Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108

Barr, Paul M.; Liu, Hongli; Spier, Catherine M.; Mahadevan, Daruka; LeBlanc, Michael; Haq, Mansoor Ul; Huber, Bryan; Flowers, Christopher R.; Wagner‐Johnston, Nina D.; Horwitz, Steven M.; Fisher, Richard I.; Cheson, Bruce D.; Smith, Sonali M.; Kahl, Brad S.; Bartlett, Nancy L.; Friedberg, Jonathan W.

doi:10.1200/jco.2014.60.6327

Cited by 101 publications

(76 citation statements)

References 25 publications

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“…50%) 241 and in combination with bortezomib (a proteasome inhibitor) in multiple myeloma (response rate 27%) 242 . Moreover, two clinical phase II studies reported promising anti-tumour activity in relapsed/refractory B-cell and T-cell non-Hodgkin lymphoma (response rate 27%) 243 and in relapsed/refractory peripheral T-cell lymphoma (response rate 30%) 244 . The potential clinical benefit for patients with peripheral T-cell lymphoma is currently being investigated in a phase III trial (see Supplementary Information S1 (table)).…”

Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…Responses were seen in patients who failed prior pralatrexate or HDAC-inhibitor treatment and in nearly half of those who showed disease refractoriness. 73 On the basis of these results, phase 3 randomized trials comparing alisertib with the investigator's choice (gemcitabine, pralatrexate, romidepsin) in relapsed or refractory PTCL patients is ongoing (#NCT01482962); according to preliminary results, however, no significant efficacy benefit of alisertib vs comparators has been documented. 74 …”

Section: Org Frommentioning

confidence: 99%

Peripheral T-cell lymphoma, not otherwise specified

Broccoli

Zinzani

2017

Blood

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Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the World Health Organization classification. Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), nowadays represent the standard first-line treatment; for patients who achieve a satisfactory response, a consolidation by means of autologous stem cell transplantation may offer a greater chance of long-term survival. Several patients, however, display treatment refractoriness or relapse soon after obtaining a response, and just a few of them are suitable transplant candidates. This is why several new agents, with innovative mechanisms of action, have been investigated in this context: pralatrexate, romidepsin, belinostat, and brentuximab vedotin have been approved for relapsed and refractory peripheral T-cell lymphomas based on their activity, although they do not significantly affect survival rates. The incorporation of such new drugs within a CHOP backbone is under investigation to enhance response rates, allow a higher proportion of patients to be transplanted in remission, and prolong survival.

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“…Despite these disappointing data, other studies in breast cancer, small cell lung cancer, and peripheral T-cell lymphoma have reported promising activity with the use of alisertib. 28,31 These findings provide initial validation of the aurora A kinase as a potentially important drug target in certain cancer types.…”

Section: Discussionmentioning

confidence: 82%

A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D

Hyman

Sill

Lankes

et al. 2017

Gynecologic Oncology

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Objective This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS). Methods Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age ≥18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6 months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6 months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts cumulative for stage 2. Confidence intervals do not correct for multiplicity. Results Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61 years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia (4), leukopenia (5), neutropenia (7), thrombocytopenia (1), mucositis (4), diarrhea (1), and palmer-planter syndrome (2). There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5 months (90% CI: 7.6- NA), respectively. Conclusion Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS.

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Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108

Cited by 101 publications

References 25 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

Peripheral T-cell lymphoma, not otherwise specified

A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D

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