Phase I Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1704-1704 ◽  
Author(s):  
Gilles Salles ◽  
Franck Morschhauser ◽  
Thierry Lamy ◽  
Noel Milpied ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Single Agent ◽  
Treatment Phase ◽  
End Of Treatment ◽  
Cd20 Antibody ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 1704 Poster Board I-730 Background RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In vitro data show GA101 exhibits increased antibody-dependent cytotoxicity (ADCC) and strongly enhanced direct cell death compared to rituximab. Methods In this first Phase I study, GA101 was administered i.v., as a single agent to patients with CD20+ NHL for whom no therapy of higher priority was available. On days 1, 8 and 22 and subsequently every 3 weeks for a total of 9 infusions, flat doses between 50 mg to 2000 mg were given in a safety-driven, dose escalation, 3 × 3 design. The aim was to determine the safety, tolerability, dose-limiting toxicity (DLT), and the pharmacokinetics of GA101. Preliminary phase I data were reported on the first 12 NHL patients (Salles et al, ASH 2008). Here, we present the definitive results of this phase I on 21 NHL patients. Their median age was 64 yrs (39-83) with the following histologies: follicular (n = 13), mantle cell (n = 4), and diffuse large B-cell, Waldenstrom's macroglobulinemia, small lymphocytic, lymphoplasmocytoid (1 each). Patients had previously received a median of 4 (range 1-7) prior regimens [time from last treatment to study entry 12 months], with 95% of patients exposed to prior rituximab and 10/21 (48%) of patients with prior stem cell transplantation. Results GA101 was well tolerated with no DLTs, no dose reductions and no GA101-related Grade 4 toxicities (CTCAE V3.0). Four patients experienced at least one SAE. The most common adverse events were Grade 1 or 2 infusion related reactions essentially limited to the first infusion. Tumor lysis syndrome (Grade 3) was observed in 1 patient. Related Grade 3 hematological toxicities were neutropenia (n = 2; no G-CSF required), anemia (1) and thrombocytopenia (1) and 11/21 patients reported Grade 1-2 infections. No significant change in complement fractions (C3, C3a, C4a, C5, C5a, Bb) was observed. Measurement of plasma cytokines during and immediately after the 1st infusion showed an increase in IL6 and IL8 with a smaller increase in IL10, TNFa and IFN-γ, with recovery by Day 8. Median T-cell (CD3, CD4 and CD8) sub-sets and NK counts were low in all patients prior to therapy. Concurrent to cytokine increase, a further decrease in these lymphocyte sub-sets was observed after the first infusion, recovering thereafter, with median values returning to baseline values by end of treatment. In contrast, B-cell (CD19+) depletion was rapid and sustained in the majority of patients \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(1921\) \end{document}. End of treatment B-cell recovery has been observed in 3 of the responding patients [recovery ranging from 410-532 days after first dose]. No significant changes from baseline immunoglobulin levels were observed. GA101 pharmacokinetics were characterized by two clearance components, one linear component and one time-dependent saturable component consistent with target-mediated disposition, also observed with rituximab. Whilst the plasma concentrations demonstrate a dose-dependent increase, there was significant inter- and intra-patient variability. The time-dependent clearance component is consistent with a reduction in target-mediated antibody clearance with increasing duration of treatment. Responses occurred at all dose levels, and across all FcγIIIRA (158F/V polymorphism) genotypes, with best overall response of 5 CR/CRu, 4 PR (ORR=43%) (all responding patients had histology of fNHL, their median measurable baseline lesions=3295mm2, and 6 patients had prior ASCT), 5 SD, 6 PD & and 1 non-evaluable (premature death unrelated to GA101). Of those 9 responses, 8 responses occurred during the treatment phase. One of the responding patients progressed during the treatment phase and in the follow-up phase one patient with a CR progressed after responding for 5.5 months. Six patients have an ongoing response [4 CR, 2 PR] [response duration ranging from 7.5+ to 17+ months] and in addition, one patient with SD has converted to PR in the follow-up phase [SD for 17 months and PR for 4+ months]. Conclusion GA101 is a next generation anti-CD20 antibody that has shown promising efficacy in this difficult-to-treat patient population. GA101 is currently being explored as a single agent in phase II in relapsed/refractory indolent/aggressive NHL and B-CLL and in combination with chemotherapy in a phase Ib study. Disclosures Salles: Roche: Honoraria. Morschhauser:Roche: Honoraria. Bieska:Roche: Employment. Carlile:Roche: Employment. Cartron:Roche: Honoraria.

