MLN8237 | Neuro Signaling

MLN8237 (alisertib) and its role in peripheral T-cell lymphoma
Doraid Alrifai & Ruth Pettengell†
†St George’ s Hospital, Division of Infection and Immunity, London

Introduction: Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. A greater understanding of how these tumours prolif- erate as well as how best to exploit these processes should lead to more dura- ble tumour regression and better clinical outcomes for patients. New approaches include the histone deacetylase inhibitors, antifolates, fusion pro- teins, nucleoside analogues and agents targeting the immune system, which are being investigated either as single agents or as a combination.
Areas covered: The authors review the evidence for the orally administered aurora A kinase inhibitor MLN8237 (alisertib) in T-cell lymphoma. No signifi- cant association between clinical response and AAK expression has been observed but inhibition of this enzyme in a Phase II study has demon- strated tumour regression in 27% of heavily pretreated B- and T-cell NHL, with 50% of PTCL patients responding and 3 of 4 patients achieving durable responses.
Expert opinion: A Phase III trial in relapsed PTCL is recruiting patients compar- ing MLN8237 against single agent comparators. With regards to the data; the response rate of MLN8237 in refractory NHL is promising. The authors believe that further preclinical work identifying the best combinations to take through into clinical trials is important, particularly as this agent is used in ear- lier lines of therapy.

Keywords: alisertib, aurora A kinase, aurora kinase inhibitor, MLN8237, non-Hodgkin lymphoma, peripheral T-cell lymphoma, T-non-Hodgkin lymphoma

Expert Opin. Investig. Drugs (2014) 23(12):1731-1736

⦁ Introduction
Non-Hodgkin lymphoma (NHL) is one of the commonest malignancies in the western world accounting for 40% of all haematological malignancies. Since the 1970s, the incidence of lymphoma has risen over time, which is mainly accounted for by improving diagnostic measures and better data recording [1]. It can display heterogeneity both in presentation and clinical course. For patients presenting with an indolent form, there are a wide range of treatment options, but for those with aggressive disease at relapse, treatment options are limited. In particular, little improvements have been made in the 15% of NHL patients with T-cell lymphoma. These patients relapse early and rapidly with a 5-year overall survival (OS) for peripheral T-cell lymphoma (PTCL) of 10 — 30%.

⦁ Unmet medical need, treatment guidelines and overview of the market
Twenty-three biologically and clinically different T-cell lymphoma subgroups exist according to the 2008 WHO classification system. We can further subclassify these into nodal, extra-nodal, cutaneous and leukaemic groups [2]. The small number of patients within each T-cell lymphoma subtype limits clinical research and

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Box 1. Drug summary.
Drug name Alisertib (MLN8237) III
T-cell lymphoma Aurora kinase inhibitor

Oral

N
N

OH
O
CH3 O
[29-36]
Phase
Indication
Pharmacology
description
Route of
administration
Chemical structure

CH3
CI

Pivotal trial(s)

