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.

Phase I Study of Intravenous PI3K Inhibitor Bay 80–6946: Preliminary Activity in Patients with Relapsed Non-Hodgkin Lymphoma (NHL) Treated in an MTD Expansion Cohort

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3704-3704 ◽  
Author(s):  
Amita Patnaik ◽  
Ramesh K Ramanathan ◽  
Leonard Joseph Appleman ◽  
Anthony W Tolcher ◽  
James M Mountz ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Clin Oncol ◽  
Research Funding ◽  
Single Agent ◽  
Pi3k Inhibitor ◽  
Pharmacokinetic Parameters ◽  
Clinical Activity ◽  
18Fdg Pet ◽  
Expansion Cohort

Abstract Abstract 3704 Background: BAY 80–6946 is a potent and highly selective, reversible, pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor, with broad antitumor activity in a panel of preclinical models including both indolent and aggressive NHL. Even in the absence of PIK3CA mutations, the PI3 pathway has been demonstrated to be constitutively activated in the majority of B-cell lymphomas. BAY 80–6946 was more potent than CAL-101 in inhibiting the in vitro growth of a panel of leukemia/lymphoma cell lines. Methods: In a phase I dose escalation study, BAY 80–6946 was previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg (MTD) on days 1, 8 and 15 every 28 days (J Clin Oncol 29: 2011 suppl; abstr 3035). Additional patients were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected patient populations, including one expansion cohort in NHL. Based upon the beneficial clinical responses observed in 5 follicular lymphoma (FL) patients (J Clin Oncol 30: 2012 suppl; abstr 3019), the NHL cohort was expanded up to a total of 12 patients. Samples were collected for pharmacokinetic analyses. Exploratory analyses of changes in several plasma proteins, chosen with emphasis on B-cell homing/survival, were performed. Response was assessed using International Working Group response criteria, including 18FDG-PET. Results: To date, 9 NHL patients have been enrolled (FL, n=6, DLBCL, n=3). There were 5 females/4 males with a median age of 72 years (range, 40–84). Among these 9 patients, 5 (56%) had received 3 or more prior regimens. All have received prior Rituximab and 6/9 prior anthracycline and 4/9 prior Bendamustine. Eight patients were evaluable for safety and tolerability. The most frequently drug-related adverse events reported in >20% of the patients were hyperglycemia, nausea, diarrhea, anemia, mucositis, and fatigue. Interstitial pneumonitis was observed in 2 patients with FL. Both patients responded to corticosteroids and one continued on treatment at full dose without recurrence of the pneumonitis. The pharmacokinetic parameters of BAY 80–6946, including the Cmax and AUC, were consistent with those seen in solid tumour patients. Changes in the plasma levels of CXCL13 and BAFF were observed in subjects treated with BAY 80–6946. Median time on study was 129 days (3–487). Best response in 6 evaluable patients (FL, n=5, DLBCL, n=1) was 5 PR and 1 PD, all 5 evaluable FL patients achieving a PR, the longest of which is >16 months. Pharmacodynamic effects were demonstrated with significant lymphoma shrinkage observed as early as 48 hours after the first dose of BAY 80–6946 on 18FDG-PET/CT in both FL and DLBCL patients. Conclusions: In this MTD expansion cohort study in NHL lymphoma, BAY 80–6986 was generally well tolerated and showed very promising clinical activity in NHL patients. Updated clinical, PK and pharmacodynamic results will be presented. Based on these preliminary results, further clinical development as a single agent or in combination regimens in NHL is warranted. Disclosures: Patnaik: Bayer: Research Funding. Ramanathan:Bayer: Research Funding. Appleman:Bristol-Myers: Research Funding; Bayer Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Abbott: Research Funding; Cougar Biotechnology/Ortho Biotech: Research Funding; Medivation: Research Funding; Excelixis: Research Funding. Beerham:Bayer: Research Funding. Weiss:Bayer: Honoraria; Roche/Ventana: Honoraria; Merrimack: Honoraria; Cephalon: Honoraria; Eli Lilly: Honoraria; Cytrx: Consultancy; Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Caris Life Sciences: Speakers Bureau; Bayer: Research Funding. Rajagopalan:Bayer Pharmaceuticals: Employment. Jeffers:Bayer Pharmaceuticals: Employment. Kelly:Bayer Pharmaceuticals: Employment. Genvresse:Bayer Pharma AG: Employment.

