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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by Verastem Oncology Inc, duvelisib (CopiktraTM) (Figure 6.90) is a dual inhibitor of PI3Kδ and PI3Kγ, and is used for the treatment of CLL, SLL (Small Lymphocytic Lymphoma) and follicular lymphoma after other treatments have failed. Despite toxicity challenges, one advantage of duvelisib is the convenience of oral availability and its use as a monotherapy in comparison to the combination of idelalisib (ZydeligTM) with rituximab (RituxanTM), which must be administered either intravenously or subcutaneously. Furthermore, as a dual δ/γ-inhibitor, duvelisib’s inhibition of multiple isoforms may prove more efficacious than more-selective inhibitors which may explain the agent’s activity as a monotherapy. However, overall, the systemic toxicities of duvelisib may limit its use with other anticancer agents. Structure of duvelisib (CopiktraTM).
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
For patients with CLL who relapse, it is important to establish whether they require treatment at the time of relapse for disease related symptoms or have active disease.160 For patients with an early relapse, defined as those who relapse within 24–36 months following treatment with chemoimmunotherapy, it is reasonable to consider ibrutunib, idelalisib, venetoclax, or duvelisib; for those who relapse after being in remission for 36 months or more, re-treatment with the initial therapy or any of the targeted drugs listed above is reasonable. The long-term efficacy of ibrutinib compared with ofatumab has now been well established.169 Idelalisib is approved for second-line therapy following at least one prior therapy. The drug is effective but associated with significant toxicities, including colitis, pneumonitis, and hepatitis (Figure 28.17). Venetoclax has been found to be remarkably effective in relapsed and/or refractory disease, with responses of about 80%, including 8% complete responses, and is now licensed for patients with relapsed disease and del(17p). The principal adverse effects are neutropenia and tumor lysis syndrome, which can be mitigated by a weekly ramp-up schedule starting at a very low dose. Duvelisib is also effective and approved for all patients with relapsed/refractory disease after they have received at least two lines of prior therapy. Ofatumumab was approved in 2016 to treat relapsed/refractory patients with CLL following two lines of prior therapy.
The future of antibody therapy in chronic lymphocytic leukemia
Published in Expert Opinion on Emerging Drugs, 2021
Jennifer L. Crombie, Jennifer R. Brown
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, has also been FDA approved for the treatment of relapsed CLL[117]. PI3K-γ, which inhibits the tumor-promoting effects of T-cell and myeloid cells in the microenvironment, is thought to add to the inhibition of PI3K-δ[118]. The initial phase I study for duvelisib monotherapy included 55 patients with CLL, in addition to patients with other hematologic malignancies [119,120]. In the CLL cohort, the ORR was 56%. The most common adverse events were neutropenia, thrombocytopenia, febrile neutropenia, and pneumonia[121]. As compared to idelalisib, the rate of grade 3 hepatotoxicity was low, occurring in only 5% of patients, and no grade 4 elevations were seen[120]. The phase II trial, DYNAMO, which included patients with indolent lymphomas, including small lymphocytic leukemia (SLL), resulted in a ORR of 68% in the SLL cohort[122]. The estimated median duration of response was 10 months, and the estimated median PFS was 9.5 months[122]. The follow-up phase III registration trial, DUO, in which patients with relapsed CLL were randomized to duvelisib versus ofatumumab, resulted in an improvement in PFS as compared to ofatumumab, with a median PFS of 13.3 months versus 9.9 months, and ultimately resulted in FDA approval for relapsed refractory CLL[123]. The most common adverse events with duvelisib were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough[123]. Duvelisib was also combined with rituximab and bendamustine plus rituximab, without increase in toxicities beyond the known safety profile of the individual agents[124].
Contemporary management of nodal and primary splenic marginal zone lymphoma
Published in Expert Review of Hematology, 2019
Lori A. Leslie, Tatyana A. Feldman, Ann McNeill, Mary Timberg, Hoshiyuki Iida, Andre H. Goy
Duvelisib is an oral inhibitor of PI3K-delta and gamma isoforms approved for the treatment of R/R FL and CLL with a toxicity profile similar to idelalisib. In the phase 2 DYNAMO study 129 patients with R/R iNHL with a median of 3 prior therapies (range 1–18) refractory to rituximab and chemotherapy or radioimmunotherapy received duvelisib 25 mg twice daily until progression or unacceptable toxicity. The ORR was 46% (0% CR) overall, 41% in FL (n = 83), 68% in SLL (n = 28) and 33% in MZL (n = 18). Duvelisib treatment led to a reduction of tumor burden in 83% of patients. The mDOR was 9.9 months, time to response 1.9 months, mPFS 8.4 months, and mOS 18.4 months. The most common grade 3 or higher AEs were neutropenia (28%), infection (20%), diarrhea (15%), thrombocytopenia (13%), anemia (12%) and 17% of patients discontinued duvelisib due to AEs. Six patients died due to AEs, 4 related to duvelisib including viral infection, septic shock, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome [39]. Prior to FDA approval, several trials evaluating duvelisib monotherapy and combinations in earlier lines of therapy were terminated or withdrawn to focus resources on registration trials for CLL and FL.
Development of new agents for peripheral T-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2019
Yuta Ito, Shinichi Makita, Kensei Tobinai
The results of the phase I study of duvelisib in patients with relapsed/refractory hematologic malignancies were recently reported [59,60]. In total, 210 patients were administered duvelisib orally twice daily for a 28-day cycle until disease progression or unacceptable toxicity. The MTD was determined to be 75 mg BID. However, based on the results of pharmacodynamic studies, maximal inhibition of phospho-AKT, a key biomarker of PI3K inhibition, was reported at 25 mg BID. Therefore, duvelisib at a dose of 25 mg BID was determined to be a recommended dose for further studies. In terms of safety, duvelisib was generally well tolerated. Hematological adverse events, such as grade 3 or higher neutropenia (32%), anemia (14%), and thrombocytopenia (14%), were relatively common. Grade 3 or higher diarrhea was observed in 11% of patients. Among the 16 evaluable patients with PTCL, the ORR was 50% (8 out of 16 patients) with 3 CRs. Based on these results, subsequent clinical trials which include patients with T-cell lymphoma are ongoing.