Results of A Phase I Study of Milatuzumab, a Humanized Anti-CD74 Antibody, and Veltuzumab, a Humanized Anti-CD20 Antibody, In Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3707-3707
Author(s):  
Beth Christian ◽  
Lapo Alinari ◽  
Jeffrey A. Jones ◽  
Don M Benson ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
Prior Therapy ◽  
Infusion Reactions ◽  
Cd20 Antibody ◽  
Grade 3 ◽  
Anti Cd20 ◽  
Dose Levels

Abstract Abstract 3707 Background: Preclinical studies conducted at our institution (Alinari et al. Blood. 2011;117:4530–41) demonstrated superior efficacy of milatuzumab (Immunomedics, Inc.), a humanized anti-CD74 antibody, in combination with rituximab in vitro and in an in vivo preclinical model of mantle cell lymphoma (MCL), compared to either agent alone. Veltuzumab (Immunomedics, Inc.), a humanized anti-CD20 antibody, has been reported to have several advantages over rituximab including slower off-rates, shorter infusion times, higher potency, and improved therapeutic responses in animal models. As a result of the anti-tumor activity observed in vitro with combined veltuzumab and milatuzumab, we initiated a phase I/II trial in pts with relapsed or refractory B-cell NHL after at least 1 prior therapy to determine the safety, tolerability, and overall response rate with this combination. Methods: Pts received veltuzumab 200 at mg/m2 weekly combined with escalating doses of milatuzumab at 8, 16, and 20 mg/kg twice per wk of wks 1–4, 12, 20, 28, and 36. All pts received premedication with acetaminophen, diphenhydramine, hydrocortisone 50 mg, and famotidine prior to veltuzumab and milatuzumb doses. Dose limiting toxicity (DLT) was defined during weeks 1–4. Although not defined as DLT, 3 of the first 6 pts enrolled at dose levels 1–2, had significant grade 3 infusion reactions with milatuzumab. The study was amended to separate veltuzumab and milatuzumab dosing days and add 20 mg dexamethasone immediately prior to and 10 mg post-milatuzumab. Enrollment resumed with 3 additional pts at dose levels 1 and 2 in order to determine if tolerability was improved. Results: The phase I study has completed enrollment with 18 pts (follicular NHL grade 1–2 n=5; grade 3 n=5; transformed follicular n=1; diffuse large B-cell lymphoma (DLBCL) n=4; marginal zone lymphoma (MZL) n=1; MCL n=1; and lymphoplasmacytic lymphoma n=1) that have completed at least 4 weeks of combination therapy. Median age was 65 years (range 44–81), and pts received a median of 3 prior therapies (range 1 – 9), including 3 pts who had undergone prior autologous stem cell transplant. Ten of 18 (56%) pts were refractory to rituximab defined as having less than a partial response to the last rituximab-containing regimen. No DLTs were observed, and no pts experienced grade 3 infusion reactions after the protocol was modified. Other grade 3–4 toxicities at least possibly related to protocol therapy consisted of lymphopenia (n=8, 44%), fatigue (n=2, 11%), neutropenia (n=1, 6%), hyperglycemia (n=1, 6%), and anemia (n=1, 6%). Grade 1–2 infections (n=5, 27%) included thrush, sinusitis, and pneumonia with no pts requiring dose delays or hospitalization. Other frequently observed grade 1–2 toxicities were transient hyperglycemia (n=12, 66%), thrombocytopenia (n=11, 61%), reversible infusion reactions (n=9, 50%), fatigue (n=8, 44%), leukopenia (n=8, 44%), and anemia (n=7, 39%). Human anti-veltuzumab and anti-milatuzumab antibodies, collected pretreatment and day 1 of weeks 4, 12, and 36, have not been detected in any pt. Pharmacokinetic data available from 16 pts through week 10 indicated mean plasma veltuzumab and milatuzumab concentrations immediately post-infusion were 108 ± 7 and 296 ± 22 μg/mL, and mean trough levels were 47 ± 7 and 3 ± 0.3 μg/mL, respectively. All 18 pts were assessable for response at wk 5 with 5 pts currently remaining on active therapy and 4 pts completing treatment through wk 36. To date, complete response was observed in 1 pt with grade 1–2 follicular NHL (3 prior therapies) who was rituximab-refractory and ultimately underwent allogeneic transplant. Partial responses were observed in 3 pts; 2 with grade 3 follicular NHL refractory to rituximab (3 prior therapies including autologous transplant and 5 prior therapies, respectively) and 1 with MZL (1 prior therapy). All responding pts achieved response following induction therapy. Stable disease was observed in 10 pts; of these pts, 6 pts had SD of a median duration of 6 months (range 2.5–10 months) and 4 remain on active therapy. Conclusions: Combination therapy with veltuzumab and milatuzumab was well-tolerated in a population of heavily pre-treated pts with relapsed or refractory NHL. 14/18 pts had evidence of antitumor activity with 22% having an objective overall response, including rituximab-refractory pts. Disclosures: Christian: Immunomedics, Inc.: Research Funding. Off Label Use: Veltuzumab and milatuzumab in non-Hodgkin's lymphoma is off-label drug use. Wegener:Immunomedics, Inc.: Employment, Management and Stock / Stock-options. