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

NCT02583542 | Unknown Phase 1

• 2 other identifiers: 009896QM2014-002613-31
• Study Type: interventional
• Target: 118
• Locations: 1 country
• Sites: 4

Brief Summary

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

Conditions

Triple-Negative Breast Cancer; Squamous Cell Lung Cancer; Non-squamous Cell Lung Cancer With KRAS Mutations; Non-squamous Cell Lung Cancer With Wild-type KRAS

Keywords

breast; lung; squamous; KRAS; AZD; selumetinib

Outcome Measures

Primary Outcomes (2)

• Establish feasible dose levels and regimens of AZD2014 and selumetinib when given in combination by close observation of any dose limiting toxicities

  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.

  First 21 days of treatment.

• Assess clinical activity, as measured by disease control rate, of AZD2014 in combination with selumetinib.

  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

  Day 1 to > 12 weeks.

Secondary Outcomes (12)

• Single dose and/or multiple dose AZD2014 PK Tmax parameters will be used to determine the PK of AZD2014 when given in combination with selumetinib.

  Until Day 9

• Single dose and/or multiple dose AZD2014 PK Cmax parameter will be used to determine the PK of AZD2014 when given in combination with selumetinib.

  Until Day 9

• Single dose and/or multiple dose AZD2014 PK AUC parameters will be used to determine the PK of AZD2014 when given in combination with selumetinib.

  Until Day 9

• Assess clinical activity of AZD2014 and Selumetinib, as measured by objective response rate.

  12 weeks.

• Assess clinical activity of AZD2014 and Selumetinib, as measured by change in tumour size.

  12 weeks.

Study Arms (2)

Dose Escalation Phase (Phase Ib)

EXPERIMENTAL

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).

Drug: AZD2014; Drug: AZD6244

Dose Expansion Phase (Phase IIa)

EXPERIMENTAL

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

Drug: AZD2014; Drug: AZD6244

Interventions

AZD2014 DRUG

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.

Dose Escalation Phase (Phase Ib); Dose Expansion Phase (Phase IIa)

AZD6244 DRUG

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.

Also known as: Selumetinib

Dose Escalation Phase (Phase Ib); Dose Expansion Phase (Phase IIa)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent prior to admission to this study
• Age ≥18 years
• ECOG performance status 0 or 1
• Life expectancy ≥12 weeks
• Patients must have at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements
• Radiological or clinical evidence of disease progression
• Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
• Adequate haematologic and end organ function, defined by the following laboratory results obtained within 7 days prior to the first study treatment:
• ANC ≥ 1.5 x 109/l (without granulocyte colony-stimulating factor support within 2 weeks prior to the first study treatment)
• Platelet count ≥ 100 x 109/l (without transfusion within 2 weeks prior to the first study treatment)
• Haemoglobin ≥ 9 g/dl (transfusion permitted to establish target haemoglobin levels prior to the first study treatment)
• Serum creatinine ≤1.5 times the upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 ml/min
• Bilirubin level ≤1.5 x ULN (patients with known Gilbert disease who have bilirubin levels ≤ 3 x ULN may be enrolled)
• AST or ALT \<2.5 x ULN or \<5 x ULN in the presence of liver metastases
• Alkaline phosphatase (ALP) \<2.5 x ULN or \<5 x ULN in the presence of liver and/or bone metastases

You may not qualify if:

• Symptomatic CNS involvement or CNS involvement requiring steroid therapy; patients with treated brain metastases that are asymptomatic and have been clinically stable for 1 month will be eligible for protocol participation
• Prior chemotherapy, biological therapy, radiation therapy, immunotherapy, other anticancer agents and any investigational agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites)
• Any unresolved toxicity \> CTCAE Grade 1 from previous anti-cancer therapy, with the exception of alopecia
• Current refractory nausea and vomiting, chronic gastrointestinal disease or inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the study medication
• Significant cardiovascular disease, such as;
• History of myocardial infarction, acute coronary syndromes (including unstable angina), or coronary angioplasty/stenting/bypass grafting within past 6 months.
• Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)
• History of symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) Classes II-IV or Left ventricular ejection fraction (LVEF) \<55% measured by echocardiography
• Severe cardiac arrhythmia requiring medication or severe conduction abnormalities (unless compensated by ventricular pacemaker); atrial fibrillation with a ventricular rate \>100 bpm on ECG at rest
• Poorly controlled hypertension (resting diastolic blood pressure \>115 mmHg)
• Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or prior or current cardiomyopathy
• QTc prolongation defined as a QTc interval \>470 msecs
• Concomitant medications known to prolong QT interval
• Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥ 10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) use for ≥ 28 days at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose (\<10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) of corticosteroids for at least two weeks before registration are allowed
• Evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung disease)

Sponsors & Collaborators

• Queen Mary University of London: lead
• Cancer Research UK: collaborator
• AstraZeneca: collaborator

Study Sites (4)

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2TT, United Kingdom

Location

Barts Health NHS Trust

London, EC1M 6BQ, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, W1T 7HA, United Kingdom

Location

Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

vistusertib; AZD 6244

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Peter Schmid, Professor

  Queen Mary University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2015
• First Posted: October 22, 2015
• Study Start: June 1, 2015
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: February 25, 2020

Record last verified: 2020-02

Locations

GB (4)