression-free survival (PFS) of responders was 25.5 months. ORR (82% vs. 81%), CR (50% vs. 50%) and median PFS (25.7 vs. 25.1 months) were similar for previously untreated and relapsed pts. Thirteen pts remain in remission with a median PFS of 33.5 months (range, 17.5–59.5), and 3 other pts died of unrelated causes. Eight of 10 MCL pts (median age 68, range 62–81) responded (7 CR, 1 PR). Two responders with blastoid variant MCL relapsed within 1 year, but median PFS of the other 6 responding MCL pts was 33.5 months. All 9 FL pts responded (5 CR, 2 CRu, 2 PR) with a median PFS of 25.1 months (range, 4.0–46.3). Conclusions: FFR exhibited significant clinical activity in indolent B-NHL, MCL and CLL. FFR was effective in both relapsed and previously untreated pts and showed promising clinical activity in older MCL pts. Changing from 1-hr IV bolus dosing to 30- min IV bolus followed by 4-hr IV infusion did not improve the response rate, suggesting that 1-hr IV bolus dosing may be effective when flavopiridol is given as part of combination chemotherapy. This regimen warrants further study.

CHOP-R + Bortezomib as Initial Therapy for Mantle Cell Lymphoma (MCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2682-2682 ◽  
Author(s):  
Jia Ruan ◽  
Peter Martin ◽  
Richard R Furman ◽  
Julie M. Vose ◽  
Ann LaCasce ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Single Agent ◽  
Elevated Serum ◽  
Serum Lactate Dehydrogenase ◽  
Antitumor Effects ◽  
Cox Regression Analysis ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 2682 Poster Board II-658 BACKGROUND: Bortezomib is a proteasome inhibitor with single agent activity in mantle cell lymphoma. Preclinical studies have demonstrated that addition of bortezomib to chemoimmunotherapy can enhance antitumor effects. We report findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab (R) in previously untreated MCL patients. METHODS: From 6/2004 to 10/2007, 36 patients with previously untreated MCL received standard CHOP-21 with rituximab (375 mg/m2 per cycle) plus bortezomib at 1.0 mg/m2 (n=4) or 1.3 mg/m2 (n=32) on days 1 and 4 of each cycle for a total of 6 cycles. Study endpoints included safety and efficacy assessment. RESULTS: At study entry, median age (n=36) was 66 years (range 45–80), and M:F ratio was 5:1. Thirty-four subjects (94%) had stage III/IV disease, and 18 (50%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores (42% with IPI of 2, and 47% with IPI of 3–5), as well as MIPI scores (28% with intermediate risk and 39% with high risk). Treatment was generally well tolerated. Peripheral neuropathy (sometimes reversible) occurred in 20 subjects (56%) with 16 grade 1, 3 grade 2, and 1 grade 3. Grade 3/4 cytopenias included anemia (11%), neutropenia (23%) and thrombocytopenia (14%). At a median followup of 30 months (range 8–61 months), 32 patients are evaluable for efficacy. For all patients (n=36), the intent-to-treat (ITT) overall response rate (ORR) is 81% with 64% CR/CRu. For evaluable patients (n=32), the ORR is 91%, and CR/CRu 72%. The median progression free survival for all patients (n=36) is 21 months (95% CI 17-29) by Kaplan-Meier estimate, and 2 year overall survival is 86% (95% CI 69–94%). Currently eight patients remain in ongoing response (range 15–39 months). In a univariate Cox regression analysis, IPI correlated with PFS (HR 1.85, p=0.023), while MIPI correlated with both PFS (HR 1.81, p=0.027) and OS (HR 2.6, p=0.033). CONCLUSIONS: Bortezomib in conjunction with R-CHOP-21 can be safely administered in an outpatient regimen to previously untreated MCL patients, including the elderly. Further evaluation of combinations of bortezomib with R-CHOP is warranted. Disclosures: Vose: Genentech, Inc.: Consultancy, Research Funding. Coleman:Millenium: Speakers Bureau. Leonard:Millenium: Consultancy, Honoraria; Johnson & Johnson: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Biogen Idec: Consultancy, Honoraria.

scholarly journals Ibrutinib, Venetoclax Plus Obinutuzumab in Newly Diagnosed Mantle Cell Lymphoma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1530-1530 ◽  
Author(s):  
Steven Le Gouill ◽  
Franck Morschhauser ◽  
Kamal Bouabdallah ◽  
Guillaume Cartron ◽  
Olivier Casasnovas ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Dose Intensity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Good Safety Profile ◽  
Mantle Cell ◽  
Grade 3

Background. Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor, is currently under investigation in prospective trials in R/R MCL. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody approved in frontline and R/R follicular lymphoma which has shown efficacy in MCL (Chiron Blood 2016, Le Gouill ICML/EHA 2019). Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016) The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study that was designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. The study is divided into three steps (A, B,C, respectively) : step A enrolled nine R/R MCL who were treated with Ibrutinib plus Obinutuzumab and step B enrolled 24 R/R MCL patients who were treated with Ibrutinib/Venetoclax/Obinutuzumab (Venetoclax dose from 200 to 800mg ). The Ibrutinib/Venetoclax/Obinutuzumab combination demonstrated a good safety profile and high response rates in R/R MCL (step B). No DLT was reported in either step (Le Gouill et al, ASH 2018). Herein, we present the safety (primary objective), clinical and MRD results for Oasis step C where Ibrutinib/Venetoclax/Obinutuzumab was given to newly-diagnosed, untreated MCL patients. Methods: Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment. Results. Fifteen untreated MCL patients were enrolled from August 2018 to April 2019, in 6 participating centers (France and UK). Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass >5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 13 patients (one was not informative and two are ongoing) of these one presented TP53 mutation. IGHV status (assessed in 13 patients, ongoing in 2) was mutated in two cases including the p53mutcase and not mutated in 8 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis - grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 7 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 8 patients (others are ongoing) were assessed at end of cycle 3 and all were MRD negative in BM (n=6) and/or in blood (n=8), including the p53mutpatient. Seven patients completed 6 cycles, all reached CR according to Lugano criteria (6 in CR/Cru according to Cheson criteria) and were MRD neg (in blood in all cases and in BM in 6 cases -one not done), including the P53mut patient. At date of last monitoring (Jul 2019), no disease progression is reported and all patients remain under the planned treatment. Conclusion. Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL. Disclosures Le Gouill: Janssen-cilag: Consultancy, Honoraria; Novartis: Consultancy; Abbvie: Consultancy, Honoraria; Roche Genentech: Consultancy, Honoraria; Gilead-Kite: Consultancy, Honoraria; Servier: Consultancy; loxo: Consultancy, Honoraria; Takeda: Consultancy. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Napp: Consultancy; TG Therapeutics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. OffLabel Disclosure: Venetoclax, obinutuzumab in mantle cell lymphoma

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