Phase 1 Completed N=4 Other

Absorption, Metabolism, Excretion and Pharmacokinetics of a Single Dose [14C]AZD2014 Followed by a Multiple Dose Phase

Source: ClinicalTrials.gov NCT02640755 ↗

Enrolled (actual)

Serious AEs

50.0%

Results posted

Apr 2019

Primary outcomePrimary: Total Radioactivity in Plasma Following Administration of [14C]-AZD2014 — 4013; 3415; 2901; 2693 nanogram equivalent/millilitre (ngEq/mL)

Summary

This Phase 1, open label, single centre, non-randomised study in patients with advanced solid malignancies consists of two parts: 1. Single Dose Period - will characterise the absorption, metabolism, excretion and pharmacokinetics of a single oral dose of [14C]AZD2014 from the body 2. Multiple Dose Period - will further assess the safety and tolerability and anti-tumour activity of multiple doses of AZD2014 when given as a monotherapy or given in combination with paclitaxel or fulvestrant.

Outcome Measures

Outcome	Result	p-value
PRIMARY Total Radioactivity in Plasma Following Administration of [14C]-AZD2014	4013; 3415; 2901; 2693; 2105; 1818	—
PRIMARY AZD2014 Concentrations in Plasma Following Administration of [14C]-AZD2014	3704; 3090; 2758; 2409; 1768; 1439	—
PRIMARY Total Radioactivity Concentrations in Saliva Following Administration of [14C]-AZD2014	5495; 650.2; 264.3; 135.4; 158.5; 105.2	—
PRIMARY AZD2014 Concentrations in Saliva Following Administration of [14C]-AZD2014	4159; 416.3; 169.1; 75.08; 73.27; 32.59	—
PRIMARY Total Radioactivity Concentrations in Blood Following Administration of [14C]-AZD2014	2725; 2293; 1980; 1783; 1421; 1255	—
PRIMARY Cumulative Percentage of [14C]-AZD2014 Recovered by Day 8	92.02	—
PRIMARY Maximum Observed Concentration (Cmax) of AZD2014 in Plasma and Saliva	4254; 5410	—
PRIMARY Time to Maximum Observed Concentration (Tmax) for AZD2014 in Plasma and Saliva	0.53; 1.00	—
PRIMARY Time to Last Measurable Concentration (t[Last]) for AZD2014 in Plasma and Saliva	17.04; 10.57	—
PRIMARY Area Under the Plasma Concentration-time Curve (AUC) for AZD2014	17170	—
PRIMARY Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) for AZD2014 in Plasma and Saliva	16510; 6025	—
PRIMARY Apparent Total Body Clearance (CL/F) of AZD2014	7.282	—
PRIMARY Mean Residence Time (MRT) of AZD2014	5.200	—
PRIMARY Apparent Volume of Distribution at Steady State (Vss/F) for AZD2014 in Plasma	37.86	—
PRIMARY Terminal Elimination Rate Constant (lambda_z) for AZD2014 in Plasma	0.1941	—
PRIMARY Half-life Associated With Terminal Slope (lambda_z) of a Semi-logarithmic Concentration-time Curve (t1/2[lambda_z]) for AZD2014 in Plasma	3.571	—
PRIMARY Cmax for Total [14C] Radioactivity in Whole Blood and Saliva	3004; 6966	—
PRIMARY Tmax for [14C] Radioactivity in Whole Blood and Saliva	0.53; 1.00	—
PRIMARY T(Last) for [14C] Radioactivity in Whole Blood and Saliva	18.26; 15.33	—
PRIMARY Ratio of Whole Blood Total Radioactivity to Plasma Total Radioactivity	0.6861; 0.6713; 0.6825; 0.6623; 0.6750; 0.6904	—
PRIMARY Ratio of AZD2014 Concentration to Total Radioactivity Concentration in Saliva	1.011; 0.8217; 0.7001; 0.4993; 0.4671; 0.3648	—
PRIMARY Fraction of AZD2014 Excreted in Urine as a Percentage of the Dose (fe%[R])	1.575; 0.7471; 0.3472; 0.0460; 0; 0	—
PRIMARY Renal Clearance (CL[R]) of AZD2014 From Plasma.	0.1596	—
PRIMARY Cumulative Percentage of Total [14C] Radioactivity Excreted in Urine as a Percentage of the Dose (fe Cum%[R])	5.514; 8.990; 11.06; 11.81; 11.96; 12.03	—
PRIMARY Cumulative Percentage of Total [14C] Radioactivity Excreted in Stool as a Percentage of the Dose (fe Cum%[f])	18.23; 52.85; 77.04; 78.59; 79.25; 79.70	—
SECONDARY Number of AEs Experienced by Patients.	3; 1; 3; 1; 1; 1	—
SECONDARY Best Overall Response (BOR) Assessment	0; 0; 0; 0; 3; 0	—
SECONDARY Best Percentage Change in Tumour Size From Baseline	-8.75; 3.1	—

