Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Lung Neoplasms

Carcinoma

Carcinoma, Non-Small-Cell Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Breast Diseases

Skin Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Docetaxel

Sirolimus

Temsirolimus

MTOR Inhibitors

This phase will investigate two different dosing schedules of AZD2014: a continuous daily schedule (CC-Schedule) and an intermittent schedule of 2 days on and 5 days off treatment (IC-Schedule). The dose of Selumetinib (AZD6244) will remain unchanged in both schedules. The outcome of this investigation will determine whether an additional schedule of combined intermittent Selumetinib (AZD6244) (3 days on and 4 days off treatment) with intermittent AZD2014 will be considered (II-Schedule). The II-Schedule will be initiated following the completion of the corresponding continuous regimens and will only be investigated if escalation of the AZD2014 dose in the IC-Schedule is not feasible with the corresponding continuous Selumetinib (AZD6244) regimen. Up to three individual dose levels of Selumetinib (AZD6244) might subsequently be explored within the intermittent schedule of Selumetinib (AZD6244).

Following the definition of the recommended Phase 2 Dose (RP2D), three NSCLC and one TNBC dose expansion cohorts are planned to perform a preliminary assessment of the anti-tumour efficacy in different molecular settings and to further establish the safety profile of the selected RP2D. These cohorts are:

* Triple-negative breast cancer (TNBC)
* Squamous cell lung cancers
* Non-squamous cell lung cancers with KRAS mutations
* Non-squamous cell lung cancers with wild-type KRAS

AZD2014 is a dual inhibitor of both mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin insensitive); compared to rapalogues, AZD2014 has a broader range of growth inhibitory activity in preclinical models based on a more profound mTORC1 inhibition and the additional inhibition of mTORC2. AZD2014 is currently in phase 2 studies in renal cell cancers and metastatic breast cancer.

AZD2014

Selumetinib (AZD6244, ARRY-142886) is an orally available, potent, selective, non-ATP competitive inhibitor of MEK1/MEK2 kinases. Selumetinib has demonstrated clinical efficacy in pre-treated KRAS-mutant NSCLC, leading to a significantly improved progression-free survival in combination with docetaxel compared to docetaxel alone.

AZD6244

Peter Schmid, Professor

Open-label, multicentre phase Ib/IIa study of AZD2014 administered with selumetinib. There are two parts to this study: a dose-escalation part in treatment-refractory advanced solid tumours and a subsequent separate expansion cohort part for TNBC, squamous cell lung cancers, non-squamous cell lung cancers with KRAS mutations and non-squamous cell lung cancers with wild-type KRAS

A Study of AZD2014 in Combination With Selumetinib in Patients With Advanced Cancers

A Phase Ib/IIa Study of AZD2014 in Combination With Selumetinib in Patients With Advanced Cancers

Dose limiting toxicity is defined as occurrence of any of the following toxicities during the first 21 days of treatment:

* Any grade \>3 non-haematological toxicity (excluding nausea, vomiting or diarrhoea)
* Grade 3 nausea, vomiting or diarrhoea lasting \>48 hours despite supportive care or any Grade 4 hause, vomiting or diarrhoea
* Grade 4 neutropenia lasting \>7days or febrile neutropenia
* Grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia
* Inability to receive at least 75% of the planned doses due to unresolved toxicity
* Any treatment delays for \>14 days due to unresolved toxicity

NB: This primary outcome relates to the Phase Ib part of study.

Disease control rate is defined as number of patients with complete or partial response or stable disease maintained \>12weeks (as assessed by the site radiologist and/or investigator, using RECIST 1.1) divided by the number of patients in the analysis. Patients without a post-baseline tumour assessment will be considered to have no disease control.

NB: This primary outcome relates only to the Phase IIa part of this study

Objective response, defined as a complete or partial response (as assessed by the site radiologist and/or investigator, using RECIST 1.1) divided by the number of patients of risk

Average change (%) in tumour size at 12 weeks compared to baseline, as assessed by RECIST 1.1; tumour size is defined as the sum of the diameters of the target lesion.

i.e. Incidence of serious adverse events; Incidence of Grade 3 and 4 adverse events; Incidence of all adverse events of all grades; Adverse events leading to discontinuation of the study medication; Clinically significant changes in vital signs and clinical laboratory results during and following study drug administration; Clinically significant changes in ECG measurements

Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first.

PFS defined as the time from the date of registration to the date of first documented tumour progression (RECISTv1.1) or death from any cause, whichever occurs first.

Spots Global Cancer Trial Database for A Study of AZD2014 in Combination With Selumetinib in Patients With Advanced Cancers

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