A Placebo Controlled Study Comparing AZD1775+ Docetaxel Versus Placebo+Docetaxel to Treat Lung Cancer

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02087176
• Collaborator: (none)
• Enrollment: 48
• Locations: 12
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

A Lead-in Phase II Multicentre, Randomised, Double-Blind Study Comparing AZD1775 plus antimitotic agent and Placebo plus an antimitotic agent in Previously Treated Non-Small-Cell Lung Cancer Patients

Condition or Disease	Intervention/Treatment	Phase
Previously Treated Non Small Cell Lung Cancer	Drug: AZD1775; Drug: AZD1775 Placebo; Drug: Antimitotic Agent; Drug: pegfiligrastim	Phase 2

Detailed Description

This multicentre trial consists of an open-labelled single cohort lead-in (Part A) followed by a phase II double-blind, randomised, placebo-controlled comparison of AZD1775 (or placebo) and an antimitotic agent. Review by a central laboratory of fresh tumour or archival tumour samples will be required prior to study entry to assess TP53 mutation status. However, subjects will be allowed to enter the single cohort (Part A) regardless of TP53 mutation status (wild-type or mutant). In addition, patients in the single cohort Part A treatment group will be asked to consent to limited sample collections for assessment of pharmacokinetic parameters.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Lead-in Phase II Multicentre, Randomised, Double-Blind Study Comparing AZD1775 Plus Docetaxel and Placebo Plus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer Patients
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD 1775, antimitotic, pegfilgrastim AZD 1775, antimitotic agent + pegfilgrastim 21 day Cycle, maximum of 4 cycles	Drug: AZD1775; AZD 1775 + antimitotic agent+ pegfilgrastim, restage every 2 cycles; continue until disease progression or unacceptable toxicity; Other Names: MK-1775; Neulasta ; Drug: Antimitotic Agent; The antimitotic is a drug that stops cells from dividing. This leads to cell death. Because cancer cells divide faster than normal cells, they are more likely than normal cells to be affected by this drug.; Other Names: antiimitotic agent ; Drug: pegfiligrastim; Pegfilgrastim is a man-made version of a protein called granulocyte-colony stimulating factor (G-CSF). This protein is made by cells in the body to stimulate the bone marrow to make more infection-fighting white blood cells.Pegfilgrastim is made by attaching filgrastim to a molecule called polyethylene glycol (PEG). This addition helps it stay in the body longer than filgrastim, which means it can be given less often.; Other Names: Neulasta
Placebo Comparator: Placebo + antimitotic + pegfilgrastim Placebo + antimitotic+pegfilgrastim 21 day cycle, maximum of 4 cycles	Drug: AZD1775 Placebo; Placebo (to match dose) + antimitotic+ pegfilgrastim, restage every 2 cycles; continue until disease progression or unacceptable toxicity; Other Names: MK-1775; Neulasta ; Drug: Antimitotic Agent; The antimitotic is a drug that stops cells from dividing. This leads to cell death. Because cancer cells divide faster than normal cells, they are more likely than normal cells to be affected by this drug.; Other Names: antiimitotic agent ; Drug: pegfiligrastim; Pegfilgrastim is a man-made version of a protein called granulocyte-colony stimulating factor (G-CSF). This protein is made by cells in the body to stimulate the bone marrow to make more infection-fighting white blood cells.Pegfilgrastim is made by attaching filgrastim to a molecule called polyethylene glycol (PEG). This addition helps it stay in the body longer than filgrastim, which means it can be given less often.; Other Names: Neulasta

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [Up to 20 months]

   Response evaluation is determined by using Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions assessed by medical imaging scan (e.g. CT or MRI). The same method of assessment and the same technique was to be used to characterize each identified and reported lesion at baseline and during subsequent imaging procedures. The objective response rate is defined as the percentage of patients with a confirmed best overall response of Complete Response (CR) or Partial Response (PR). Complete Response is defined as disappearance of all target lesions since baseline. Any pathological lymph nodes selected as target lesions must have a reduction in short axis to < 10 mm. Partial Response is defined as at least a 30% decrease in the sum of the diameters of the Target Lesion, taking as reference the baseline sum of diameters.

