Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Hun Ju Lee ◽  
Michael Y. Choi ◽  
Tanya Siddiqi ◽  
Jacqueline Claudia Barrientos ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
Best Response ◽  
Car T ◽  
Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16184-e16184
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Li ◽  
Roland Ching-Yu Leung ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Refractory Ascites ◽  
Time To Progression ◽  
Advanced Hcc ◽  
Grade 3 ◽  
Experienced Grade ◽  
Systemic Therapies

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1094-1100 ◽  
Author(s):  
Bertrand Coiffier ◽  
Stéphane Lepretre ◽  
Lars Møller Pedersen ◽  
Ole Gadeberg ◽  
Henrik Fredriksen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Partial Remission ◽  
Phase 1 ◽  
Objective Response ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Safety And Efficacy ◽  
Anti Cd20

Abstract Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.

FCR-3 as Frontline Therapy for Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2117-2117 ◽  
Author(s):  
Susan O’Brien ◽  
William G. Wierda ◽  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
Carlos E. Bueso-Ramos ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Single Agent ◽  
Response Rates ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Consensus Primer ◽  
Dose Dense ◽  
Wbc Count

Abstract The combination regimen of Fludarabine, Cyclophosphamide, and Rituximab (FCR) has produced high overall response (OR) rates and complete remission (CR) rates in patients receiving this as initial treatment for CLL. Earlier studies have shown that dose-dense or dose-intensified regimens of single-agent Rituximab produced higher response rates in patients with CLL. The current regimen, FCR-3, was based on the hypothesis that increasing the amount of Rituximab in the combination might improve response rates and remission duration. Doses of chemotherapy were Fludarabine 25 mg/m2/Dx3, and Cyclophosphamide 250 mg/m2/Dx3 given monthly. Rituximab was given at 375 mg/m2 as the first dose and 500 mg/m2 for all subsequent doses. On each day of the chemotherapy a dose of Rituximab was given so 3 doses were given monthly. With the previous FCR regimen 45% of patients achieved a CR or nPR and had <5% CD19+ 5 positive cells in the marrow at the completion of 3 cycles of therapy (rapid response, RR). The median time to progression (TTP) in that group has not been reached; it was 3 years in patients who did not achieve that endpoint (p<.001). The current protocol aimed to increase that response rate from 45% to 60%. Sixty-five patients were treated. Eighty percent were men. The median age was 59 years (27–82). Rai Stage 3–4 disease was present in 25% of patients. Median WBC count was 92.4 x 103/ul (7.9–363). Median B2-microglobulin was 3.8 (1.6–10.1). Unfavorable FISH abnormalities were present in 35% of 52 evaluable patients. Somatic hypermutation status was available for 44 patients; 61% were unmutated. ZAP-70 expression analysis performed by immunostaining or flow cytometry was positive in 62% of 47 evaluable patients. Results of FCR-3 in comparison to FCR are shown in the table. 3 Cycles 6 Cycles No. RR(%) OR CR Flow<5% FCR 300 45 95 72 82 FCR-3 65 45 94 65 74 PCR negativity using consensus primer PCR was achieved in 49% of patients at the end of therapy. Median number of days between courses ranges from 29–35 per course (overall range 27–95). Eighty-five percent of patients completed 6 cycles. No patient has progressed with a median follow-up of 10 months. With limited follow-up the addition of 3 doses of Rituximab to FC chemotherapy does not appear to provide greater benefit than one dose.