Phase I Trial of Sphingosomal Vincristine (SV, Marqibo®) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4539-4539
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Leonard Heffner ◽  
Wendy Stock ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Dose Intensity ◽  
Complete Response ◽  
Antifungal Prophylaxis ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Pulse Dexamethasone

Abstract Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (Thomas et al., Cancer106:1641, 2006). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.

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.

Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4528-4528
Author(s):  
Richard Sposto ◽  
Elizabeth A. Raetz ◽  
Charles P. Reynolds ◽  
Paul S. Gaynon
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Phase I Trials ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a > 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia. Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity. Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time. Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.

A Phase II Trial of Ofatumumab In Subjects with Waldenstrom's Macroglobulinemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1795-1795 ◽  
Author(s):  
Richard R. Furman ◽  
Herbert Eradat ◽  
Julie C. Switzky ◽  
Suzanne R. Hayman ◽  
Craig C. Hofmeister ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Rapid Rise ◽  
Grade 3

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3252-3252 ◽  
Author(s):  
Shyamala C. Navada ◽  
Guillermo Garcia-Manero ◽  
Francois Wilhelm ◽  
Katherine Hearn ◽  
Rosalie Odchimar-Reissig ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Stable Disease ◽  
Blood Count ◽  
Single Agent ◽  
Complete Response ◽  
Leukemic Cells ◽  
Cell Transplant ◽  
Transfusion Requirements ◽  
Count Recovery

Abstract Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML. Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards. Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone. Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination. Table Patient ID Diagnosis Prior HMA % Blasts in BM at Baseline % Blasts in BM after Treatment IWG Response 1 MDS No 2 1 CRi 2 AML No 40 0 CRi 3 AML No 22 N/A NE 4 MDS Azacitidine 0 0 NE 5 AML No 59 N/A NE 6 MDS No 21 <5 CRi 7 MDS No 2 1 CR 8 MDS No 2.5 2 SD 9 AML Decitabine 25 N/A NE 10 MDS Decitabine 12 3 CRi 11 CMML Azacitidine 2 3 SD 12 MDS Azacitidine 4 1 HI-E 13 AML Azacitidine 47 40 TE 14 AML Decitabine 7 7 TE 15 MDS No 9 5 TE 16 AML No 25 6 TE 17 AML No 15 19 TE 18 AML Azacitidine 64 45 TE IWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early Disclosures Wilhelm: Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.

Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1528-1528 ◽  
Author(s):  
Wojciech Jurczak ◽  
Pier Luigi Zinzani ◽  
Gianluca Gaidano ◽  
Andre Goy ◽  
Mariano Provencio ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Cd20 Antibody ◽  
Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting CD19, in subjects with relapsed or refractory advanced B-cell malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8065-8065 ◽  
Author(s):  
Trishna Goswami ◽  
Andres Forero ◽  
Mehdi Hamadani ◽  
Anne Sonet ◽  
Gregor Verhoef ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
B Cell ◽  
Transmembrane Protein ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Antibody Targeting

