378 A first-in-human (FIH) safety and pharmacological study of SAR405838, a novel HDM2 antagonist, in patients with solid malignancies

Weger, Vincent de; Lolkema, Martijn P.; Dickson, Mark A.; Cesne, Axel Le; Wagner, Andrew J.; Merqui-Roelvink, M.; Varga, Andréa; Tap, W.; Schwartz, G.; Demetri, George D.; Zheng, Wei; Tuffal, Gilles; Macé, Sandrine; Miao, Hongzhi; Schellens, J.H.M.; Jonge, M. de

doi:10.1016/s0959-8049(14)70504-0

Cited by 9 publications

(10 citation statements)

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“…Additionally, MDM2 inhibitors commonly induce complete regression of the MDM2‐amplified ostesoarcoma line SJSA‐1 . Despite this impressive in vitro activity against liposarcoma cell lines and in vivo activity against an MDM2‐amplified xenograft, MDM2 inhibitors have shown few objective responses for patients with MDM2‐amplified liposarcoma, with response rates in the range of 5–10% . Additionally, the treatment with the MDM2 inhibitor SAR405838 appeared to rapidly select for TP53 mutations as evidenced by the appearance of TP53 mutations in circulating cell‐free DNA following initiation of treatment with SAR405838 …”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38][39] Despite this impressive in vitro activity against liposarcoma cell lines and in vivo activity against an MDM2-amplified xenograft, MDM2 inhibitors have shown few objective responses for patients with MDM2-amplified liposarcoma, with response rates in the range of 5-10%. [18,21,22] Additionally, the treatment with the MDM2 inhibitor SAR405838 appeared to rapidly select for TP53 mutations as evidenced by the appearance of TP53 mutations in circulating cell-free DNA following initiation of treatment with SAR405838. [40] Comparison of the the MK-8242 drug exposure in SCID mice to that observed in humans is important in interpreting the PPTP data for MK-8242.…”

Section: Discussionmentioning

confidence: 99%

“…[20] Seven other MDM2 inhibitors have subsequently entered clinical evaluation, [15] and thrombocytopenia is a prominent toxicity at higher doses for all for which clinical data are publicly reported. [18,19,21,22] RG7112 was previously tested against the in vitro and in vivo tumor panels by the Pediatric Preclinical Testing Program (PPTP). [23] While in vitro cell line sensitivity correlated well with TP53 mutation status, there were only five objective regressions in 26 solid tumor models with wild-type TP53.…”

Section: Introductionmentioning

confidence: 99%

“…[22,24] Like RG7112 and other MDM2 inhibitors, dosing of MK-8242 is limited by hematologic toxicity with thrombocytopenia being notable at the higher doses evaluated. [18,19,21,22] Using a twice-daily schedule of administration on days 1-7 of planned 21 day treatment cycles, the maximum tolerated dose (MTD) was 400 mg for patients with solid tumors. Objective responses were noted among two of 27 liposarcoma patients treated.…”

Section: Introductionmentioning

confidence: 99%

“…RG7112 induced thrombocytopenia in its phase 1 and 2 evaluations, and subsequent preclinical evaluations documented thrombocytopenia as an on‐target adverse effect of MDM2 inhibition . Seven other MDM2 inhibitors have subsequently entered clinical evaluation, and thrombocytopenia is a prominent toxicity at higher doses for all for which clinical data are publicly reported …”

Section: Introductionmentioning

confidence: 99%

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Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Kang

Reynolds

Kolb

et al. 2016

Pediatric Blood & Cancer

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Background MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction. Procedures MK-8242 was tested against the PPTP in vitro cell line panel at concentrations from 1.0 nM to 10.0 μM and against the PPTP in vivo xenograft panels using oral gavage on Days 1–5 and Day 15–19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg [acute lymphoblastic leukemia (ALL) models]. Results The median IC50 for MK-8242 was 0.07 μM for TP53 wild-type cell lines versus > 10 μM for TP53 mutant cell lines. MK-8242 induced a two-fold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in 7 solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among 8 xenografts there were 2 complete responses (CR) and 6 partial responses (PR). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that observed in adult phase 1 trials. Conclusions MK-8242 induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Kang

Reynolds

Kolb

et al. 2016

Pediatric Blood & Cancer

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Drug Design Methods to Regulate Protein–Protein Interactions

Poluri,

Gulati,

Tripathi

et al. 2023

Protein-Protein Interactions

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Discovery of Novel Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2–p53 Interaction

et al. 2016

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Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).

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378 A first-in-human (FIH) safety and pharmacological study of SAR405838, a novel HDM2 antagonist, in patients with solid malignancies

Cited by 9 publications

References 0 publications

Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Initial Testing (Stage 1) of MK‐8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program

Drug Design Methods to Regulate Protein–Protein Interactions

Discovery of Novel Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2–p53 Interaction

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