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Last Updated: 06/19/17

Information below provided by the Pharmaceutical Company.

Vistusertib (AZD2014)

Agent Description

Selective inhibitor of the kinase activity of mammalian Target of Rapamycin (mTOR) serine threonine kinase, which plays a critical role in regulating cellular energy, sensing, growth and metabolism. Vistusertib delivers efficacy in several different tumor types, particularly breast cancer models which are sensitive or resistant to endocrine therapy.

Mechanism of Action

Dual mTORC1 and mTORC2 inhibition

Classification

mTOR kinase inhibitor

Molecular Targets

mTOR kinase

Monograph

Vistusertib is being developed in a range of solid tumor and hematological malignancies, both as a single agent and in combination. The core focus of the AstraZeneca sponsored clinical program is breast cancer and DLBCL. In ER+, HER2- advanced breast cancer that is resistant to prior endocrine therapy, AstraZeneca is exploring a combination trial with fulvestrant (MANTA) and a triplet combination trial of vistusertib, palbociclib and fulvestrant (PASTOR). In addition, two doses and schedules are being explored: a continuous schedule (50mg BID) and an intermittent schedule (125mg BID 2 days on, 5 days off). These clinical studies are ongoing and the efficacy of vistusertib in breast cancer is not yet known. In DLBCL a combination trial with the BTK inhibitor, acalabrutinib is planned for 2017.

In May, 2017, a combination trial of vistusertib and durvalumab in bladder cancer (BISCAY) was initiated.

The remainder of the clinical portfolio is largely made up of externally sponsored research studies that are assessing the clinical activity of vistusertib in a range of solid tumors and hematological malignancies. A combination based approach is favored and the ongoing studies include:

  • Vistusertib + selumetinib: advanced cancers, NF1 MPNST and other pediatric; NSCLC (WT and KRASm); TNBC; CRC (RASm); LGSOv (RASm); uveal melanoma expansion cohorts. RP2D established.
  • Vistusertib + olaparib: TNBC, ovarian, endometrial expansion cohorts. RP2D established.
  • Vistusertib + navitoclax: SCLC. RP2D not established.
  • Vistusertib + AZD8186: Prostate cancer and TNBC
  • Vistusertib + durvalumab + tremelimumab: HNSCC
  • Vistusertib + paclitaxel: solid tumors; high grade serous ovarian; squamous NSCLC; gastric cancer
  • Vistusertib + rituximab: DLBCL
  • Vistusertib + temozolomide + topotecan: Pediatric Phase 1
  • Vistusertib + temozolomide: GBM

No clinical data suggests vistusertib crosses the BBB but all the preclinical evidence suggests that it is a poor BBB penetrator.

Clinical activity of vistusertib in tumors with genetic alterations that might result in hyperactivation of the mTORC complexes, e.g., TSC1/2 mutation (mTORC1 activation) and RICTOR amplification (mTORC2 activation) are being explored. Several basket/umbrella studies are either recruiting or in set-up across tumor types including lung cancer, breast cancer, gastric cancer and sarcomas.

Studies of Interest

Areas of interest:

Proposals should be supported by strong preclinical data, considering potential future changes in the clinical landscape of the proposed indication. Clinical proposals should align to the following core scientific hypotheses:

  • Inhibition of mTORC1/2 to prevent early adaptation and feedback responses (mTORC1/2 mediates feedback responses and resistance to a number of agents). A combination based approach is preferred.
  • Inhibition of mTOR to enhance the immune response: Regulation of immune metabolism, generation of memory T cells and negative modulation of MDSCs.
  • Target genetic alterations proximal to the mTORC1/2 complexes e.g. TSC1/2 and RICTOR

Areas NOT of interest:

  • Combinations with selumetinib and other MEK inhibitors
  • Combinations with chemotherapy agents
  • In general, clinical studies that select patients for molecular alterations in the PI3K pathway such as PIK3CAm or AKT1m are not supported because there is no preclinical or clinical evidence that these predict response to vistusertib.
  • Clinical studies that overlap with our internal development program

Proposals considered for agent support only:

  • Combinations with immune-checkpoint inhibitors (primarily durvalumab). Tolerability data and RP2D from clinical studies is still pending. Proposals in tumor types where mTOR might play a key role and that are amenable to immune-checkpoint inhibition are of interest.
  • Combinations with the AstraZeneca DNA Damage Response portfolio e.g. AZD1775 (wee1 inhibitor) or olaparib.
  • Combinations with endocrine therapy and other targeted agents in breast cancer might be considered from Q4 2017 onward.
  • Other combinations can be considered where there is compelling preclinical data and a strong applicability to the clinic

Information collaborator would like included in investigator proposals

N/A