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

NCT02640755 | Completed Phase 1 Results

• 2 other identifiers: D2270C000152015-000198-11
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase 1, open label, single centre, non-randomised study in patients with advanced solid malignancies consists of two parts:

1. 1.Single Dose Period - will characterise the absorption, metabolism, excretion and pharmacokinetics of a single oral dose of \[14C\]AZD2014 from the body
2. 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.

Conditions

Solid Malignancies

Keywords

Radiolabelled

Outcome Measures

Primary Outcomes (25)

• Total Radioactivity in Plasma Following Administration of [14C]-AZD2014

  The mean concentrations of total radioactivity in plasma collected from each patient who received a single oral dose of 125 mg \[14C\]-AZD2014 are presented for time points of plasma sampling up to 48 hours post-dose. Geometric mean concentrations were not quantifiable after 48 hours. The total \[14C\] radioactivity in plasma was converted to concentration equivalents of AZD2014 based on the actual specific activity of the dose.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32 and 48 hours (h) post [14C]-AZD2014 dose in the Single Dose Period.

• AZD2014 Concentrations in Plasma Following Administration of [14C]-AZD2014

  The mean concentrations of AZD2014 in plasma collected from each patient who received a single oral dose of 125 mg \[14C\]-AZD2014 are presented for time points of plasma sampling up to 24 hours post-dose. Geometric mean concentrations were not quantifiable after 24 hours.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Total Radioactivity Concentrations in Saliva Following Administration of [14C]-AZD2014

  The mean concentrations of total radioactivity in saliva collected from each patient who received a single oral dose of 125 mg \[14C\]-AZD2014 are presented for time points of saliva collection up to 12 hours post-dose. Geometric mean concentrations were not quantifiable after 12 hours. The total \[14C\] radioactivity in saliva was converted to concentration equivalents of AZD2014 based on the actual specific activity of the dose.

  Saliva was collected at 1, 2, 4, 6, 8, 10 and 12 h post [14C]-AZD2014 dose in the Single Dose Period.

• AZD2014 Concentrations in Saliva Following Administration of [14C]-AZD2014

  The mean concentrations of AZD2014 in saliva collected from each patient who received a single oral dose of 125 mg \[14C\]-AZD2014 are presented for time points of plasma sampling up to 12 hours post-dose. Geometric mean concentrations were not quantifiable after 12 hours.

  Saliva was collected at 1, 2, 4, 6, 8, 10 and 12 h post [14C]-AZD2014 dose in the Single Dose Period.

• Total Radioactivity Concentrations in Blood Following Administration of [14C]-AZD2014

  The mean concentrations of total radioactivity in blood collected from each patient who received a single oral dose of 125 mg \[14C\]-AZD2014 are presented for time points of blood sampling up to 12 hours post-dose. Geometric mean concentrations were not quantifiable after 12 hours. The total \[14C\] radioactivity in plasma was converted to concentration equivalents of AZD2014 based on the actual specific activity of the dose.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post [14C]-AZD2014 dose in the Single Dose Period.

• Cumulative Percentage of [14C]-AZD2014 Recovered by Day 8

  The mean cumulative percentage of \[14C\]-AZD2014 dose recovered as total radioactivity by the end of the Single Dose Period (Day 1 - 8) is presented. The total \[14C\] radioactivity in plasma was converted to concentration equivalents of AZD2014 based on the actual specific activity of the dose. Radioactivity excreta data for 1 patient was not included due to technical issues with radioactivity sample collection.

  From pre-dose Day 1 to Day 8 of the Single Dose Period.

