A Phase Ib/IIa study of AZD2014 in combination with Selumetinib in patients with advanced cancers

• Conditions: Triple-Negative Breast CancerNon-squamous Small Cell Lung CancerSquamous Cell Lung Cancer; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-002613-31-GB
• Lead Sponsor: Queen Mary University of London

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-02-26
• Last Update Posted: 28 September 2015

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 118

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 been at least one lesion, not previously irradiated, that can be measured accurately at baseline as =10mm in the longest diameter (except lymph nodes which must have short axis =15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeatede 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 laboratory results obtained within 14 days prior to the first study treatment
9) 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, and agrees to use adequate contraception beginning 2 weeks before the first dose of investigational product and for 30 days after the final dose of investigational product. Male patients must agree to use appropriate contraception during the trial and for 3 months afterwards

Criteria unique to the Dose Escalation Part (Phase 1b part):
1) Histologically or cytologically advanced solid tumour; the study will be limited to
a) tumour types with frequent activation of MAPK and/or PI3K pathways (pancreatic, thyroid, endometrial, renal, breast or ovarian carcinoma, colorectal cancer, NSCLC or melanoma
b) 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
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

Criteria unique to the lung cancer dose expansion cohorts (phase IIa part):
1) Histologically confirmed non-small cell lung cancer
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

Criteria unique to the triple-negative breast cancer dose expansion cohort (phase IIa):
1) Histologically confirmed triple negative breast cancer
2) Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent
3) Prior chemotherapy for advanced disease
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 118
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 0

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
3) Any unresolved toxicity > CTCAE Grade 1 from previous anti-cancer therapy
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
6) QTc prolongation defined as a QTc interval >470msecs
7) Concomitant medications known to prolong QT interval
8) Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids for =28 days at the time of study entry
9)Evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung disease)
10) Clinically significant abnormalities of glucose metabolism
11) Opthalmological conditions as follows:
a) Intra-ocular pressure >21mmHg, or uncontrolled glaucoma
b) 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 period before the first dose of study treatment
13) Exposure to potent or moderate inhibitors or inducers of CYP2C8 within the stated washout periods before the first dose of study treatment
14) Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp and BCRP within the appropriate wsh-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 of recurrence during the study
16) Any evidence 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 investigators 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. Participation in another clinical trial with any investigational drug within 30 days prior to study entry

Criteria specific to dose expansion cohorts:
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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified