Clinical trial NCT02640755: Absorption, Metabolism, Excretion and Pharmacokinetics of a Single Dose [14C]AZD2014 Followed by a Multiple Dose Phase
Official title: A Phase I, Open-Label, Non-randomised, Single Centre Study of the Absorption, Metabolism, Excretion and Pharmacokinetics of AZD2014 After a Single Oral Dose of [14C]AZD2014, Followed by Multiple Doses of AZD2014 Either As Monotherapy or In Combination With Either Fulvestrant or Paclitaxel in Patients With Advanced Solid Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Malignancies
Keywords: Radiolabelled
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Quintiles, Inc.
First posted: 2015-12-29
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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.

Detailed description: This is a Phase I, open label, single centre, non-randomised study in patients with advanced solid malignancies that is refractory or resistant to standard treatment or where no suitable effective standard treatment exists or for whom paclitaxel or fulvestrant are appropriate treatment choices. The study will be divided in two parts:

1. Single Dose Period - will enrol up to 6 evaluable patients to characterise the absorption, metabolism, excretion and pharmacokinetics of a single radiolabelled \[14C\] oral dose of 125mg AZD2014 via residential intensive PK sampling over 8 days. An evaluable patient is defined as patient who does not vomit within 2 hours post dose and who has completed the scheduled PK sampling.
2. Multiple Dose Period - patients who have completed the Single Dose Period may continue to receive treatment as outpatients. Patients will be allocated to different treatment regimes as decided between Investigator and patient on a risk / benefit basis. From Day 1, Cycle 1, non-radiolabelled AZD2014 treatment will be administered as oral tablets to patients, either as:

i. 50mg BD monotherapy ii. 125mg BD taken on first 2 days of treatment each week in combination with 500mg intramuscular fulvestrant on Day 1, Cycle 1, Day 15, Cycle 1; Day 1, Cycle 2, then Day 1 of each monthly cycle thereafter iii. 50mg BD taken on first 3 days of treatment each week for 6 weeks in combination with a single weekly paclitaxel infusion (80mg/m2 ) followed by a one week break from treatment where no AZD2014 or paclitaxel will be given. This 7 week schedule composes one cycle of treatment. Patients will be given up to 6 cycles of paclitaxel, although additional cycles of paclitaxel may be given if deemed appropriate by the Investigator.

Radiolabelled AZD2014 will be administered to fasted patients (i.e. no food 2 hours before and 1 hour after each dose). Non-radiolabelled AZD2014 will be administered either under fasted or non-fasted conditions. The safety and tolerability and anti-tumour activity of AZD2014 and combination with paclitaxel or fulvestrant will be evaluated in all enrolled patients respectively using conventional safety parameters, AEs/SAEs and RECIST 1.1.

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 arrhythmias requiring continuous therapy
  * Uncontrolled supraventricular arrhythmias including atrial fibrillation
  * Haemorrhagic or thrombotic stroke, including transient ischaemic attacks or other central nervous system bleeding
* Abnormal echocardiogram at baseline (left ventricular ejection fraction \[LVEF\] \<55% and shortening fraction \[SF\] \<15%)
* Torsades de Pointes either currently or within 12 months
* Mean resting QTcF ≥470 ms
* Medications known to prolong QT interval, or that increase the risk of QTc prolongation or arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of either long QT syndrome), or unexplained sudden death under 40 years of age
* Laboratory values as listed below:

  * Absolute neutrophil count \<1.5x109/L
  * Platelet count \<100x109/L
  * Haemoglobin \<90 g/L
  * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or \>5xULN in the presence of liver metastases
  * Total bilirubin \>1.5xULN if no demonstrable liver metastases or \>3xULN in the presence of liver metastases
  * Serum creatinine \>1.5xULN concurrent with creatinine clearance \<50 mL/min (measured or calculated by Cockcroft and Gault equation), confirmation of creatinine clearance is only required when creatinine is \>1.5xULN
  * Clinically relevant and treatment resistant abnormalities in potassium, sodium, calcium (corrected for plasma albumin) or magnesium
* Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis
* Abnormal fasting glucose \>126 mg/dL (\>7 mmol/L)
* Patients with diabetes Type 1 or uncontrolled Type 2 (glycosylated haemoglobin \[HbA1c\] \>8% \[64 mmol/mol\] assessed locally)
* 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
* History of hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure or class to AZD2014
* Judgment that patient is unsuitable to participate in study and unlikely to comply with study procedures, restrictions \& requirements

