Evidence of Clinical Activity in a Phase 1 Study of CAL-101, An Oral P110Δ Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase, in Patients with Relapsed or Refractory B-Cell Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 922-922 ◽  
Author(s):  
Ian W Flinn ◽  
John C. Byrd ◽  
Richard R Furman ◽  
Jennifer R Brown ◽  
Don M Benson ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Response ◽  
Dose Escalation ◽  
Phase 1 ◽  
Clinical Activity ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
Drug Concentrations ◽  
Dose Levels ◽  
Phosphatidylinositol 3

Abstract Abstract 922 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate a variety of cellular functions relevant to oncogenesis, including metabolism, proliferation and survival. The PI3K p110Δ isoform is primarily expressed in cells of hematopoietic origin and plays a key role in normal B cell maturation and function. CAL-101 is an oral, potent inhibitor of PI3K p110Δ (IC50 of 2.5 nM against purified enzyme and EC50 of 65 nM in a whole blood basophil assay) with 40 to 300-fold selectivity compared to other PI3K isoforms. This selectivity may provide a better therapeutic index relative to pan-PI3K inhibitors. In vitro studies of 0.1 to 10 uM CAL-101 showed inhibition of AKT phosphorylation and/or apoptotic effects against primary chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) cells and against a range of leukemia, lymphoma and multiple myeloma (MM) cell lines. Methods and Patients: A Phase 1 study was undertaken to evaluate the safety and clinical activity of CAL-101 in patients with select hematologic malignancies. During initial dose escalation, sequential cohorts of 3 patients with relapsed/refractory CLL or select B-cell non-Hodgkin's lymphoma (NHL) were enrolled to determine dose limiting toxicity (DLT). During subsequent cohort expansion, approximately 12 patients each with CLL, indolent NHL, aggressive NHL, and AML were to be enrolled. CAL-101 was administered orally twice daily (BID) continuously for 28 days per cycle. Clinical response was evaluated at the end of Cycles 1 and 2 and every 2 cycles thereafter. Results: To date, 43 patients have been enrolled and followed for at least 4 weeks, consisting of 17 patients with CLL, 9 patients with indolent NHL, 10 patients with aggressive NHL and 7 patients with AML. The demographic and disease characteristics were 33% female, mean age 65 (60% over age 65), 49% had refractory disease and the median number of prior regimens was 5. During dose escalation (n=12), 3 patients per cohort were administered dose levels of 50 mg, 100 mg, 200 mg or 350 mg BID. In cohort expansion 31 patients were enrolled to either 200 mg (n=17) or 350 mg (n=14) BID. The median duration of treatment at data cutoff was 3 cycles (range 1 to 10). Two patients discontinued early due to adverse events, one for acute on chronic renal failure and one for abnormal liver function tests (LFTs). DLTs were observed in 5 patients with increases in LFTs, which resolved following discontinuation of CAL-101 dosing. No patient had Grade 4 hematological toxicity. Serious infections were reported in 9 patients, with pneumonia being the most frequent. 41 patients were evaluable for clinical response. At data cutoff, the response rate in NHL was 10/18 (56%); all were partial responses (PR). Of the 9 patients with indolent NHL, 5 patients had PR and 2 patients had stable disease (SD) and remained on study. Of the 9 patients with aggressive NHL, 5 patients had PR (all with mantle cell lymphoma) and 1 patient had SD on study. Of the 17 patients with CLL, 6 patients had PR and 7 other patients had >50% reduction in lymphadenopathy and concurrent increase in peripheral blood lymphocytosis to >50% of baseline, suggesting compartmentalization shift of CLL cells. Lymphocytosis was maximal during the first 2 cycles and decreased thereafter. This effect of dislocating CLL cells from the tissue microenvironment suggests that CAL-101 treatment in combination with cytotoxic agents may be particularly active. Of the 6 patients with AML, no patient had responded and 2 patients remained on study. Clinical responses were observed in patients at all 4 dose levels administered. At data cutoff, the longest duration of response was 9 months in a patient with follicular lymphoma, which was longer than the response to any of the 6 prior regimens this patient received, including autologous hematopoietic stem cell transplant. Plasma exposure increased from 50 mg to 200 mg, without further change at 350 mg. At the 200 mg and 350 mg dose levels, mean peak and trough drug concentrations at the end of Cycle 1 were 5 uM and 1 uM, respectively. Enrollment in cohort expansion is continuing with the addition of patients with MM and updated data will be presented at the meeting. Conclusions: Interim results from the first Phase 1 study to evaluate an oral PI3K p110Δ inhibitor, CAL-101, show promising activity in patients with relapsed or refractory B-cell malignancies with acceptable toxicity. Disclosures: Byrd: Calistoga Pharmaceuticals, Inc: Consultant. Furman:Calistoga Pharmaceuticals, Inc: Consultant. Brown:Calistoga Pharmaceuticals, Inc: Consultant. Giese:Calistoga Pharmaceuticals, Inc: Employment, Ownership Interest. Yu:Calistoga Pharmaceuticals, Inc.: Employment, Ownership interest.