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Phase I Study of PRO131921, a Novel Anti-CD20 Monoclonal Antibody in Patients with Relapsed/Refractory CD20+ Indolent NHL: Correlation Between Clinical Responses and AUC Pharmacokinetics.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3742-3742 ◽  
Author(s):  
Jonathan W. Friedberg ◽  
Julie M. Vose ◽  
Brad S Kahl ◽  
Mark W. Brunvand ◽  
Andre Goy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Drug Exposure ◽  
Single Agent ◽  
Dose Cohort ◽  
Clinical Responses ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 3742 Poster Board III-678 PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody engineered to have significantly increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab as shown in in vitro models. In preclinical in vivo lymphoma models, PRO131921 has superior anti-tumor efficacy compared to rituximab. In this Phase I study, PRO131921 was administered as a single agent to patients (pts) with CD20+, relapsed or refractory indolent non-Hodgkin's lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The aim of the study was to determine the safety and tolerability of PRO131921, the maximum tolerated dose (MTD), its pharmacokinetics (PK), and to establish a Phase II dose. Pts were treated with PRO131921 by intravenous infusion (premedication with acetaminophen and anti-histamine) weekly for 4 weeks on days 1, 8, 15 and 22. The dose of the first infusion was approximately 50% that of subsequent infusions. The dose was escalated based on safety in a 3+3 design. PK samples were obtained pre- and post-infusion on days 1, 8, 15, and 22, and once each on days 2, 23, 29, 50, and 78 (and at later time points for up to a year). Twenty-four pts were treated with PRO131921 at doses from 25 mg/m2 to 800 mg/m2. Median age was 58 yrs (38-78). Histologies were follicular NHL (n=20), small lymphocytic lymphoma (n=3) or marginal zone NHL (n=1). Pts had received a median of 2 (range 1-6) prior regimens. PRO131921 was generally well-tolerated and no MTD was reached in the study. The most common adverse events were Grade 1 or 2 (CTCAE V3.0) chills, flushing, itching, fatigue, fever, nausea, dizziness, diarrhea, and hypotension, most of which were part of infusion-related reactions limited in general to the first infusion. These responded well to slowing or interruption of the infusion, and symptomatic treatment (including steroids). Grade 3 AEs (related and unrelated to study drug) included 3 episodes each of transient neutropenia and hypoxia, and single episodes of throat tightness, bronchospasm, syncope, fatigue, periarthritis, pneumonia, and deep venous thrombosis. There was 1 unrelated Grade 4 pulmonary embolism. Two pts did not receive all 4 doses of therapy due to DLTs. One dose limiting toxicity (DLT) was observed in the 200/400 mg/m2 dose cohort due to a significant infusion reaction, and a second was observed at the 300/800 mg/m2 dose cohort due to Grade 3 joint pain and fatigue after 2 infusions. Detailed PK studies of PRO131921 in all patients were broadly similar to rituximab with a dose-dependent increase in exposure, but with significant inter- and intra-patient variability. Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and both tumor shrinkage (p=0.049) and clinical response (p=0.034), consistent with the hypothesis that rapid drug clearance (e.g. by tumor in excess of drug) may result in decreased clinical efficacy. Best investigator-assessed responses to treatment in the 22 evaluable pts by day 78 or later were 6 PR, 13 SD, and 3 PD; 5/10 pts in the two highest dose cohorts responded. In conclusion, PRO131921 has shown clinical activity in rituximab-relapsed and refractory indolent NHL pts. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy. Disclosures: Friedberg: Genentech, Inc.: Honoraria, Research Funding. Vose:Genentech, Inc.: Consultancy, Research Funding. Kahl:Genentech, Inc.: Consultancy, Research Funding. Brunvand:Genentech, Inc.: Speakers Bureau. Goy:Genentech/Biogen IDEC: Consultancy, Speakers Bureau. Kasamon:Genentech/Biogen IDEC: Research Funding. Burington:Genentech, Inc.: Employment. Li:Genentech, Inc.: Employment. Ho:Genentech, Inc.: Employment. Cheson:Genentech, Inc.: Consultancy, Speakers Bureau.

