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Digitally Augmenting Therapies: A DTx Opportunity for Pharma Portfolio Development
Published in Oleksandr Sverdlov, Joris van Dam, Digital Therapeutics, 2023
Benjamin D'hont, Romain Marmot
In 2015, Voluntis and AstraZeneca initiated a feasibility study to test eCO, a digital companion app for women undergoing treatment for ovarian cancer in clinical trials with cediranib/olaparib combination therapy (NCI 9825). The solution was designed to support self-management and remote management of hypertension and diarrhea. These two side-effects affected the patient experience and caused treatment interruptions and discontinuations (between 27% and 39% for cediranib in the ICON6 trial in 2016) (Ledermann et al., 2016).
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Cediranib, the small molecule inhibitor of VEGF 1/2/3 has been shown to produce responses in patients with recurrent ovarian cancer [78]. In preclinical models, PARP inhibition has been shown to inhibit angiogenesis in vivo; PARP-1 knockout mice have decreased in vivo angiogenesis when compared to wild-type animals [120]. Also, there is limited overlapping toxicity between PARP inhibitors and VEGF inhibitors, prompting investigation of this combination in clinical trials. The phase 1 study combining olaparib and cediranib in recurrent ovarian cancer and triple-negative breast cancer demonstrated manageable toxicities for the combination, with promising activity in ovarian cancer but not in breast cancer [73]. A follow-up phase 2 trial enrolled 90 eligible patients with recurrent ovarian cancer who were randomized to receive either olaparib alone at 400 mg twice daily or olaparib 200 mg twice daily with cediranib 30 mg daily. The combination demonstrated a significant improvement in median PFS (17.7 months) when compared to olaparib alone (9.0 months). However, the combination did cause more grade 3 toxicity than the single agent (70% vs. 11%), primarily hypertension, fatigue, and diarrhea [72].
Soft Tissue Sarcomas
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Thomas F. DeLaney, David C. Harmon, Karol Sikora, Francis J. Hornicek
Although the foregoing generalizations apply to most STSs, different histologic subtypes of sarcomas display their own patterns of chemosensitivity. Myxoid/round cell liposarcomas appear sensitive to doxorubicin and to trabectedin. Synovial sarcoma has a strong dose response to ifosfamide. Non-uterine leiomyosarcomas appear to have lower response rates to doxorubicin and ifosfamide, but may respond to trabectedin. Angiosarcomas are almost unique in being sensitive to paclitaxel. Rhabdomyosarcoma, desmoplastic small round cell tumors, and peripheral neuroectodermal tumors respond to combinations that include ifosfamide, etoposide, vincristine, doxorubicin, dactinomycin cyclophosphamide, and topotecan/irinotecan. Sunitinib has proven useful against solitary fibrous tumor/hemangiopericytoma, alveolar soft part sarcoma, and clear cell sarcoma. Everolimus has activity against tumors with perivascular epithelioid cell differentiation. Imatinib can help in metastatic dermatofibroma protuberans. Cediranib is effective against alveolar soft part sarcoma. Crizotinib is active against ALK translocated inflammatory myofibroblastic tumor. Bevacizumab with temozolomide has been employed for solitary fibrous tumor.
Alveolar soft tissue sarcoma: a report of 50 cases at a single institution
Published in Acta Chirurgica Belgica, 2023
Pengyuan Zhao, Huixiang Li, Huayan Ren
ASPS is driven by the fusion of der(17)t(X;17) (p11;q25), which creates the characteristic ASPSCR1-TFE3 fusion. This fusion protein results in the upregulation of transcripts involved in angiogenic and proliferation pathways. The use of angiogenic inhibitors may therefore be an appropriate option to control ASPS progression. Several recent clinical trials using tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, cediranib, and apatinib, are active and show that treatment with these inhibitors results in a clinical response [24,28]. Among them, cediranib may be preferred for metastatic disease. Among 48 ASPS patients treated with cediranib, the PR + SD rate was 84% at 6 months, and cediranib has been confirmed to downregulate angiogenic targets [29]. Additionally, several reports show a positive tumor response to antiangiogenic therapy combined with ICIs for ASPS [30]. Our observations are consistent with those of recent studies where patients with metastatic disease treated with antiangiogenic therapy or combined immunosuppressors had a higher rate of disease control.
