scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

Flavopiridol Administered as a Pharmacologically-Derived Schedule Demonstrates Marked Clinical Activity in Refractory, Genetically High Risk, Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 341-341 ◽  
Author(s):  
John C. Byrd ◽  
Thomas S. Lin ◽  
James T. Dalton ◽  
Di Wu ◽  
Beth Fischer ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Opportunistic Infections ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Calf Serum ◽  
Potassium Phosphate ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Tumor Lysis

Abstract Flavopiridol is a broad cyclin dependent kinase inhibitor that induces p53/IL4 independent apoptosis in CLL cells. Despite potent pre-clinical activity, phase I/II studies of both a 24 and 72-hour continuous IV (CI) schedule demonstrated no activity in CLL or other cancers. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling from the Aventis-sponsored CI studies. This suggested optimal dosing would be a 30-minute IV bolus followed by 4-hour infusion. We report a mature phase I dose escalation study of flavopiridol with this schedule. We enrolled 23 pts (median age 61, range 44–84, 8 female) previously treated for CLL (median prior therapies 3, range 2–13) . At study entry, 21 pts had no response to their last therapy, 9 had intermediate risk disease, and 14 were stage III/IV. Pts received 50% of the flavopiridol dose IV over 30 minutes, the remaining 50% followed over 4 hours. This was repeated weekly 4 times on a 6-week cycle. Six pts in cohort 1 received 60 mg/m2/dose with 1 dose limiting toxicity (DLT, neutropenic fever) and 3 pts in cohort 2 received 80 mg/m2/dose. The maximally tolerated dose was exceeded in cohort 2. Acute tumor lysis syndrome (TLS) following the first flavopiridol dose was the DLT. One pt developed TLS that was controlled with aggressive medical management. The 2nd pt with TLS died with hyperkalemia before dialysis could be initiated, and on autopsy had extensive apoptosis/necrosis of diffuse intra-abdominal lymphadenopathy. No additional pts were treated at this dose, but a 3rd pt previously without TLS at the 80 mg/m2/dose developed TLS on day 1,cycle 2 at the 60 mg/m2 dose. An inpatient management plan to prevent further life-threatening TLS was initiated. We enrolled 14 additional pts. Several pts developed transient tumor lysis upon initial treatment, with increased serum potassium, phosphate, and LDH, but only 1 pt required temporary dialysis. Other manageable toxicities observed included neutropenia, anemia, thrombocytopenia, fatigue, nausea, diarrhea, and anorexia. Twenty-two patients have been followed long enough for NCI 96 response assessment. Nine pts achieved a PR (41%); 7 pts remain in remission (3–11+ months), and 2 pts relapsed at 7 and 12 months, respectively. Of the 9 responding pts, 8 were fludarabine refractory or intolerant, 8 had bulky LN (> 5cm), and 8 had del(11q) [n=6] or del(17p) [n=3] abnormalities. Additionally, opportunistic infections have not been noted to date. Eight of 9 responding pts with enlarged LN had a 50% reduction with the 1st treatment, compared to 2 of 10 who did not ultimately achieve a PR. The AUC of flavopiridol did not increase proportionally with dose, but pharmacologic data support our hypothesis that the clinical activity and toxicity of flavopiridol may be directly related to the Cmax, AUC, and Css. In summary, single agent flavopiridol given with this novel, pharmacologically modeled schedule has significant clinical activity in pts with fludarabine-refractory, genetically high-risk CLL. Further study of flavopiridol in CLL and other B-cell diseases using this pharmacokinetically modeled schedule is warranted.

Safety and Efficacy Results from a Phase I Trial of Single-Agent Lumiliximab (Anti-CD23 Antibody) for Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2503-2503 ◽  
Author(s):  
John C. Byrd ◽  
Susan O’Brien ◽  
Ian Flinn ◽  
Thomas J. Kipps ◽  
Mark A. Weiss ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Patient Characteristics ◽  
Outpatient Setting ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Treatment Regimens

