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.

scholarly journals Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies

Blood ◽  
2019 ◽  
Vol 133 (16) ◽  
pp. 1742-1752 ◽  
Author(s):  
Andres Forero-Torres ◽  
Radhakrishnan Ramchandren ◽  
Abdulraheem Yacoub ◽  
Michael S. Wertheim ◽  
William J. Edenfield ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
B Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Janus Kinase ◽  
B Cell Malignancies ◽  
Once Daily ◽  
Grade 3

Abstract This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.

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.

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.

An Ongoing Open-Label Phase 1/2 Study of INCB050465, a Selective PI3Kδ Inhibitor, in Patients with Previously Treated B-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4195-4195 ◽  
Author(s):  
Tycel Phillips ◽  
Rod Ramchandren ◽  
Michael S Wertheim ◽  
Martin E Gutierrez ◽  
William J Edenfield ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Linear Pharmacokinetics ◽  
B Cell Malignancies ◽  
Once Daily ◽  
Food And Beverage ◽  
Grade 3

Abstract Background: Signaling of PI3Kd has been implicated in proliferation, migration, and function of B cells. PI3Kd inhibitors have demonstrated clinical activity in a number of lymphoid tumor types. INCB050465 is a novel, potent, and highly specific inhibitor of PI3Kd (≥19,000-fold more selective for the d vs other isoforms) with no hepatotoxicity in preclinical evaluation at clinically relevant exposures. Here we report the emerging safety, pharmacokinetics, and efficacy results of INCB050465 monotherapy in B-cell malignancies. Methods: This phase 1/2 study (NCT02018861) enrolled patients aged ≥18 years with relapsed/refractory B-cell malignancies. After an initial single-patient cohort of oral INCB050465 5 mg once daily, a 3+3 dose escalation was conducted with doses ranging from 10 to 45 mg once daily; the dose-limiting toxicity observation period was 21 days. The 20 mg and 30 mg once daily doses were selected for monotherapy expansion. Efficacy was assessed every 9 weeks by Lugano Classification or International Working Group on Chronic Lymphocytic Leukemia (CLL) criteria. Results: As of the data cutoff (May 20, 2016), 39 patients had been enrolled and treated with INCB050465 monotherapy. The median age was 63 and 62% were men. Subtypes included diffuse large B-cell lymphoma (n=13); Hodgkin lymphoma (HL; n=8); follicular lymphoma (FL; n=6); CLL (n=5); marginal zone lymphoma (MZL; n=4); and mantle cell lymphoma (n=3). At baseline, the median number of prior systemic regimens was 3, and the median time since diagnosis was 4.9 years. INCB050465 demonstrated low oral clearance and linear pharmacokinetics, with a terminal half-life that supports once-daily dosing. The steady-state Cavg was 15-fold greater than the whole blood IC90 at the 30-mg dose. Pharmacodynamic analysis indicated maximal inhibition of the target throughout the dosing interval at all doses tested. Patients received INCB050465 for a median duration of 82 days (range: 4+ to 382+ days); no DLTs were observed. Treatment was discontinued in 16 patients due to disease progression (n=12), adverse events (AEs; n=3), or loss to follow-up (n=1). Dose interruption occurred in 6 patients (15%) and dose reduction in 1 (3%). The most common nonhematologic AEs were nausea (33%), pyrexia (21%), and cough (18%), all of which were grade 1 or 2. All observed alanine aminotransferase (15%) and aspartate aminotransferase elevations (15%) were grade 1. Nine patients (23%) experienced 16 grade ≥3 nonhematologic AEs, 3 of which were considered treatment-related by the investigator. New or worsening grade ≥3 anemia, thrombocytopenia, and neutropenia occurred in 8%, 10%, and 15% of patients, respectively. There was 1 instance (3%) each of colitis (grade 3) and pneumonitis (grade 2). Thirteen patients (33%) experienced a serious AE (SAE); SAEs occurring in more than 1 patient included diarrhea, exfoliative dermatitis, and hypotension (n=2 each). Among efficacy-evaluable patients (n=35), the objective response rate (ORR) was 57% and varied by disease subtype (Table 1). The ORRs for non-Hodgkin lymphoma (NHL) and HL were 66% (19/29) and 17% (1/6), respectively. Objective responses were observed in both transformed and non-transformed DLBCL, and both germinal center B-cell (GCB) and non-GCB subtypes. Objective responses were observed for all 10 patients with FL or MZL. Ninety percent of objective responses were observed at the first response assessment, and responses occurred at all but the 5-mg dose. Conclusion: The linear pharmacokinetics and absence of DLTs allow INCB050465 to achieve higher levels of target inhibition at the recommended phase 2 dose (30 mg once daily) than have been reported for other PI3Kd inhibitors. INCB050465 monotherapy was well tolerated at all doses tested with no significant transaminase elevations or early-onset diarrhea, and no cases of Pneumocystis jirovecii pneumonia. Objective responses, including complete responses, were observed in both aggressive and indolent NHL. Enrollment is ongoing at the 30 mg once daily dose level. Disclosures Gutierrez: Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage; Incyte Corporation: Consultancy; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging. Edenfield:Astellas/Medivation: Speakers Bureau; Novartis: Speakers Bureau; Greenville Health System Cancer Institute: Employment. Dawkins:Incyte Corporation: Employment, Other: Stocks. DeMarini:Incyte Corporation: Employment, Other: Stocks. Zhou:Incyte Corporation: Employment, Other: Stocks. Yeleswaram:Incyte Corporation: Employment, Other: Stocks. Newton:Incyte Corporation: Employment, Other: Stocks. Chen:Incyte Corporation: Employment, Other: Stocks. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

