Kooperativer Bibliotheksverbund

In: Cancers, MDPI AG, Vol. 15, No. 17 ( 2023-09-01), p. 4381-

Abstract: The emerging field of small-molecule–drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvβ3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor. Pharmacokinetics studies of VIP236 in tumor-bearing mice demonstrated high stability of the SMDC in plasma and high tumor accumulation of the cleaved payload. Studies in bile-duct-cannulated rats showed that biliary excretion of the unmodified conjugate is the primary route of elimination. Treatment- and time-dependent phosphorylation of H2AX, a marker of DNA damage downstream of topoisomerase 1 inhibition, verified the on-target activity of the payload cleaved from VIP236 in vivo. Treatment with VIP236 resulted in long-lasting tumor regression in subcutaneous patient-derived xenograft (PDX) models from patients with non-small-cell lung, colon, and renal cancer as well as in two orthotopic metastatic triple-negative breast cancer PDX models. In these models, a significant reduction of brain and lung metastases also was observed.

Type of Medium: Online Resource

ISSN: 2072-6694

URL: Article

DOI: 10.3390/cancers15174381

Language: English

Publisher: MDPI AG

Publication Date: 2023

detail.hit.zdb_id: 2527080-1

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3039-3039

Abstract: Background: Targeted inhibition of Bruton tyrosine kinase (BTK) has improved clinical outcomes for patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a highly selective, covalent BTK inhibitor. A recently completed phase 3 trial showed acalabrutinib improved progression-free survival (PFS) vs idelalisib or bendamustine + rituximab in relapsed/refractory (R/R) CLL patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). This is an updated analysis with extended follow-up of a phase 1-2 multicenter study (NCT02029443) in patients with R/R CLL/small lymphocytic lymphoma (SLL), to demonstrate the durability of response and long-term tolerability of acalabrutinib. Methods: Patients with CLL or SLL were eligible if they were R/R after ≥1 prior treatment. Eligible patients were ≥18 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Oral acalabrutinib 100 mg was administered twice daily. All patients were treated until progressive disease or unacceptable toxicity occurred. Study endpoints included overall response rate (ORR), PFS, duration of response (DOR) and safety, with post hoc analysis of event-free survival (EFS). Response rates were based on the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria (Hallek et al., 2008) with modification for lymphocytosis (Cheson et al., 2012). Nine patients had longitudinal peripheral blood mononuclear cell samples from pre-treatment baseline, during treatment and at progression analyzed for whole exome sequencing, to assess acquired mechanisms of treatment resistance. Results: In total, 134 patients with R/R CLL/SLL received ≥ 1 dose of acalabrutinib. The median age was 66 years (range, 42-85 years). Baseline characteristics included ECOG PS ≤1 (97%), bulky lymph nodes ≥5 cm (39%), unmutated immunoglobulin heavy chain variable region (IGHV; 73%), chromosome 17p13.1 deletion (23%), chromosome 11q22.3 deletion (18%), and complex karyotype (≥3 abnormalities; 35%). The median number of prior therapies was 2 (range, 1-13). Patients received acalabrutinib for a median of 41 months (range, 0.2-58 months). Most adverse events (AEs) were mild to moderate, and most commonly were diarrhea (52%), headache (46%), and upper respiratory tract infection (36%). Grade ≥3 AEs occurred in 66% of patients; most commonly (≥5% of patients) neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%) and diarrhea (5%). AEs of interest included atrial fibrillation (7% all grades; 3% Grade ≥3) and major bleeding events (5% all grades; 3% Grade ≥3). Most patients (56%) remained on treatment. The most common reasons for discontinuing treatment were progressive disease (21%) and AEs (11%). AEs leading to discontinuation occurring in ≥1 patient included pneumonia (4 events), anemia, neutropenia, and thrombocytopenia (2 events each). The ORR (partial response with lymphocytosis or above) was 94% (95% confidence interval [CI]: 89-97%); with 4% of patients having complete response, 84% having partial response and 6% having partial response with lymphocytosis (Table). The median DOR, PFS and EFS were not reached; the estimated 42-month DOR was 61% (95% CI: 49-71%), PFS was 68% (95% CI: 59-76%) and EFS was 64% (95% CI: 54-71%). Responses were similar regardless of genomic features, including unmutated IGHV, chromosomal deletions and complex karyotype (Table). Upon relapse during acalabrutinib treatment, whole exome sequencing detected BTK mutations in 6 of 9 (67%) tested patients that were not detectable at baseline. Of the 6 patients with detectable BTK C481X mutations, 4 had expansion to high allele frequency of the BTK mutation at progression (up to 58%). In a longitudinal analysis of patients who had a sample after 6 months of treatment, the BTK mutation was not detectable. No PLCG2 gene mutations were detected using exome analysis in the 9 patients analyzed. Conclusions: These updated results confirm the earlier reports of acalabrutinib efficacy for the treatment of CLL and provide additional data on DOR and long-term tolerability. Reported AEs indicate a tolerable and consistent safety profile, with a low rate of major bleeding events. Genomic profiling in a small subset of patients indicated that acquired mutation of BTK was the most frequent mechanism of acalabrutinib resistance. Disclosures Furman: Genentech: Consultancy. Wierda:Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. Schuh:Roche: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Devereux:Servier: Speakers Bureau; Roche: Consultancy, Other: Travel expenses, Speakers Bureau; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brown:Pfizer: Consultancy; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Martin:Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy. Awan:Sunesis: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Innate Pharma: Research Funding; Gilead: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Stephens:Acerta: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding. Ghia:Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barrientos:Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Burke:AstraZeneca: Employment, Equity Ownership. Covey:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Gulrajani:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership. Rothbaum:Acerta Pharma: Employment, Equity Ownership. Wang:AstraZeneca: Equity Ownership; Acerta Pharma: Employment. O'Brien:Eisai: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau. OffLabel Disclosure: This is a Phase 1/2 investigational study of acalabrutinib in chronic lymphocytic leukemia