Phase I Study of RO5072759 (GA101) in Relapsed/Refractory Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 884-884 ◽  
Author(s):  
Franck Morschhauser ◽  
Guillaume Cartron ◽  
Thierry Lamy ◽  
Noel-Jean Milpied ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Time Dependent ◽  
T Cell Subsets ◽  
Cell Counts ◽  
End Of Treatment ◽  
Grade 3

Abstract Abstract 884 Background: RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In vitro, GA101 exhibits increased antibody-dependent cytotoxicity (ADCC) and strongly enhanced direct cell death compared to rituximab. Methods: A Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), and pharmacokinetics of GA101 given as a single agent to patients with CD20+ B-CLL for whom no therapy of higher priority was available. A flat, intravenous dose ranging from 400 mg to 2000 mg was given in a safety-driven, dose escalating, 3 × 3 design on days 1, 8 and 22 and subsequently every 3 weeks for a total of 9 infusions. Here, we present the phase I data on 13 B-CLL patients, 33% [9/13 evaluable] with high risk cytogenetics (17p or 11q) and 70% [7/10 evaluable] displaying unmutated IgVH status, who received a median of 3 [1-8] prior regimens, including fludarabine (13/13) and rituximab-containing therapy, (8/13). Baseline median hematology parameters included hemoglobin 12.6 g/dL [9.4 -14.9], WBC 51.8 × 109/L [10-124], platelets 191 × 109/L [48-404], lymphocytes 47.4 × 109/L [7.0-119.3]. Results: GA101 was well tolerated with no DLTs and no dose reductions. The most common adverse events were Grade 1 or 2 infusion related reactions essentially limited to the first infusion. GA101-related Grade 3/4 hematological toxicities included transient neutropenia (n=9), febrile neutropenia (n=1) and transient thrombocytopenia (n=1). Neutropenia recovered spontaneously or with G-CSF. SAEs were reported in 3 patients (febrile neutropenia, thrombocytopenia, bronchitis, gingivitis, neutropenia and tumor lysis syndrome). Ten patients had infections (17 episodes with only three being Grade 3). No significant changes to baseline immunoglobulin levels were observed. Measurement of plasma cytokines during and immediately after the 1st infusion showed a transient increase in IL6 and IL8 with smaller increases in IL10, IFN-γ and TNFa. Activation of complement was not observed (C3a, C4a, C5a). Concurrent to cytokine increase was a decrease in T-cell subsets and NK cell counts (peripheral blood) after the first infusion. At the end of treatment, CD3 and CD8 counts had recovered while median CD4 and CD16/56 counts remained just below the normal range, with no clinical sequelae observed. Immunologic monitoring is ongoing. B-cell (CD19+) depletion was almost complete for all 13 patients and sustained following the first infusion. Best overall response rate according to IWCLL criteria was 62% (8/13) with 1 CRi, 7 PR and 5 SD observed across all FcγIIIRA [158F/V polymorphism] genotypes with no clear dose relationship established. Responses are ongoing with durations ranging from 3.5+ to 8+ months. End of treatment minimal residual disease (MRD) from 7/11 evaluable patients was detectable for 6 patients (median reduction of 2 log, range 2-4) and negative for one (despite a stable disease, as assessed by CT-scan). GA101 pharmacokinetics were characterized by one linear and one time-dependent saturable clearance components, consistent with target-mediated disposition, which is also observed with rituximab. Whilst the plasma concentrations demonstrate a dose-dependent increase, there was significant inter and intra-patient variability. Time-dependent clearance is consistent with a reduction in target-mediated antibody clearance with increasing duration of treatment. With the same doses of GA101, clearance is faster in B-CLL patients than NHL patients (Salles et al ASH 2008, 2009). Conclusion: These phase I results indicate that GA101 has promising activity when given as single agent to heavily pre-treated B-CLL patients and has a similar safety profile to that observed in NHL patients (Salles et al, ASH 2008, 2009) with an increased incidence of transient neutropenia in B-CLL. GA101 is currently being explored as a single agent in phase II in relapsed/refractory B-CLL and indolent/aggressive NHL and in combination with chemotherapy in a phase Ib study. Disclosures: Morschhauser: Roche Products Limited : Honoraria. Cartron:Roche Products Limited : Consultancy, Honoraria. Milpied:Roche Products Limited : Honoraria. Weisser:Roche Diagnostics : Employment. Birkett:Roche Products Limited : Employment. Salles:Roche Products Limited : Honoraria.