scholarly journals Phase 2A Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1701-1701 ◽  
Author(s):  
Martin Dreyling ◽  
David Cunningham ◽  
Krimo Bouabdallah ◽  
Sarit Assouline ◽  
Eric Van den Neste ◽  
...  
Keyword(s):  
Exploratory Study ◽  
Research Funding ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Pi3k Inhibitor ◽  
Aggressive Lymphoma ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-d and PI3K-α isoforms. Preliminary results from a phase II study of copanlisib in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort for patients with aggressive lymphoma still ongoing. We report here the final results of this exploratory study for patients with indolent NHL or CLL treated with copanlisib. Methods: Patients with histologically confirmed indolent NHL or CLL and relapsed or refractory to ≥2 prior lines of treatment were eligible. Copanlisib was administered at a dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of CLL (Hallek et al., Blood 111:5446-56, 2008). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability. Results: A total of 33 patients were treated in the indolent group, including: follicular NHL (FL) = 16, CLL = 13, marginal zone lymphoma (MZL) = 3, and small lymphocytic lymphoma (SLL) = 1. Median age was 68 years (range 46-89), M/F= 15/18. The median number of previous lines of treatment was 4. Thirty patients (91%) were previously exposed to rituximab. The median number of cycles received was 5.7 (mean 7.2); the median dose and median cumulative dosage of copanlisib administered were 52 mg (87% of planned dose) and 687 mg, respectively. Five patients were dose reduced to 0.6 mg/kg and 1 to 0.4 mg/kg. The ORR as determined by independent radiologic review in 32 evaluable patients was 47%, with 1 CR, 1 uCR, and 13 PRs. By histology, there were 1 CR, 1 uCR and 5 PRs for patients with FL (ORR 47%), and 2/3 PRs for patients with MZL and 1/1 PR for the patient with SLL, for an overall ORR for patients with indolent NHL (excluding CLL) of 53%. The ORR for patients with CLL was 38% (all PRs). Overall, the median DOR was 287 days (95% CI: 56; not yet reached); median PFS was 240 days (95% CI: 173; 419). The most common adverse events (AEs) of all grades were hyperglycemia (70%), hypertension (70%), fatigue (64%), diarrhea (36%), neutropenia (36%) and anemia (33%). Grade 3-4 AEs occurring in >10% of patients included: hypertension (49% grade 3), neutropenia (30%), hyperglycemia (30% grade 3), and anemia (15%). Dose reductions, interruptions, or permanent discontinuations due to AEs were reported in 4 (12%), 21 64%), and 11 (33%) patients, respectively. There was one drug-related grade-5 event; meningitis in a heavily-pretreated CLL patient with longstanding disease-related immunodeficiency, occurring shortly after first administration of copanlisib. Conclusions: Copanlisib is active as a single-agent in heavily pretreated, advanced refractory/relapsed FL, MZL, SLL, and CLL. Copanlisib exhibited an acceptable toxicity profile, consistent with previous reports. Based on the results of this exploratory study, a phase 2B study of copanlisib in relapsed or refractory indolent NHL (after prior treatment with an alkylating agent and rituximab) has been initiated and is ongoing. Disclosures Dreyling: Bayer HealthCare: Scientific advisory board/consultant Other. Cunningham:Roche: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merck Serono: Research Funding; Novartis: Research Funding; Astra Zeneca: Research Funding. Giurescu:Bayer Pharma AG: Employment. Mappa:Bayer S.p.A.: Employment. Grunert:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7555-7555
Author(s):  
Sattva Swarup Neelapu ◽  
Caron A. Jacobson ◽  
Olalekan O. Oluwole ◽  
Javier Munoz ◽  
Abhinav Deol ◽  
...  
Keyword(s):  
T Cell ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.

Continued Late Conversion to Complete Remission (CR/CRu) and Durability of Remission (DUR) in Pts with B-Cell Follicular Lymphoma (FL) Treated with Rituximab Followed by Mitumprotimut-T (Id-KLH, FavId®) Active Immunotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3427-3427 ◽  
Author(s):  
Omer N. Koc ◽  
Charles Redfern ◽  
Peter H. Wiernik ◽  
Fred Rosenfelt ◽  
Jane N. Winter ◽  
...  
Keyword(s):  
Complete Remission ◽  
Single Agent ◽  
Objective Response ◽  
Active Immunotherapy ◽  
Clinical Activity ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Best Response ◽  
Long Term Follow Up