scholarly journals Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

Blood ◽  
2019 ◽  
Vol 134 (11) ◽  
pp. 851-859 ◽  
Author(s):  
Constantine S. Tam ◽  
Judith Trotman ◽  
Stephen Opat ◽  
Jan A. Burger ◽  
Gavin Cull ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
End Points ◽  
Once Daily ◽  
Grade 3

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Safety Profile and Clinical Response To MEDI-551, a Humanized Monoclonal Anti-CD19, In a Phase 1/2 Study In Adults With Relapsed Or Refractory Advanced B-Cell Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1810-1810 ◽  
Author(s):  
Andres Forero-Torres ◽  
Mehdi Hamadani ◽  
Michelle A. Fanale ◽  
Celeste M. Bello ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Safety Profile ◽  
Stock Options ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Phase 2 ◽  
B Cell Malignancies

Abstract Background MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa monoclonal antibody directed against CD19 and induces malignant clone destruction by antibody-dependent cellular cytotoxicity. This study evaluates the safety profile and clinical activity of MEDI-551 in patients with relapsed/refractory B-cell malignancies. These include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Objectives Determine the safety profile and maximum tolerated dose (MTD) of MEDI-551 in patients with relapsed/refractory B-cell malignancies. Secondary objectives include clinical activity of MEDI-551. Methods In this phase 1/2 open-label multicenter, global dose-escalation and expansion study, patients with relapsed or refractory CLL, DLBCL, FL, or MM received MEDI-551 (at 0.5, 1, 2, 4, 8, or 12 mg/kg) by intravenous infusion administered over 28-day cycles using standard 3+3 dose escalation. Dose escalation continued to the maximum dose ≤12 mg/kg or until MTD was reached. Therapy continued for 2 cycles beyond complete response (CR), or until unacceptable toxicity or disease progression. Dose-limiting toxicity was defined as a MEDI-551-related adverse event (AE) that prevented completion of a full first cycle of MEDI-551, or as a ≥grade 3 toxicity (excluding hematologic toxicity) that could not be ascribed to another cause. Results Of 91 patients who received ≥1 dose of MEDI-551, 25 patients (CLL [3], DLBCL [6], FL [12], MM [4]) were enrolled in the phase 1 escalation portion (Jun 2010–Aug 2011). No MTD was achieved. The phase 2 expansion phase included 66 patients (CLL [23], DLBCL [20], FL [22], MM [1]) as of 14Jul2013. Three patients were re-treated with MEDI-551 upon relapse. Median age of patients treated was 66 years; median lines of prior therapy was 6. The median number of treatment cycles was 5 with a maximum of 28 cycles. There were 14 deaths due to AEs (none were drug-related) and 15 subjects discontinued treatment. One subject each discontinued due to drug-related neutropenia and infusion reaction. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Of 91 patients, 5 (5.5%) patients had grade 4 TEAEs (2 with drug-related neutropenia) and 9 (9.9%) had grade 5 events, none were drug related. Of 19 patients with 38 serious AEs (SAE), 2 patients had 3 events that were considered drug-related; pneumonia and sepsis in 1 patient and infusion related reaction in the other. Of 83 patients in the efficacy evaluable population (includes all patients who received any treatment of MEDI-551 and completed at least 1 post-baseline disease assessment), 9 had CR, 12 had partial responses (PR) and 42 had stable disease (SD; Figure 1). ORR to single-agent MEDI-551 was 24%, 24%, or 31% respectively in heavily pre-treated patients with CLL, DLBCL, or FL. Median progression-free survival was ≈9 months (Figure 2). Conclusions MEDI-551 has an acceptable safety profile warranting further study. Anti-tumor activity was achieved in a heavily pre-treated population of DLBCL, CLL, and FL patients respectively in this single-agent study. Phase 2 studies of MEDI-551 in combination with chemotherapy in DLBCL and CLL are ongoing. Funding Source This study was sponsored by MedImmune. Disclosures: Forero-Torres: MedImmune: Research Funding. Hamadani:MedImmune: Research Funding. Fanale:MedImmune: Research Funding. Bello:MedImmune: Research Funding. Kipps:MedImmune: Research Funding. Offner:MedImmune: Research Funding. Verhoef:MedImmune: Research Funding. Federico:MedImmune: Research Funding. Gregory:MedImmune: Research Funding. Sonet:MedImmune: Research Funding. Assouline:MedImmune: Research Funding. Pérez de Oteyza:MedImmune: Research Funding. Tomas:MedImmune: Research Funding. Cuneo:MedImmune: Research Funding. Elgeioushi:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Goswami:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Ibrahim:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Herbst:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Cheson:MedImmune: Research Funding.

A Phase 1 Study of Moxetumomab Pasudotox, An Anti-CD22 Recombinant Immunotoxin, In Relapsed/Refractory Hairy Cell Leukemia (HCL): Updated Results

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2516-2516 ◽  
Author(s):  
Robert J. Kreitman ◽  
Martin S. Tallman ◽  
Steven Coutre ◽  
Tadeusz Robak ◽  
Wyndham H. Wilson ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Dose Escalation ◽  
Treatment Cycle ◽  
Phase 1 ◽  
Clinical Activity ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Investigational Product ◽  
B Cell Malignancies

Abstract Abstract 2516 Currently no adequate therapies exist for patients with refractory hairy cell leukemia (HCL). The CD22 antigen is commonly expressed on the cell surface of B cells and B-cell malignancies. CD22 is highly expressed in HCL, even in chemoresistant disease, and is therefore a potential target for antibody-directed therapy in refractory/resistant HCL. We developed CD22-specific targeted immunotoxins composed of the variable domains of a monoclonal anti-CD22 antibody fused to a truncated form of a Pseudomonas exotoxin. The first anti-CD22 immunotoxin we studied was CAT-3888 (BL22), which demonstrated remarkable activity in patients with relapsed/refractory HCL. Moxetumomab pasudotox (also known as CAT-8015 or HA22) is a derivative of CAT-3888 with a higher affinity to CD22 and an improved cytotoxicity profile ex vivo against HCL and other B-cell malignancies. A phase 1 dose-escalation study is being conducted to determine the maximum tolerated dose (MTD) of moxetumomab pasudotox and to assess its safety and immunogenicity profiles and clinical activity in HCL. Preliminary safety data and antitumor activity from the study were previously reported (Kreitman et al, ASH 2009, ASCO 2010). Eligibility criteria include age ≥18 years, ≥2 previous systemic therapies (including purine analogs), ECOG performance status of 0–2, and the presence of cytopenia or symptomatic splenomegaly. A standard 3+3 dose-escalation design with an expanded cohort at the MTD or highest dose level is being used. Patients receive moxetumomab pasudotox as a 30-min IV infusion administered on days 1, 3, and 5 (QODx3) of a 28-day treatment cycle, up to a total of 10 cycles. Patients receive prophylaxis with low-dose aspirin (if platelets >100,000/μL) and IV hydration to prevent hemolytic uremic syndrome (HUS), the dose-limiting toxicity (DLT) in clinical studies with CAT-3888. Additionally, patients receive hydroxyzine, ranitidine, and acetaminophen to avoid infusion reactions. Response is evaluated before cycle 2 and thereafter before even-numbered cycles. Enrollment and treatment are ongoing. At the time of reporting, a total of 32 patients had received moxetumomab pasudotox at one of five dose levels: 5, 10, 20, and 30 μg/kg (n=3 in each cohort), and 40 μg/kg (n=4), and in an expanded cohort at the 50-μg/kg dose level (n=16). Median age was 59 years (range, 40–77 years). Patients were heavily pretreated; 19 (59%) were previously treated with rituximab. No DLTs have been observed, and an MTD has not been reached. Adverse events have been mostly mild and consistent with those seen in clinical studies with CAT-3888. The most frequently reported drug-related adverse events have been hypoalbuminemia (53%), peripheral edema (44%), pyrexia (34%), elevated ALT (34%) and AST (31%), fatigue (28%), headache (28%), localized edema (22%), and nausea (22%). Capillary leak syndrome (grade 2) has developed in 7 patients (22%); 5 patients were in the 50-μg/kg dose cohort. Reversible grade 2 HUS has been reported in 2 patients (6%; 30 μg/kg, n=1; 50 μg/kg, n=1); both began on day 8 of the treatment cycle. Treatment-related toxicities ≥grade 3 have been observed in 3 patients (30 μg/kg, n=1; 50 μg/kg, n=2) and include decreased haptoglobin levels, elevated gamma-glutamyltransferase, and lymphopenia. Moxetumomab pasudotox has shown clinical activity in 47% of recipients, and responses have been observed in both the dose-escalation and expansion cohorts. Overall response (OR), complete response (CR), and partial response (PR) rates observed to date are listed in the table. The median time to response is currently 2.79 months. Neutralizing antibodies have developed in 14 patients (44%). Moxetumomab pasudotox appears to have a safety profile similar to that of CAT-3888 (BL22), and with a lower incidence of HUS at the highest dose tested (50 μg/kg QODx3). Moxetumomab pasudotox has demonstrated antitumor activity in patients with relapsed/refractory HCL, including 44% of patients in the expansion cohort. Further studies in HCL and other B-cell malignancies expressing CD22 are warranted. Clinical Activity 5 μg/kg (n=3) 10 μg/kg (n=3) 20 μg/kg (n=3) 30 μg/kg (n=3) 40 μg/kg (n=4) 50 μg/kg (n=16) Total (N=32) OR 33% 67% 67% 33% 50% 44% 47% CR 0% 33% 67% 33% 50% 25% 31% PR 33% 33% 0% 0% 0% 19% 16% ClinicalTrials.gov Identifier: NCT00462189 This study was sponsored by MedImmune, LLC. Disclosures: Kreitman: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Robak: MedImmune, LLC: Research Funding. Noel: NIH: Patents & Royalties. FitzGerald: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Buzoianu: MedImmune, LLC: Employment. Lechleider: MedImmune, LLC: Employment. Pastan: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties.

A Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Combination with Rituximab and/or Bendamustine In Patients with Relapsed or Refractory B-Cell Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2832-2832 ◽  
Author(s):  
Ian W. Flinn ◽  
Marshall T. Schreeder ◽  
Nina Wagner-Johnston ◽  
Ralph V. Boccia ◽  
John P. Leonard ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Reduction ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Selective Inhibitor ◽  
Clinical Activity ◽  
Phase 1 Study ◽  
Number Of Patients ◽  
Phosphatidylinositol 3

Abstract Abstract 2832 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate a variety of cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B cell proliferation and survival. CAL-101 is an isoform-selective inhibitor of PI3Kδ (EC50 of 8 nM in a cell-based assay with >200-fold selectivity relative to other PI3K isoforms). A Phase 1 study of single-agent CAL-101 demonstrated clinical activity in patients with indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma, and chronic lymphocytic leukemia (CLL); a favorable safety profile suggested that CAL-101 might successfully be combined with other agents active against lymphoid malignancies. Methods and Patients: This Phase 1 study was undertaken to evaluate the safety and activity of CAL-101 in combination with rituximab and/or bendamustine in patients with relapsed or refractory B-cell indolent NHL and CLL. All patients received CAL-101 100 mg orally twice per day (BID) in 28-day cycles for up to 12 cycles. Patients also received either rituximab 375 mg/m2 administered weekly for 8 weeks, starting on Day 1 of Cycle 1, or bendamustine 90 mg/m2 administered on Days 1 and 2 of each cycle for 6 cycles. Tumor response was evaluated according to standard criteria. Results: At data cutoff, 12 patients were enrolled in the study, including 6 with NHL and 6 with CLL. Patients included: males/females n=8 (67%)/4 (33%) with median age [range] of 65 [55-80] years, and relapsed/refractory disease n=8 (67%)/4 (33%). The median [range] number of prior therapies was 3 [1-11]. The number (%) of patients with specific prior therapies included: rituximab n=12 (100%), alkylating agent n= 10 (83%), purine analog n=9 (75%), and anthracycline/anthracenedione n=6 (50%). All patients received CAL-101 100 mg BID; 6 patients received rituximab and 6 received bendamustine. One patient with NHL had a dose reduction of bendamustine due to hiccups and 1 patient with NHL had a dose reduction of CAL-101 due to increased ALT/AST; all other patients received the full-dose regimen with acceptable tolerability. Preliminary clinical response assessments were available for 6 patients who had completed 2 cycles of combination treatment; the results are shown in the table. Enrollment is ongoing and dose escalation of CAL-101 is planned. Updated data will be presented at the meeting. Conclusions: Early results from this Phase 1 study of CAL-101, an oral PI3Kδ isoform-selective inhibitor, in combination with rituximab or bendamustine show acceptable safety and promising clinical activity in patients with relapsed or refractory indolent B-cell NHL and CLL. Disclosures: Flinn: calistoga: Research Funding. Off Label Use: CAL-101 for NHL. Leonard:Calistoga: Consultancy, Research Funding. Holes:Calistoga: Employment. Peterman:Calistoga: Employment. Yu:Calistoga: Employment.

