AZD2014 in Combination with Paclitaxel in Patients with Relapsed or Refractory Squamous Non-small Cell Lung Cancer

Phase 1

• Conditions: Squamous Non-Small Cell Lung Cancer; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-000159-26-ES
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-04-27
• Last Update Posted: 13 February 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1.Histologically or cytologically proven squamous non-small cell lung cancer (NSCLC) where treatment with weekly paclitaxel is an appropriate treatment option.
2.Relapsed or refractory disease after at least one line of prior therapy. Subjects must have previously received appropriate lines of standard of care (SOC) treatment.
3.Measurable disease by RECIST v1.1 criteria
4.Life expectancy of at least 12 weeks.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening (with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening), defined as:
?Absolute neutrophil count ?? 1500 cells/mm3 (1.5 x 109/L)
?Platelet count ? ?100,000 cells/mm3 (100 x 109/L)
?Haemoglobin ? ?9.0 g/dL
7.Adequate hepatic and renal function defined as:
?Serum aspartate transaminase (AST) or alanine transaminase (ALT) ?? 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or ?? 5 x ULN in the presence of liver metastases
?Alkaline phosphatase (ALP) < 5 x ULN
?Serum bilirubin ?? 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
?Estimated Creatinine Clearance ? ? 50 ml/min (Cockroft Gault) or serum creatinine ?? 1.5 x ULN
8.PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN
9.Fasting glucose ?? 125 mg/dL (7 mmol/L) and erythrocyte-HbA1c ?? 59 mmol/mol
10.Men and women ? ? 18 years of age
11.Female patients must fulfil either of the 2 following main criteria:
?Not of childbearing potential, defined as:
?Post-menopausal women: Either women aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years old who have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteininzing hormone (LH) levels in the postmenopausal range for the institution.
Or
?Have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
?Have a negative pregnancy test prior to start of dosing, shoudl not be breastfeeding, and willing to use two forms of highly effective contraception (per institution standards) from the time of screening until 4 weeks after discontinuing study treatment (see Section 3.8)
12.Male patients must use an effective barrier method of contraception during the study and for 16 weeks following the last dose if sexually active with a female of childbearing potential
13.Able to swallow and retain oral medication
14.Written (signed and dated) informed consent (including provision of consent for collection of formalin fixed paraffin-embedded blocks or slides from archival histology or cytology samples, where available) and be capable of co-operating with treatment and follow up

Inclusion in biopsy research
For inclusion in the biopsy research of the study, patients must fulfil the following additional criterion:
?Provision of signed, written and dated informed consent for biomarker sampling analyses. Sampling will include the provision of tumour biopsies . If a patient declines to participate in this research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the stud;
1.Histologically or cytologically proven squamous non-small cell lung cancer (NSCLC) where treatment with weekly paclitaxel is an appropriate treatment option.
2.Relapsed or refractory disease after at least one line of prior therapy. Subjects must have previously received appropriate lines of standard of care (SOC) treatment.
3.Measurable disease by RECIST v1.1 criteria
4.Life expectancy of at least 12 weeks.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening (with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening), defined as:
?Absolute neutrophil count ?? 1500 cells/mm3 (1.5 x 109/L)
?Platelet count ? ?100,000 cells/mm3 (100 x 109/L)
?Haemoglobin ? ?9.0 g/dL
7.Adequate hepatic and renal function defined as:
?Serum aspartate transaminase (AST) or alanine transaminase (ALT) ?? 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or ?? 5 x ULN in the presence of liver metastases
?Alkaline phosphatase (ALP) < 5 x ULN
?Serum bilirubin ?? 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
?Estimated Creatinine Clearance ? ? 50 ml/min (Cockroft Gault) or serum creatinine ?? 1.5 x ULN
8.PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN
9.Fasting glucose ?? 125 mg/dL (7 mmol/L) and erythrocyte-HbA1c ?? 59 mmol/mol
10.Men and women ? ? 18 years of age
11.Female patients must fulfil either of the 2 following main criteria:
?Not of childbearing potential, defined as:
?Post-menopausal women: Either women aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years old who have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteininzing hormone (LH) levels in the postmenopausal range for the institution.
Or
?Have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
?Have a negative pregnancy test prior to start of dosing, shoudl not be breastfeeding, and willing to use two forms of highly effective contraception (per institution standards) from the time of screening until 4 weeks after discontinuing study treatment (see Section 3.8)
12.Male patients must use an effective barrier method of contraception during the study and for 16 weeks following the last dose if sexually active with a female of childbearing potential
13.Able to swallow and retain oral medication
14.Written (signed and dated) informed consent (including provision of consent for collection of formalin fixed paraffin-embedded blocks or slides from archival histology or cytology samples, where available) and be capable of co-operating with treatment and follow up