development of new therapies in this area. Historically, treat- ment has been similar to that of diffuse large B-cell lymphoma (DLBCL); however, the median OS at 5 years is <40% for anthracycline-based treatment [3]. Platinum-based combina- tions as salvage therapy can offer response rates (RR) of 54% but an associated 5-year progression free survival (PFS) of only 29% [4].
Novel therapies with activity in T-cell lymphoma being investigated include nucleoside analogues, monoclonal antibodies, fusion proteins, antifolates, histone deacetylase inhibitors (HDACi), agents targeting the immune system and small molecule kinase inhibitors.
The purine nucleoside analogues pentostatin and gemcita- bine have been explored in Phase II trials. Despite high RR in patients with Sezary syndrome (62%) and prolymphocytic leukaemia (45%), pentastatin has a RR of only 19% in PTCL [5]. RR for single agent gemcitabine in pretreated patients with PTCL can range from 51 to 69% with complete response (CR) rates between 8 and 23%, although this data is from small patient numbers (up to 39 patients in the largest study). Gemcitabine is more commonly combined with a platinum agent at relapse with a RR around 45%, but there is no reported outcome data [6-8].
Monoclonal antibodies have been investigated in T-cell lymphoma. The antibody drug conjugate brentuximab vedotin, targeting the CD30 receptor, has shown RR of up
to 86%, including 57% CRs, with a median duration of
12.6 months in relapsed anaplastic large cell lymphoma (ALCL). In PTCL, not otherwise specified (NOS), and angioimmunoblastic T-cell lymphoma (AITL), lower objec- tive response rates (ORR) are seen in the order of 41% with a median duration of response of 7.6 months [9,10]. Alemtuzu- mab, which targets CD52, has shown high RR but results indicate severe immunocompromise and neutropenia, limit- ing its future use [11]. Other monoclonal antibodies include zanolimumab, which binds against CD4, reporting a RR of 24%, and mogamulizumab, a CC chemokine receptor 4, with an associated RR of 50% [12,13].
A fusion protein comprised of IL-2 and diphtheria toxin (denileukin diftitox) is licensed in the USA for the treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL). As a single agent in 27 patients with relapsed/refrac- tory PTCL, an ORR of 48% was observed and a median PFS of 6 months reported [14]. In the Phase II setting, 49 patients had shown overall RR as high as 65% in an untreated PTCL population, when combined with CHOP chemotherapy. A median PFS of 12 months was recorded. Treatment was well tolerated with bone marrow depression, nausea and fatigue constituting grade 3 or more toxicities [15]. Pralatrex- ate, a novel folate antagonist, has been approved in PTCL in the USA based on a Phase II trial showing a RR of 29% (including 11% CR) and a median response duration of
10.1 months in 115 heavily pretreated patients with PTCL. The commonest grade 3 or more toxicities included bone marrow depression (thrombocytopenia 32%, neutropenia 22% and anaemia 18%) and mucositis 22% [16].
Romidepsin, a HDACi, is also FDA approved in CTCL and more recently in PTCL. The Phase II trial in 130 pre- treated patients with relapsed/refractory PTCL demonstrated ORR of 25%, a CR rate of 15% and a median duration of response of 28 months. The most common grade 3 or more toxicities included thrombocytopenia (24%), infection (19%) and neutropenia (13%) [17]. Also of interest is the pan-HDACi belinostat, which has also been evaluated in Phase II with 129 relapsed/refractory patients. This confirmed an ORR of 26 -- 28%, including a CR of 10% and a median duration of response of 8.3 months with a similar toxicity profile to romidepsin [18].
Other drugs that have also shown promise in PTCL include the immunomodulatory agent lenalidomide, which reported a RR of 30%, a median PFS of 3.2 months and OS of 7.9 months. Neutropenia and thrombocytopenia were the commonest toxicities [19]. The proteasome inhibitor bortezomib has demonstrated an ORR of 67% [20], while plitidepsin recorded an ORR of 21% [21] and bendamustine an ORR of 50%, with a median duration of response of
3.5 months [22]. As clearly seen, a better understanding of cell signalling pathways and the role of immune modulation are leading the way for more targeted therapeutic treatments. The aurora A kinase (AAK) inhibitors with their novel mechanism of action are a promising new approach.

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⦁ Mechanism of action

MLN8237 (alisertib) is a novel, orally administered inhibitor of AAK (Box 1) and is a member of the serine/threonine kin- ases. Aurora kinases facilitate cell cycle division by interacting with the mitotic spindle formations. An association between AAK and centrosome amplification has been demonstrated in many preclinical models of malignancy. This disturbance in the mitotic spindle is what is thought to lead to genetic instability and overall tumour development. Aurora kinase inhibitors allow cells to bypass the mitotic checkpoint; therefore, antitumor activity is dependent on activation of apoptosis in response to increasing genomic instability [23].
It is also thought that aurora kinases are upregulated by MYC and play a role in the development of B-cell lymphoma. Preclinical models have suggested that these patients may be more susceptible to aurora kinase inhibition. MYC and p53 may be useful biomarkers in the future [24].