The Safety, Pharmacokinetics and Pharmacodynamics of KW-2478, a Novel Hsp90 Antagonist, in Patients with B-Cell Malignancies: A First-in-Man, Phase I, Multicentre, Open-Label, Dose Escalation Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2777-2777 ◽  
Author(s):  
J. D. Cavenagh ◽  
K. Yong ◽  
J. Byrne ◽  
J. Cavet ◽  
P. Johnson ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
B Cell ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Hsp70 Expression ◽  
B Cell Malignancies ◽  
Once Daily ◽  
Exposure Levels ◽  
Clinically Significant ◽  
Grade 3

Abstract Treatment of cancer cells with Hsp90 inhibitors/antagonists results in cell cycle arrest, destabilisation and apoptosis. This ability of Hsp90 antagonists to modulate tumour microenvironments and initiate the selective degradation of various factors needed for cell proliferation and survival make them potential candidates for the treatment of B-cell malignancies such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin’s lymphoma (NHL). KW-2478 is a novel non-ansamycin, non-purine analogue antagonist for Hsp90. This study investigated KW-2478 in patients (aged ≥18 y) with relapsed/refractory MM, CLL or NHL. Fifteen patients (5 cohorts of 3) received escalating doses of KW-2478 at 14, 28, 47, 71, 99 mg/m2, IV over 60 min, once daily on Days 1 to 5 of a 14-day cycle. Patients could receive further cycles for up to one year, with a dose escalation option. Study objectives were to determine safety, tolerability, pharmacokinetic and pharmacodynamic profiles of KW-2478. Safety was assessed throughout the study (AEs, dose-limiting toxicities [DLTs], vital signs, ECG, physical examination, safety laboratory tests and visual ophthalmological examination with electroretinogram [ERG]). DLT was defined as an event during the first cycle which was considered related to KW-2478 and either led to treatment delay, persisted beyond Day 14, was a clinically significant ERG change, was a grade 4 or clinically significant grade 3 non-hematological event, or was a grade 4 hematological toxicity not related to primary disease that had not recovered to ≤ grade 3 by Day 14. On Days 1 and 5 (first cycle), blood samples were collected at pre-dose, 50 min post start of infusion and 10 and 30 min, and 1, 2, 4 and 8 h post infusion for KW-2478 pharmacokinetic analysis. Blood was sampled for pharmacodynamic analysis at pre-dose and 8 h on Days 1 and 5. Hsp70 expression in PBMCs was analyzed by Western blot. Results showed good tolerability with no DLTs between KW-2478 doses of 14 and 99 mg/m2. Patients received a median of three treatment cycles though one MM patient underwent 19 treatment cycles and had two dose escalations with no toxicity. Overall, six patients (40%) had KW-2478 related toxicities (seven grade 1, seven grade 2 and two grade 3) and there were three grade 4 toxicities, not related to KW-2478. There were no trends noted for any specific toxicities associated with KW-2478, though one grade 1 and one grade 2 KW-2478 related episodes of hypertension were observed in a single patient, leading to hospitalization overnight. Two grade 3 related episodes of QTc interval prolongation were reported in one patient. Overall, KW-2478 related toxicities led to dose interruption (6%) or withdrawal from the study (13%). Two patients died from disease progression and no patients died from treatment related causes. Peak plasma concentrations were observed at the end of the infusion, after which KW-2478 plasma concentrations decayed in a biphasic manner with a dose-independent half-life of approximately 6 h. For Day 1, maximum plasma concentration (Cmax) and area under the KW-2478 concentration-time curve from time zero to infinity (AUC0–∞) values increased in a dose-dependent manner at all doses. Repeated 5-day administration had no effect on plasma concentration at all doses. Mean [range] Day 5 KW-2478 Cmax varied from 656 [482–1050] ng/mL at the 14 mg/m2 dose to 2977 [2440–3640] ng/mL at 99 mg/m2. Mean [range] Day 5 KW-2478 AUC to last measurable concentration (AUC0-t) varied from 836 [532–1336] ng/mL at the 14 mg/m2 dose to 3465 [2997–4318] ng/mL at 99 mg/m2. Pharmacodynamic data were variable but there was a trend toward increased Hsp70 expression with increasing doses of KW-2478. This trend was most evident at 71 and 99 mg/m2, at 8 h post dose on Day 5. Once-daily infusions at doses of up to 99 mg/m2 achieved exposure levels similar to those that showed anti-tumor activity in pre-clinical models including models of human MM. Hsp70 induction data suggested that these exposure levels may be sufficient to affect function of Hsp90 in B-cell malignancies. Overall, KW-2478 was well tolerated with no DLTs at doses up to 99 mg/m2 and demonstrated a predictable pharmacokinetic profile in its target population. The study is proceeding with a KW-2478 dose of 132 mg/m2; further dose escalation is planned.