Inclusion in biopsy research
For inclusion in the biopsy research of the study, patients must fulfil the following additional criterion:
?Provision of signed, written and dated informed consent for biomarker sampling analyses. Sampling will include the provision of tumour biopsies . If a patient declines to participate in this research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the stud;
1.Histologically or cytologically proven squamous non-small cell lung cancer (NSCLC) where treatment with weekly paclitaxel is an appropriate treatment option.
2.Relapsed or refractory disease after at least one line of prior therapy. Subjects must have previously received appropriate lines of standard of care (SOC) treatment.
3.Measurable disease by RECIST v1.1 criteria
4.Life expectancy of at least 12 weeks.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening (with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening), defined as:
?Absolute neutrophil count ?? 1500 cells/mm3 (1.5 x 109/L)
?Platelet count ? ?100,000 cells/mm3 (100 x 109/L)
?Haemoglobin ? ?9.0 g/dL
7.Adequate hepatic and renal function defined as:
?Serum aspartate transaminase (AST) or alanine transaminase (ALT) ?? 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or ?? 5 x ULN in the presence of liver metastases
?Alkaline phosphatase (ALP) < 5 x ULN
?Serum bilirubin ?? 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
?Estimated Creatinine Clearance ? ? 50 ml/min (Cockroft Gault) or serum creatinine ?? 1.5 x ULN
8.PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN
9.Fasting glucose ?? 125 mg/dL (7 mmol/L) and erythrocyte-HbA1c ?? 59 mmol/mol
10.Men and women ? ? 18 years of age
11.Female patients must fulfil either of the 2 following main criteria:
?Not of childbearing potential, defined as:
?Post-menopausal women: Either women aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years old who have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteininzing hormone (LH) levels in the postmenopausal range for the institution.
Or
?Have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
?Have a negative pregnancy test prior to start of dosing, shoudl not be breastfeeding, and willing to use two forms of highly effective contraception (per institution standards) from the time of screening until 4 weeks after discontinuing study treatment (see Section 3.8)
12.Male patients must use an effective barrier method of contraception during the study and for 16 weeks following the last dose if sexually active with a female of childbearing potential
13.Able to swallow and retain oral medication
14.Written (signed and dated) informed consent (including provision of consent for collection of formalin fixed paraffin-embedded blocks or slides from archival histology or cytology samples, where available) and be capable of co-operating with treatment and follow up

Inclusion in biopsy research
For inclusion in the biopsy research of the study, patients must fulfil the following additional criterion:
?Provision of signed, written and dated informed consent for biomarker sampling analyses. Sampling will include the provision of tumour biopsies . If a patient declines to participate in this research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the stud