• Maximum Observed Concentration (Cmax) of AZD2014 in Plasma and Saliva

  Mean AZD2014 Cmax values in plasma and saliva following administration of \[14C\]-AZD2014 on Day 1 are presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Time to Maximum Observed Concentration (Tmax) for AZD2014 in Plasma and Saliva

  AZD2014 Tmax values for plasma and saliva following administration of \[14C\]-AZD2014 on Day 1 are presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Time to Last Measurable Concentration (t[Last]) for AZD2014 in Plasma and Saliva

  AZD2014 t(last) values in plasma and saliva following administration of \[14C\]-AZD2014 on Day 1 are presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Area Under the Plasma Concentration-time Curve (AUC) for AZD2014

  Mean AUC for AZD2014 following administration of \[14C\]-AZD2014 on Day 1 is presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose in the Single Dose Period.

• 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

  Mean AUC(0-t) values in plasma and saliva for AZD2014 following administration of \[14C\]-AZD2014 on Day 1 are presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Apparent Total Body Clearance (CL/F) of AZD2014

  The mean CL/F of AZD2014 in plasma following administration of \[14C\]-AZD2014 on Day 1 is presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Mean Residence Time (MRT) of AZD2014

  The MRT of AZD2014 in plasma following administration of \[14C\]-AZD2014 on Day 1 is presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Apparent Volume of Distribution at Steady State (Vss/F) for AZD2014 in Plasma

  The mean Vss/F of AZD2014 in plasma following administration of \[14C\]-AZD2014 on Day 1 is presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Terminal Elimination Rate Constant (lambda_z) for AZD2014 in Plasma

  The mean lambda\_z of AZD2014 in plasma following administration of \[14C\]-AZD2014 on Day 1 is presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Half-life Associated With Terminal Slope (lambda_z) of a Semi-logarithmic Concentration-time Curve (t1/2[lambda_z]) for AZD2014 in Plasma

  The mean t1/2(lambda\_z) for AZD2014 in plasma following administration of \[14C\]-AZD2014 on Day 1 is presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h ost [14C]-AZD2014 dose in the Single Dose Period.

• Cmax for Total [14C] Radioactivity in Whole Blood and Saliva

  Mean \[14C\] radioactivity Cmax values in whole blood and saliva following administration of \[14C\]-AZD2014 on Day 1 are presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Tmax for [14C] Radioactivity in Whole Blood and Saliva

  \[14C\] radioactivity tmax in whole blood and saliva following administration of \[14C\]-AZD2014 on Day 1 is presented .

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• T(Last) for [14C] Radioactivity in Whole Blood and Saliva

  Mean \[14C\] radioactivity t(last) values in whole blood and saliva following administration of \[14C\]-AZD2014 on Day 1 are presented.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose. Saliva was collected at 1, 2, 4, 6, 8, 10, 12 and 24 h post [14C]-AZD2014 dose in the Single Dose Period.

• Ratio of Whole Blood Total Radioactivity to Plasma Total Radioactivity

  The mean ratios of whole blood total radioactivity to plasma total radioactivity are presented for the timepoints of sample collection up to 12 hours post-dose. Geometric mean ratios were not calculated after 12 hours.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post [14C]-AZD2014 dose.

• Ratio of AZD2014 Concentration to Total Radioactivity Concentration in Saliva

  The mean ratios of saliva AZD2014 to saliva radioactivity concentrations are presented for the timepoints of saliva collection up to 10 hours post-dose. Geometric mean ratios were not calculated after 10 hours. Radioactivity excreta data for 1 patient was not included due to technical issues with radioactivity sample collection.

  Saliva was collected at 1, 2, 4, 6, 8 and 10 h post [14C]-AZD2014 dose in the Single Dose Period.

• Fraction of AZD2014 Excreted in Urine as a Percentage of the Dose (fe%[R])

  Mean fe%(R) values per urine collection period are presented as a percentage of the total \[14C\]-AZD2014 dose administered on Day 1.

  Urine was collected during the following periods: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Renal Clearance (CL[R]) of AZD2014 From Plasma.

  CL(R) of AZD2014 from plasma up to 168 h post-dose.