Abstract The CD23 antigen is expressed at high density on the cell surface of certain B-cell malignancies, including chronic lymphocytic leukemia (CLL). Lumiliximab (L-mab), a macaque-human chimeric anti-CD23 monoclonal antibody, has been reported to have antitumor activity against CLL in preclinical studies. In this Phase I multicenter study, the safety, efficacy, and pharmacokinetics of single-agent L-mab were evaluated in 46 patients with relapsed or refractory CLL. Therapy consisted of intravenous L-mab given as 6 regimens: (1) 125 mg/m2/wk for 4 weeks; (2) 250 mg/m2/wk for 4 weeks; (3) 375 mg/m2/wk for 4 weeks; (4) 500 mg/m2/wk for 4 weeks; (5) 500 mg/m2 for 3 doses during Week 1, then 500 mg/m2/wk during Weeks 2 to 4; and (6) 500 mg/m2 three times a week for 4 weeks. Patient characteristics were as follows: median age of 62 years (range 47 to 80 years), 93% Caucasian, 72% male, 54% fludarabine-refractory, 48% Rai stage III/IV, and 78% WHO Performance Status 1. At study entry, patients had progressive CLL after 1 to 13 prior treatment regimens (median = 4 prior regimens). Antibody infusions, administered over 2 hours in an outpatient setting, were well tolerated. Study-related adverse events (probable, possible, or unknown relationship to study treatment) were reported in 40 of 46 patients (87%). The majority of events were Grade 1 or 2; the most common were headache, constipation, nausea, and cough. Grade 3 or 4 study-related adverse events were reported in 7 of 46 patients (15%) and included neutropenia and dyspnea. Evidence of clinical activity consisted of reductions in absolute lymphocyte counts (ALC) and lymphadenopathy. Decreases in ALC were observed in 42 of 46 (91%) patients, and decreases ≥ 50% were observed in 11 of 40 (28%) patients enrolled at 375 mg/m2/week or higher. Of 37 patients evaluated for change in lymphadenopathy, reductions were observed in 22 (59%). Flow cytometry revealed that L-mab saturated CD23 sites on CLL cells at doses above 375 mg/m2/week without down regulating CD23 expression. These results suggest that single-agent L-mab can be administered safely with evidence of clinical activity in patients with heavily pretreated CLL. Ongoing clinical studies are assessing the potential of L-mab in combination with rituximab and fludarabine-based chemotherapy.

scholarly journals Phase II Study of Flavopiridol in Relapsed Chronic Lymphocytic Leukemia Demonstrating High Response Rates in Genetically High-Risk Disease

2009 ◽  
Vol 27 (35) ◽  
pp. 6012-6018 ◽  
Author(s):  
Thomas S. Lin ◽  
Amy S. Ruppert ◽  
Amy J. Johnson ◽  
Beth Fischer ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Treatment Schedule ◽  
Genomic Features

PurposePatients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.Patients and MethodsPatients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.ResultsSixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P ≤ .01), resulted in improved tolerability and treatment delivery.ConclusionFlavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

A Phase I Open Label Dose Escalation Study To Evaluate MEDI-507 in Patients with CD2-Positive T-Cell Lymphoma/Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2727-2727 ◽  
Author(s):  
Deborah A. Casale ◽  
Nancy L. Bartlett ◽  
David D. Hurd ◽  
Francine Foss ◽  
Barbara Pro ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
T Cell Lymphoma ◽  
Cell Recovery ◽  
Open Label ◽  
Dose Escalation Study

Abstract This ongoing multicenter study is a Phase I trial with MEDI-507 (Siplizumab) [a humanized IgG1k class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells] to determine the maximum tolerated dose (MTD) or the optimum biologic dose (OBD) in patients with relapsed/refractory CD2-positive T-cell lymphoma/leukemia [CD2-positive adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and large granular lymphocytic leukemia (LGL).] Open label 3+3 dose escalation was conducted in which patients receive bi-weekly infusions of MEDI-507 over 3 consecutive days at total doses of 0.7 mg/kg, 3.4 mg/kg or 4.8 mg/kg. Predose and serial MEDI-507 pharmacokinetics (ELISA) at Visit 2 and anti MEDI-507 antibodies (ELISA), peripheral blood total T-Cell and CD2-positive T-cells (flow cytometry), and C3 and C4 complement are obtained for each patient. Patients are followed for one year after their last dose of MEDI-507 for tumor assessment and CD2-positive T-cell recovery. 16 patients have been enrolled: 3 (0.7 mg/kg); 9 (3.4); 4 (4.8). Three additional patients were added to the 3.4 mg/kg cohort to replace patients who progressed early and one patient with tumor lysis syndrome. Diagnoses of the 16 patients: PTCL (9), CTCL (6) and NK-LGL (1). Frequent adverse events reported, to date, are infusion reaction (7/16) patients; hypertension (4/16); lymphopenia (4/16); fatigue (4/16) and leukopenia (3/16). Two DLT’s have been observed. The first, erythematous confluent dermatitis, occurred in one patient at 3.4 mg/kg and the cohort was expanded with eventual dose escalation. The second, pulmonary edema, occurred in one patient at 4.8 mg/kg and the cohort is currently being expanded without further DLT identified to date. Two responses have been observed, one PR in an NK-LGL patient at 3.4 mg/kg and one CR in a PTCL patient at 3.4 mg/kg. MEDI-507 has been well tolerated and shown anti-tumor activity. Dosing will change to weekly dosing with dose escalation (3+3) starting at 1.2 mg/kg as 0.8 mg/kg was seen to be safe in the single center study. MTD and/or OBD have not been determined.