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study

2020 ◽  
Vol 7 (9) ◽  
pp. e649-e659 ◽  
Author(s):  
Jean-Marie Michot ◽  
Reda Bouabdallah ◽  
Umberto Vitolo ◽  
Jeanette K Doorduijn ◽  
Gilles Salles ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Expansion Phase ◽  
Non Hodgkin Lymphoma

Clinical Activity of the Immunoconjugate CMC-544 in B-Cell Malignancies: Preliminary Report of the Expanded Maximum Tolerated Dose (MTD) Cohort of a Phase 1 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2711-2711 ◽  
Author(s):  
Luis Fayad ◽  
Hemant Patel ◽  
Gregor Verhoef ◽  
Myron Czuczman ◽  
James Foran ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Remission Rate ◽  
International Workshop ◽  
Phase 1 ◽  
Objective Response ◽  
Safety Data ◽  
Clinical Activity ◽  
B Cell Lymphomas ◽  
Grade 3

Abstract Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a humanized antibody that specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Malignant cells of mature B-lymphocyte lineage express CD22, suggesting that CMC-544 may be useful for treating lymphomas of B-cell origin. A phase 1 dose-escalation trial of CMC-544 was performed at 14 European and US sites with 36 patients in the dose escalation portion and 48 in the expanded MTD portion. The MTD dose was 1.8 mg/m2 every 4 weeks. In the dose escalation phase the main toxicities observed were thrombocytopenia, asthenia, nausea, neutropenia, elevated liver function tests (LFTs) and anorexia. Grade 3–4 levels were only seen for thrombocytopenia, asthenia, neutropenia and LFTs (incidence of 40%, 13%, 9% and 9% respectively). Responses were seen in 8/22 (36%) patients (Advani A, et. al. Blood, abstract# 230, 2005:106). We now report the results of the expanded cohort at the MTD. Patients and Methods: Relapsed/refractory lymphoma patients were treated at the 1.8 mg/m2 dose level every 4 weeks. In addition to safety data, preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) were collected. Results: As of July 2006, 48 patients were treated: median age 57 years (range 26–75); 51% females; 61% with ≥ 4 prior lines of therapy; 22 (46%) follicular lymphomas (FL) and 26 (54%) diffuse large B-cell lymphomas (DLBCL). Data were available on 48 patients evaluable for safety and 34 patients (19 FL and 15 DLBCL) evaluable for response. The overall safety profile was manageable; the most common drug-related adverse events (all grades) included thrombocytopenia (90%; the only bleeding noted was grade 1–2 epistaxis [12%]), asthenia (57%), nausea (39%), neutropenia (37%) and elevated levels of AST/SGOT (41%), ALT/SGPT (18%), alkaline phosphatase (27%) and bilirubin (18%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included thrombocytopenia (57%) and neutropenia (29%). Responses in evaluable patients are shown in Table 1. The objective response rate was 69% and 33% for patients with FL and DLBCL, respectively. Conclusions: CMC-544 exhibits effficacy against recurrent/refractory B-cell lymphomas, with the main toxicity being clinically manageable, self limited thrombocytopenia. These encouraging data support the continuing development of CMC-544. Number (%) of Responses in Evaluable Patients: Response Follicular Lymphoma (n=19) DLBCL (n=15) ORR = Overall Remission Rate, (CR/CRu+PR) CR/CRu 6 (31.7) 2 (13.3) PR 7 (36.8) 3 (20.0) ORR 13 (68.5) 5 (33.3)