Exclusion Criteria

1.Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy, or immunotherapy during the previous 3 weeks (4 weeks for investigational medicinal products and 6 weeks for nitrosoureas and Mitomycin-C) before treatment .
2.Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or Grade 1 toxicities, which in the opinion of the Investigator should not exclude the patient.
3.Known leptomeningeal involvement, brain metastases or spinal cord compression.
4.History of hypersensitivity (> Grade 2) to active or inactive excipients of AZD2014, drugs containing Cremophor, taxanes or structurally/chemically similar drugs
5.Current refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014
6.Patients with Diabetes Type I or uncontrolled Type II (HbA1c > 59 mmol/mol assessed locally) as judged by the investigator
7.Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered
8.Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.
9.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 (see Appendix G)
10.Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment (see Appendix G)
11.Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period (a minimum of 5 times reported elimination half-life) before the first dose of study treatment (see Appendix G)
12.At high medical risk because of non-malignant systemic disease including active uncontrolled infection e.g. interstitial lung disease, severe hepatic impairment, uncontrolled chronic renal disease
13.Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
14.Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:
?coronary artery bypass graft
?angioplasty
?vascular stent
?myocardial infarction (MI)
?uncontrolled angina pectoris
?congestive heart failure NYHA Grade 2
?ventricular arrhythmias requiring continuous therapy
?supraventricular arrhythmias including AF, which are uncontrolled
?Torsades de Pointes
?haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding
15.Resting ECG with measurable QTcF interval of >470 msec at 2 or more time points within a 24 hour period.
16.Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome), or unexplained sudden death under 40 years of age. Inability to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation
17.Left ventricular (LV) dysfunction (LVEF outside institutional range of normal) by MUGA or Echocardiogram
18.;
1.Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy, or immunotherapy during the previous 3 weeks (4 weeks for investigational medicinal products and 6 weeks for nitrosoureas and Mitomycin-C) before treatment .
2.Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or Grade 1 toxicities, which in the opinion of the Investigator should not exclude the patient.
3.Known leptomeningeal involvement, brain metastases or spinal cord compression.
4.History of hypersensitivity (> Grade 2) to active or inactive excipients of AZD2014, drugs containing Cremophor, taxanes or structurally/chemically similar drugs
5.Current refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014
6.Patients with Diabetes Type I or uncontrolled Type II (HbA1c > 59 mmol/mol assessed locally) as judged by the investigator
7.Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered
8.Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.
9.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 (see Appendix G)
10.Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment (see Appendix G)
11.Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period (a minimum of 5 times reported elimination half-life) before the first dose of study treatment (see Appendix G)
12.At high medical risk because of non-malignant systemic disease including active uncontrolled infection e.g. interstitial lung disease, severe hepatic impairment, uncontrolled chronic renal disease
13.Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
14.Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:
?coronary artery bypass graft
?angioplasty
?vascular stent
?myocardial infarction (MI)
?uncontrolled angina pectoris
?congestive heart failure NYHA Grade 2
?ventricular arrhythmias requiring continuous therapy
?supraventricular arrhythmias including AF, which are uncontrolled
?Torsades de Pointes
?haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding
15.Resting ECG with measurable QTcF interval of >470 msec at 2 or more time points within a 24 hour period.
16.Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome), or unexplained sudden death under 40 years of age. Inability to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation
17.Left ventricular (LV) dysfunction (LVEF outside institutional range of normal) by MUGA or Echocardiogram
18.;
1.Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy, or immunotherapy during the previous 3 weeks (4 weeks for investigational medicinal products and 6 weeks for nitrosoureas and Mitomycin-C) before treatment .
2.Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or Grade 1 toxicities, which in the opinion of the Investigator should not exclude the patient.
3.Known leptomeningeal involvement, brain metastases or spinal cord compression.
4.History of hypersensitivity (> Grade 2) to active or inactive excipients of AZD2014, drugs containing Cremophor, taxanes or structurally/chemically similar drugs
5.Current refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014
6.Patients with Diabetes Type I or uncontrolled Type II (HbA1c > 59 mmol/mol assessed locally) as judged by the investigator
7.Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered
8.Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.
9.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 (see Appendix G)
10.Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment (see Appendix G)
11.Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period (a minimum of 5 times reported elimination half-life) before the first dose of study treatment (see Appendix G)
12.At high medical risk because of non-malignant systemic disease including active uncontrolled infection e.g. interstitial lung disease, severe hepatic impairment, uncontrolled chronic renal disease
13.Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
14.Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:
?coronary artery bypass graft
?angioplasty
?vascular stent
?myocardial infarction (MI)
?uncontrolled angina pectoris
?congestive heart failure NYHA Grade 2
?ventricular arrhythmias requiring continuous therapy
?supraventricular arrhythmias including AF, which are uncontrolled
?Torsades de Pointes
?haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding
15.Resting ECG with measurable QTcF interval of >470 msec at 2 or more time points within a 24 hour period.
16.Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome), or unexplained sudden death under 40 years of age. Inability to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation
17.Left ventricular (LV) dysfunction (LVEF outside institutional range of normal) by MUGA or Echocardiogram
18.

Study & Design

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