Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies

Vergote, Ignace; Lund, Bente; Peen, Ulla; Umajuridze, Z.; Kranich, Anne L.; Nieuwenhuysen, Els Van; Haslund, Charlotte Aaquist; Nøttrup, Trine Jakobi; Han, Sang-Seop; Concin, Nicole; Unger, Thaddeus J.; Chai, Yi; Au, Nurov; Rashal, Tami; Joshi, Anita; Crochiere, Marsha; Landesman, Yosef; Shah, Jatin J.; Shacham, Sharon; Kauffman, Michael; Mirza, Mansoor Raza

doi:10.1016/j.ygyno.2019.11.012

Cited by 38 publications

(27 citation statements)

References 20 publications

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“…These results suggest that selinexor is a viable single-drug option for patients with either germinal centre B-cell or non-germinal centre B-cell DLBCL. These observations are consistent with the broad mechanism of action of XPO1 inhibition in the treatment of malignancies, and similar to the absence of disease subtype specificity in myeloma 12 and other haematological 9,31 and solid tumour 22,32,33 neoplasms.…”

Section: Discussionsupporting

confidence: 86%

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Kalakonda

Maerevoet

Cavallo

et al. 2020

The Lancet Haematology

229

194

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Background Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. Methods SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling).

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Section: Discussionsupporting

confidence: 86%

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Kalakonda

Maerevoet

Cavallo

et al. 2020

The Lancet Haematology

229

194

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“…Among the small molecules that inhibit exportin-1 function, selinexor (KPT-330) is under clinical trials for most cancer types, including leukemia, and lung, prostate, gastric, breast, ovarian, and cervical cancers [32]. Although the synergistic effects of the combination of selinexor and cisplatin have been evaluated in the ovarian cancer preclinical models [33], but in cervical cancer, selinexor is only been reported to be effective as a single-agent [34]. Herein, we suggest for the first time that exportin-1 inhibitor can be used in combination with cisplatin to ameliorate cervical cancer progression.…”

Section: Discussionmentioning

confidence: 99%

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

Kim

Yoo

et al. 2020

IJMS

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Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.

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“…Although they showed some efficacy- 2 (25 %) patients achieving PR and 4 (50 %) patients with SD, 36 % experienced treatment-related grade 3/4 AEs and 21 % came off study due to intolerability. In another phase II study employing selinexor in gynecological cancers, single agent selinexor led to PR in 8 %, 9 %, and 4 % (DCR of 30 %, 35 and 24 %) in ovarian, endometrial and cervical cancers, respectively [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi‐arm phase Ib study

et al. 2021

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SummaryBackground Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a “basket type” expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22–68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2–48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495

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Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies

Cited by 38 publications

References 20 publications

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi‐arm phase Ib study

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