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Academic literature on the topic 'Navitoclax'

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Published: 4 June 2021

Last updated: 27 April 2022

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Journal articles on the topic "Navitoclax"

Nor Hisam, Nur Syahidah, Azizah Ugusman, Nor Fadilah Rajab, Mohd Faizal Ahmad, Michael Fenech, Sze Ling Liew, and Nur Najmi Mohamad Anuar. "Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence." Pharmaceutics 13, no. 9 (August 28, 2021): 1353. http://dx.doi.org/10.3390/pharmaceutics13091353.

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Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.

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Kipps, Thomas J., William G. Wierda, Jeffrey A. Jones, Lode J. Swinnen, Jianning Yang, Yue Cui, Todd Busman, Andrew Krivoshik, Sari Enschede, and Rod Humerickhouse. "Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)." Blood 116, no. 21 (November 19, 2010): 2455. http://dx.doi.org/10.1182/blood.v116.21.2455.2455.

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Abstract Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

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Puglisi, Martina, L. Rhoda Molife, Maja JA de Jonge, Khurum H. Khan, Leni van Doorn, Martin D. Forster, Montserrat Blanco, et al. "A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors." Future Oncology 17, no. 21 (July 2021): 2747–58. http://dx.doi.org/10.2217/fon-2021-0140.

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Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1–5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov)

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Chteinberg, Emil, Suzan Wetzels, Wouter Gerritsen, Lieve Temmerman, Joost van den Oord, Erik Biessen, Anna Kordelia Kurz, et al. "Navitoclax combined with Alpelisib effectively inhibits Merkel cell carcinoma cell growth in vitro." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592097562. http://dx.doi.org/10.1177/1758835920975621.

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Background: Merkel cell carcinoma (MCC) is a highly malignant skin cancer. Despite major treatment improvements during the last decade, up to 50% of patients do not respond to therapy or develop recurrent disease. For these patients, alternative treatment options are urgently needed. Here, we assessed the efficacy of the combination of the BCL-2 inhibitor Navitoclax and the PI3K p110α inhibitor Alpelisib in MCC cell lines. Methods: The expression of BCL-2 was assessed by immunohistochemistry in MCC and MCC cell lines. Treatment with Navitoclax and Alpelisib alone and in combination was performed on four MCC cell lines. The decrease of cell viability during treatment was assessed by XTT assay and visualized for the combinations by 3D combinatorial index plotting. The increase of apoptotic cells was determined by cleaved PARP Western blotting and Annexin V staining. Results: Some 94% of MCCs and all three MCPyV-positive cell lines showed BCL-2 expression. Navitoclax monotreatment was shown to be highly effective when treating BCL-2-positive cell lines (IC50-values ranging from 96.0 to 323.0 nM). The combination of Alpelisib and Navitoclax resulted in even stronger synergistic and prolonged inhibitions of MCC cell viability through apoptosis up to 4 days. Discussion: Our results show that the anti-apoptotic BCL-2 is frequently expressed in MCC and MCC cell lines. Inhibition of BCL-2 by Navitoclax in combination with Alpelisib revealed a strong synergy and prolonged inhibition of MCC cell viability and induction of apoptosis. The combination of Navitoclax and Alpelisib is a novel potential treatment option for MCC patients.

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Roberts, Andrew W., John F. Seymour, Jennifer R. Brown, William G. Wierda, Thomas J. Kipps, Seong Lin Khaw, Dennis A. Carney, et al. "Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease." Journal of Clinical Oncology 30, no. 5 (February 10, 2012): 488–96. http://dx.doi.org/10.1200/jco.2011.34.7898.

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Purpose BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-xl and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. Patients and Methods Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. Results Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-xl inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. Conclusion BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.

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Marczyk, Michal, Gauri A. Patwardhan, Jun Zhao, Rihao Qu, Xiaotong Li, Vikram B. Wali, Abhishek K. Gupta, et al. "Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells." Cancers 12, no. 9 (September 8, 2020): 2551. http://dx.doi.org/10.3390/cancers12092551.