Secondary Outcome Measures

1. Pharmacokinetic Profile of AZD 1775 in Combination With Docetaxel [Up to projected 20 months, subjects will be restaged after every 2 cycles (every 6 weeks.) continue until disease progression or unacceptable toxicity]

   Venous blood samples taken for determination of AZD1775, metabolites of 1775 on Cycle 1, Day 1 pre-dose and 2 hours post dose, Cycle 2 Day 1 pre-dose and 2 hours post dose, and Cycle 4 pre-dose and 2 hours post dose. However, the study was terminated early by the sponsor; therefore, pharmacokinetic data were not collected.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Provision of informed consent prior to any study specific procedures

• Histologic or cytologic diagnosis of advanced NSCLC, excluding large cell neuroendocrine, and mixed NSCLC/small-cell histologies

• Failure of one prior platinum-based doublet treatment for advanced NSCLC (either due to progressive disease or toxicity)

• Measurable disease as measured by Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

• Mandatory availability of tumour tissue (archival or fresh if archival is not available) for TP53 testing

• Male or female ≥18 years-of-age

• Subjects may have received radiation for palliation prior to starting study treatment if they have recovered from the side effects of such therapy

• Absolute neutrophil count (ANC) ≥1500/μL

• Haemoglobin (Hgb) ≥9 g/dL

• Platelets ≥100,000/uL

• Adequate liver function defined as:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal limits (WNL) or ≤2.5 x upper limit of normal (ULN), if liver metastases are present

• Serum bilirubin WNL

• Adequate renal function

• Ability to swallow oral medication

• Fertile male subjects willing to use at least one medically acceptable form of birth control for the duration of the study and for 2 weeks after treatment stops

• Female subjects who are not of childbearing potential and fertile female subjects of childbearing potential who agree to use adequate contraceptive measures

• Predicted life expectancy ≥12 weeks

• Willingness and ability to comply with study and follow-up procedures

• Ability to understand the investigational nature of this study and give written informed consent

• Most recent chemotherapy ≤21 days or have not recovered from the side effects > Grade

• Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775

• Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting AZD1775 or has not recovered from side effects of such therapy

• Major surgical procedures ≤28 days of beginning AZD1775, or minor surgical procedures ≤7 days

• Known central nervous system (CNS) disease

• Any known hypersensitivity or contraindication to the components of study treatment (AZD1775 and docetaxel)

• Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association [NYHA] ≥ Class 2

• Pregnant or lactating

• Concurrent administration of medications or foods that are strong inhibitors of

• Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the subject to receive protocol treatment

• Presence of other active cancers, or history of treatment for invasive cancer ≤3 years

• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States
2	Research Site	Scottsdale	Arizona	United States
3	Research Site	Fayetteville	Arkansas	United States
4	Research Site	Englewood	Colorado	United States
5	Research Site	Orlando	Florida	United States
6	Research Site	Wichita	Kansas	United States
7	Research Site	Louisville	Kentucky	United States
8	Research Site	Durham	North Carolina	United States
9	Research Site	Cincinnati	Ohio	United States
10	Research Site	Pittsburgh	Pennsylvania	United States
11	Research Site	Nashville	Tennessee	United States
12	Research Site	Milwaukee	Wisconsin	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Chair: David R Spigel, MD, SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02087176
• Other Study ID Numbers: D6011C00001
• First Posted: Mar 14, 2014
• Last Update Posted: Jun 14, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by AstraZeneca: NSCLC
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antimitotic Agents; Adavosertib

Study Results

Participant Flow

Recruitment Details	The study was conducted at 12 clinical sites in the United States. A total of 32 subjects were enrolled between May 20, 2014 and January 22, 2015.
Pre-assignment Detail	48 participants were screened. 16 did not meet criteria. In Part A, 32 participants were enrolled. The study was terminated early by the sponsor. Part B of the study was not done.

Arm/Group Title	Part A: AZD1775 Plus Docetaxel
Arm/Group Description	Six subject safety lead-in followed by single arm cohort. All patients were to receive AZD 1775 plus Docetaxel in 21 day cycles for a maximum of 4 cycles.
Period Title: Overall Study
STARTED	32
COMPLETED	0
NOT COMPLETED	32

