PMID- 33418486
OWN - NLM
STAT- MEDLINE
DCOM- 20210917
LR  - 20210917
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 144
DP  - 2021 Feb
TI  - A phase 1b trial of selinexor, a first-in-class selective inhibitor of nuclear 
      export (SINE), in combination with doxorubicin in patients with advanced soft 
      tissue sarcomas (STS).
PG  - 360-367
LID - S0959-8049(20)31322-8 [pii]
LID - 10.1016/j.ejca.2020.10.032 [doi]
AB  - BACKGROUND: Selinexor is a first-in-class selective inhibitor of nuclear export 
      (SINE) compound with single-agent activity in soft tissue sarcoma (STS). The 
      study's aim was to determine the safety and efficacy of selinexor in combination 
      with doxorubicin in patients with locally advanced/metastatic STS. METHODS: This 
      phase 1b study used a mTPI design. Patients received selinexor at either 60 or 
      80 mg weekly PO plus doxorubicin (75 mg/m(2) IV q21 days). Patients with clinical 
      benefit (defined as >/=stable disease via RECIST 1.1) after six cycles of 
      combination treatment received maintenance selinexor until disease progression or 
      unacceptable toxicity. Disease assessments were conducted every two cycles. 
      Pharmacokinetic data were collected on the first three patients per dose level. 
      RESULTS: Twenty-five patients were enrolled (20 female, ECOG 0/1: 13/12, median 
      age 57 years [range 21-74]). Disease subtypes included leiomyosarcoma (n = 6), 
      malignant peripheral nerve sheath tumour (n = 3) and other sarcomas (n = 16). 
      Three (12%) and 22 (88%) patients were treated at 60 mg and 80 mg of selinexor, 
      respectively. The most common >/=G3 drug-related adverse events (AEs) were 
      haematological, including neutropenia (56%), febrile neutropenia (28%) and 
      anaemia (24%). There were four dose-limiting toxicities (febrile neutropenia 
      (x2), vomiting, fatigue) all at the 80 mg dose level. There was one death 
      secondary to heart failure. Of the 24 evaluable patients, 5 (21%) had a partial 
      response and 15 (63%) had SD as best response. The estimated median 
      progression-free survival (PFS) and overall survival (OS) were 5.5 (95% 
      CI:4.1-5.7) and 10.5 (95% CI:7.5-14) months. CONCLUSION: In a heterogeneous group 
      of patients with locally advanced/metastatic STS, the combination of selinexor 
      and doxorubicin fulfilled the prespecified boundary for tolerability.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Lewin, Jeremy
AU  - Lewin J
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Malone, Eoghan
AU  - Malone E
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Al-Ezzi, Esmail
AU  - Al-Ezzi E
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Fasih, Samir
AU  - Fasih S
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Pedersen, Pernille
AU  - Pedersen P
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Accardi, Sarah
AU  - Accardi S
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Gupta, Abha
AU  - Gupta A
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada.
FAU - Abdul Razak, Albiruni
AU  - Abdul Razak A
AD  - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 
      University of Toronto, Canada. Electronic address: albiruni.razak@uhn.ca.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210105
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - 0 (Hydrazines)
RN  - 0 (Triazoles)
RN  - 31TZ62FO8F (selinexor)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use
MH  - Doxorubicin/administration & dosage
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Hydrazines/administration & dosage
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Non-Randomized Controlled Trials as Topic
MH  - Prognosis
MH  - Sarcoma/*drug therapy/pathology
MH  - Tissue Distribution
MH  - Triazoles/administration & dosage
OTO - NOTNLM
OT  - Doxorubicin
OT  - Small molecule
OT  - Soft tissue sarcoma
OT  - XPO-1
COIS- Conflict of interest statement ARA: Honoraria: Boehringer Ingelheim; 
      Consulting/advisory: Lilly; Merck; Boehringer Ingelheim; Adaptimmune; Research 
      funding: CASI Pharmaceuticals; Boehringer Ingelheim; Lilly; Novartis; Deciphera; 
      Karyopharm Therapeutics; Pfizer; Roche/Genentech; Boston Biomedical; 
      Bristol-Myers Squibb; MedImmune; Amgen; GlaxoSmithKline; Blueprint Medicines; 
      Merck; Abbvie; Adaptimmune; Iterion. JL: Consulting/advisory: Bayer. The rest of 
      the authors have no disclosures or conflicts of interest.
EDAT- 2021/01/09 06:00
MHDA- 2021/09/18 06:00
CRDT- 2021/01/08 20:22
PHST- 2020/06/15 00:00 [received]
PHST- 2020/10/13 00:00 [revised]
PHST- 2020/10/29 00:00 [accepted]
PHST- 2021/01/09 06:00 [pubmed]
PHST- 2021/09/18 06:00 [medline]
PHST- 2021/01/08 20:22 [entrez]
AID - S0959-8049(20)31322-8 [pii]
AID - 10.1016/j.ejca.2020.10.032 [doi]
PST - ppublish
SO  - Eur J Cancer. 2021 Feb;144:360-367. doi: 10.1016/j.ejca.2020.10.032. Epub 2021 
      Jan 5.