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Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells. Cells were sampled before treatment, at 72 h of exposure, and after 10-day drug-free recovery from treatment. We observed transient alterations in the expression of stress response genes that were accompanied by corresponding changes in chromatin accessibility. Most of these changes returned to baseline after the recovery period. We also detected lasting alterations in methylation states and genome structure that suggest permanent changes in cell population composition. Using single-cell analyses, we identified 2350 genes significantly upregulated in navitoclax-resistant cells and derived an 18-gene navitoclax resistance signature. We assessed the navitoclax-response-predictive function of this signature in four additional TNBC cell lines in vitro and in silico in 619 cell lines treated with 251 different drugs. We observed a drug-specific predictive value in both experiments, suggesting that this signature could help guiding clinical biomarker studies involving navitoclax.

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Kipps, Thomas J., Lode J. Swinnen, William G. Wierda, Jeffrey Alan Jones, Steven E. Coutre, Mitchell R. Smith, Jianning Yang, et al. "Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL),." Blood 118, no. 21 (November 18, 2011): 3904. http://dx.doi.org/10.1182/blood.v118.21.3904.3904.

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Abstract Abstract 3904 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50≤1 μM) against T and B lymphoid malignancies that overexpress Bcl-2. In preclinical models of B-cell lymphoma, navitoclax enhanced efficacy of rituximab (R) when used alone or in combination with chemotherapy. Based on phase 1 trial data, oral navitoclax monotherapy was well-tolerated and had anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). Thrombocytopenia was the dose-limiting toxicity (DLT). We examined whether navitoclax could be used safely in combination with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) for treatment of pts with CLL. Methods: This ongoing, phase 1 dose-escalation study is evaluating the safety and pharmacokinetics (PK) of oral navitoclax used in combination with FCR (Arm A) or BR (Arm B) for treatment of pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥1000/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. Enrolled pts (6 pts/cohort) were assigned to Arm A or Arm B based on physician preference. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent 28-day cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Oral navitoclax was administered once daily (starting dose of 110 mg) pre-chemotherapy on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. Dose escalation decisions were made independently in each arm via a continuous reassessment method, and the objective was to identify a dose of navitoclax in combination with chemotherapy in which <33% of subjects experienced DLTs. Tumor responses were evaluated using NCI-WG 1996 criteria. Adverse events (AE) were graded by NCI CTCAE V3. Pts continued on navitoclax monotherapy up to the recommended phase 2 dose of 250 mg daily for 1 year or until progressive disease or intolerable toxicity. Results: As of July 2011, 28 pts (median age 59 yr [39–80]) have enrolled; 5 in Arm A (FCR+navitoclax; 110 mg) and 23 in Arm B (BR+navitoclax; 110–250 mg). The median number of prior therapies was 2 (range 1–13). In Arm A, 1 pt had a DLT of febrile neutropenia (110 mg). In Arm B, 5 pts had DLT; 1 had elevated ALT and AST (110 mg), 1 had grade 4 febrile neutropenia (200 mg), and 3 had grade 4 thrombocytopenia (250 mg). Overall, the most common (>20%) navitoclax-related AEs of any grade were nausea (73%), fatigue (50%), neutropenia (50%), cough (39%), vomiting (35%), chills (31%), diarrhea (31%), constipation (27%), headache (27%), anemia (23%), and thrombocytopenia (23%). The most common (>19%) grade 3/4 navitoclax-related AE was neutropenia (35%) and thrombocytopenia (19%); but only 2 of the latter pts had hemorrhagic events (Grade 1 epistaxis) unlikely related to navitoclax. Of the 28 pts evaluated for safety, 6 remain active and 22 discontinued (DC); 1 due to AE, 1 due to AE and progressive disease (PD), 3 due to PD, 6 withdrew consent, 3 due to physician discretion, 4 completed therapy, 2 proceeded to transplant, and 2 due to toxicity. Preliminary best anti-tumor responses were assessed in 20 pts. Of the 16 pts assessed in Arm B (BR), 6 achieved complete responses (CR), 7 partial responses (PR), 2 stable disease (SD) and 1 with PD. The ORR was 81% (13/16). In this arm, 3/5 pts with 17p deletion achieved PR. Of the 4 pts assessed in Arm A (FCR), 2 achieved PR, 1 SD and 1 with PD. Preliminary PK results suggest that there is no apparent PK interaction between navitoclax and bendamustine. Conclusions: The combination of navitoclax with BR appears well-tolerated and to have anti-tumor activity. The maximum tolerated dose of navitoclax has been reached at 250 mg for Arm B, but not for Arm A where escalation continues. To date, we have not observed unacceptable myelotoxicity when this bcl-2 antagonist was used in combination with standard cytotoxic chemo-immunotherapy regimens for treatment of pts with CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Off Label Use: R05429083 is a novel humanized antibody direct against the standard region of CD44. R05429083 is currently intensive pre-clinical studies and fist dosing of cancer patients has started in Europe in 2011. Swinnen:Abbott Laboratories: Research Funding. Yang:Abbott Laboratories: Employment. Cui:Abbott Laboratories: Employment, Stock Holder at Abbott Laboratories. Busman:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Enschede:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Humerickhouse:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock.