⦁ Preclinical data

Animal models of DLBCL, MCL, BL and transformed follic- ular lymphoma have been studied and the expression of AAK established. In comparison to normal tissue, AAK and aurora B kinase (ABK) have higher expression in these histopatholog- ical subtypes. For example, 89% and 75% of MCL cases have recorded increased expression of AAK and ABK, respectively. High levels of aurora kinase were associated with poorer outcomes. MLN8237 has shown antitumour activity both independently and in combination with chemotherapy. In vitro, studies with docetaxel, rituximab and vincristine have shown synergistic activity with MLN8237. Rituximab in combination with MLN8237 has demonstrated up to 50% tumour growth inhibition when compared to a control group in a MCL xenograft mouse model. Tumour inhibition increased to 85% when docetaxel was added to rituximab and MLN8237 [25-27].
T-cell lymphoma has shown elevated AAK expression. One hundred percent of selected cases demonstrated increased levels of AAK to varying degrees in PTCL NOS. Other subtypes with high AAK expression included anaplastic lymphoma kinase-positive ALCL (87% of cases), cutaneous ALCL (69.2% of cases) and anaplastic lymphoma kinase-negative ALCL (68%) [28]. MLN8237 has independently shown inhibi- tion of PTCL cell proliferation, leading to apoptosis in a dose- and time-dependant manner and strongly correlated with endo-reduplication [29]. Other aurora kinase inhibitors such as MK-0457 and MK-5108 have also shown evidence of their abil- ity to halt proliferation of lymphoma cell lines in preclinical models by approximately 50%. These inhibitors in combination with Vorinostat (HDACi) accelerate tumour regression further by exploiting the apoptosis intracellular pathway encouraging further cell kill as well as working in synergy with mitotic spe- cific agents such as aurora kinases leading to apoptosis [30].
⦁ Phase I studies

MLN8237 has been investigated in many types of malignancy including sarcoma, breast, lung, prostate, head and neck tumours with ongoing trials in sarcoma and ovarian cancer. Cervantes et al. investigated the dose limiting toxicities (DLT) and the maximum tolerated dose for MLN8237 in patients with advanced solid tumours who had exhausted all treatment options. Fifty-nine patients were involved in identifying the most suitable dose using a 3+3 design. The agreed recommended dose for Phase II was 50 mg twice daily for 7 consecutive days in a 21-day cycle. Toxicities included alopecia (41%), neutropenia (41%), somnolence (32%), stomatitis (31%), asthenia (24%) and gastrointestinal distur- bances such as diarrhoea and nausea (19 and 22%, respec- tively). DLTs included grade 3 stomatitis, somnolence, enteritis and grade 4 neutropenia and thrombocytopenia. This study reported a median Tmax of 2 h, a steady state con-
centration of 1.5 µmol/l reached within 1 week and a half-life
of 19.2 h. Pharmacodynamic effects were observed by taking skin and/or tumour biopsies at day 1 and day 7 of treatment. It has been shown that chromosomal activity in the mitotic tumour cells was inhibited on day 7. Thirty-seven percent of patients demonstrated stable disease with an associated median duration of 7.3 months [31].
Kelly et al. looked at the optimal formulation (enteric-coated tablet vs. powder in capsule) of MLN8237 in a Phase I setting for relapsed/refractory haematological malignancies (DLBCL, FL, MCL, PTCL, CLL/ SLL and multiple myeloma). Tmax was calculated at 2 h for powder in capsule and 2.6 h for enteric-coated tablets. The mean steady state was measured at 19 h. The enteric-coated formulation at a dose of 50 mg twice daily for 7 days in a 21-day cycle was recommended for the Phase II studies. Six of the 47 response evaluable patients had a partial response and a further 13 patients had stable disease. AAK and phosphorylated histone H3 (pHH3) at serine 10 levels (as a marker of mitotic cells) were analysed on pretreatment biopsies. Significantly increased levels of AAK were seen in three patients, two of these patients achieved a partial response and a third progressed (Epstein-Barr virus associated PTCL). pHH3 levels were variable in these samples [32]. The outcome was similar in a study looking at solid tumour patients, of whom 65 received capsules and 22 enteric-coated tablets. Tmax was recorded at 2 h for powder in capsule and 2.4 h for the enteric-coated drug. Mean steady state was approximately 23 h. Again, the mitotic index of AAK was measured on pre- and post-treatment dose skin biopsies with an increase in pHH3 and mitotic protein monoclonal-2-immunopositive mitotic cells post-treatment, indicating AAK inhibition. AAK inhibition was highest 24 h and 6 h post oral dosing on day 1 and day 7, respectively. One patient with platinum and radi- ation refractory ovarian cancer achieved a durable partial response lasting 2.9 years and 20 patients had stable disease. Fatigue, nausea, neutropenia, alopecia and somnolence were the highest rated toxicities reported [33].

