We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. ...There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non–germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.
•We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.•ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.
Summary
The B‐cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting ...of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti‐apoptotic functions of BCL2 proteins using structure‐based design to produce specific inhibitors of protein–protein interactions has been achieved for BCL2, MCL1 and BCL‐XL (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3‐mimetics. The first BCL2‐specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia (CLL), with surprisingly little toxicity given the expression of BCL2 in normal tissues. Despite success in CLL, where sensitivity to BCL2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B‐cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL2 inhibition. In this review, we summarise the biology of BCL2 proteins, the mechanism of action of BH3‐mimetics and the status of their clinical development in haematological malignancies.
This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory ...(R/R) or previously untreated (first line 1L) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response CR/CR with incomplete marrow recovery CRi, 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
•Dose finding established venetoclax 400 mg combined with obinutuzumab; this regimen had an acceptable safety profile in R/R and 1L CLL.•Venetoclax-obinutuzumab elicited high response rates with deep remissions in R/R and 1L CLL, irrespective of cytogenetic risk factors.
Display omitted
This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 ...dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737.
Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors.
The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer.
SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. ...However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL.
Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have ...reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12–15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.
PDF