Multicentre Phase I Study with an 8-Dose Regimen of Single Agent Anti-CD20 Monoclonal Antibody LFB-R603 in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2862-2862 ◽  
Author(s):  
Bruno Cazin ◽  
Stéphane Leprêtre ◽  
Bertrand Coiffier ◽  
Thérèse Aurran ◽  
Guillaume Cartron ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Stable Disease ◽  
Dose Regimen ◽  
Phase I Study ◽  
Single Agent ◽  
Safety Data ◽  
Advanced Stage ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 2862 Background: LFB-R603 is a next generation anti-CD20 monoclonal antibody (mAb) with an optimised glycosylation profile resulting in high antibody-dependent cellular cytotoxicity. A weekly × 4 dose regimen of LFB-R603 has been found to induce rapid, profound and sustained blood lymphocyte depletion in patients (pts) with advanced stage CLL in a multicentre first-in human dose-escalation phase I study*. Aims: A second part of the phase I study designed to evaluate a weekly × 8 dose regimen was initiated in April 2010. Objectives were to assess the safety, pharmacokinetics and potential efficacy of LFB-R603 in pts with CLL relapsing after at least one prior course of therapy with fludarabine. Methods: Twelve pts were included. A flat dose of LFB-R603 was administered once a week for 8 weeks consisting of an initial dose of 150 mg followed by 7 doses of 450 mg (total dose 3300 mg). Premedication consisted of allopurinol, dexchlorpheniramine and acetaminophen, combined with methylprednisolone 1mg/kg before the first two infusions. Results: Median age was 69.5 years [62–77], median time from diagnosis to inclusion was 10.4 years [4.0–23.6], number of prior therapies was 3 [1–8]. Seven pts received at least one prior rituximab-containing regimen (median number was 1 [1–3]). Two pts presented with 17p deletion. Bulky (>5cm) lymph node enlargement was observed in 4 pts, splenomegaly in 9 pts, and hepatomegaly in 4 pts. Median WBC count at baseline was 48.5×109/l [9.9–154.2], hemoglobin 11.9 g/dl [7.3–14.0] and platelets 102×109/l [13–193]. Median lymphocyte bone marrow infiltration was 85% [40–94]. Pharmacokinetic (PK) data showed an increase of mean Cmax, AUC¥ and t1/2 term from the first to the eighth infusion from 23.4 to 220.5 mg/L, 732 to 50, 760 mg.h/L, and 13.4 to 147.8 h, respectively whereas mean CL decreased from 424 to 38.6 mL/h. Median lymphocyte counts and relative circulating lymphocyte depletions from baseline at D8, D29, M2, M 4, and M 6 are presented in the table below. Response was evaluated at month 4 according to updated NCI-WG guidelines. Among 11 evaluable pts, overall response rate was 45% (5/11) corresponding to 5 pts in durable partial response (PR). Two additional pts were in PR at month 4 not confirmed 2 months later and 4 pts were in stable disease. Pts with 17p deletion and/or bulky tumor were in stable disease. All pts but one received the planned 8 infusions without any dose reduction. One patient was prematurely withdrawn from the study due to a concomitant secondary leukemia diagnosed after the 2nd infusion of LFB-R603. Interim safety data indicate that all pts presented with at least one drug-related adverse event (AE). Forty percent of the AEs were related to the first infusion, 18% to the second, and 21% to the subsequent infusions. The most frequent (> 10%) drug-related AEs were infusion related reactions (IRR) (75% of the pts, including 33% of pts with grade 3 (CT-CAE v3.0) IRR), neutropenia (58%; 33% with grade 3 and 25% with grade 4), grade 1–2 pyrexia (42%), grade 1–2 thrombocytopenia (42%), grade 1–2 infections (25%), chills (17%), asthenia (17%), and grade 3 hepatic cytolysis (17%). One pt experienced a grade 4 drug-related pancytopenia. All AEs were reversible spontaneously or with supportive care intervention. Conclusion: LFB-R603 induces a promising 45% of ORR in pts with advanced stage CLL at a relatively low dose regimen. PK data indicates that the dose and the schedule of administration could be optimized. Toxicity of LFB-R603 is manageable and makes possible a combination with chemotherapy. Disclosures: Cazin: LFB Biotechnologies: Honoraria. Leprêtre:LFB Biotechnologies: Honoraria. Coiffier:LFB Biotechnologies: Honoraria. Cartron:GSK: Honoraria; Roche: Consultancy, Honoraria; LFB: Honoraria. Sadoun:LFB Biotechnologies: Employment. Segaud:LFB Biotechnologies: subcontractor. Ribrag:LFB Biotechnologies: Honoraria, Research Funding.