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Kahl, Brad, Andrew W. Roberts, John F. Seymour, Ranjana H. Advani, Daniel Oscar Persky, Jianning Yang, Yue Cui, et al. "Navitoclax (ABT-263) Plus Rituximab: Interim Results of a Phase 1 Study In Patients with CD20-Positive Lymphoid Malignancies." Blood 116, no. 21 (November 19, 2010): 3943. http://dx.doi.org/10.1182/blood.v116.21.3943.3943.

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Abstract Abstract 3943 Background: Navitoclax (ABT-263) is a novel, orally bioavailable, small molecule that binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. Navitoclax shows potent targeted cytotoxicity (EC50 ≤1μM) in vitro against T and B lymphoid malignancies that over-express Bcl-2. As monotherapy in phase 1 trials, oral navitoclax is well-tolerated and with daily dosing has shown activity in patients (pts) with lymphoid malignancies and many pts (response rate approximately 35%) with chronic relapsed or refractory lymphocytic leukemia (CLL). Thrombocytopenia is the dose-limiting toxicity (DLT). Rituximab mono- or combination therapy is an established treatment for pts with indolent, CD20-positive B-cell malignancies. In multiple preclinical models of B-cell lymphoma, the efficacy of rituximab (monotherapy and in combination with chemotherapy) was enhanced by the addition of navitoclax. Methods: This international, phase 1, dose-escalation study employing a modified Fibonacci 3+3 design, assessed the safety and pharmacokinetics (PK), and determined the maximum tolerated dose (MTD) and the recommended phase 2 dose (RPTD) of oral navitoclax added to standard rituximab monotherapy in pts with CD20-positive malignancies. Secondary objectives were evaluation of progression-free survival, response rate, duration of response, and overall survival. Patient eligibility included ≥1 lesion ≥1.5 cm, ECOG score ≤1, and platelet count of ≥100,000/mm3. For all dose cohorts, after a 7–14 day 150 mg/day dose lead-in, navitoclax was given once daily at 200 mg (Cohort 1), 250 mg (Cohort 2), or 325 mg (Cohort 3). At least 3 pts were enrolled in each cohort. At MTD determination, a safety expansion cohort of up to 12 pts was added. Pts proceeded from lead-in to the combination regimen, if the pre-dose platelet count on Lead-in Day 7 was ≥50,000/mm3. Rituximab was given 375 mg/m2 IV once weekly for 4 doses, starting Day 1 of Week 1. A cycle was 28 days of therapy. Patients were allowed to continue on navitoclax therapy for 2 years in the absence of progressive disease or significant toxicity. Safety was assessed by NCI-CTCAE v3.0, and tumor responses by IWG or NCI-WG criteria (for CLL pts) every 2 months by CT or MRI. Results: As of July 2010, 19 pts, median age 58 years (range 45–92), have been enrolled (11 with follicular lymphoma [FL], 3 with CLL/SLL, and 1 each with diffuse large B-cell lymphoma, transformed disease, lymphoplasmacytic lymphoma [LPL], lymphoblastic lymphoma, and Hodgkin lymphoma, respectively); 4 in the 200 mg, 7 in the 250 mg, 3 in the 325 mg, and 5 in the 250 mg expanded safety cohort. The median number of prior therapies was 3. Seventeen pts had navitoclax-related AEs, the most common being diarrhea (11 pts), nausea (11), and fatigue (8). DLTs were Grade 3 diarrhea (1 pt in the 250 mg cohort), Grade 3 fatigue (1 pt in the 325 mg cohort), and Grade 4 thrombocytopenia (1 pt in the 325 mg cohort). MTD was defined as 250 mg. Preliminary antitumor activity and best response data are available for 12 pts. Eight pts responded (ORR 67%) with 4 CRs (all FL), 4 PRs (SLL, FL, CLL, LPL), 1 SD, and 3 PDs. Five other pts are continuing treatment but have not yet reached the first tumor assessment at 12 weeks. One pt discontinued due to disease progression prior to the first tumor assessment, and 1 pt discontinued after 3 days of dosing due to the taste of the oral drug solution. Twelve pts remain on study at a median of 19.4 weeks (4.4–49.1 weeks). Preliminary PK results indicated that navitoclax PK at doses of 200–325 mg in this combination study was comparable to that in the navitoclax monotherapy study. Conclusions: The combination of navitoclax and rituximab is well tolerated and shows encouraging preliminary evidence of activity. The MTD of navitoclax in combination with rituximab is 250 mg. An expanded cohort of pts is being enrolled at 250 mg of navitoclax to further assess tolerability, confirm this dose as the RPTD, and to better define efficacy. Disclosures: Kahl: Abbott: Consultancy, Research Funding. Roberts:Abbott: Research Funding. Seymour:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani:Abbott: Research Funding. Persky:Millennium, Takeda: Consultancy, Research Funding. Yang:Abbott: Employment. Cui:Abbott: Employment. Busman:Abbott: Employment. Krivoshik:Abbott: Employment. Enschede:Abbott: Employment. Humerickhouse:Abbott: Employment.