Abstract Background: We have previously reported results from a Phase 2 trial in which both treatment naïve (TN) and relapsed/refractory (R/R) pts with stable disease (SD) or a clinical response (PR or CR/CRu) following 4 weekly doses of rituximab received mitumprotimut-T active immunotherapy (Koc et al, Blood2006; 108: #691). We report here 4-year follow up of conversion of pts into complete remission (CR/CRu) and an assessment of the DUR in this population. Treatment: Pts received rituximab (375mg/m2 iv weekly x 4) and those with ≥SD assessed at Week 11 received mitumprotimut-T, 1 mg sq every month (mo) x 6 starting on Week 12 along with Leukine (sargramostim, GM-CSF), 250 mcg, sq on Days 1–4. Pts continued to receive booster injections on a reduced schedule (every 2 mos x 6, then quarterly) until disease progression. Radiological scans were performed every 3 mos for the first 2 years then every 6 mos, and reviewed centrally. Objective response and progression were assessed using modified IWG criteria. Results: 89 pts (54 RR, 35 TN) had ≥SD following rituximab received mitumprotimut-T + Leukine. Two pts (RR) achieved a CR following rituximab and prior to receiving mitumprotimut-T. As shown in Fig. 1, an additional 16 pts (9 TN, 7 RR) converted to CR/CRu over the next 31 mos. At a median follow-up of 42 mos, only 6 (3 TN, 3 RR) of the 18 CR pts have relapsed (Fig. 2). Discussion: Long-term follow-up has shown a continuing conversion of pts into CR occurring as late as 31 mos. These data suggest clinical activity of mitumprotimut-T in these pts as determined by the increasing CR rate and the durability of this response. These data are of particular interest since a blinded interim analysis of best response in an ongoing controlled Phase 3 study of single agent rituximab vs. rituximab followed by mitumprotimut-T showed 47% of pts in this study to be in CR/CRu with 12–18 mos of follow-up (Freedman et al, Blood2006; 108: #2756). Figure Figure Figure Figure

FCgamma Receptor Polymorphisms Do Not Influence the Outcome of Treatment with Rituximab Followed by Active Immunotherapy with Mitumprotimut-T (FavId®, Id-KLH).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3416-3416 ◽  
Author(s):  
David G. Maloney ◽  
Barbara Pender ◽  
Erin McCarthy ◽  
Daniel P. Gold
Keyword(s):  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Response To Therapy ◽  
Phase Iii ◽  
Active Immunotherapy ◽  
Patient Specific ◽  
Best Response ◽  
Response To Chemotherapy

Abstract Background: Patient specific active idiotype immunotherapy with immunoglobulin idiotype is a promising new therapy for follicular NHL. Response to therapy may include both humoral and cellular anti-idiotypic immunity, but it is not clear which is most important. Prior studies have suggested that immunoglobulin FCgammaRIIIa (FCgRIIIa) polymorphisms at position 158 valine (V) or phenylalanine (F) effect the response to treatment with rituximab as well as outcomes from idiotype immunotherapy following objective response to chemotherapy. Here we present data assessing the correlation of FCgRIIIa polymorphisms and outcomes from idiotype immunotherapy following treatment with rituximab. Treatment: We determined the FCgRIIIa genotype using a SSCP method with genomic DNA isolated from 55 rituximab-naïve patients treated on a Phase II trial of mitumprotimut-T (FavId®, Id-KLH) (Koc et al, Blood, 2006; 108: #691). Four patients who progressed following rituximab and therefore did not receive mitumprotimut-T were excluded from this analysis. All 55 patients in this analysis had follicular NHL with a median age of 55 years. Thirty five patients were treatment naïve and 20 had relapsed following prior chemotherapy. Patients received rituximab (375mg/m2 i.v. weekly x 4) and those with stable or responding disease assessed at Week 11 received Id-KLH (1 mg s.q. monthly x 6) starting on Week 12 along with Leukine® (sargramostim, GM-CSF, 250 mcg, s.q.) on Days 1–4. Pts continued to receive booster injections on a reduced schedule, every other month x6 then quarterly thereafter, until disease progression. Radiological scans were performed every 3 months for the first 2 years of follow up, then every 6 months thereafter and reviewed centrally. Objective response and time to tumor progression (TTP) were assessed using modified IWG criteria (Cheson et al, J Clin Oncol1999; 17:1244). Response at 3 months, best response, TTP and progression free survival (PFS) at 1 year and 3.5 years were all assessed with respect to FCgRIIIa genotypes. Results: DNA was isolated from all 55 patients and successfully analyzed by SSCP for polymorphisms at position 158 of FCgRIIIa. Nine of 55 patients were V/V (16%), 27 were F/F (49%) and 19 were heterozygous V/F (35%). Overall, the 3 month response rate CR+PR) was 31/55 (56%) and the best overall response rate was 39/55 (71%). The 3 month response (post rituximab) was 5/9 (56%) for V/V, 9/19 (47%) for V/F and 17/27 (63%) for F/F patients. Best response was 6/9 (67%) for V/V, 12/19 (63%) for V/F and 21/27 (78%) for F/F patients. Median TTP was 19.5 months for V/V, 22.3 months for V/F and 18 months for F/F patients. The PFS at 1 year post initiation of rituximab was 57% for V/V, 61% for VF and 68% for FF patients while at the median follow-up of 3.5 years the PFS was 31% for V/V, 42% for V/F and 31% for F/F patients. Conclusions: FCgRIIIa polymorphisms were not associated with response rate or time to progression following a treatment program consisting of single agent rituximab followed by idiotype vaccination with mitumprotimut-T in rituximab-naïve patients. Results from an ongoing randomized Phase III study will assess the efficacy of this combined therapy, but these data suggest that long term PFS in patients receiving an idiotype vaccine following rituximab may rely more on a cell mediated immune response rather than a humoral response to idiotype.