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3576-3576 ◽  
Author(s):  
Mohamad A. Hussein ◽  
James R. Berenson ◽  
Ruben Niesvizky ◽  
Nikhil C. Munshi ◽  
Jeffrey Matous ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Aseptic Meningitis ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Grade 3

Abstract SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

Phase 2 Trial of Intracycle Sequential Ofatumumab and Lenalidomide for the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3933-3933 ◽  
Author(s):  
Luciano J Costa ◽  
Suzanne Fanning ◽  
Joseph Stephenson ◽  
Lawrence Afrin ◽  
Tricia Bentz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Stable Disease ◽  
Nk Cell ◽  
Single Agent ◽  
Objective Response ◽  
Hiv Treatment ◽  
Lymphocytic Leukemia ◽  
Control Measures ◽  
High Rate ◽  
Hematological Toxicity

Abstract Abstract 3933 Background Ofatumumab is a novel fully humanized anti-CD20 monoclonal antibody with antigenic target distinct from rituximab and enhanced antibody dependent cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) with single agent activity in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including heavily pretreated patients. The immunomodulatory agent (IMID) lenalidomide has been shown to induce T cell and NK cell activation and in vitro enhances rituximab induced killing of B-CLL cells via NK cell-mediated and monocyte-mediated ADCC. We hypothesized that the sequential treatment of patients with ofatumumab and lenalidomide would provide optimal pharmacodynamic interaction and be active in R/R patients previously treated with rituximab containing regimens. Methods Eligibility criteria included confirmed diagnosis of R/R CLL meeting criteria for treatment, prior therapy containing rituximab, age≥ 18 years, ECOG performance status ≤ 2 adequate hepatic, renal and bone marrow function and willingness to comply with the required birth control measures. Patients were excluded if they had been previously exposed to any of the experimental agents, had active hepatitis B or carried HIV. Treatment consisted of ofatumumab 2000 mg (300 mg on the first cycle) intravenously on day 1 and lenalidomide 10 mg (5mg on the first cycle) on days 8–28. Treatment was administered for up to 6 cycles of 28 days duration. Patients received prophylaxis with acyclovir and trimethoprim + sulfamethoxazole. Toxicity was assessed according to CTC v.4.0 and response was evaluated following the 2008 National Cancer Institute Working Group criteria. Results Seventeen patients have been enrolled and 14 have sufficient follow-up to be assessed for response. Median age of patients was 65 years (range 51–80). Median number of prior lines of therapy was 2 (range 1–4) and median baseline white blood cell count was 75,000/mm3. The proportions of cases with unmutated IgvH chain and positive ZAP-70 expression were 15/17 (88%) and 13/16 (81%), respectively. There were 4/16 (25%) cases with del17p and 4/16 (25%) with del11q detected by fluorescence in situ hybridization (FISH). Thirteen cases (76%) were refractory to, or had relapsed after treatment containing a purine analogue. The most frequent adverse event (AE) > Grade 1 was tumor flare reaction (TFR), seen in 8/14 (57%) patients and infusion reactions seen in 6/14 (43%) patients. Four patients with TFR were managed successfully with non-steroidal anti inflammatory agents while 4 required glucocorticoids allowing continuation of therapy in all patients. The most common Grade 3+4 AE was neutropenia (11/14, 79%) although it was associated with infection in only 1 episode. One subject had early discontinuation due to toxicity (elevation in AST and ALT precluding further administration of ofatumumab). The majority of patients (11/14, 79%) required dose reduction or could not have the planned dose increase of lenalidomide after cycle 1 due to hematological toxicity. Overall 6/14 (43%) had objective response and 3/14 (21%) had stable disease for an overall clinical benefit in 64% of patients. All patients with TFR> Grade 1 had at least stable disease. Conclusion Intracycle sequential ofatumumab plus lenalidomide is well tolerated in advanced, high-risk CLL except for high rate of TFR and neutropenia without infection. Sequential ofatumumab and lenalidomide may be associated with higher rate of TFR than concomitant therapy. Approximately half the patients treated with this combination will obtain disease control. Further investigation is warranted in earlier lines and/or for more prolonged therapy. Disclosures: Costa: GSK: Research Funding. Off Label Use: Lenalidomide for treatment of CLL.