Pharmacotherapeutic treatment options for recurrent epithelial ovarian cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Nilanchali Singh, Aarthi S Jayraj, Avir Sarkar, Trishala Mohan, Amlin Shukla, Prafull Ghatage
ICON 6 was an international, three-arm, double-blind, placebo-controlled randomized trial in which an oral anti-angiogenic VEGFR 1–3 and c-kit receptor inhibitor, cediranib, was studied in 456 women with platinum-sensitive ROC. The study participants were randomized to receive chemotherapy with placebo followed by maintenance placebo (arm A), chemotherapy with cediranib followed by maintenance placebo (arm B), or chemotherapy with cediranib followed by cediranib (arm C). The trial was originally designed to recruit 2000 patients, However, AstraZeneca stopped manufacturing cediranib in October 2011, leading to stoppage of trial after enrollment of 456 patients. At a median follow up of 19.5 months, median PFS was 8.7 months in arm A as compared to 9.9 months in arm B and 11 months in arm C (hazard ratio arm A vs arm C 0.56, 95% CI: 0 .44–0 · 72, p < 0.0001). Side effects such as hypertension, neutropenia, and voice changes lead to discontinuation of cediranib in 32% patients during the chemotherapy phase, prior to disease progression [48]. A final update of survival analysis was published in February 2021 when 90% of trial participants had died at a median follow-up period of 25.6 months. It was seen that concurrent and maintenance cediranib (arm C) showed improved PFS outcomes compared to arms A and B. The median OS in arm A was 19.9 months compared to 27.3 months in arm C (HR 0.86, 95% CI of 0.67–1.11, p = 0.24). The relative reduction in risk of death was 14% [49].
Experimental drugs for fallopian cancer: promising agents in the clinical trials and key stumbling blocks for researchers
Published in Expert Opinion on Investigational Drugs, 2022
Raffaella Cioffi, Federica Galli, Emanuela Rabaiotti, Massimo Candiani, Francesca Pella, Giorgio Candotti, Luca Bocciolone, Patrizia De Marzi, Giorgia Mangili, Alice Bergamini
Cediranib inhibits all three isoforms of VEGF-R. Single-agent cediranib in recurrent EOC showed a 30% clinical response rate in a phase II trial. The main trial evaluating cediranib in EOC was ICON-6: a phase III, three-arm, placebo-controlled double-blind trial of cediranib plus platinum-based chemotherapy and cediranib alone as maintenance in relapsed platinum-sensitive EOC. The best PFS outcome was seen in the cohort of cediranib plus chemotherapy followed by cediranib maintenance. PFS was 11 months with maintenance cediranib, similar to that reported with bevacizumab maintenance after chemotherapy in a similar population. Diarrhea, voice changes, and neutropenia were more frequent in the cediranib arms and sometimes this led to poor compliance [14]. Cediranib has been recently investigated in combination with olaparib in different disease settings. CONCERTO trial reported positive outcomes of a combination between cediranib and olaparib in heavily pretreated, platinum-resistant, relapsed high-grade FC. Eighty percent of the cohort was BRCA wild-type (NCT02889900) [15]. In platinum-sensitive patients, a randomized phase III trial (NCT 02446600) did not show a superiority of cediranib plus olaparib compared to standard of care [16]. An important ongoing trial for future clinical application is ICON9 (NCT03278717), which is investigating the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based chemotherapy, in comparison with olaparib alone. Enrollment will be completed in 2024; results should be presented in 2025 [17].