scholarly journals 8MO CC-90010, a reversible, potent oral bromodomain and extraterminal inhibitor (BETi) in patients (pts) with advanced solid tumours (aSTs) and relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): Longer follow-up from parts A & B and first reporting of part C of a phase I study

2021 ◽  
Vol 32 ◽  
pp. S5
Author(s):  
V. Moreno ◽  
M. Vieito Villar ◽  
J.M. Sepulveda Sanchez ◽  
V. Galvao ◽  
T. Hernández Guerrero ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Solid Tumours ◽  
Part C ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Safety, Pharmacokinetics, and Preliminary Clinical Activity of Inotuzumab Ozogamicin, a Novel Immunoconjugate for the Treatment of B-Cell Non-Hodgkin's Lymphoma: Results of a Phase I Study

2010 ◽  
Vol 28 (12) ◽  
pp. 2085-2093 ◽  
Author(s):  
Anjali Advani ◽  
Bertrand Coiffier ◽  
Myron S. Czuczman ◽  
Martin Dreyling ◽  
James Foran ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Inotuzumab Ozogamicin ◽  
Large B Cell Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Large B Cell

Purpose Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22+ B-cell non-Hodgkin's lymphoma (NHL). Patients and Methods Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m2. Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m2. Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. Conclusion Inotuzumab ozogamicin has demonstrated efficacy against CD22+ B-cell NHL, with reversible thrombocytopenia as the main toxicity.

scholarly journals Valproate in Combination with Rituximab and CHOP As First Line Therapy in Diffuse Large B-Cell Lymphoma (VALFRID): Preliminary Results from a Phase I Trial with a Dose Expansion Cohort

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3939-3939
Author(s):  
Kristina Drott ◽  
Hans Hagberg ◽  
Thomas Relander ◽  
Cecilia Graffman ◽  
Johan Drott ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dose Finding ◽  
Large B Cell Lymphoma ◽  
Cd20 Expression ◽  
Expansion Cohort ◽  
Large B Cell

Abstract Rationale: The anticonvulsant valproate is an HDAC inhibitor, which has in vitro been shown to sensitize lymphoma cell lines for CHOP chemotherapy, and to upregulate CD20 expression. Based on these findings, we initiated a dose finding trial of valproate in combination with R-CHOP in primary treatment of diffuse large B-cell lymphoma (DLBCL), including a dose expansion cohort. Methods: Eligibility criteria were: age 18-80 years, histologically confirmed (according to the WHO classification) diffuse large B-cell lymphoma stage II-IV, WHO performance status 0-2. R-CHOP was given at standard dose in 14 or 21 day cycles, 6 cycles. Valproate was given in escalating doses days 1-3, starting at 10 mg/kg every 8 hrs, by a standard 3+3 design. Prednisone was given days 1-5, R-CHOP on day 3. Response was evaluated according to the Lugano criteria. Results: In the phase I portion, the MTD of valproate was established as 20 mg/kg every 8 hrs (total 60 mg/kg). At a dose of 80 mg/kg, 2 of 3 patients experienced tinnitus (grade 1 and 2) during the latter part of the treatment course. At a dose of 100 mg/kg, 1 of 5 patients developed hearing impairment, grade 1, after 3 cycles, which worsened to grade 2 after 4 cycles, leading to omission of valproate. By August 1, 2015, 28 patients have been included, of which 17 in the dose finding portion. The median age is 69 years (range 47-78). According to the IPI, 43, 36 and 21% were low, low-intermediate and high intermediate/high risk, respectively. Apart from the auditory adverse effects presented above, toxicity was comparable to that of standard R-CHOP, without any impact on hematological toxicity. Presently, 17 patients are evaluable for response after 6 cycles VR-CHOP, ORR 17/17 CR 15/17 (88%). After a median time of follow-up of 16 months, median PFS has not been reached, and estimated PFS at 18 months is 77%. One patient has died due to progressive lymphoma, 21 months after inclusion. By flow cytometry of fine needle aspirates from lymphoma lesions before and after 3 days of valproate, we could show significant upregulation of CD20 expression in 3 patients. Conclusions: Sensitization to rituximab and CHOP by pretreatment with an HDAC inhibitor is a novel therapeutic strategy for the treatment of DLBCL. At a dose of 60 mg/kg, divided into 3 doses, the combination of valproate with R-CHOP is feasible in 1st line treatment of DLBCL. Higher doses of valproate was associated with intolerable auditory side effects. Early data show promising efficacy, which may form the basis for a randomized phase III trial. The long-term efficacy of this regimen remains to be established by longer follow-up. Disclosures Drott: Respiratorius: Membership on an entity's Board of Directors or advisory committees. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL. Drott:Respiratorius: Employment. Off Label Use: Valproate for treatment of diffuse large B-cell lymphoma..