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⦁ Phase II studies

Matulonis et al. conducted a Phase II study observing MLN8237 at 50 mg, twice daily in a 21-day cycle in 31 patients with platinum resistant/refractory gynaecological malignancies. Three patients achieved a response. Overall, the median PFS was 1.94 months (95% CI, 1.41 -- 3.98). Interestingly, this study showed us that there was no clear association between AAK overexpression in the diagnostic biopsy samples and clinical response, although these biopsies were not taken immediately before treatment [34].
Friedberg et al. have looked at MLN8237 activity in 48 patients with relapsed aggressive B and T-cell lymphoma (DLBCL, MCL, PTCL, BL and transformed FL). These patients were heavily pretreated with a median of 3 prior therapies, including autologous stem cell transplant as a line of treatment. MLN8237 50 mg was given twice daily for 7 consecutive days in a 21-day cycle. Both complete and partial responses were recorded in 27% of patients (10% CR and 17% PR) and 33% achieved stable disease. Response was not exclusive to one pathological subtype but durable responses were recorded in 3 of 4 responsive patients with PTCL (8 patients in total assessed). Again, there appeared to be no association between clinical response and AAK expression, performed on the diagnostic biopsy samples [35].
In a Phase II study in histologically confirmed relapsed/ refractory peripheral T-cell lymphoma, with a median of three prior treatment lines, including stem cell transplantation, MLN8237 was given at 50 mg twice daily for 7 days in a 21-day cycle. Thirty-seven patients were recruited, including PTCL NOS, AITL, transformed MF, ATLL, ALCL and extranodal natural killer/T-cell lymphoma. Toxicities included bone marrow suppression (neutropenia 30%, anae- mia 27% and thrombocytopenia 24%), febrile neutropenia, mucositis and rash. Results included two complete responses, seven partial responses and an ORR of 24% (95% CI: 12 -- 41%). RR were slightly higher at 33% in the more com- mon tumour groups (PTCL NOS, AITL and ALCL). None of the tumours expressed AAK; however, six expressed ABK [36].
Future studies are being conducted including a randomised Phase III, open-label international study in patients with relapsed/refractory PTCL treated with either MLN8237 or single-agent comparators such as gemcitabine, pralatrexate or romidepsin (NCT01482962). Primary outcome measures include ORR and PFS. Inclusion criteria include patients 18 years old or over with relapsed PTCL following at least one line of treatment. Prior AAK inhibitor exposure and allo- geneic but not autologous stem cell transplant are exclusion criteria [37]. Further Phase I studies that are recruiting include MLN8237 in combination with romidepsin (HDACi) in patients with relapsed or refractory B- or T-cell lymphoma who have received at least one line of treatment and MLN8237 in combination with Vorinostat (HDACi)
for patients with relapsed or recurrent Hodgkin lymphoma, B-cell NHL or PTCL following at least one line of treatment
[38,39].

⦁ Conclusion

MLN8237 has shown promising single-agent activity in both B- and T-cell NHL. The challenge of managing patients who have relapsed through early lines of treatment remains difficult. Clinical trial data has suggested that there may be a role for MLN8237 in PTCL, although its best effects may occur in combination rather than when used alone. Durable responses have been reported at 50 mg twice daily for 7 conse- cutive days in a 21-day cycle. The most common toxicities at this dose are bone marrow suppression (neutropenia, lymphopenia, leucopenia and thrombocytopenia) and stomatitis. The results of ongoing trials are eagerly awaited.