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128706

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2869-2869

Abstract: Aggressive B-cell lymphomas are genetically and clinically heterogeneous. Standard clinical trial designs do not efficiently evaluate the safety and efficacy of multiple drug combinations within the context of underlying molecular biology. The rapid identification of oncogenic driver pathways and development of multiple targeted drugs in lymphomas create many potential combinations. To address this need, we developed a Phase 1 master protocol termed PRISM (NCT03527147) to evaluate multiple targeted therapies alone or in combination for the treatment of relapsed/refractory (R/R) aggressive B-cell lymphoma. Each study arm is conducted in a predefined disease subset with the aim of addressing clinical and translational questions within an overarching protocol. All study arms are open label and not randomized. Enrolment of subjects into a given study arm is based on meeting inclusion/exclusion criteria and available slots. Pertinent inclusion criteria for the master protocol are: (a) a diagnosis of R/R non-Hodgkin lymphoma based on established World Health Organization criteria; (b) ≥1 prior line of therapy for the treatment of current histology, no known curative treatment options available, or the subject is ineligible for potential curative options; (c) the presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy and; (d) an ECOG performance status ≤2. Exclusion criteria for the master protocol include: (a) a history of prior malignancy, severe or uncontrolled disease or conditions; (b) use of anti-lymphoma therapy within 14 days of the first dose of study drug and; (c) a requirement for ongoing immunosuppressive therapy. Treatment-specific inclusion/exclusion criteria are also provided (see www.clinicaltrials.gov). As PRISM has multiple study arms, subjects can be simultaneously screened for multiple arms. In each arm, a safety review for dose-limiting toxicity (DLT) is performed after 6 subjects have completed the protocol-defined DLT window. Further enrolment will only proceed in that arm if ≤1 subject experiences a DLT (Figure 1). The sample size for each respective arm is determined based on prior clinical/experimental data on anticipated/clinically meaningful activity of each drug combination. This determines a minimally acceptable response and a desirable response. For each arm, a futility analysis occurs after approximately 10 sequentially enrolled subjects. An arm is considered futile if there is 〈 10% probability for the overall response rate (ORR) to be above the desirable response. A final analysis after approximately 21 enrolled subjects will determine whether the treatment should be studied further. The primary criterion for success is set as having 〉 80% chance for the response rate to be above the minimally acceptable response. The study endpoints include safety, ORR, duration of response, progression-free survival, overall survival, and standard pharmacokinetic parameters. Exploratory analyses include in depth translational studies employing peripheral blood and tumor tissue collected at screening and during treatment. These investigations aim to discover predictive biomarkers, identify the molecular correlates of response based on known genetic subtypes, investigate pharmacodynamic and pathway changes and define the depth of response using assays for measurable residual disease (MRD). Exploratory translational endpoints may inform additional biomarker selection strategies for future arms of the PRISM study. All study arms within PRISM to date have combined acalabrutinib, a highly selective BTK inhibitor, with additional targeted agents in subjects with R/R diffuse large B-cell lymphoma. The mechanism of action of the drugs combined with acalabrutinib are as follows: 1. AZD9150 is a 16-nucleotide antisense oligonucleotide designed to target and down-regulate expression of human STAT3 mRNA; administered intravenously. 2. AZD6738 is an inhibitor of ATR; administered orally. 3. Hu5F9-G4 is an anti-CD47 antibody and rituximab is an anti-CD20 antibody; both administered intravenously. 4. AZD5153 is a BRD4 inhibitor; administered orally. In summary, PRISM is a unique platform protocol designed to efficiently evaluate targeted agents in R/R aggressive B-cell lymphoma with an emphasis on comprehensive translational and molecular investigations. Disclosures Izumi: AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Hamdy:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Arkenau:Acerta Pharma: Research Funding. de Vos:Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Zinzani:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Davies:BioInvent: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Pharmacyclics, Inc.: Consultancy. Vose:Legend Pharmaceuticals: Honoraria; Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Bitman:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Brock:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Clark:AstraZeneca: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Ware:Acerta Pharma: Employment; Astrazeneca: Employment, Equity Ownership. Yang:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Staudt:Nanostring: Patents & Royalties. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. OffLabel Disclosure: acalabrutinib in DLBCL