Eligibility Criteria

Inclusion Criteria

Provision of signed, written & dated informed consent prior to any study specific procedures.
Male or female patients aged at least 18 years.
Have a body mass index (BMI) ≥18 kg/m2 and ≤35 kg/m2 & weigh at least 50 kg.
Histological or cytological confirmation of a solid malignant tumour that is refractory or resistant to standard therapies or for which no suitable effective standard therapies exist. SqNSCLC patients are excluded from the 50mg BD AZD2014 in combination with paclitaxel cohort.
For patients intending to enter combination therapy with fulvestrant or paclitaxel, this should be deemed as an appropriate treatment option by Investigator.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 with no deterioration over previous 2 weeks & minimum life expectancy of 12 weeks.
At least one lesion (measurable and/or non-measurable but evaluable) that can be accurately assessed at baseline by computerised tomography (CT) magnetic resonance imaging (MRI) or plain X-ray & is suitable for repeated assessment
Able & willing to stay in hospital for approximately 9 days
Females should be using adequate contraceptive measures, should not be breast feeding & must have negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential
Male patients should be surgically sterile or willing to use barrier contraception ie, condoms and spermicide &refrain from donating sperm from start of dosing until 16 weeks after discontinuing of study treatment.
Regular bowel movements (ie, on average production of at least 1 stool per day)

Exclusion Criteria

Involvement in planning and/or conduct of the study
Previous enrolment in present study
Another study with an investigational product in last 28 days
Chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents & any investigational agents within 21 days of starting treatment (not including palliative radiotherapy at focal sites), or corticosteroids within 14 days
Major surgery within 4 weeks, or minor surgery within 14 days
Exposure to strong and moderate inhibitors or inducers of cytochrome P450 (CYP) 3A4/5, P-glycoprotein (Pgp) (multidrug resistance gene [MDR1]), and breast cancer resistance protein (BCRP), if taken within stated washout periods
Exposure to specific substrates of the drug organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporting polypeptide (OCT)1 and OCT2 within appropriate washout period
Any haemopoietic growth factors (eg, filgrastim [granulocyte colony-stimulating factor; G-CSF], sargramostim [granulocyte-macrophage colony-stimulating factor; GM-CSF]) within 14 days prior to receiving study treatment
Previous treatment with AZD2014 or AZD8055
Patients who have received fulvestrant within 3 months
With exception of alopecia, any unresolved toxicities chemotherapy/radiotherapy should be no greater than CTCAE grade 1
Participated in another absorption, distribution, metabolism and excretion study within 1 year
Spinal cord compression and/or brain metastases unless asymptomatic or treated & stable off steroids for at least 4 weeks
Severe or uncontrolled systemic diseases (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, active bleeding diatheses or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
Recent history of drug abuse or alcohol abuse
Patients who have undergone any of the following procedures or experienced conditions currently or in preceding 12 months:
Coronary artery bypass graft
Angioplasty
Vascular stent
Myocardial infarction
Angina pectoris
Congestive heart failure New York Heart Association Grade 2
Ventricular a

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Data sourced from ClinicalTrials.gov (NCT02640755). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.