Clinical Trials /

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

NCT02583542

Description:

Selumetinib (AZD6244) and AZD2014 are two new anti-cancer treatments that AstraZeneca are developing; they are both not yet approved for clinical use. Selumetinib (AZD6244) is a drug that acts by blocking a protein called MEK, which has been linked to the development and growth of multiple cancers. AZD2014 is a drug that blocks a protein called mTOR that is involved in the growth and spread of cancer. Blocking the action of either MEK or mTOR alone may slow down or stop the cancer growing. Combining both drugs may make the cancer more sensitive than if Selumetinib (AZD6244) or AZD2014 are used alone and therefore this dual treatment may lead to increased anti-tumour effects. Although Selumetinib (AZD6244) and AZD2014 given alone and in combination with other anti-cancer drugs have been tested in people with advanced cancer, the specific combination of Selumetinib (AZD6244) and AZD2014 has not been used in people before. Therefore Phase 1b (Dose Escalation Phase) will determine what the recommended dose to use in Phase IIa (Dose Expansion Phase) will be. Efficacy, progression free survival, duration of response, and overall survival, will then be assessed in patients with triple-negative breast cancer, and Non small cell lung cancer within Phase IIa.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Endometrial Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Pancreatic Carcinoma
  • Renal Cell Carcinoma
  • Squamous Cell Lung Carcinoma
  • Thyroid Gland Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

A Study of AZD2014 in Combination With <span class="go-doc-concept go-doc-intervention">Selumetinib</span> in Patients With Advanced Cancers

Title

  • Brief Title: A Study of AZD2014 in Combination With Selumetinib in Patients With Advanced Cancers
  • Official Title: A Phase Ib/IIa Study of AZD2014 in Combination With Selumetinib in Patients With Advanced Cancers
  • Clinical Trial IDs

    NCT ID: NCT02583542

    ORG ID: Torcmek

    Trial 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

    Trial Interventions

    Drug Synonyms Arms
    AZD2014 Dose Escalation Phase (Phase Ib), Dose Expansion Phase (Phase IIa)
    AZD6244 Selumetinib Dose Escalation Phase (Phase Ib), Dose Expansion Phase (Phase IIa)

    Trial Purpose

    Selumetinib (AZD6244) and AZD2014 are two new anti-cancer treatments that AstraZeneca are
    developing; they are both not yet approved for clinical use.

    Selumetinib (AZD6244) is a drug that acts by blocking a protein called MEK, which has been
    linked to the development and growth of multiple cancers. AZD2014 is a drug that blocks a
    protein called mTOR that is involved in the growth and spread of cancer. Blocking the action
    of either MEK or mTOR alone may slow down or stop the cancer growing. Combining both drugs
    may make the cancer more sensitive than if Selumetinib (AZD6244) or AZD2014 are used alone
    and therefore this dual treatment may lead to increased anti-tumour effects.

    Although Selumetinib (AZD6244) and AZD2014 given alone and in combination with other
    anti-cancer drugs have been tested in people with advanced cancer, the specific combination
    of Selumetinib (AZD6244) and AZD2014 has not been used in people before. Therefore Phase 1b
    (Dose Escalation Phase) will determine what the recommended dose to use in Phase IIa (Dose
    Expansion Phase) will be. Efficacy, progression free survival, duration of response, and
    overall survival, will then be assessed in patients with triple-negative breast cancer, and
    Non small cell lung cancer within Phase IIa.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    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). AZD2014, 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 AZD2014, AZD6244

    Eligibility Criteria

    Inclusion Criteria:

    1. Written informed consent prior to admission to this study

    2. Age 18 years

    3. ECOG performance status 0 or 1

    4. Life expectancy 12 weeks

    5. 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

    6. Radiological or clinical evidence of disease progression

    7. Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer
    must be available for central testing

    8. 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

    - INR and aPTT 1.5 x ULN; this applies only to patients who are not receiving
    therapeutic anticoagulation; patients receiving therapeutic anticoagulation
    should be on a stable dose.

    - Female patients of child-bearing potential are eligible, provided they have a
    negative serum or urine pregnancy test within 2 weeks prior to the first dose of
    study treatment, preferably as close to the first dose as possible. All patients
    with reproductive potential must agree to use adequate contraception beginning
    two weeks before the first dose of investigational product and for three months
    after the discontinuation of treatment. Adequate contraception methods include:
    intrauterine device [IUD], birth control pills unless clinically
    contraindicated, or a barrier device.

    Inclusion Criteria unique to the Dose Escalation Part (phase Ib part):

    1. Histologically or cytologically advanced solid tumour limited to:

    - Tumour types with frequent activation of MAPK and/or PI3K pathways (pancreatic,
    thyroid, endometrial, renal, breast or ovarian carcinoma, colorectal cancer,
    NSCLC or melanoma) OR

    - Tumours with known alteration in 1 gene involved in PI3K/AKT/mTOR or Ras/MEK
    pathway signalling, such as: KRAS, NRAS, BRAF, PIK3CA, PTEN, AKT, LKB1, EGFR,
    FGFR, HER2, MET, RET, KIT, NF1

    2. Metastatic or locally advanced disease, which is refractory to conventional treatment
    or for which no conventional therapy exists; locally recurrent disease must not be
    amenable to resection with curative intent (patients who are considered suitable for
    surgical or ablative techniques following potential down-staging with study treatment
    are not eligible).