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125939

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 135, No. 15 ( 2020-04-9), p. 1204-1213

Abstract: Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13] ) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2018884940

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 3, No. 9 ( 2019-05-14), p. 1553-1562

Abstract: Acalabrutinib had good tolerability in patients with relapsed or refractory CLL who were intolerant to ibrutinib. Acalabrutinib demonstrated a high response rate (81%) in patients with relapsed or refractory CLL who were intolerant to ibrutinib.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2018030007

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 2876449-3

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 7 ( 2022-04-01), p. 1285-1293

Abstract: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. Patients and Methods: Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. Results: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in & gt; 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). Conclusions: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-21-3617

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2022

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 270-270

Abstract: Background: Chronic Lymphocytic Leukemia (CLL) is a genetically heterogeneous disease characterized by clonal expansion of B-lymphocytes that induce secondary immune suppression. CLL is now treated with inhibitors of Bruton tyrosine kinase (BTK) and BCL2. Virtually all patients respond to therapy, however resistance to these therapies has been described justifying the need for novel CLL therapies. Broad inhibition of cyclin dependent kinases (CDK) and associated alternative target enzymes with agents such as flavopiridol or dinaciclib have demonstrated significant clinical activity in CLL but are hindered by a relatively narrow therapeutic window. VIP152 is a highly specific inhibitor of CDK9 - considered the most important CDK kinase member for CLL clinical activity. VIP152 has favorable pharmacokinetic properties and has demonstrated durable, preliminary single-agent clinical activity in double-hit diffuse large B-cell lymphoma. Herein, we report the efficacy of VIP152 preclinically in CLL. Methods: On-target activity of VIP152 was measured using a KinomeScan from DiscoveryRx at 100nM and 1000nM. Kinase profiling for VIP152 was performed on 6 kinases in a 10-dose assay at ReactionBio. Cell-based viability and proliferation assays (MTS, Annexin-V (AV), and propidium iodine (PI)) were performed in primary CLL cells and the CLL cell lines, HG3 and MEC1. Transcriptional activity after VIP152 exposure was measured via qPCR and limiting-cell RNA sequencing (lcRNAseq). Proteomic and immunoblot studies were performed to measure perturbations in CDK9 binding partners and on-target activity of VIP152. A genome-wide CRISPR/CAS9 knockout screen was performed to identify any synthetically lethal targets and pathways. Results: The KinomeScan identified CDK9 as the kinase with maximal inhibition upon VIP152 treatment and no other CDKs were identified at 100nM. Kinase profiling revealed the IC 50 of VIP152 was lowest for CDK9/Cyclin T1 and CDK9/Cyclin T2 with close similarity to dinaciclib and greater than 1 log superiority over KB-0742. Co-immunoprecipitation and proteomics experiments have identified a CDK9 specific mechanism of action relating to perturbations of CDK9 binding partners. Specifically, we showed that CDK9 nuclear immunoprecipitation resulted in decreased co-immunoprecipitation of 7SK RNA components (HEXIM1 & MEPCE) as well as decreased RNA Polymerase II (RNAP2). The decrease in RNAP2 CoIP was further seen via proteomics. A 2-hour exposure of VIP152 against HG3 and MEC1 demonstrated growth inhibition, with an IC 50 of 0.9814µM and 1.092µM respectively. Continuous exposure of the compound for 24 hours resulted in a statistically significant drop in relative viability of 30% across a 10-fold dose range (0.1µM to 1.0µM) as measured by AV/PI. Primary CLL cells (n=10) responded with similar dosing strategies with a 54% reduction in viability at 1µM; moreover, stromal cell co-culture experiments demonstrated