A Clinical Study of Bortezomib in Combination with Dexamethasone and/or Doxorubibcin for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5216-5216
Author(s):  
Jie Jin ◽  
Jiejing Qian ◽  
Haitao Meng ◽  
Wenbin Qian ◽  
Hongyan Tong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Objective Response ◽  
Median Number ◽  
Refractory Multiple Myeloma ◽  
Mean Response Time ◽  
Best Response ◽  
Common Grade ◽  
Grade 3 ◽  
Lost To Follow Up

Abstract Purpose: This study assessed the safety, tolerability, and response rate of bortezomib in combination with dexamethasone and/or doxorubibcin in patients with relapsed or refractory multiple myeloma. Methods: Botezomib was administered 1.3mg/m2 on days 1, 4, 8, 11 of a 28-day cycle. Intravenous dexamethasone was administered 20–40mg/d on day 1–2, 4–5, 8–9,11–12, and 5 patients were also given 20mg/d doxorubibcin on day 1–4. Results: Thirty relapsed or refractory myeloma patients (table 1) were enrolled; two patients could not be evaluated because they were lost to follow-up. Of the remaining patients 19 are male, 9 are female. Median age of the patients were 61(49–78). Median number of prior therapies was 4 (1–11). 22 of 28 patients who had been evaluated were assessable for response according to the EBMT criteria (European Group for Blood and Marrow Transplantation criteria). One CR(3.6%), twelve immunofixation-positive CRs[nCR] (42.9%), six PRs(21.4%), and three MR (10.7%) were observed. All patients who had an objective response were alive as of this analysis. Nine patients died during follow-up. Mean response time (time to best response)for the 28 patients was 25 days. Most common Grade ≥3 toxicities (table 2) were peripheral neuropathy(3/28), thrombocytopenia (3/28), rash(one in 28 patients). Six patients(21.4%) suffered herpes after one or two cycles. Table 1. Patents and Disease Characteristics (N=28) No. % Abbreviations: Ig, immunoglobulin; Parameter 61 49–78 Age, years Median Range 19 Sex Male Female 9 Paraprotein type IgG IgA Light-chain only 18 β2..Cmicroglubulin, 3 64.3 10.7 Range 7 25.0 Prior treatments 1262–8691 Median 4 Range 1–11 Table 2. Treatment-emergent adverse events Total No. of patients with event(%) Adverse event 0 Hematologic Neutropenia No. with 3(10.7) grade ≥3 event Thrombocytopenia No. 0 with grade ≥3 event Anemia No. with 6(21.4) grade ≥3 event 5(17.8) Nonhematologic herpes Diarrhea 10(35.7) Fatigue Rash No. with 1(3.6) grade ≥3 event Tachycardia Peripheral 1(3.6) neuropathy Total No. No. 16(57.1) with grade ≥ 3 event 3(10.7) Conclusion: Bortezomib plus dexamethasone given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for multiple myeloma patients.

A Dose Escalation Study of Ibrutinib with Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1987-1987 ◽  
Author(s):  
Daniel A. Pollyea ◽  
Steven Coutre ◽  
Lia Gore ◽  
Nichole Adler ◽  
Pamela Harris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Bcr Signaling ◽  
Expansion Cohort