A Phase I Trial of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Combination with Rituximab (R) and Bendamustine in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1643-1643 ◽  
Author(s):  
Kristie A. Blum ◽  
Beth Christian ◽  
Joseph M. Flynn ◽  
Samantha M. Jaglowski ◽  
Jeffrey Alan Jones ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Irreversible Inhibitor ◽  
Grade 3 ◽  
Dose Reductions

Abstract Abstract 1643 Introduction: Ibrutinib is an orally available, irreversible inhibitor of BTK, a downstream protein in the B-cell receptor signaling pathway critical for normal B-cell development. In a phase I study in patients with relapsed B-cell malignancies (Fowler ASH 2010), the overall response rate (ORR) was 43%, with responses observed in patients with relapsed mantle cell (MCL), diffuse large B-cell (DLBCL), follicular (FL), and marginal zone lymphoma (MZL). In a phase II single agent study in MCL (Wang ASH 2011), ORR was 67% with several responding patients remaining on ibrutinib over 1 year. Rituximab (R) and bendamustine is a highly active regimen with ORR ranging from 52–92% in patients with relapsed/refractory NHL. This phase I study was designed to determine the maximum tolerated dose, dose limiting toxicity (DLT), toxicities, and preliminary efficacy of R-bendamustine in combination with ibrutinib in patients with relapsed/refractory NHL. Methods: Eligibility included patients with relapsed/refractory FL, MZL, MCL, transformed NHL, and DLBCL, and patients with previously untreated MCL not candidates for autologous stem cell transplantation (ASCT). ANC ≥1000/mm3, platelets ≥50,000/mm3, and creatinine ≤ 2.0 mg/dL were required at study entry. Prior ASCT, rituximab, bendamustine, and ibrutinib were permitted. Treatment consisted of R 375 mg/m2 day 1, bendamustine 90 mg/m2days 1 and 2, and escalating doses of ibrutinib (280 mg or 560 mg) days 1–28 every 28 days for 6 cycles. Six patients were enrolled at each dose level. Responding patients could continue ibrutinib alone after cycle 6 until disease progression or unacceptable toxicity. Pegfilgrastim was permitted for patients with grade 4 neutropenia during cycles 1–6. Response was assessed after cycles 3 and 6 by International Harmonization Criteria (Cheson, JCO 2007). Results: Eleven patients (9 males) with a median age of 72 (range 45–84) previously treated with a median of 3 prior therapies (range 0–10) were enrolled. Six patients were refractory to their most recent therapy, 4 patients had prior ASCT, 2 patients had received prior bendamustine, and no patients had prior ibrutinib. Other characteristics included stage III-IV disease in 82%, extranodal involvement in 64%, elevated IPI ≥3 in 55%, bulky adenopathy ≥5 cm in 45%, B-symptoms in 45%, and elevated LDH in 36%. Histologies included MCL (n=3), DLBCL (n=3, all germinal center origin by Hans immunohistochemical criteria), transformed NHL (n=2), FL (n=2), MZL (n=1). Nine patients completed two or more cycles of therapy (median 3, range 1–6) with 280 mg of ibrutinib (n=6) and 560 mg of ibrutinib (n=3). Two patients who discontinued therapy prior to completing cycle 1 for progressive disease (PD) at 280 mg and 560 mg of ibrutinib, respectively, were replaced. Six patients continue to receive protocol treatment. The 5 patients off study included the 2 patients with DLBCL and transformed NHL who were replaced for PD prior to completing cycle 1, 2 patients with DLBCL and PD after cycles 3 and 4, and 1 patient with MCL receiving 280 mg ibrutinib with R-bendamustine who discontinued due to grade 3 neutropenia lasting > 14 days after cycle 4. No DLTs have been observed. Grade 3–4 events included lymphopenia (64%), neutropenia (27%), thrombocytopenia (18%), pancreatitis (9%), vomiting (9%), shingles (9%), and rash (9%). Dose reductions from 280 mg ibrutinib to 140 mg were required in 3 patients for grade 3 thrombocytopenia, pancreatitis, and rash. Bendamustine dose reductions to 60 mg/m2were required in 1 patient for grade 3 thrombocytopenia. ORR was 38% in 8 evaluable patients, with 3 patients currently receiving protocol treatment who have not yet undergone restaging scans. Responses included 2 complete responses and 1 partial response in the 3 patients with MCL. Conclusions: Combined ibrutinib with R-bendamustine appears well tolerated without unexpected toxicity and with preliminary activity in patients with previously untreated and relapsed MCL. Three additional patients will be accrued to the 560 mg dose level and expansion cohorts examining this combination specifically in patients with FL, DLBCL, and MCL are planned. Disclosures: Blum: Pharmacyclics: Research Funding. Off Label Use: Ibrutinib is not approved for the treatment of NHL. Jaglowski:Pharmacyclics: Research Funding. Maddocks:Pharmacyclics: Research Funding. Byrd:Pharmacyclics: Research Funding.

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.