VIP152's ability to induce cell death and overcome stromal protection with short exposure. Induction of apoptosis was observed with pro-caspase-3 and PARP cleavage on immunoblot. qPCR and immunoblot studies demonstrated a time dependence of phosphorylated serine 2 (pS2) RNAP2 decreases alongside diminishment of MYC and MCL1 mRNA and protein. pS2 was shown to decrease as early as 2 hours after VIP152 treatment with similar decreases in MCL1 and MYC at both the protein and mRNA levels. We identified several pathways which are disrupted following treatment via lcRNAseq, including TNFR1 and TNFR2 signaling as well as upregulation of autophagy signals. Finally, CRISPR screen identified several potentially synergistically lethal targets, including transcriptional co-activators, DNA binding proteins, and cell proliferation pathways. Validation of these is ongoing as is an in vivo study of VIP152 in a CLL mouse model. Conclusions: Our data demonstrate VIP152 to be a highly selective and potent CDK9 inhibitor that disrupts the CDK9 nuclear complex and mediates significant preclinical activity against CLL cell lines and primary CLL cells. VIP152 also demonstrates predictable and new pharmacodynamic markers to assess target engagement. Collectively, these data support the recently initiated CLL clinical trial (NCT04978779). Disclosures Johnson: Vincerx: Current Employment; Janssen: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Frigault: Vincerx Pharma Inc: Current Employment; AstraZeneca: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months, Patents & Royalties. Greer: Gilead: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vincerx Pharma Inc: Current Employment. Hamdy: Vincerx Pharma Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma Inc: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Patents & Royalties. Izumi: Acerta Pharma Inc: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Patents & Royalties; Vincerx Pharma Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hwang: Vincerx Pharma Inc: Current Employment, Current equity holder in publicly-traded company. Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-153812

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Biophysical Journal, Elsevier BV, Vol. 96, No. 3 ( 2009-02), p. 30a-

Type of Medium: Online Resource

ISSN: 0006-3495

URL: Article

DOI: 10.1016/j.bpj.2008.12.047

Language: English

Publisher: Elsevier BV

Publication Date: 2009

detail.hit.zdb_id: 1477214-0

SSG: 12

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 7500-7500

Abstract: 7500 Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor. This Phase 1b/2 trial evaluated acalabrutinib with the CD20 antibody Ob in TN and R/R CLL. Methods: Patient (pts) with TN and R/R (≥1 prior therapy) CLL were eligible. In 28-day cycles, acalabrutinib was given at 100 mg BID or 200 mg QD PO (n=15; all switched to 100 mg BID) until progressive disease (PD); Ob was given in standard fashion for 6 cycles starting with Cycle 2. The primary endpoints were overall response rate (ORR) and safety. Minimal residual disease (MRD) was assessed using flow cytometry (sensitivity 10 -4 ). Results: 19 TN and 26 R/R pts were treated; median age of all pts was 61 y (range 42-76). Pt characteristics, disposition, efficacy and MRD are in the Table. Common adverse events (AEs; any grade) were upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%) and dizziness (47%). Common Gr 3/4 AEs were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight and cellulitis (9% each). There were 2 (4%) Gr 3 bleeding events (hematuria, muscle hemorrhage) and 1 (2%) Gr 3 atrial fibrillation event. Conclusions: Acalabrutinib plus Ob was well tolerated and yielded high response rates that were durable and deepened over time in TN and R/R CLL patients. Clinical trial information: NCT02296918. [Table: see text]

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2019.37.15_suppl.7500

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2019

detail.hit.zdb_id: 2005181-5

In: Leukemia, Springer Science and Business Media LLC, Vol. 37, No. 2 ( 2023-02), p. 326-338

Abstract: Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-022-01758-z

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2008023-2