The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 57-57 ◽  
Author(s):  
Jan A. Burger ◽  
Susan O'Brien ◽  
Nathan Fowler ◽  
Ranjana Advani ◽  
Jeff Porte Sharman ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Study Drug ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Bcr Signaling ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 57 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor (BCR) signaling and is not expressed in T-cells or NK-cells. As such, Btk represents an ideal therapeutic target for B-cell malignancies dependent upon BCR signaling. Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) has been reported to have constitutively active BCR signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk that has pre-clinical activity in B-cell malignancies (Proc Natl Acad Sci 2010;107(29):13075-80). PCI-32765 was therefore moved forward to a Phase 1 study in B-cell malignancies including patients (pts) with CLL/SLL. A subsequent CLL/SLL-specific Phase 1b study was initiated to further explore safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PCI-32765. This report includes a composite summary of the CLL/SLL experience in both of these studies. Pts and Methods: Pts with CLL/SLL who had relapsed or refractory disease after >1 prior treatment regimens were eligible for treatment in each of the studies whereas the second Phase 1b study also included a cohort of elderly pts (aged ≥ 65 years) with CLL/SLL who required treatment and were “treatment-naive”. Responses were assessed by the investigator using the International Working Group CLL criteria (Hallek et al, Blood 2008 for pts with CLL) and the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al, J Clin Oncol 2007 for pts with SLL). Results: To date, 30 CLL/SLL patients (including 4 treatment-naive) have been enrolled across the 2 studies. Eighty-four percent of subjects are men with an overall median age of 68 (range 44–82) years. Of the subjects with prior therapy for CLL/SLL the median number of prior therapies is 3 (range 1–4). Treatment has been well-tolerated; Grade ≥ 3 toxicities have been infrequent (10/30 pts; 33%). Two study-drug related serious adverse events have been reported: 1 case of viral adenitis (Grade 3) and 1 case of viral infection (Grade 2). Two adverse events have led to discontinuation of study drug: a small bowel obstruction (Grade 3) and exacerbation of chronic obstructive disease (Grade 3); both events were reported as unrelated to study drug. No study-drug related deaths have reported. There has been no change in either NK cell or T cell counts. Target inhibition as measured by a probe of Btk drug occupancy showed inhibition of Btk at PCI-32765 exposure levels of ≥ 245 ng•h/mL. Of the 14 patients currently evaluable for response using the pre-defined criteria, the overall response rate is 64% (1 complete remission [CR], 8 partial remissions [PR], and 4 SD). Both studies are ongoing and open to enrollment. An update on response rate, response duration, safety, and PD information will be presented on enrolled patients based on a November 2010 database cut-off. Conclusion: PCI-32765 is a novel oral and selective “first-in-human” inhibitor of Btk that induces objective partial and complete responses in a substantial proportion of pts with CLL/SLL and has a favorable safety profile. These data support further studies of both monotherapy and also combination treatment with PCI-32765 in CLL/SLL. Disclosures: O'Brien: Pharmacyclics, Inc: Honoraria, PI grant. Fowler:Pharmacyclics: Consultancy, Research Funding. Advani:Pharmacyclics, Inc: Honoraria, PI grant. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Furman:Pharmacyclics, Inc: PI grant. Izumi:Pharmacyclics, Inc: Employment. Buggy:Pharmacyclics, Inc: Employment, Equity Ownership. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:Pharmacyclics, Inc: Employment, Equity Ownership.

scholarly journals Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study

Blood ◽  
2013 ◽  
Vol 122 (17) ◽  
pp. 2965-2973 ◽  
Author(s):  
Conrad Russell Y. Cruz ◽  
Kenneth P. Micklethwaite ◽  
Barbara Savoldo ◽  
Carlos A. Ramos ◽  
Sharon Lam ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
B Cell ◽  
Stem Cell Transplant ◽  
Phase 1 ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
Key Points

Key Points Allogeneic CD19-CAR VSTs are well tolerated by patients with relapsed B-cell malignancies post-HSCT. At periods of CD19-CAR VST persistence, these cells demonstrate antitumor activity.

