Copanlisib in Patients With Relapsed or Refractory Indolent B‐cell Lymphoma (Chronos‐1)

Dreyling, Martin; Santoro, Armando; Mollica, Luigina; Leppä, Sirpa; Follows, George; Lenz, Georg; Kim, W.; Nagler, Arnon; Panayiotidis, P.; Demeter, Judit; Özcan, Muhıt; Kosinova, Marina; Bouabdallah, Krimo; Morschhauser, Franck; Stevens, Don A.; Trevarthen, David R.; Giurescu, Marius; Liu, L.; Koechert, Karl; Peña, Carol; Cupit, Lisa; Yin, Shi; Hiemeyer, Florian; Garcia‐Vargas, J.; Childs, Barrett H.; Zinzani, Pier Luigi

doi:10.1002/hon.2437_107

Cited by 5 publications

(6 citation statements)

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“…These findings are consistent with preclinical and early-phase studies of buparlisib 14,16,28,29 as well as with the phase III trial BELLE-2 in human epidermal growth factor receptor 2-negative metastatic breast cancer. 30 In this study, a higher rate of psychiatric adverse effects, including depression and anxiety, was observed with buparlisib, which were not reported with other PI3K inhibitors [31][32][33][34][35] and were attributed to the high BBB penetration of buparlisib.…”

Section: Discussionmentioning

confidence: 45%

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

Wen

Touat

Alexander

et al. 2019

JCO

119

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PURPOSE Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway–activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

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Section: Discussionmentioning

confidence: 45%

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

Wen

Touat

Alexander

et al. 2019

JCO

119

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“…The lower incidence of diarrhea/colitis and transaminitis could be attributed to an intermittent dosing schedule, a broader spectrum of kinase inhibition, or bypass of hepatic first-pass metabolism, since the drug is administered intravenously. Results from part B of CHRONOS-1 confirmed efficacy in iNHL, with ORRs of 59% (12% CR) in FL (n = 104) and 70% (9% CR) in marginal zone lymphoma (n = 23) [90]. The most common adverse events were again transient hyperglycemia (49%/40%) and hypertension (29%/23%).…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 86%

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

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“…After a median treatment duration of 6 months, ORR was 60.6% in the full population and 58.7% in patients with FL; overall median duration of response was 14.1 months, and median PFS was 12.5 months . The safety profile differs from that of daily oral PI3K inhibitors, with low rates of liver toxicity, colitis, pneumonitis, and opportunistic infections . Unique toxicities associated with copanlisib included transient hypertension and hyperglyemia.…”

Section: Fl Treatmentmentioning

confidence: 98%

“…Copanlisib was licensed in the U.S. for patients with relapsed FL who have received ≥2 prior systemic therapies . Accelerated approval was based on the phase II CHRONOS‐1 trial in patients with indolent BCL (73% had FL) relapsing after or refractory to ≥2 prior therapies and who had received prior treatment with rituximab and an alkylating agent . After a median treatment duration of 6 months, ORR was 60.6% in the full population and 58.7% in patients with FL; overall median duration of response was 14.1 months, and median PFS was 12.5 months .…”

Section: Fl Treatmentmentioning

confidence: 99%

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs

et al. 2019

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Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early‐ and advanced‐stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first‐line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. Implications for Practice In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first‐line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies.

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Copanlisib in Patients With Relapsed or Refractory Indolent B‐cell Lymphoma (Chronos‐1)

Cited by 5 publications

References 0 publications

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs

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