A Phase I Trial Of Anti-KIR Monoclonal Antibody IPH2101 and Lenalidomide For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3181-3181 ◽  
Author(s):  
Don M. Benson ◽  
Adam D Cohen ◽  
Craig C Hofmeister ◽  
Munshi C Nikhil ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Nk Cells ◽  
Nk Cell ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Low Grade ◽  
Dosing Interval ◽  
Infusion Reactions

Abstract Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if > 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin < 1.5 ULN, and ALT / AST < 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

Unexpected and Serious Toxicity Observed with Combined Idelalisib, Lenalidomide and Rituximab in Relapsed/Refractory B Cell Lymphomas: Alliance A051201 and A051202

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3091-3091 ◽  
Author(s):  
Sonali M. Smith ◽  
Brandelyn Pitcher ◽  
Sin-Ho Jung ◽  
Nancy L. Bartlett ◽  
Nina Wagner-Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Clin Oncol ◽  
Research Funding ◽  
Treatment Initiation ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Cell Transplant

Abstract Background: A number of targeted and orally available agents show promising activity in lymphoid malignancies, and a rational strategy is to evaluate combinations for safety and efficacy. Idelalisib (idela) is a highly specific and potent inhibitor of the delta isoform of PI3K, downstream of B-cell receptor signaling and upstream of other survival pathways in lymphoma. Idela has single agent activity in both follicular lymphoma (FL) and mantle cell lymphoma (MCL), with response rates over 50% (N Engl J Med. 2014;370:1008). Idela and rituximab (ritux) have been safely combined in chronic lymphocytic leukemia (N Engl J Med. 2014;370:997) and other indolent lymphomas. Two previous Cancer and Leukemia Group B and Alliance studies demonstrated high levels of clinical activity of lenalidomide (len) and ritux in combination without significant toxicity. In relapsed/refractory FL, len plus ritux had higher overall (ORR) and complete response (CR) rates (75% ORR, 32% CR) versus len alone (49% ORR, 13% CR)(J Clin Oncol. 2012;30(suppl; abstr 8000). In frontline FL, len plus ritux achieved 93% ORR and 72% CR rates (J Clin Oncol 32:5s, 2014 (suppl; abstr 8521). A051201 and A051202 were designed to evaluate the safety and activity of len and ritux, in combination with idela, in pts with relapsed MCL or FL, respectively. Methods: Both A051201 and A051202 are phase I trials with 3+3 designs and pre-specified dose-limiting toxicities (DLT). Treatment in the two trials was similar but not identical. A051201 started with len 15mg po day (d) 1-21 q28d idela 150mg bid with continuous 28-d cycles, and ritux weekly during cycle 1. A051202 started with len 10mg po d1-21 q28d and idela 150mg po bid with continuous 28-d cycles, and ritux on C1d8, C1d15, C1d22 and C2d1. Both studies included a maintenance component (data not presented). Biweekly conference calls for safety were established. After 3 patients (pts) from A051202 and 1 pt from A051201 developed severe and unexpected DLT, both trials were suspended and modified. Results: At the time of study suspension, 7 FL pts and 1 MCL pt had been enrolled. Pt characteristics include median age 58.5 years (y) (range, 47-77), 5 male/3 female, and median 1 (range, 1-7) prior treatment; all pts had prior ritux. The MCL pt had an autologous stem cell transplant 3 y prior to enrollment. This pt had a DLT consisting of grade (gr) 4 AST/ALT elevation in the setting of fevers, chills, hypotension at 22 d after treatment initiation. 3 FL pts had DLT consisting of gr 3 lung infection, gr 3 hypotension and rash, and gr 4 sepsis syndrome (culture-negative), respectively. Each of the 3 FL pts with DLT developed fevers and hypotension with or without a rash 11-17 d after treatment initiation and within 24-120 hours of last ritux exposure; 2 pts had pulmonary infiltrates. 3 DLT pts required ICU level support. Other notable toxicities in all 8 pts include gr 1/2 AST/ALT elevation (n=5), gr 3 lymphopenia (n=5), gr 1/2 thrombocytopenia (n=4), grade1/2/3 neutropenia (n=4). Conclusion: Whereas doublet therapy with len/ritux and idela/ritux has been safely combined in other trials and disease settings, we observed 4 DLTs among the first 8 pts, all concerning for high-level immune activation. Although the mechanism of these toxicities is unknown, the combination of rash, fevers, and hypotension is suggestive of cytokine release syndrome (CRS), which is a known but uncommon IL-6-mediated event seen with ritux, rarely reported after single agent len, and, to date, not observed with idela. Our observation of 4 potential CRS-like reactions among 8 pts suggests an additive and previously undescribed risk of this combination. Based on the severe toxicities noted, both trials have been amended to remove ritux and pursue a phase I safety assessment of idela and len without ritux in pts with relapsed FL or MCL. Disclosures Smith: Celgene: Consultancy, Research Funding; Gilead: Consultancy; Genentech: Consultancy, DSMB for another compound, DSMB for another compound Other. Off Label Use: Phase I results of combined idela/len and rituximab. Bartlett:Gilead: Consultancy, Research Funding; Celgene: Research Funding. Wagner-Johnston:Gilead: Consultancy; Celgene: Research Funding. Richards:Genentech: Consultancy; Celgene: Honoraria. Cashen:Celgene: Speakers Bureau. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Leonard:Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy.

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