    Inclusion Criteria unique to the lung cancer dose expansion cohorts (phase IIa part):

    1. Histologically confirmed NSCLC

    2. Stage III disease that is unsuitable to radio-chemotherapy or Stage IV disease or
    recurrent NSCLC; recurrent disease must not be amenable to resection or radical
    radiotherapy with curative intent.

    3. Prior chemotherapy and/or, if indicated/accessible, EGFR-directed or ALK-directed
    therapy for advanced disease

    Inclusion Criteria unique to the TNBC dose expansion cohort (Phase IIa):

    1. Histologically confirmed TNCB defined as tumour cells being:

    - Negative for ER with <1% of tumour cells positive for ER on IHC or IHC score
    (Allred) of 2

    - Negative for PR with <1% of tumour cells positive for PR on IHC or IHC score
    (Allred) of 2 or PR unknown, and

    - Negative for HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of
    amplification on ISH.

    2. Metastatic or locally recurrent disease; locally recurrent disease must not be
    amenable to resection with curative intent (patients who are considered suitable for
    surgical or ablative techniques following potential down-staging with study treatment
    are not eligible).

    3. Prior chemotherapy for advanced disease

    Exclusion Criteria:

    1. 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

    2. 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)

    3. Any unresolved toxicity > CTCAE Grade 1 from previous anti-cancer therapy, with the
    exception of alopecia

    4. 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

    5. 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

    6. QTc prolongation defined as a QTc interval >470 msecs

    7. Concomitant medications known to prolong QT interval

    8. 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

    9. Evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung
    disease)

    10. Clinically significant abnormalities of glucose metabolism as defined by any of the
    following

    - Diagnosis of diabetes mellitus type I or II (irrespective of management).

    - Glycosylated haemoglobin (HbA1C) 8.0% at screening (64 mmol/mol) (conversion
    equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) - 2.15] x 10.929)

    - Fasting Plasma Glucose 7.0mmol/L (126 mg/dL) at screening. Fasting is defined
    as no caloric intake for at least 8 hours.

    11. Ophthalmological conditions as follows:

    - Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of
    intra-ocular pressure)

    - Current or past history of central serous retinopathy or retinal vein occlusion

    12. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the
    stated washout periods before the first dose of study treatment

    - Inhibitors (competitive): ketoconazole, itraconazole, indinavir, saquinovir,
    nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin,
    telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole,
    fluvoxamine, P-glycoprotein, grapefruit juice, or seville oranges (1 week
    minimum wash-out period), amiodarone (27 week minimum wash-out period)

    - Inhibitors (time dependent): erythromycin, clarithromycin, verapamil, ritonavir,
    diltiazem (2 week minimum wash-out period)

    - Inducers: phenytoin, rifampicin, St. John's Wort, carbamazepine, dexamethasone,
    primidone, griseofulvin, carbamazepine, barbiturates, troglitazone,
    pioglitazone, oxcarbazepine, nevirapine, efavirenz, rifabutin (3 week minimum
    wash-out period) and phenobarbitone (5 week minimum wash-out period)

    13. Exposure to potent or moderate inhibitors or inducers of CYP2C8 within the stated
    washout periods before the first dose of study treatment

    - Inhibitors: Gemfibrozil, trimethoprim, glitazones, montelukast, quercetin (1
    week minimum wash-out period)

    - Inducers: Rifampicin (3 week minimum wash-out period)

    14. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising
    enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1) and BCRP
    within the appropriate wash-out period before the first dose of study treatment

    15. Active second malignancy (except non-melanomatous skin cancer): active secondary
    malignancy is defined as a current need for cancer therapy or a high possibility
    (>30%) of recurrence during the study.

    16. Any evidence of severe or uncontrolled systemic disease, active infection, active
    bleeding diatheses or renal transplant, including any patient known to have hepatitis
    B, hepatitis C or human immunodeficiency virus (HIV)

    17. Any other disease, metabolic dysfunction, physical examination finding, or clinical
    laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
    a disease or condition that contraindicates the use of an investigational drug, may
    affect the interpretation of the results, render the patient at high risk from
    treatment complications or interferes with obtaining informed consent.

    18. Psychological, familial, sociological or geographical conditions that do not permit
    compliance with the study protocol.

    19. Concurrent treatment with other experimental drugs or participation in another
    clinical trial with any investigational drug 30 days prior to study entry depending
    on the half-life of the investigational drug and/or guidance issued by the TORCMEK
    IMP manufacturer. Please contact the TORCMEK Coordinating team for further
    information.

    Exclusion Criteria unique to the dose expansion cohorts (phase IIa part):

    1. Prior treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitors or MEK, Ras or
    Raf inhibitors.

    2. Prior radiotherapy to the indicator lesion(s); Newly arising lesions in previously
    irradiated areas are accepted.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

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

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

    Secondary Outcome Measures

    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.

    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.

    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.

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

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

    To assess the safety and tolerability of AZD2014 when given in combination with selumetinib by the continuous assessment of Adverse Events.

    Overall survival defined as the time from date of registration to the date of death due to any cause will be used to assess the efficacy of AZD2014 when given in combination with selumetinib.

    Duration of response will be used to assess of AZD2014 when given in combination with selumetinib.

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

    Single dose and/or multiple dose of AZD2014 and selumetinib PK Cmax parameters will be used to investigate the PK of Selumetinib when given in combination with AZD2014.

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

    Progression-free survival (PFS) will be used to assess the efficacy of AZD2014 when given in combination with selumetinib.

    Trial Keywords

    breast

    lung

    squamous

    KRAS

    AZD

    selumetinib