scholarly journals Phase I Study Combining Ibrutinib with Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE) in Patients with Relapsed or Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL): NCI-Cancer Therapeutics Evaluation Program (CTEP) #9588

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4198-4198 ◽  
Author(s):  
Craig S. Sauter ◽  
Stephanie L. Verwys ◽  
Susan J. McCall ◽  
Shoshana T. Miller ◽  
Amanda I. Courtien ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Fdg Pet ◽  
Phase I Study ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: In the post-rituximab era, half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response with standard salvage therapy, and are thus ineligible to proceed to consolidative autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, predominately of the non-germinal center B-cell (non-GCB) phenotype, with minimal toxicity. This single center, NCI-CTEP sponsored phase I study is the first to evaluate the combination of ibrutinib with standard salvage therapy of rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in transplant-eligible rel/ref DLBCL patients. Methods: Patients with rel/ref DLBCL, including transformed B-cell non-Hodgkin lymphoma, are eligible for study. The phase I study design is a standard 3 x 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 mg (DL #2) and 840 mg (DL #3) on days 1-21 with standard dosing of R-ICE for 3 cycles, every 21 days. The primary objective is to determine safety and the maximum tolerated dose (MTD) of ibrutinib in combination with R-ICE. Secondary objectives include response rate according to computed tomography (CT) and functional imaging (FDG-PET) per Deauville criteria. Results: To date, 16 patients are evaluable for toxicity, and 15 are evaluable for response. The median age of the 16 evaluable patients is 51 years (range 19-75 years). Histologies of the patients evaluable for response are: GCB DLBCL n=3, non-GCB DLBCL n=4, primary mediastinal large B-cell lymphoma n=4, and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (tCLL/SLL) n=4. There were no dose-limiting toxicities (DLTs) seen at DL #1 (n=3), 2 (n=3), or 3 (n=10, currently in expansion). Of the 16 patients evaluable for toxicity, 15 experienced expected and transient grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. The median number of cumulative platelet transfusions per patient for 3 cycles was 2 (range 0-11). Eleven of the 15 patients evaluable for response underwent chemotherapy-primed CD34+ hematopoietic progenitor cells (HPCs) apheresis procedures on study; 10 of the 11 patients successfully collected HPCs with a median of 5.6 x 106CD34+/kg (range 1.7-8.6). The only patient that failed to collect HPCs was an HIV-positive patient at DL #3 in the setting of febrile illness. One patient experienced grade 3 atrial fibrillation/flutter and was subsequently removed from study per treating physician's decision. Per CT criteria, five patients achieved complete remission (CR), eight patients achieved partial remission (PR), and two patients had stable disease for an overall response rate of 87%. All eight patients with non-GCB DLBCL and tCLL/SLL that were evaluable for response achieved chemosensitive remission per CT criteria (CR=4, PR=4). Seven of the 15 total patients (47%) evaluable for response achieved a complete metabolic remission (Deauville 1-3) per FDG-PET, including all 4 patients of non-GCB phenotype. Conclusions: Currently, no DLTs have been observed with ibrutinib at dosing up to 840 mg daily in combination with R-ICE. We are currently expanding DL #3. Manageable and expected hematologic toxicities have been observed. Importantly, hematologic toxicity has not resulted in failure to complete protocol therapy on-schedule or mobilize HPCs. Encouragingly, 87% of patients achieved a CT response (CR/PR) and 47% of patients achieved a complete metabolic remission per FDG-PET, including 100% of patients with non-GCB phenotype. These results compare favorably to historic cohorts. Given the safety and efficacy observed in this phase I, later phase studies for this treatment program are warranted. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Phase I/II Trial of Vorinostat (SAHA) in Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0806