scholarly journals A Phase 1 a/b Dose Escalation Trial to Evaluate the Safety and Tolerability of CG-806 in Patients with Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5477-5477
Author(s):  
Stephen B Howell ◽  
Hongying Zhang ◽  
William G Rice
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Signaling Pathways ◽  
Dose Escalation ◽  
Phase 1 ◽  
Recommended Dose ◽  
Mrna Levels ◽  
Starting Dose ◽  
Hodgkin's Lymphomas ◽  
Dose Levels

INTRODUCTION: CG-806 is a first-in-class, oral, non-covalent, and potent inhibitor of the wild type and all known mutant forms of Bruton's tyrosine kinase (BTK, including the C481S mutation), as well as all forms of the FLT3 receptor tyrosine kinase and multiple oncogenic signaling pathways, but with a selectivity that spares normal cells by avoiding off-target inhibition of kinases known to produce toxicities. Such a kinase inhibitory profile is key to the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and certain B-cell malignancies, which are driven by dysregulated BTK, can become resistant to covalent BTK inhibitors (ibrutinib and others) by BTK C481S mutation, and may become refractory to various therapies by other compensatory kinase signaling pathways such as SYK, SRC, STATs, ERK, AKT, NFĸB and MYC. In cell lines and primary samples from CLL and B-cell ALL patients, CG-806 potently suppressed the driver and compensatory pathways (inhibited phosphorylation of BTK, FLT3, PDGFRα, SYK, SRC, ERK, STAT5 and AKT, decreased MYC levels), induced cleavage of caspase 3, potently killed cells insensitive to ibrutinib or venetoclax, and caused enhanced cell killing in combination with venetoclax. Consequently, CG-806 is currently being evaluated in a Phase I a/b trial in patients with CLL/SLL or non-Hodgkin's lymphomas (NHLs). METHODS: A Phase 1 a/b trial of CG-806 in patients with CLL/SLL or non-Hodgkin's lymphomas (NCT03893682) is underway to evaluate the safety, tolerability and potential effectiveness of CG-806 for the treatment of patients for which either the standard treatment has failed, is no longer effective, or can no longer be administered safely. The starting dose is 150 mg PO BID and the dose will be escalated in 150 mg increments with only 1 patient at the two lowest dose levels and a minimum of 3 at the higher dose levels. Once the maximum tolerated dose or recommended dose is reached, up to 100 patients will be enrolled in the expansion cohort at the recommended dose. Primary objectives of the trial are to determine the safety and tolerability of CG-806 at the dose given orally every 12 hours that maintains a biologically active plasma concentration over a period of 28 days and to establish the recommended Phase 2 dose (RP2D) of CG-806 for future clinical trials in patients with advanced CLL/SLL or NHL. Key secondary objectives are to observe patients for any evidence antitumor activity using FDG PET-CT imaging evaluations and to measure pharmacodynamic biomarkers of drug effect including phospho-BTK levels and selected mRNA levels in peripheral white blood cells, as well as CCL3 and CCL4 circulating levels. RESULTS: CG-806 oral capsules have been administered at a starting dose of 150 mg BID on a 28-day cycle to the first CLL patient who previously failed ibrutinib, venetoclax, rituximab, idelalisib and other medications. To date (as of July 2019), in this first patient who has received more than 40 doses of CG-806 150mg oral capsules, no dose limiting toxicities have been observed, there are no impediments to continuing dosing on study, and the tolerability is consistent with preclinical tolerability findings in rodents and dogs when CG-806 was delivered as an oral gavage. Safety and tolerance vigilance, as well as pharmacokinetic (PK) and pharmacodynamic analyses, will continue into subsequent cycles and dose levels. CONCLUSIONS: CG-806 is an oral, non-covalent pan-BTK/pan-FLT3 inhibitor designed to suppress multiple oncogenic driver and compensatory signaling pathways in order to directly and potently kill B-cell cancer cells including those insensitive to the ibrutinib covalent BTK inhibitor and the venetoclax Bcl-2 inhibitor. Recruitment and enrollment of patients with R/R CLL/SLL and non-Hodgkin's lymphomas are continuing in a Phase 1a/b dose escalation/expansion trial, and updated safety, PK, and available biomarker data will be presented at the meeting. Disclosures Howell: Aptose Biosciences, Inc: Consultancy, Research Funding. Zhang:Aptose Biosciences, Inc: Employment. Rice:Aptose Biosciences, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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