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Phillips, D. C., Y. Xiao, L. T. Lam, E. Litvinovich, L. Roberts-Rapp, A. J. Souers, and J. D. Leverson. "Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)." Blood Cancer Journal 5, no. 11 (November 2015): e368-e368. http://dx.doi.org/10.1038/bcj.2015.88.

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Abstract As a population, non-Hodgkin’s lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2 High ) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2 High cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2 High NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2 Low NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2 Low ) that could benefit from BCL-XL (navitoclax)-driven combination therapy.

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Eradat, Herbert, Sebastian Grosicki, John Catalono, Walter Cosolo, Irina Dyagil, Thomas J. Kipps, Beiyao Zheng, et al. "Preliminary Results of a Phase II Open-Label, Randomized Study of the BH3 Mimetic Protein Navitoclax (ABT-263) with or without Rituximab for Treatment of Previously Untreated B-Cell Chronic Lymphocytic Leukemia." Blood 120, no. 21 (November 16, 2012): 190. http://dx.doi.org/10.1182/blood.v120.21.190.190.

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Abstract Abstract 190 Introduction: Overexpression of Bcl-2 in Chronic Lymphocytic Leukemia (CLL) is associated with enhanced CLL-cell resistance to spontaneous or chemotherapy-induced apoptosis. The BH3 mimetic protein navitoclax (ABT-263) specifically inhibits Bcl-2, and related proteins Bcl-xL and Bcl-w, and can induce apoptosis of CLL cells in vitro. Phase I evaluation in relapsed/refractory CLL patients demonstrated 35% overall response rate (Roberts, 2012). Dose-limiting thrombocytopenia due to Bcl-xL inhibition was mitigated using a lead-in dosing schedule to allow the bone marrow to achieve a compensatory increase in platelets prior to dose escalation to the MTD of 250 mg. Based on the promising single-agent data, a Phase II trial randomized trial compared the safety, pharmacokinetics, and biologic activity of treatment with navitoclax and rituximab (RTX) versus RTX alone. Methods: Patients with CLL who required initial treatment according to iwCLL criteria (Hallek et al, 2008) were stratified by Binet stage and high-risk cytogenetic features (17p deletion and/or 11q deletion), and randomized 1:1:1 to receive RTX weekly for 8 wks (375 mg/m2 wk 1, 500 mg/m2 wks 2–8) (Arm A), or RTX for 8 wks plus navitoclax daily for 12 wks (250 mg/day following a 7–14 day lead-in period of 100 mg/day) (Arm B), or RTX for 8 wks plus navitoclax daily as in Arm B, but continued treatment with navitoclax until disease progression, relapse, or unacceptable toxicity (Arm C). Arm A to Arm B crossover was permitted. Response rate was assessed by iwCLL CLL response criteria at week 12, and every 12 weeks during follow-up. The study was stopped after the last patient had completed ≥ 12 weeks of treatment and week-12 response assessment. Results: Baseline characteristics and prognostic factors for the 118 randomized patients were generally balanced among the three treatment arms. Median age was 63 years (range 38–94), and 55% were Binet stage B+C. Median baseline lymphocyte count was 53,000 mm3 (range 7,000–552,000/mm3). FISH analyses identified higher than expected rates of deletion of 11q or 17p in the CLL cells of 32% or 28% of patients, respectively. Median time on study was 32 weeks overall (24 wks for Arm A, 33 wks Arm B, and 44 wks Arm C). AEs of Grade 3–4 that were more common (> 5% greater) in a navitoclax-treated arm compared with the RTX arm included thrombocytopenia, neutropenia, leukopenia, anemia, GI symptoms (diarrhea, abdominal pain), chills, fatigue, ALT/AST/bilirubin elevations, and infusion-related reactions (to RTX). Thrombocytopenia, neutropenia, and hepatic enzyme elevations were