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3931-3931 ◽  
Author(s):  
Daniel O. Persky ◽  
Hongli Li ◽  
Lisa M. Rimsza ◽  
Paul M. Barr ◽  
Leslie L. Popplewell ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Loss of major histocompatibility Class II antigens (MHCII) in diffuse large B-cell lymphoma (DLBCL) is associated with a decreased CD8+ tumor-infiltrating T-lymphocyte (TIL) response and poor patient survival. Transcription of the MHCII gene complex is under the control of the master transactivator, CIITA, which in part is regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor vorinostat with standard chemotherapy will enhance MHCII expression and improve patient outcome in DLBCL. Methods: SWOG S0806 was a phase I/II open label trial of vorinostat given at 400 mg po daily on days 1-9 (subsequently reduced to days 1-5) combined with Rituximab-CHOP (R-CHOP) at standard doses, given on day 3 of a 21-day cycle for 8 cycles. Eligibility criteria included having newly diagnosed advanced stage DLBCL, international prognostic index (IPI) of at least 1, and lack of known CNS involvement or HIV. Primary endpoint of phase I was to establish maximum tolerated dose (MTD) of vorinostat with standard R-CHOP. Primary endpoint of phase II was to estimate 2-year progression free survival (PFS). Translational endpoints included correlation of pre-treatment acetylation status of histones, expression of MHCII genes, and percentage of TIL to PFS; and correlation of cytokine profile to response and outcomes. Results: Phase I was open in 5 SWOG institutions and enrolled 11 patients. There were only 2 patients who had dose limiting toxicities in the first cycle - grade 3 febrile neutropenia and grade 4 hypokalemia - allowing phase II to proceed with the original vorinostat dosing of 400 mg daily days 1-9, at all SWOG institutions. However, excess rates of febrile neutropenia and sepsis were seen upon further follow up, and the study was amended to reduce the duration of vorinostat to days 1-5. A total of 72 patients were enrolled in phase II, of which 8 were ineligible and 2 withdrew consent prior to treatment. For the remaining 62 patients, median age was 64 years, 92% had stage III/IV disease, 39% B symptoms, 61% elevated LDH, 39% had more than 1 extranodal site of involvement, with IPI breakdown of 13/26/47/13/2%. Notable grade 3-4 non-hematologic toxicities included febrile neutropenia (39%), sepsis (18%), fatigue (15%), hypokalemia (11%), hyponatremia (10%), and small bowel perforation (3%). Grade 3-4 hematologic toxicities included neutropenia (60%), anemia (35%), and thrombocytopenia (35%). There was one death in phase I from sepsis and multi-organ failure at the end of 8 cycles of treatment, but no deaths from toxicity in phase II. Overall response rate was 81% (95% CI: 69-90%). With median follow-up of 24.3 months, estimate of 2-year PFS is 72% (95% CI: 58%, 81%) and of 2-year OS is 85% (95% CI: 74%, 92%). Analysis of the panel of 30 cytokines performed on matched serum specimens of 40 patients showed correlation of baseline elevated IL-2R levels with worsened PFS and OS, and correlation of decrease in Epidermal Growth Factor level with improved PFS and OS. Results of immunohistochemical stains for expression of MHCII genes and percentage of TIL will be reported at the meeting. Conclusions: The regimen of vorinostat-R-CHOP achieved 2-year PFS estimate of 72%, which is slightly more than 68% expected from R-CHOP alone per IPI adjusted historical rate, but less than an IPI adjusted target of 78% that would be sufficient to warrant further investigation. It also resulted in unexpected excess rates of febrile neutropenia and sepsis. This regimen cannot be recommended for the broad DLBCL population. Current studies are focused on finding biomarkers of response to histone deacetylase inhibitors. Disclosures Persky: Gilead Sciences, Inc: Speakers Bureau. Off Label Use: vorinostat in diffuse large B-cell lymphoma. Barr:Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

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