scholarly journals Adverse Events in Clinical Trials of Ibrutinib and Acalabrutinib for B-Cell Lymphoproliferative Disorders: A Systematic Review and Network Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-23
Author(s):  
Talal Hilal ◽  
William B Hillegass ◽  
Miguel Gonzalez-Velez ◽  
Jose F. Leis ◽  
Allison C. Rosenthal
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Meta Analysis ◽  
Significant Difference ◽  
Prospective Trials ◽  
Btk Inhibitor ◽  
Cd20 Antibody ◽  
Grade 3 ◽  
Anti Cd20

Introduction: Bruton tyrosine kinase (BTK) inhibitors are a class of drugs that inhibit B-cell receptor (BCR) and are increasingly used in B-cell lymphoproliferative neoplasms, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia. Ibrutinib, a first-generation BTK inhibitor has been associated with increased risk of cardiovascular adverse events (AEs), including atrial fibrillation (AF), hypertension (HTN) and bleeding. These unique AEs are thought to be due to off-target effects. Acalabrutinib, a second-generation BTK inhibitor is characterized by less off-target effects, and is thought to be associated with a decreased risk of cardiovascular and other AEs. However, a head to head comparison of ibrutinib and acalabrutinib has not been conducted. Herein, we conducted a systematic review and network meta-analysis of AEs from prospective clinical trials of ibrutinib and acalabrutinib in B-cell lymphoproliferative disorders to compare their safety profile. Methods: We searched PubMed, Embase, Scopus, and Web of Science from database inception through November 15th 2019. Only full-text articles were included. Other inclusion criteria included prospective trials (single arm or randomized) with ibrutinib, ibrutinib plus anti-CD20 antibody, or acalabrutinib as investigational agents. Trials investigating BTK inhibitor plus chemotherapy were excluded. When updated results of prospective trials were available, data were extracted from the most recent publication with the longest follow-up. Reports of 17 AEs of interest, including number of events (any grade and grade 3 or higher) were documented. Rate of discontinuation was investigated. Results: Twenty-seven prospective clinical trials, 12 multicenter single-arm, 9 multicenter randomized, 5 single center single-arm, and 1 single center randomized, were included. Data from 29 study arms including 3207 patients were analyzed in 3 groups - ibrutinib, ibrutinib plus anti-CD20 antibody, and acalabrutinib with augmented Bayesian network meta-analysis and meta-regression implemented in R including packages gemtc and rjags. The most common any grade AEs (>20%) with ibrutinib were diarrhea (46%, 95% CI 36-55%), myalgias/arthralgias (37%, 95%CI 28-46%), fatigue (33%, 95% CI 24-42%), cough (26%, 95% 17-36%), anemia (23%, 95% 15-30%), thrombocytopenia (22%, 95% 15-30%), and pyrexia (21%, 95% 13-30%). The most common any grade AEs with acalabrutinib were headache (37%, 95%CI 26-48%), diarrhea (30%, 95% 20-41%), peripheral edema (21%, 95% 15-28%), fatigue (20%, 95% 11-29%), and myalgias/arthralgias (16%, 95% 8-24%). The most common any grade cardiovascular AEs with ibrutinib were bleeding/bruising (32%, 95% 23-41%), HTN (23%, 95% 15-32%), AF (9%, 95% 3-15%). The most common any grade cardiovascular AEs with acalabrutinib were bleeding/bruising (41%, 95% CI 30-52%), and HTN (6%, 95% 1-11%). The rate of AEs with ibrutinib compared to ibrutinib plus anti-CD20 antibody were similar so the data was pooled. Of all AEs of interest, there was a significant difference in any grade AEs favoring ibrutinib for headache (12% vs. 37%), and infections (35% vs 57%). There was a significant difference in any grade AEs favoring acalabrutinib for myalgias/arthralgias (16% vs. 37%), anemia (6% vs. 23%), thrombocytopenia (5% vs. 22%), and HTN (6% vs. 23%). After adjusting for median follow-up and age, there was no significant difference in rates of bleeding/bruising and any grade infections between ibrutinib and acalabrutinib. However, there was a significant difference favoring acalabrutinib for any grade HTN (OR 0.26, 95% CI 0.17-0.40) p<0.0001, grade 3 HTN (OR 0.15, 95% 0.08-0.27) p<0.0001, any grade AF (OR 0.35, 95% 0.18-0.66), p=0.0012, grade 3 AF (OR 0.04, 95% 0.01-0.25) p=0.0009, and grade 3 infections (OR 0.62, 95% 0.46-0.85),p=0.003. Conclusions: Acalabrutinib appears to have an overall improved safety profile compared to ibrutinib. This is particularly true for anemia, thrombocytopenia, and cardiovascular AEs, including AF and HTN. Figure 1 Disclosures No relevant conflicts of interest to declare.