Preliminary results of the phase 2 study of zanubrutinib in patients with previously treated B-cell malignancies intolerant to ibrutinib and/or acalabrutinib.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19506-e19506
Author(s):  
Mazyar Shadman ◽  
Jeff Porter Sharman ◽  
Moshe Y. Levy ◽  
Ryan Porter ◽  
Syed Farhan Zafar ◽  
...  
Keyword(s):  
B Cell ◽  
Kinase Inhibitors ◽  
Median Number ◽  
Additional Treatment ◽  
Lymphocytic Leukemia ◽  
Continuous Treatment ◽  
Duration Of Treatment ◽  
B Cell Malignancies ◽  
Preliminary Results ◽  
Grade 3

e19506 Background: Many patients (pts) with B-cell malignancies require continuous treatment with Bruton tyrosine kinase inhibitors (BTKi). Adverse events (AEs) are a common reason for ibrutinib (ibr) or acalabrutinib (acala) discontinuation. Early data from BGB-3111-215 showed zanubrutinib (zanu) was well tolerated in pts with B-cell malignancies intolerant to ibr or acala. We report preliminary results with a median follow-up of 4.2 mo. Methods: Pts meeting protocol criteria for intolerance to ibr, acala or both (without documented progressive disease) were given zanu monotherapy (160 mg twice daily or 320 mg once daily). Recurrence of AEs that led to intolerance of prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline. Results: As of November 1, 2020 (cutoff), 44 pts (n=34 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=6 Waldenström macroglobulinemia, n=2 mantle cell lymphoma, n=2 marginal zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed for safety. Median age was 70.5 y (range, 49-91); median duration of treatment was 4.2 mo (range, 0.1-12.6). Median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 39 pts received ibr only, 4 received ibr and acala, and 1 received acala only. The median number of ibr- or acala-intolerant AEs per pt was 2 (range, 1-5). 83% of ibr and 78% of acala intolerant events did not reccur on zanu; Table. At data cutoff, 43 pts remained on treatment; 1 withdrew consent due to zanu-unrelated grade 3 syncope. Overall, 34 pts (77.3%) reported any AE; most commonly reported AEs were myalgia (n=9; 20.5%), contusion (n=8; 18.2%), dizziness (n=7; 15.9%), fatigue (n=7; 15.9%), and cough (n=5; 11.4%). Grade ≥3 AEs were reported in 6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and salmonella infection), AEs requiring dose interruptions in 6 pts (13.6%), and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu discontinuation. No deaths were reported. All efficacy evaluable pts (26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16 [61.5%]) of their response. Conclusions: Zanu provides an additional treatment option after intolerance to other BTKi, demonstrating tolerability and sustained or improved efficacy. Updated results will be presented. Recurrence and Severity Change of AEs Leading to Ibr or Acala Intolerance. Clinical trial information: NCT04116437. [Table: see text]