Baseline Characteristics

Arm/Group Title	Part A: AZD1775 Plus Docetaxel
Arm/Group Description	Six subject safety lead-in followed by single arm cohort. All patients were to receive AZD 1775 plus Docetaxel in 21 day cycles for a maximum of 4 cycles.
Overall Participants	32
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.9 (9.41)
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	62.0
Age, Customized (Number) [Number]
< 65	18 56.3%
>= 65	14 43.8%
Sex: Female, Male (Count of Participants)
Female	13 40.6%
Male	19 59.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.3%
Not Hispanic or Latino	30 93.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 9.4%
White	28 87.5%
More than one race	0 0%
Unknown or Not Reported	1 3.1%
Region of Enrollment (Number) [Number]
United States	32 100%
Tobacco Use (Number) [Number]
Smoker	29 90.6%
Non-Smoker	1 3.1%
Smoking Status Missing	2 6.3%
ECOG Performance Status (Number) [Number]
ECOG Performance Status = 0	15 46.9%
ECOG Performance Status = 1	17 53.1%

Outcome Measures

1. Secondary Outcome

Title	Pharmacokinetic Profile of AZD 1775 in Combination With Docetaxel
Description	Venous blood samples taken for determination of AZD1775, metabolites of 1775 on Cycle 1, Day 1 pre-dose and 2 hours post dose, Cycle 2 Day 1 pre-dose and 2 hours post dose, and Cycle 4 pre-dose and 2 hours post dose. However, the study was terminated early by the sponsor; therefore, pharmacokinetic data were not collected.
Time Frame	Up to projected 20 months, subjects will be restaged after every 2 cycles (every 6 weeks.) continue until disease progression or unacceptable toxicity

Outcome Measure Data

Analysis Population Description

The study was terminated early by the sponsor. Pharmacokinetic data have not been analyzed.

Arm/Group Title	Part A: AZD1775 Plus Docetaxel
Arm/Group Description	Six subject safety lead-in followed by single arm cohort. All patients were to receive AZD 1775 plus Docetaxel in 21 day cycles for a maximum of 4 cycles.
Measure Participants	0

2. Primary Outcome

Title	Objective Response Rate
Description	Response evaluation is determined by using Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions assessed by medical imaging scan (e.g. CT or MRI). The same method of assessment and the same technique was to be used to characterize each identified and reported lesion at baseline and during subsequent imaging procedures. The objective response rate is defined as the percentage of patients with a confirmed best overall response of Complete Response (CR) or Partial Response (PR). Complete Response is defined as disappearance of all target lesions since baseline. Any pathological lymph nodes selected as target lesions must have a reduction in short axis to < 10 mm. Partial Response is defined as at least a 30% decrease in the sum of the diameters of the Target Lesion, taking as reference the baseline sum of diameters.
Time Frame	Up to 20 months

Outcome Measure Data

Analysis Population Description

Thirty-two (32) subjects were enrolled in Part A, but the study was terminated early. Patients on-study at the time the study was terminated have been censored.

Arm/Group Title	Part A: AZD1775 Plus Docetaxel
Arm/Group Description	Six subject safety lead-in followed by single arm cohort. All patients were to receive AZD 1775 plus Docetaxel in 21 day cycles for a maximum of 4 cycles.
Measure Participants	32
Number (90% Confidence Interval) [Percentage of Participants]	9.4 29.4%

