XPOVIO (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with selinexor.

Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.

Fertility studies in animals have not been conducted with selinexor. In repeat-dose oral toxicity studies, selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed in rats at ≥1 mg/kg, decreased ovarian follicles were observed in rats at ≥2 mg/kg, and single cell necrosis of testes was observed in monkeys at ≥1.5 mg/kg. These dose levels resulted in systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure (AUClast ) in humans at the recommended human dose of 80 mg.

14 CLINICAL STUDIES

14.1 Relapsed or Refractory Multiple Myeloma

The efficacy of XPOVIO plus dexamethasone was evaluated in STORM (KCP-330-012; NCT02336815). STORM was a multicenter, single-arm, open-label study of adults with relapsed or refractory multiple myeloma (RRMM). STORM Part 2 included 122 patients with RRMM who had previously received three or more anti-myeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy.

In STORM Part 2, a total of 122 patients received XPOVIO 80 mg orally in combination with dexamethasone 20 mg orally on Days 1 and 3 of every week. Treatment continued until disease progression or unacceptable toxicity. Eighty-three patients had RRMM that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. Baseline patient demographics and disease characteristics of these 83 patients are summarized in Table 9 and Table 10, respectively.

Efficacy was based on overall response rate (ORR), as assessed by an Independent Review Committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. The approval of XPOVIO was based upon the efficacy and safety in a prespecified subgroup analysis of the 83 patients whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, as the benefit-risk ratio appeared to be greater in this more heavily pretreated population than in the overall trial population. Overall response rate results are presented in Table 11. The median time to first response was 4 weeks (range: 1 to 10 weeks). The median duration of response was 3.8 months (95% CI: 2.3, not estimable).

Table 9: Baseline Demographics (STORM)
Demographic STORM(n=83)
Median age, years (range) 65 (40, 86)
Age category, n (%)
<65 years 40 (48)
65 – 74 years 31 (37)
≥75 years 12 (15)
Sex, n (%)
Male 51 (61)
Female 32 (39)
Race, n (%)
White 58 (70)
Black or African American 13 (16)
Asian 2 (2)
Native Hawaiian or other Pacific Islander 1 (1)
Other 6 (7)
Missing 3 (4)
Table 10: Disease Characteristics (STORM)
Parameter STORM(n=83)

a. Includes any of del(17p)/p53, t(14; 16), t(4; 14), 1q21.

Median years from diagnosis to start of study treatment (range) 7 (1, 23)
Prior treatment regimens, median (range) 8 (4, 18)
Documented refractory status, n (%)
Lenalidomide 83 (100)
Pomalidomide 83 (100)
Bortezomib 83 (100)
Carfilzomib 83 (100)
Daratumumab 83 (100)
Documented refractory status to specific combinations, n (%)
Bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab 83 (100)
Daratumumab in any combination 57 (69)
Daratumumab as single agent (+/- dexamethasone) 26 (31)
Previous stem cell transplant, n (%) 67 (81)
Revised International Staging System at Baseline, n (%)
I 10 (12)
II 56 (68)
III 17 (21)
Unknown 0
High-risk cytogeneticsa , n (%) 47 (57)
Table 11: Efficacy Results per IRC in Relapsed or Refractory Multiple Myeloma (STORM)

a. Includes sCR + CR + VGPR + PR.

Response STORM(n=83)
Overall Response Rate (ORR) a , n (%) 21 (25.3)
95% CI 16.4, 36
Stringent Complete Response (sCR) 1 (1)
Complete Response (CR) 0
Very Good Partial Response (VGPR) 4 (5)
Partial Response (PR) 16 (19)

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