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)

ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1860-1860 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey Zonder ◽  
Adam Cohen ◽  
Robert Z. Orlowski ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3663-3663 ◽  
Author(s):  
Ian W. Flinn ◽  
Steven M. Horwitz ◽  
Manish Patel ◽  
Anas Younes ◽  
James R. Porter ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Dose Levels

Abstract Abstract 3663 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. Impaired development and function of B and T lymphocytes has been demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients (pts) with hematologic malignancies. The activity of IPI-145 via PI3K-δ and PI3K-γ isoform inhibition has been characterized in biochemical and cellular assays and demonstrated in preclinical models of B- and T-cell mediated disease. Early results of the Phase 1 study in pts with advanced hematologic malignancies are reported here. Methods and Patients: This Phase 1 dose-escalation study is designed to evaluate the safety, pharmacokinetics (PK) and activity of orally administered IPI-145 in pts with advanced hematologic malignancies, including T-cell lymphomas/leukemias. Sequential cohorts of pts are enrolled at progressively higher dose levels with expansion cohorts of pts with select hematologic malignancies. IPI-145 is administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response is evaluated based on disease-specific standard criteria. Results: As of 16 July 2012, the study had enrolled 20 pts; 5 pts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 4 with indolent non-Hodgkin's lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2 and Richter's transformation n=1], 3 with multiple myeloma (MM), 2 with Hodgkin's lymphoma (HL), 2 with T-cell lymphoma [anaplastic large-cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these pts, 11 are male and 9 female, with a median [range] age of 63 years [30–81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1–8]. IPI-145 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), 35 mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) pts continuing on treatment. Adverse events (AEs) have occurred in 13 (65%) pts, including 7 (35%) pts with AEs Grade ≥3. Treatment-related AEs occurred in 11 pts (55%) with Grade ≥3 occurring in 5 pts (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade ≥3 hematological laboratory abnormalities included neutropenia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM pt with onset 6 weeks after IPI-145 initiation. Preliminary PK show dose-proportional increases in plasma Cmax and AUC over the dose range studied. Further, the PK and initial pharmacodynamic (PD) data from the first 3 cohorts (8–25 mg BID) predict continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater. In the evaluable pts (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 CLL/SLL pts (0 CR/2 PR/1 SD), 1/2 iNHL pts (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). No responses have been observed to date in evaluable pts with MM (0/3) or aggressive NHL (0/2). All pts with at least SD after 2 cycles (n=6) remain on treatment including the first pt dosed. Based on the PK/PD and the preliminary activity observed in pts with CLL, iNHL and MCL, an expansion cohort is enrolling pts in these select hematologic diseases dosed at 25 mg BID to further evaluate the safety and preliminary activity of IPI-145. Dose escalation continues with a focus on pts with T-cell malignancies and DLBCL where increasing suppression of the PI3K-γ isoform may improve the efficacy profile. Additional expansion cohorts in T-cell lymphoma, DLBCL, myeloproliferative neoplasms and the acute leukemias will better define disease specific activity. Conclusions: IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears to be well tolerated and has shown initial clinical activity in pts with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits PI3K-δ, providing a rationale for expansion in CLL/iNHL/MCL. Additional safety and efficacy data from the ongoing dose escalation evaluation in T-cell/aggressive NHL and the CLL/iNHL/MCL expansion cohort will be presented. Disclosures: Flinn: Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc. : Research Funding. Patel:Infinity Pharmaceuticals, Inc. : Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc. : Research Funding; Gilead: Research Funding. Porter:Infinity Pharmaceuticals, Inc. : Employment. Sweeney:Infinity Pharmaceuticals, Inc. : Employment. Allen:Infinity Pharmaceuticals, Inc. : Employment. Kelly:Infinity Pharmaceuticals, Inc. : Employment. Kahl:Infinity Pharmaceuticals, Inc. : Research Funding.

Sign in / Sign up

Export Citation Format

Share Document