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Adverse event data were collected from the time the first patient received the first dose of investigational drug on May 20, 2014 until the study was closed on May 12, 2015.
Arm/Group Title	Part A: AZD1775 Plus Docetaxel
Arm/Group Description	Six subject safety lead-in followed by single arm cohort. All patients were to receive AZD 1775 plus Docetaxel in 21 day cycles for a maximum of 4 cycles.
All Cause Mortality
	Part A: AZD1775 Plus Docetaxel
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Part A: AZD1775 Plus Docetaxel
	Affected / at Risk (%)	# Events
Total	17/32 (53.1%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/32 (3.1%)	1
Haemolytic Anaemia	1/32 (3.1%)	1
Leukopenia	1/32 (3.1%)	1
Neutropenia	1/32 (3.1%)	1
Thrombocytopenia	2/32 (6.3%)	4
Gastrointestinal disorders
Abdominal Pain	2/32 (6.3%)	2
Enterocolitis	1/32 (3.1%)	1
Gastrointestinal Haemorrhage	1/32 (3.1%)	1
Gastrointestinal Haemorrhage	1/32 (3.1%)	1
Nausea	2/32 (6.3%)	3
Vomiting	1/32 (3.1%)	1
General disorders
Asthenia	2/32 (6.3%)	2
Fatigue	1/32 (3.1%)	1
Infections and infestations
Pneumonia	1/32 (3.1%)	1
Sepsis	1/32 (3.1%)	1
Urinary Tract Infection	1/32 (3.1%)	1
Investigations
Neutrophil Count Decreased	1/32 (3.1%)	1
Metabolism and nutrition disorders
Dehydration	1/32 (3.1%)	1
Failure to Thrive	1/32 (3.1%)	1
Hypovolaemia	1/32 (3.1%)	1
Nervous system disorders
Partial Seizures	1/32 (3.1%)	1
Syncope	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/32 (3.1%)	1
Dyspnoea	1/32 (3.1%)	1
Respiratory Failure	1/32 (3.1%)	1
Vascular disorders
Haemorrhage	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Part A: AZD1775 Plus Docetaxel
	Affected / at Risk (%)	# Events
Total	31/32 (96.9%)
Blood and lymphatic system disorders
Anaemia	16/32 (50%)	34
Leukopenia	7/32 (21.9%)	8
Neutropenia	10/32 (31.3%)	16
Thrombocytopenia	11/32 (34.4%)	24
Cardiac disorders
Sinus Tachycardia	2/32 (6.3%)	2
Gastrointestinal disorders
Abdominal Pain	5/32 (15.6%)	7
Abdominal Pain, Upper	4/32 (12.5%)	7
Constipation	4/32 (12.5%)	4
Diarrhoea	21/32 (65.6%)	39
Nausea	15/32 (46.9%)	27
Stomatitis	3/32 (9.4%)	4
Vomiting	14/32 (43.8%)	19
General disorders
Asthenia	7/32 (21.9%)	13
Chest Pain	2/32 (6.3%)	2
Chills	5/32 (15.6%)	5
Face Oedema	2/32 (6.3%)	2
Fatigue	14/32 (43.8%)	25
Malaise	2/32 (6.3%)	2
Mucosal Inflammation	4/32 (12.5%)	5
Oedema Peripheral	3/32 (9.4%)	4
Pain	7/32 (21.9%)	10
Pyrexia	8/32 (25%)	10
Infections and infestations
Pneumonia	2/32 (6.3%)	2
Upper Respiratory Tract Infection	5/32 (15.6%)	8
Urinary Tract Infection	2/32 (6.3%)	2
Investigations
Platelet Count Decreased	4/32 (12.5%)	9
Weight Decreased	7/32 (21.9%)	7
Metabolism and nutrition disorders
Decreased Appetite	10/32 (31.3%)	12
Dehydration	10/32 (31.3%)	18
Hyperglycaemia	3/32 (9.4%)	7
Hypokalaemia	4/32 (12.5%)	5
Hypomagnesaemia	3/32 (9.4%)	4
Hyponatraemia	7/32 (21.9%)	8
Musculoskeletal and connective tissue disorders
Arthralgia	3/32 (9.4%)	5
Back Pain	5/32 (15.6%)	5
Bone Pain	6/32 (18.8%)	8
Myalgia	3/32 (9.4%)	3
Pain in Extremity	4/32 (12.5%)	6
Nervous system disorders
Dizziness	5/32 (15.6%)	6
Dysgeusia	5/32 (15.6%)	5
Headache	4/32 (12.5%)	5
Neuropathy, Peripheral	3/32 (9.4%)	4
Syncope	2/32 (6.3%)	2
Psychiatric disorders
Confusional State	2/32 (6.3%)	2
Depression	3/32 (9.4%)	3
Insomnia	6/32 (18.8%)	6
Renal and urinary disorders
Pollakiuria	2/32 (6.3%)	2
Respiratory, thoracic and mediastinal disorders
Cough	4/32 (12.5%)	4
Dyspnoea	5/32 (15.6%)	6
Dyspnoea, Exertional	2/32 (6.3%)	2
Epistaxsis	5/32 (15.6%)	6
Haemoptysis	2/32 (6.3%)	3
Nasal Congestion	2/32 (6.3%)	2
Oropharyngeal Pain	3/32 (9.4%)	3
Upper Airway Cough Syndrome	3/32 (9.4%)	3
Wheezing	2/32 (6.3%)	2
Skin and subcutaneous tissue disorders
Alopecia	9/32 (28.1%)	10
Rash	2/32 (6.3%)	4
Vascular disorders
Hypotension	6/32 (18.8%)	7

Limitations/Caveats

The sponsor terminated the study early. The study was closed on May 12, 2015. Part B of the study was not done.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.