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).

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/m2 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.

EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression.

PURPOSE: PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance. PATIENTS AND METHODS: The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib-olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing. RESULTS: Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes. CONCLUSIONS: This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib-olaparib varied according to the PARPi resistance mechanism.