⦁ Expert opinion

The poor outcomes for patients with PTCL underlie the need for new compounds with novel mechanisms of action. The challenge for investigators and investors developing these compounds is the heterogeneity and relative rarity of the T-cell lymphomas. The early progression and fulminant course for the majority of patients with PTCL suggests that resistance pathways are a significant problem. Inhibition of the aurora kinases temporarily delays mitosis, leading to apoptosis or senescence, perhaps overcoming some of the resistance mechanisms [26]. The early data with MLN8237 is very promising. If the impressive single agent activity and encouraging toxicity profile is confirmed, it is likely to gain a place in the future of PTCL prescribing. The novel action of the AAK inhibitors compared to the other agents in development and its favourable toxicity profile makes future combination therapy feasible. As we have learnt from preclinical models, combining MLN8237 with drugs such as vincristine, rituximab, docetaxel and HDACi will encour- age earlier integration into clinical practice.
In the evidence to date, the elevated expression of AAK does not appear to be a suitable biomarker for MLN8237. The Phase I studies suggest AAK inhibition following MLN8237 dosing; however, overall response is likely code- pendent on the length of mitotic arrest and the activation of apoptotic pathways, two factors that are independent of AAK expression [40]. Pretreatment biopsies are important when defining accurately the AAK levels or other potential biomarkers of sensitivity, as the diagnostic biopsies rather than pretreatment biopsies may not take into account tumour evolution and heterogeneity, misrepresenting the current clin- ical picture. Clarifying whether patients with lymphoma are more prone to the induction of apoptosis and are more likely to benefit from treatment will define the future development of MLN8237.

As with other therapeutic agents in PTCL, the durability of responses is limited. It is likely that MLN8237 will be more effective in combination than as a single agent, in particular with drugs that further disrupt antiapoptotic protein activity or prolong mitosis. More preclinical work identifying the best combinations to take through into clinical trials is important, particularly as the agent is used in earlier lines of therapy. The myelosuppressive effects of MLN8237 in heavily pretreated patients and those with extensive bone marrow involvement may limit its use, especially when combined with other agents.
The preliminary data with alisertib is very encouraging, particularly in T-cell malignancy. In these rare diseases, the pharmaceutical and academic communities need to work
closely together using preclinical modelling and locating bio- markers to identify patients who will benefit and rationalise clinical trial design, in a disease where patient numbers are small and life expectancy short.

Declaration of interest

The authors have no relevant affiliations or financial involve- ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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.. Important Phase II study describing activity of MLN8237 in T-cell lymphoma.
⦁ Barr PM, Li H, Spier CM, et al. U.S. Intergroup phase II trial (SWOG 1108) of alisertib, an investigational aurora
A kinase (AAK) inhibitor, in patients with peripheral T-cell lymphoma.
J Clin Oncol
2014;32(Suppl 5):abstract 8523; PTCL; NCT01466881
⦁ Alisertib (MLN8237) of investigator’s choice in patients with relapsed/refractory peripheral T-cell lymphoma: clinicalTrials.gov. Available from: ⦁ www. ⦁ clinicaltrials.gov/show/NCT01482962
⦁ Alisertib and Romidepsin in treating patients with relapsed or refractory B-cell or T-cell lymphomas, ClinicalTrials.gov. Available from: ⦁ www.clinicaltrials.gov/ ⦁ ct2/show/NCT01897012
⦁ Alisertib in combination with vorinostat in treating patients with relapsed or recurrent Hodgkin lymphoma, B-cell non-Hodgkin lymphoma or peripheral T-cell lymphoma, ClinicalTrials.gov. Available from: ⦁ https://clinicaltrials.gov/ ⦁ ct2/show/NCT01567709? ⦁ term=mln8237⦁ &⦁ rank=1
⦁ Hilton JF, Shapiro GI. ⦁ Aurora ⦁ kinase ⦁ inhibition⦁ ⦁ as⦁ ⦁ an⦁ ⦁ anti-cancer⦁ ⦁ strategy. J Clin Oncol 2014;32(1):57-9
⦁ Background of aurora A kinase in lymphoma and provides further clarity/ hypothesis to why we haven’t isolated suitable biomarkers yet.

Affiliation
Doraid Alrifai1 MBChB MRCP &
Ruth Pettengell†2 FRACP MBChB PhD
†Author for correspondence
1Specialist Registrar in Medical Oncology, St George’s Hospital, Blackshaw Road SW17 0QT, London
2Reader in Haemato-Oncology,
St George’s Hospital, Division of Infection and Immunity, Cranmer Terrace SW17 0RE, London Tel: +44 208 725 5454;
Fax: +44 208725;
E-mail: [email protected]