Final Results Of a Phase I Study Of The Anti-CD22 Antibody-Drug Conjugate (ADC) DCDT2980S With Or Without Rituximab (RTX) In Patients (Pts) With Relapsed Or Refractory (R/R) B-Cell Non-Hodgkin’s Lymphoma (NHL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4399-4399 ◽  
Author(s):  
Ranjana Advani ◽  
Andy I. Chen ◽  
Daniel Lebovic ◽  
Mark W. Brunvand ◽  
Andre Goy ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase I ◽  
B Cell ◽  
Median Time ◽  
Research Funding ◽  
Phase I Study ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Antibody Drug

Abstract Background DCDT2980S (DCDT) is an anti-CD22 monoclonal antibody (Ab) conjugated to MMAE, a potent anti-microtubule inhibitor. We have previously reported clinical activity and acceptable toxicity in pts with R/R B-cell NHL treated at DCDT doses of 1.8 and 2.4 mg/kg. The maximum tolerated dose (MTD) was defined as 2.4 mg/kg either as a single agent or in combination with RTX (375 mg/m2) every 21 days (q21d) (Advani et al. ASH 2012, abstract 59). In this report, we provide updated results from pts treated at 1.8 mg/kg as well as an expanded cohort treated at 2.4 mg/kg. Methods We evaluated safety, tolerability, pharmacokinetics (PK), and activity of DCDT q21d with or without RTX (375 mg/m2) in pts with R/R B-cell NHL. Expanded cohorts of pts with R/R diffuse large cell lymphoma (DLBCL) or indolent (i)NHL were evaluated at the single-agent MTD of 2.4 mg/kg q21d. Results Forty-six pts enrolled in DCDT ≥ 1.8 mg/kg (7 at 1.8 mg/kg, 39 at 2.4 mg/kg) and 16 in the DCDT+RTX cohort (5 at 1.8 mg/kg, 11 at 2.4 mg/kg). Median age was 66 yrs; 92% had an ECOG PS<2; median of 3 prior regimens (range 1-11); 100% prior RTX, 8% prior stem cell transplant. Patients received a median of 5 cycles (range 1, 24) of DCDT and 6 cycles (range 1, 15) of DCDT + RTX; 7 patients continue to receive study treatment. The DCDT+RTX safety profile did not differ from DCDT monotherapy and toxicities were mostly Grade 1-2. Grade ≥ 3 treatment-emergent adverse events (TEAEs) in ≥5% of pts included neutropenia (26%), hyperglycemia (10%), peripheral sensory neuropathy (10%), fatigue (5%), and diarrhea (5%). Febrile neutropenia and Grade 3-4 infection occurred in 1 pt and 7 pts respectively. The median time to first onset peripheral neuropathy (PN) was 50 days. Worsening PN (at least one grade increase) occurred in 18/33 pts (55%) with median time to worsening of 48 days. PN was managed with dose delays and dose reductions resulting in complete reversal in 5 (15%) pts. Serious AEs were seen in 37% of pts, the most common (≥ 3 pts) included pyrexia (3), pneumonia (3) and dyspnea (3). Treatment discontinuations for AEs were reported in 16 (26%) pts including 12 for peripheral neuropathy. Twenty-four pts (39%) had at least one dose delay including 10 for neutropenia and 5 for peripheral neuropathy. Twelve pts (19%) had at least one dose reduction including 8 for peripheral neuropathy and 7 for neutropenia. Three deaths occurring within 60 days of the last dose of DCDT judged unrelated to DCDT were reported. Exposure of Ab-conjugated (ac) MMAE, total Ab, and unconjugated MMAE increased with dose. Maximal concentrations of unconjugated MMAE were >100-fold lower than acMMAE with average Cycle 1 value of 5-7 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Concurrent RTX administration did not impact DCDT PK. Overall objective responses were observed in 19/46 (41%) DCDT and 5/16 (31%) DCDT+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows: The median PFS for DLBCL patients treated with DCDT or DCDT + RTX was 115 days. The median PFS for iNHL patients treated with DCDT or DCDT + RTX was 227 days. Conclusions DCDT alone or combined with RTX was generally well-tolerated. PN and neutropenia are the principal toxicities associated with DCDT. PN was reversible in some patients with dose delays and reductions. Encouraging antitumor activity was observed in heavily pre-treated pts with R/R NHL. Updated results from this Phase I study will be presented. The addition of rituximab does not appear to enhance the efficacy of DCDT based on the small number of patients treated with the combination and continues to be evaluated in an ongoing randomized Phase II study in patients with R/R DLBCL and FL of DCDT+RTX versus a CD79b-directed ADC (DCDS4501A) with the same linker-cytotoxic agent. Additional studies of DCDT combined with immunochemotherapy are planned. Disclosures: Advani: Genentech, inc.: Research Funding. Off Label Use: Anti-CD22 Antibody-Drug Conjugate. Chen:Genentech, inc.: Consultancy, Research Funding. Lebovic:Genentech, inc.: Speakers Bureau. Brunvand:Genentech, inc.: Speakers Bureau. Goy:Genentech, inc.: Research Funding. Chang:Genentech, inc.: Research Funding. Hochberg:Genentech, inc.: Consultancy. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Olivia Campagne ◽  
Tong Lin ◽  
Haitao Pan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Pi3k Pathway ◽  
Neurosurgical Procedures ◽  
Common Grade ◽  
Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

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