generally reversible when navitoclax was stopped and/or dose-reduced; however, 12 patients (15%) discontinued navitoclax due to laboratory abnormalities (9 due to ALT elevations). Neutropenia responded to growth factors. One serious event of epistaxis occurred related to the thrombocytopenia. Two deaths occurred on study, one on the RTX-only arm due to a pulmonary embolus and one on Arm B due to hypotension and dyspnea related to a severe RTX infusion reaction. Investigator-assessed objective response (CR and PR) rate was 35% for Arm A, 55% for Arm B (p=0.19 vs A), and 70% for Arm C (p=0.0034 vs A). All responses were PRs except for 2 CRs in Arm C. All responses were confirmed by CT (and BM for CR) ≥ 8 wks after clinical response assessment. While the presence of 17p deletion appeared to result in a lower response rate to RTX alone (Arm A, ORR 18%, 2/11 pts), it did not appear to affect the response to ABT-263 and RTX (Arm B, ORR 73%, 8/11 pts); Arm C, ORR 50%, 5/10 pts. Limited PFS results appeared consistent with the responses by arm, with a longer PFS associated with the longer duration of ABT-263 treatment on Arm C; however, the magnitude of PFS differences could not be precisely quantified due to the limited follow-up and patient number. Preliminary pharmacokinetic analysis did not detect any drug interaction between navitoclax and RTX. Conclusions: Navitoclax in combination with RTX weekly × 8 was generally well-tolerated as initial therapy for CLL patients and demonstrated greater clinical activity than treatment with RTX alone as well as responses in patients with 17p deletion. The preliminary results of this study indicate that a BH3-mimetic inhibitor of Bcl-2 could be highly effective when used in combination with RTX for treatment of patients with CLL. Disclosures: Eradat: Genentech: Research Funding. Off Label Use: BH3 Mimetic Protein Navitoclax (ABT-263). Catalono:Genentech: Consultancy. Kipps:Genentech: Research Funding. Zheng:Genentech: Employment. Yalamanchili:Genentech: Employment. Sahasranaman:Genentech: Employment. Hurst:Genentech: Employment. Ho:Genentech: Employment.

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Dissertations / Theses on the topic "Navitoclax"

Stamelos, Vasileios Antoniou. "Investigation of the BH3-mimetics navitoclax and obatoclax as potential therapeutics for ovarian cancer." Thesis, Keele University, 2014. http://eprints.keele.ac.uk/2439/.

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Ovarian cancer is treated in most cases with a combination of surgery and chemotherapy. However, despite the overall improvement in survival rates, over the last 30 years there has not been a break-through therapeutic development. Following first-line treatment, the majority of patients experience periods of relapse characterised by resistance to anticancer drugs. Factors which contribute to ovarian cancer chemoresistance have been identified as potential targets for drug discovery, such as the Bcl-2 family of proteins, which regulates apoptosis. The strategy of targeting the anti-apoptotic members of the Bcl-2 family that are overexpressed in ovarian cancer has led to the discovery of BH3-mimetics. ABT-737, a selective BH3-mimetic, has been found to be synergistic with chemotherapy in ovarian cancer. In this study the activity of navitoclax, an orally available analogue of ABT-737 and obatoclax, a pan-Bcl-2 inhibitor, were evaluated in a series of ovarian cancer models. Navitoclax demonstrated synergy with both carboplatin and paclitaxel. Obatoclax potently inhibited the growth of ovarian cancer cell cultures. In part this was due to the anticipated induction of apoptosis, but in other cell lines an additional mechanism of cell death was implicated. Surprisingly, obatoclax was neither synergistic with carboplatin nor paclitaxel. These observations may be used to inform the design of clinical trials of these agents in ovarian cancer.

