Results From the Safety Run‐in Period of the Sympatico Study Evaluating Ibrutinib in Combination With Venetoclax in Patients With Relapsed/Refractory Mantle Cell Lymphoma

Wang, M.; Ramchandren, Rod; Chen, R.; Karlin, Lionel; Chong, Geoff; Jurczak, Wojciech; Wu, Kalung; Bishton, Mark; Collins, Graham P.; Eliadis, Paul; Peyrade, F.; Freise, Kevin J.; Sukbuntherng, Juthamas; Lee, Y.; Dobkowska, Edyta; Федоров, В. Э.; Neuenburg, Jutta K.; Tam, Constantine S.

doi:10.1002/hon.146_2630

Cited by 4 publications

(9 citation statements)

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“…Our approach was novel in finding the optimal dose, instead of the maximum tolerated dose, utilizing a CRM to allocate participants based on prior participant's efficacy and toxicity. Our primary finding shows that the optimal dose was Arm B (IBR 420mg PO daily, VEN 200mg PO daily), which is lower than other studies are using (SYMPATICO study, NCT03112174) 33,34 or have used (AIM or OAsIs study) 28,29,35 in relapsed MCL. The SYMPATICO 33,34 , AIM 28,35 , and OAsIs 29 studies utilize IBR 560mg PO daily and VEN 400mg PO daily in MCL, a dose combination that we were not able to test due to DLTs and adequate response at lower dose levels.…”

Section: Discussionmentioning

confidence: 72%

“…Our primary finding shows that the optimal dose was Arm B (IBR 420mg PO daily, VEN 200mg PO daily), which is lower than other studies are using (SYMPATICO study, NCT03112174) 33,34 or have used (AIM or OAsIs study) 28,29,35 in relapsed MCL. The SYMPATICO 33,34 , AIM 28,35 , and OAsIs 29 studies utilize IBR 560mg PO daily and VEN 400mg PO daily in MCL, a dose combination that we were not able to test due to DLTs and adequate response at lower dose levels. The reports of these studies [33][34][35] have reported frequent dose reductions in upwards of 60% of patients.…”

Section: Discussionmentioning

confidence: 72%

“…The SYMPATICO 33,34 , AIM 28,35 , and OAsIs 29 studies utilize IBR 560mg PO daily and VEN 400mg PO daily in MCL, a dose combination that we were not able to test due to DLTs and adequate response at lower dose levels. The reports of these studies [33][34][35] have reported frequent dose reductions in upwards of 60% of patients. The OAsIs study had a dose finding portion of the study (evaluating higher doses of VEN) with limited DLTs; however, our definition of DLTs was conservative and our DLT interval was long (8 weeks).…”

Section: Discussionmentioning

confidence: 99%

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Dose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

et al. 2021

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Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's Tyrosine Kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib(IBR) has shown synergy in pre-clinical MCL models. Prior MCL studies of the combination report promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual re-assessment method of 6 combinations of IBR (280mg, 420 mg, and 560mg PO daily) and VEN (max dose of 200mg and 400mg PO daily). Eligible participants were not previously exposed to BTKi's and not high risk for Tumor Lysis Syndrome (TLS). VEN, initiated first at 100mg, then at 20mg PO daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level. Combination treatment continued for six 28 day cycles. 35 participants were enrolled and treated. One TLS event occurred with starting dose of 100mg VEN; no TLS was seen with 20mg. The optimal dosing combination was considered to be VEN 200mg and IBR 420mg with an ORR of 93.8% (95% CI: 73.6-99.7%) and DLT incidence of 6.2% (95% CI: 0.3-26.4%). Overall response for all arms was 82.3% (28/34; 95% CI: 65.5-93.2%) with a CR rate of 42.4% (14/33; 95% CI: 25.5-60.8%). A participant was not allocated to IBR 560mg and VEN 400mg. ORR benefit was not seen with higher dosing combinations and toxicity was higer; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Dose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

et al. 2021

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“…117,118 Given these encouraging outcomes in this heavily pretreated sample, venetoclax has become a frequently used agent in R/R MCL and is being studied in several combination regimens in both frontline and R/R settings. 119-128…”

Section: Developments In the Management Of Relapsed Or Refractory Dismentioning

confidence: 99%

“…134 Given the promising efficacy of this combination, a phase 3 trial comparing ibrutinib plus venetoclax with ibrutinib alone is underway to further elucidate place in therapy in the R/R setting and confirm optimal dose titration of venetoclax, with early safety results indicating a low rate of dose-limiting toxicity. 127 With ongoing study of this regimen, it will be important to continually assess its additive toxicity and appropriately select patients for its use.…”

Section: Ibrutinib Plus Venetoclaxmentioning

confidence: 99%

Management of Mantle Cell Lymphoma in the Era of Novel Oral Agents

et al. 2020

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Objectives: To discuss (1) recent and emerging data for pharmacological management of untreated and relapsed/refractory (R/R) mantle cell lymphoma (MCL) with agents approved in the United States, (2) important considerations for toxicity monitoring and management, and (3) preliminary data and ongoing studies for agents in MCL-specific clinical trials. Data Sources: PubMed/MEDLINE, EMBASE, Google Scholar, product labeling, National Comprehensive Cancer Network, American Cancer Society, and ClinicalTrials.gov were searched for studies published between January 1, 2017, and January 31, 2020, and key historical trials. Study Selection and Data Extraction: Relevant studies conducted in humans and selected supporting preclinical data were reviewed. Data Synthesis: MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the older population. Traditionally, the treatment of MCL has been determined based on transplant eligibility. Newer data suggest that more tolerable frontline therapy may produce outcomes similar to intensive historical induction regimens, possibly precluding fewer patients from autologous stem cell transplant and producing better long-term outcomes in transplant-ineligible patients. In the R/R setting, novel regimens are improving outcomes and changing the landscape of treatment. Relevance to Patient Care and Clinical Practice: This review summarizes and discusses recent and emerging data for management of newly diagnosed and R/R MCL; key supportive care considerations for agents are also discussed. Conclusions: Recent study results are changing management of MCL. Although these data have complicated the picture of regimen selection, increasingly effective and tolerable therapy and additional anticipated data point to a brighter future for patients with MCL.

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Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL)

Tbakhi

Reagan

2022

Therapeutic Advances in Hematology

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Mantle cell lymphoma (MCL) is a rare B-cell malignancy that remains challenging to treat with high rates of relapse. Frontline strategies range from intensive chemotherapy followed by consolidation with autologous stem cell transplant (ASCT), to less-intensive therapies including combination regimens. The treatment landscape for relapsed patients includes Bruton tyrosine kinase (BTK) inhibitors among other targeted treatments. Novel agents such as the selective BCL2 inhibitor venetoclax showed high response rates when used as monotherapy for refractory relapsed MCL. The rituximab, bendamustine, and cytarabine (R-BAC) regimen, while response rates were high, were not durable. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have been efficacious in relapsed and refractory MCL patients. Brexucabtagene autoleucel (brexu-cel, formerly KTE-X19) was approved by US Food and Drug Administration (FDA) in July, 2020, for treatment of refractory and relapsed MCL. This article provides an overview for the available management strategies for relapsed MCL and examines the role of CAR T-cell in the current and future treatment of MCL.

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Results From the Safety Run‐in Period of the Sympatico Study Evaluating Ibrutinib in Combination With Venetoclax in Patients With Relapsed/Refractory Mantle Cell Lymphoma

Cited by 4 publications

References 0 publications

Dose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

Dose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

Management of Mantle Cell Lymphoma in the Era of Novel Oral Agents

Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL)

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