Primary outcomes:
measure: Total Radioactivity in Plasma Following Administration of [14C]-AZD2014
timeFrame: 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.
measure: AZD2014 Concentrations in Plasma Following Administration of [14C]-AZD2014
timeFrame: 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.
measure: Total Radioactivity Concentrations in Saliva Following Administration of [14C]-AZD2014
timeFrame: Saliva was collected at 1, 2, 4, 6, 8, 10 and 12 h post [14C]-AZD2014 dose in the Single Dose Period.
measure: AZD2014 Concentrations in Saliva Following Administration of [14C]-AZD2014
timeFrame: Saliva was collected at 1, 2, 4, 6, 8, 10 and 12 h post [14C]-AZD2014 dose in the Single Dose Period.
measure: Total Radioactivity Concentrations in Blood Following Administration of [14C]-AZD2014
timeFrame: 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.
measure: Cumulative Percentage of [14C]-AZD2014 Recovered by Day 8
timeFrame: From pre-dose Day 1 to Day 8 of the Single Dose Period.
measure: Maximum Observed Concentration (Cmax) of AZD2014 in Plasma and Saliva
timeFrame: 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.
measure: Time to Maximum Observed Concentration (Tmax) for AZD2014 in Plasma and Saliva
timeFrame: 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.
measure: Time to Last Measurable Concentration (t[Last]) for AZD2014 in Plasma and Saliva
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve (AUC) for AZD2014
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Apparent Total Body Clearance (CL/F) of AZD2014
timeFrame: 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.
measure: Mean Residence Time (MRT) of AZD2014
timeFrame: 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.
measure: Apparent Volume of Distribution at Steady State (Vss/F) for AZD2014 in Plasma
timeFrame: 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.
measure: Terminal Elimination Rate Constant (lambda_z) for AZD2014 in Plasma
timeFrame: 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.
measure: Half-life Associated With Terminal Slope (lambda_z) of a Semi-logarithmic Concentration-time Curve (t1/2[lambda_z]) for AZD2014 in Plasma
timeFrame: 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.
measure: Cmax for Total [14C] Radioactivity in Whole Blood and Saliva
timeFrame: 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.
measure: Tmax for [14C] Radioactivity in Whole Blood and Saliva
timeFrame: 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.
measure: T(Last) for [14C] Radioactivity in Whole Blood and Saliva
timeFrame: 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.
measure: Ratio of Whole Blood Total Radioactivity to Plasma Total Radioactivity
timeFrame: 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.
measure: Ratio of AZD2014 Concentration to Total Radioactivity Concentration in Saliva
timeFrame: Saliva was collected at 1, 2, 4, 6, 8 and 10 h post [14C]-AZD2014 dose in the Single Dose Period.
measure: Fraction of AZD2014 Excreted in Urine as a Percentage of the Dose (fe%[R])
timeFrame: 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.
measure: Renal Clearance (CL[R]) of AZD2014 From Plasma.
timeFrame: 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.
measure: Cumulative Percentage of Total [14C] Radioactivity Excreted in Urine as a Percentage of the Dose (fe Cum%[R])
timeFrame: 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.
measure: Cumulative Percentage of Total [14C] Radioactivity Excreted in Stool as a Percentage of the Dose (fe Cum%[f])
timeFrame: 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:
measure: Number of AEs Experienced by Patients.
timeFrame: From Day 1 of the Single Dose Period to 30 days after the last dose of AZD2014 administered in the Multiple Dose Period.
measure: Best Overall Response (BOR) Assessment
timeFrame: 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.
measure: Best Percentage Change in Tumour Size From Baseline
timeFrame: 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.
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: Research Site
Study officials:
affiliation: The Christie NHS Foundation Trust
name: Emma Dean, MD
role: PRINCIPAL_INVESTIGATOR
References: