China
Africa
Explore chapters and articles related to this topic
Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
A novel trial, the Beat-AML study, an umbrella phase 1b/2 study, commenced in December 2016 (Figure 4.11). It assigns personalized investigational therapies to newly diagnosed patients who are >60 years of age based on their cytogenetic and mutational findings, garnered over a 7-day period following diagnosis. The study currently has 4 arms: patients with MLL mutations to receive the spleen tyrosine kinase (Syk) inhibitor, entospletinib, which targets B-cell receptors (BCR); IDH2R140 and IDH2R172 mutations receive enasidenib as monotherapy or in combination with azacytidine, CBF mutations with samalizumab, an anti-CD200 monoclonal antibody currently; for patients who do not have a genetic marker, a CD33 antibody, BI836858, plus azacytidine are offered. It is envisioned to expand the study arms to comprise of 10–12 novel molecularly targeted or immunotherapy. Indeed, there are many drugs that have now been developed rationally to target a specific molecular abnormality, which are in different stages/phases of clinical trials in newly diagnosed and relapsed/refractory disease, either as monotherapy or in combination with chemotherapy. The preliminary findings for many have been encouraging and provide ‘proof-of-concept’ that inhibition of specific mutants in AML may have a clinical application. OXi4503, a novel vascular disrupting agent was recently granted an FDA fast-track designation for the treatment of relapsed and refractory AML. A topical challenge is the actual design of a clinical trial where the objective is to find treatments which make a clinical difference in addition to survival benefits. Moreover, in AML trials the impact of a post-remission strategy is important and can easily negate any potential improvements achieved with a newer induction regimen.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Following the success of ibrutinib and venetoclax inhibitors in high- and ultra-high-risk patients, particularly those with mutated TP53 clones, research is assessing not only the earlier use of these agents in an effort to prevent the emergence of chemorefractory disease but also their use in combination regimens; venetoclax is being tested in patients receiving bendamustine initially, followed by a combination of obinutuzumab and venetoclax. The interim results of this study are impressive, with an overall response rate of 97%, and 89% MRD negative. Studies are also assessing venetoclax-based combinations with other anti-CD20 antibodies and with/without ibrutinib. There is also renewed interest in navitoclax, another BCL2 inhibitor, which is more active against BCL-xL, as opposed to venetoclax, which is more potent against BCL2. Other candidate investigational approaches include acalabrutinib, a second-generation BTK inhibitor, alisertib (MLN8237), an aurora A kinase inhibitor, and several forms of immunotherapy. Acalabrutinib appears to have a better BTK occupancy compared with ibrutinib, and it will be of interest to determine whether this reduces the emergence of resistance. SYK inhibitors, such as fostamatinib and entospletinib, remain in clinical trials at present, with impressive results so far. The immunotherapy efforts include several monoclonal antibodies, such as lumiliximab (anti-CD23), epratuzumab (anti-CD22), and apolizumab (anti-HLA-DR), IDEC-114 (anti-CD80), immune-modulatory drugs, such as lenalidomide, and adoptive immunotherapy using CD19-specific CAR T-cells in patients who progress on ibrutinib. There has also been much interest in the use of immune checkpoint inhibitors, but the results of these Phase I/II studies have not been encouraging so far.
An overview of novel therapies in advanced clinical testing for acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Sangeetha Venugopal, Zhuoer Xie, Amer M. Zeidan
Recently, the results of an international multicenter phase 1b/2 study evaluating the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with ‘7 + 3’ chemotherapy in patients with previously untreated AML (n = 53), were reported (NCT02343939). Entospletinib with intensive chemotherapy was well tolerated with no dose-limiting toxicity. Adverse events attributable to entospletinib included erythematous, diffuse morbilliform rash (any grade – 43%), and indirect hyperbilirubinemia (49%; consistent with the known UGT1A1 mediated inhibition by entospletinib) which resolved with treatment interruption. Entospletinib with intensive chemotherapy demonstrated a composite complete remission (CRc) rate of 70% with potentially improved survival particularly noted among patients with high HOXA9/MEIS1 overexpression (NPM1c, KMT2A-rearranged) [25]. Given the high response rates (83%) observed in patients with NPM1c AML, a registrational phase 3 double-blind placebo-controlled AGILITY clinical trial is evaluating entospletinib in combination with 7 + 3 chemotherapy in patients with newly diagnosed NPM1c AML fit to receive intensive chemotherapy with the primary endpoint of molecular MRD negative complete remission rate [26]. Of note, AGILITY is the first trial in the AML treatment space to use MRD negativity as part of the primary endpoint (NCT05020665).
Targeting the B cell receptor pathway in non-Hodgkin lymphoma
Published in Expert Opinion on Investigational Drugs, 2018
Kelly Valla, Christopher R. Flowers, Jean L. Koff
Like acalabrutinib, entospletinib was designed to maximize its selectivity and reduce adverse effects resulting from unintended, off-target kinase inhibition. In the first-in-human study of entospletinib in healthy volunteers, headache was the most frequently reported adverse effect [74]. Expanded safety data are available in CLL, indolent NHL, MCL, and DLCBL, and early efficacy data have been reported from studies in CLL [71]. At a dose of 800 mg twice daily, entospletinib induced response in 61% of the 41 patients with CLL. Furthermore, 94.5% of patients experienced a reduction of adenopathy, with 2-year PFS of 70.1%. Hypertension was not as prevalent as with fostamatinib treatment, but this appeared to come at the cost of more patients with elevated transaminases or bilirubin. Other notable adverse effects include fatigue and gastrointestinal disturbances. Entospletinib was administered during a fasting state due to the impact of gastric pH on absorption observed in earlier studies, but a newer formulation designed to improve drug absorption at a higher gastric pH may alleviate this issue. Combination of SYK inhibitors with other agents that target the BCR pathway was explored as a strategy to enhance response rates. However, such study has been limited for now based on results of a phase 2 study combining entospletinib with the PI3K inhibitor idelalisib, where pneumonitis occurred in 12 of 66 patients treated with these two agents [75]. The majority of pneumonitis cases were severe and were thought to result from excessive inhibition of downstream BCR signaling impacting the mTOR pathway.
Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia
Published in Expert Opinion on Investigational Drugs, 2018
Sushma Bartaula-Brevik, Marte Karen Lindstad Brattås, Tor Henrik Anderson Tvedt, Håkon Reikvam, Øystein Bruserud
Combination therapy seems possible because studies from patients with autoimmune disorders suggest that the toxicity, especially hematological toxicity, is acceptable for up to one year of continuous treatment (see discussion earlier). However, the question of toxicity has to be carefully addressed in future studies because it may depend on the combination therapy [78]. Various combinations have been investigated or will be investigated in future clinical studies. Several studies of entospletinib are registered at ClinicalTrials.gov (study ids given in parenthesis), including combination therapy with conventional anthracyclin-cytarabine induction treatment (NCT03135038, NCT02343939), high-dose or intermediate-dose cytarabine and hypomethylating agents (decitabine or azacitidine) (NCT02343939). The preliminary results from a small clinical study suggest that the toxicity is acceptable when entospletinib is combined with conventional intensive induction chemotherapy [84] (see Table 3). One would also expect the toxicity to be acceptable if entospletinib is combined with low-dose cytarabine in elderly or unfit patients. The combination of entospletinib with vincristine and steroids is also investigated in patients with acute lymphoblastic leukemia (NCT02404220), but this combination is not used in AML.