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Yasuda, Yuto. "MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression." Kyoto University, 2020. http://hdl.handle.net/2433/254508.

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Book chapters on the topic "Navitoclax"

Wendt, Michael D. "The Discovery of Navitoclax, a Bcl-2 Family Inhibitor." In Topics in Medicinal Chemistry, 231–58. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-28965-1_7.

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Conference papers on the topic "Navitoclax"

Wu, Y., N. Koleci, L. Gallego-Villar, VR Mittapalli, S. Bohler, and M. Erlacher. "Analyzing the therapeutic efficacy of navitoclax and MCL-1 inhibitors in juvenile myelomonyctic leukemia." In 32. Jahrestagung der Kind-Philipp-Stiftung für pädiatrisch onkologische Forschung. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1687136.

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Coley, Helen M., Laura Lattanzio, Ornella Garrone, Marco Merlano, Daniela Vivenza, Cristiana Lo Nigro, Nelofer Syed, Alistair Thompson, Bhavya Rao, and Tim Crook. "Abstract 3197: Splicing factors and the role of Navitoclax in drug-resistant ovarian cancer." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-3197.

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Tan, Nguyen, Mehnaz Malek, Jiping Zha, Robert Kassees, Leanne Berry, Wayne J. Fairbrother, Deepak Sampath, and Lisa Belmont. "Navitoclax enhances the activity of taxanes in non-small cell lung carcinoma (NSCLC) models." In AACR International Conference: Molecular Diagnostics in Cancer Therapeutic Development– Sep 27-30, 2010; Denver, CO. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/diag-10-b24.

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Hoff, Taylor, Daniel Cho, David Panka, Alireza Sepehr, Lauren Curtis, James W. Mier, and Ryan J. Sullivan. "Abstract A27: The combination of navitoclax and PLX4720 in melanoma in vitro and in vivo." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a27.

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Marczyk, Michal, Vignesh Gunasekharan, Jun Zhao, Rihao Qu, Xiaotong Li, Gauri A. Patwardhan, Vikram B. Wali, et al. "Abstract 6333: Genomic, transcriptomic, and epigenetic profiling of triple-negative breast cancer cells after Navitoclax treatment." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-6333.

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DeStefanis, Rebecca Anna, Alyssa DeZeeuw, Gioia Sha, Autumn Olson, Samantha J. Anderson, Christopher P. Babiarz, Cheri A. Pasch, Linda Clipson, and Dustin A. Deming. "Abstract 1944: Navitoclax enhances the efficacy of copanlisib predominantly through inhibition of BCLxL inPIK3CAmutant colorectal cancer." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1944.

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Lee, Jung-Min, Alyssa Stacy, Minshu Yu, and Elise C. Kohn. "Abstract A249: Navitoclax and veliparib yield cytotoxicity with lower doses than used for single agents in women's cancers." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a249.

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He, Y. D., T. Carr, J. Wetter, L. Leys, Z. Su, A. Williams, L. Olson, et al. "The BCL-xL/BCL-2 Inhibitor Navitoclax Targets Myofibroblasts and Reduces Idiopathic Pulmonary Fibrosis (IPF) in Pre-Clinical Models." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2296.

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Mertens, Joachim C., Christian D. Fingas, John D. Christensen, Keisuke Kakisaka, Rory L. Smoot, Steven F. Bronk, Justin L. Mott, et al. "Abstract 4905: The BH3 mimetic navitoclax (ABT-263) selectively induces apoptosis in cholangiocarcinoma-associated fibroblasts thereby reducing tumor growth." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4905.

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Koubek, Emily J., Brian A. Costello, Jun Yin, Renee M. McGovern, Sarah A. Buhrow, Renee A. Schoon, Carrie A. Strand, et al. "Abstract CT114: Pharmacokinetic analysis of navitoclax in combination with sorafenib in patients with relapsed or refractory solid organ tumors." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-ct114.

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Academic literature on the topic 'Navitoclax'

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Journal articles on the topic "Navitoclax"

Dissertations / Theses on the topic "Navitoclax"

Book chapters on the topic "Navitoclax"

Conference papers on the topic "Navitoclax"