A phase 1 study of NOX66 in combination with carboplatin in patients with end stage solid tumours.

Abstract Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. Methods We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. Results Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. Conclusions This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. Clinical trials registration NCT01987362.

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Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-016-3090-y ◽

2016 ◽

Vol 78 (3) ◽

pp. 491-500 ◽

Cited By ~ 4

Author(s):

Amita Patnaik ◽

Anthony Tolcher ◽

Kyriakos P. Papadopoulos ◽

Murali Beeram ◽

Drew Rasco ◽

...

Keyword(s):

Phase 1 ◽

Mek Inhibitor ◽

Solid Tumours ◽

Cardiac Repolarization ◽

Phase 1 Study

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5067 POSTER A Phase 1 Study of Neratinib in Combination With Vinorelbine in Japanese Patients With Advanced or Metastatic Solid Tumours

European Journal of Cancer ◽

10.1016/s0959-8049(11)71509-x ◽

2011 ◽

Vol 47 ◽

pp. S350 ◽

Cited By ~ 1

Author(s):

Y. Onozawa ◽

J. Watanabe ◽

N. Yamamoto ◽

N. Boku ◽

M. Suzuki ◽

...

Keyword(s):

Phase 1 ◽

Japanese Patients ◽

Solid Tumours ◽

Phase 1 Study

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Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours

British Journal of Cancer ◽

10.1038/s41416-021-01405-x ◽

2021 ◽

Author(s):

Mark R. Middleton ◽

Emma Dean ◽

Thomas R. J. Evans ◽

Geoffrey I. Shapiro ◽

John Pollard ◽

...

Keyword(s):

Clinical Trial ◽

Protein Kinase ◽

Partial Response ◽

Ataxia Telangiectasia ◽

Phase 1 ◽

Solid Tumours ◽

Phase 2 ◽

Related Protein ◽

Phase 1 Study ◽

Best Response

Abstract Background Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. Clinical trial identifier NCT02157792.

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