  Blood samples collected: Day 1 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144 and 168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Cumulative Percentage of Total [14C] Radioactivity Excreted in Urine as a Percentage of the Dose (fe Cum%[R])

  fe cum%(R) by the end of each collection period is presented following administration of \[14C\]-AZD2014. Radioactivity excreta data for 1 patient was not included due to technical issues with radioactivity sample collection.

  Urine was collected during the following periods: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h post [14C]-AZD2014 dose in the Single Dose Period.

• Cumulative Percentage of Total [14C] Radioactivity Excreted in Stool as a Percentage of the Dose (fe Cum%[f])

  fe cum%(f) by the end of each collection period is presented following administration of \[14C\]-AZD2014. Radioactivity excreta data for 1 patient was not included due to technical issues with radioactivity sample collection.

  Stool was collected during the following periods: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h post [14C]-AZD2014 dose in the Single Dose Period.

Secondary Outcomes (3)

• Number of AEs Experienced by Patients.

  From Day 1 of the Single Dose Period to 30 days after the last dose of AZD2014 administered in the Multiple Dose Period.

• Best Overall Response (BOR) Assessment

  RECIST 1.1 assessments were performed pre-dose at screening and then once every 8 weeks relative to the start of treatment in the Multiple Dose Period.

• Best Percentage Change in Tumour Size From Baseline

  RECIST 1.1 assessments were performed pre-dose at screening and then once every 8 weeks relative to the start of treatment in the Multiple Dose Period.

Study Arms (3)

[14C]AZD2014 followed by AZD2014 Monotherapy

EXPERIMENTAL

Arm will be comprised of \[14C\]AZD2014 followed by AZD2014 Monotherapy

Drug: [14C]AZD2014; Drug: Multiple dose AZD2014

[14C]AZD2014 followed by AZD2014 + Fulvestrant

EXPERIMENTAL

Arm will be comprised of \[14C\]AZD2014 followed by AZD2014 + Fulvestrant

Drug: [14C]AZD2014; Drug: Multiple dose AZD2014; Drug: Fulvestrant

[14C]AZD2014 followed by AZD2014 + Paclitaxel

EXPERIMENTAL

Arm will be comprised of \[14C\]AZD2014 followed by AZD2014 + Paclitaxel

Drug: [14C]AZD2014; Drug: Multiple dose AZD2014; Drug: Paclitaxel

Interventions

[14C]AZD2014 DRUG

Radiolabelled dual TORC1/TORC2 inhibitor

[14C]AZD2014 followed by AZD2014 + Fulvestrant; [14C]AZD2014 followed by AZD2014 + Paclitaxel; [14C]AZD2014 followed by AZD2014 Monotherapy

Multiple dose AZD2014 DRUG

Dual TORC1/TORC2 inhibitor

[14C]AZD2014 followed by AZD2014 + Fulvestrant; [14C]AZD2014 followed by AZD2014 + Paclitaxel; [14C]AZD2014 followed by AZD2014 Monotherapy

Fulvestrant DRUG

Hormonal Agent

[14C]AZD2014 followed by AZD2014 + Fulvestrant

Paclitaxel DRUG

Taxane

[14C]AZD2014 followed by AZD2014 + Paclitaxel

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead
• Quintiles, Inc.: collaborator

Study Sites (1)

Research Site

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Interventions

Fulvestrant; Paclitaxel

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Limitations and Caveats

No patients were recruited into AZD2014 + paclitaxel treatment regimen, as per the protocol plan.

Results Point of Contact

• Title: Medical Science Director
• Organization: AstraZeneca

clinicaltrialtransparency@astrazeneca.com

Study Officials

• Emma Dean, MD

  The Christie NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: December 29, 2015
• Study Start: January 28, 2016
• Primary Completion: December 21, 2016
• Study Completion: July 6, 2017
• Last Updated: April 22, 2019
• Results First Posted: April 22, 2019

Record last verified: 2019-01

Locations

GB (1)