8065 Background: Novel B-cell targeting agents, including monoclonal antibodies such as rituximab, are among recent advances in treatment of B-cell malignancies. New approaches are needed for patients progressing after rituximab-based therapies. MEDI-551 is an afucosylated monoclonal antibody targeting CD-19, a B-cell restricted transmembrane protein with enhanced affinity and antibody-dependent cellular cytotoxicity. Methods: Pts with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, or multiple myeloma received single agent MEDI-551 at dosages ranging from 0.5 mg/kg to 12 mg/kg via intravenous infusion over 28-day cycles; cohorts 1-6 received 0.5, 1, 2, 4, 8, and 12 mg/kg, respectively. Results: 25 pts were enrolled in the phase I portion Jun 2010–Aug 2011. No maximum tolerated dose (MTD) was achieved. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Six pts had grade 3 toxicities including tumor lysis syndrome, infusion reaction, thrombocytopenia, and neutropenia, or grade 4 neutropenia. No grade 5 AEs were seen. All pts recovered. Three partial responses (PR) and 2 complete responses (CR) were seen in DLBCL and FL pts at 0.5, 4, and 8 mg/kg. Activity included a CR lasting 9 mo. in a FL pt in cohort 1, who is currently being retreated with MEDI-551 on relapse. Conclusions: MEDI-551 demonstrated a safety profile warranting further study and showed no MTD reached at the highest dose studied. Anti-tumor activity is suggested by the responses achieved across dose levels. Phase II is currently enrolling subjects. This study is funded by MedImmune, LLC. [Table: see text]

Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8073-TPS8073 ◽  
Author(s):  
Francis Guerra-Bauman ◽  
Betsy LaPlant ◽  
William R. Macon ◽  
Thomas E. Witzig ◽  
Umar Farooq ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Phase 2 ◽  
Overall Response ◽  
Lymphoma Therapy

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

scholarly journals Statins Potentiate the Cytotoxic Effect of ABT-199 in Diffuse Large B Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3969-3969
Author(s):  
David A. Fruman ◽  
Jong-Hoon Scott Lee ◽  
Thanh-Trang T Vo ◽  
Shruti Bhatt ◽  
Jonathan H. Schatz ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Lymphoma Cells ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract BCL-2 is a key pro-survival protein that is highly expressed in many leukemias and lymphomas. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2 that has demonstrated impressive responses in chronic lymphocytic leukemia (CLL) leading to FDA approval for second line treatment of patients with 17p deletion. However, other hematologic malignancies are less responsive to ABT-199 as a single agent, suggesting that combinations of targeted therapies may be required to elicit more promising responses. We have investigated the potential of combining ABT-199 with HMG-CoA reductase (HMGCR) inhibitors (statins), which have known anti-cancer potential in hematologic malignancies. Using multiple chemically distinct statin compounds, we observed profound synergistic induction of apoptosis when combined with ABT-199 in both human diffuse large B cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML) cell lines. This synergy was also seen in primary murine B lymphoma cells over-expressing MYC and BCL-2. Importantly, addition of exogenous mevalonate completely rescued cells from the combination, confirming on-target efficacy of HMGCR inhibition. Using BH3 profiling, we found that simvastatin significantly primed lymphoma cells for undergoing apoptosis (termed mitochondrial priming). Notably, the degree of priming correlated with its ability to synergize with ABT-199, suggesting that BH3 profiling may be used to predict patient responses. The combination did not synergize to kill normal human peripheral blood mononuclear cells from healthy donors, suggesting that statins may selectively prime cancer cells for apoptosis. Mechanistic studies support the hypothesis that statins synergize with ABT-199 by suppressing protein prenylation, particularly protein geranylgeranylation. In support, the addition of exogenous geranylgeranyl pyrophosphate (GGPP) completely rescued cells from the effects of simvastatin. Furthermore, selective inhibition of protein geranylgeranyl transferase (GGT) increased priming and was sufficient to recapitulate the effects of simvastatin in combination with ABT-199. Statins and GGT inhibitors increased the mitochondrial abundance of a subset of BH3-only pro-apoptotic proteins. Lastly, we have identified Rap1A de-prenylation as a marker of pharmacodynamic response to statins in vivo. Thus, this project highlights a novel combination for use in aggressive lymphomas, establishes its efficacy and tolerability using preclinical models, and provides proof-of-concept to warrant investigation of its clinical potential. Disclosures Letai: AbbVie: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

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