Abstract Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is dependent upon dysregulated signaling through the B-cell receptor (BCR) pathway. Bruton’s tyrosine kinase (BTK) mediates BCR signaling, and inhibition of BTK with ibrutinib, a selective, irreversible BTK inhibitor, is effective and well tolerated for patients (pts) with relapsed/refractory CLL/SLL. However, complete remissions (CRs) are infrequent, mechanisms of resistance to single-agent ibrutinib have been identified, and the duration of response beyond 3 years is unknown. Lenalidomide, a multi-functional immunomodulatory agent, is active in CLL/SLL, but limited by tumor flare reactions, which occur secondary to B-cell activation. Ibrutinib and lenalidomide modulate several key overlapping factors involving the CLL tumor microenvironment, and therefore a phase 1 combination study with lenalidomide dose escalation was undertaken. Methods: The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with ibrutinib. Secondary objectives included assessments of efficacy, PK/PD, and other mechanistic correlative studies. A 1-month (cycle 0) period of 420 mg of daily oral ibrutinib was administered as a single agent to decrease BCR signaling and mitigate lenalidomide-associated tumor flare. Beginning with the second month (cycle 1), ibrutinib was given concomitantly with lenalidomide. Four dose escalation cohorts of lenalidomide were planned using a 3+3 design; 2.5, 5, 7.5 and 10 mg. After the 2.5 mg cohort, intra-patient dose escalation was employed: in cohort 2, pts received 2.5 mg in week 1 followed by 5 mg subsequently; pts in cohort 3 received 2.5 mg in week 1, 5 mg in week 2 and 7.5 mg subsequently; pts in cohort 4 will receive 2.5 mg in week 1, 5 mg in week 2, 7.5 mg in week 3 and 10 mg subsequently. Ibrutinib was not dose escalated (420 mg). Pts receive 12 cycles of the combination, after which lenalidomide is discontinued and ibrutinib continues until unacceptable toxicity or disease progression. Eligible pts had relapsed/refractory CLL/SLL with adequate organ and bone marrow function. Pts who relapsed after stem cell transplantation were excluded. Results: To date, 11 pts were enrolled; 9 are evaluable (1 voluntarily withdrew consent prior to completing 3 cycles, the protocol-defined minimum to be evaluable, and 1 was a screen fail). The median age was 65 (49-81). Eight were male and 8 had CLL. Median Rai stage was 1 (1-4). The median number of prior therapies was 2 (range 1-8); 3 were purine analog resistant. Six had bulky (>5 cm) disease. Two had del(17p13.1) and 4 had del(11q22.3). The median number of cycles completed was 8 (range 1-13). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. Possibly related grade 1/2 AEs that occurred in >1 patient included: rash (n=4), muscle cramps (n=3) and abdominal discomfort (n=2). Possibly related grade 3 AEs included neutropenia (n=4), lymphocytosis (n=2), neutropenic fever (n=1), anemia (n=1) and thrombocytopenia (n=1). There was 1 possibly related grade 4 AE, neutropenia, which was pre-defined as DLT, in the 7.5 mg lenalidomide cohort. One patient experienced grade 2 tumor pain, thought to be due to a lenalidomide-associated tumor flare reaction. Four pts required a lenalidomide dose reduction, for neutropenia (n=2) and fatigue (n=2). Six required a treatment hold, of either lenalidomide or both agents, for a median 7 days (2-28), for neutropenia (n=2), anemia (n=1), fatigue/diarrhea (n=1), atrial fibrillation (n=1) and to obtain a lymph node biopsy (n=1). Lymphocytosis was noted in 5 pts, peaking at a median of 22.5 days. The ORR is 100% (9/9), with all responders experiencing PRs. One progressed with Richter’s transformation during cycle 7, 4 months after achieving a PR. All 9 remain alive with a median follow up of 263 days (range 97-391). The 7.5 mg dose cohort is currently being expanded to 6 pts; after the MTD is determined, a 10 patient dose expansion cohort will commence. Conclusions: Ibrutinib with lenalidomide appears to be well tolerated, although lenalidomide dose reductions were common. Tumor flare reactions were rare. Response assessments at higher dose cohorts of lenalidomide are ongoing. Completed phase 1 data, preliminary data from the expansion cohort and correlative findings will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for CLL/SLL. Byrd:Genentech: Research Funding; Pharmacyclics: Research Funding.

Impact of Therapy With Chlorambucil, Fludarabine, or Fludarabine Plus Chlorambucil on Infections in Patients With Chronic Lymphocytic Leukemia: Intergroup Study Cancer and Leukemia Group B 9011

2001 ◽  
Vol 19 (16) ◽  
pp. 3611-3621 ◽  
Author(s):  
Vicki A. Morrison ◽  
Kanti R. Rai ◽  
Bercedis L. Peterson ◽  
Jonathan E. Kolitz ◽  
Laurence Elias ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Single Agent ◽  
Initial Therapy ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Best Response ◽  
Stage Disease ◽  
Group B ◽  
Leukemia Group

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and χ2 tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P < .0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P = .055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P = .008 and P = .004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P = .02). Age was associated with incidence of major infection in the combination arm (P = .004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

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