Previously Untreated Stage IV Non-Squamous Non Small Cell Lung Cancer
Conditions
Keywords
Stage IV Lung Cancer
Brief summary
The aim of this study is to combine AZD1775 with standard front-line chemotherapy in subjects with advanced NSCLC.
Detailed description
This is a randomised, phase II trial comparing AZD1775 plus pemetrexed and carboplatin followed by maintenance AZD1775 and pemetrexed versus pemetrexed and carboplatin followed by maintenance pemetrexed in patients with previously untreated metastatic non-squamous NSCLC with TP53 mutations. The primary endpoint of the trial is assessment of progression-free survival (PFS).
Interventions
DRUGAZD1775
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of the WEE 1 kinase that sensitizes tumor cells to cytotoxic agents and is being developed for the treatment of advanced solid tumors and p53 pathway deficient malignancies
DRUGAZD1775 Matching Placebo
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of the WEE 1 kinase that sensitizes tumor cells to cytotoxic agents and is being developed for the treatment of advanced solid tumors and p53 pathway deficient malignancies
DRUGpemetrexed
This drug is a part of a general group of chemotherapy drugs called anti-metabolites. It prevents cells from using folate to make DNA and RNA. Because cancer cells need these substances to make new cells, this drug helps to stop the growth of cancer cells.
DRUGcarboplatin
This drug is a platinum chemotherapy drug that acts like an alkylating agent. It stops the growth of cancer cells, causing the cells to die.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study specific procedures * Histologic or cytologic diagnosis of advanced NSCLC, Recurrent or Stage IV disease (according to American Joint Committee on Cancer (AJCC) staging system, v7.0). * No prior chemotherapy for locally advanced or metastatic disease * Subjects with a known EGFR mutation must have received previous treatment with an EGFR tyrosine kinase inhibitor; and subjects with a known ALK translocation must have received previous treatment with an ALK inhibitor. * No prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow area. * At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 * Mandatory availability of tumour tissue (archival or fresh if archival is not available) for TP53 determination. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1. * Absolute neutrophil count (ANC) ≥1500/μL * Hemoglobin (Hgb) ≥10 g/dL * Platelets ≥100,000/μL * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ≤3.0 x the upper limit of normal (ULN); 5 x ULN if known hepatic metastases * Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert's disease * Serum creatinine ≤1.5 x ULN and a calculate creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method * 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 who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of study treatment * Predicted life expectancy ≥12 weeks * Must be ≥18 years of age * Willingness and ability to comply with study and follow-up procedures * Ability to understand the nature of this trial and give written informed consent
Exclusion criteria
* Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775 * Major surgical procedures ≤28 days of beginning AZD1775, or minor surgical procedures ≤7 days * Known central nervous system (CNS) disease * Subject has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates * Any known hypersensitivity or contraindication to the components of study treatment * Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (\[NYHA\] Appendix G) ≥ Class 2 * Corrected QT interval (QTc) \>470 msec (as calculated by Fridericia correction formula) at study entry or congenital long QT syndrome. * Pregnant or lactating * Any serious, active underlying medical condition that would impair the ability of the subjects to receive study treatment * Unable or unwilling to take folic acid or vitamin B12 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 6 months | Progression free survival is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from randomised therapy or receives another anti-cancer therapy prior to progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess the Objective Response Rates in Each Arm | Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days) | The objective response rate is defined as the number of the subjects with a confirmed best overall response of CR or PR divided by the number of subjects in the Full Analysis Set (FAS) for whom measureable disease is present at baseline |
| Assess the Disease Control Rate in Each Treatment Arm | Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days) | the disease control rate is defined as the percentage of FAS subjects with a best overall response of CR, PR or SD). |
| Assess the Duration of Response in Each Treatment Arm | Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days) | Duration of response is defined as the time from the date of first documented response until the date of documented progression or any cause death. |
| Assess Overall Survival in Each Treatment Arm | Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days) | Overall survival is defined as the time from the date of randomization until death due to any cause. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 16 clinical sites in the United States. A total of 14 subjects were enrolled between March 19, 2014 and April 16, 2015.
Pre-assignment details
22 subjects were consented; 3 subjects failed screening. The study was terminated prior to the start of screening for 5 participants. 14 participants were treated with AZD1775. The study was terminated early by the sponsor. Part 2 was not done. The 14 participants were enrolled in 4 Cohorts, designated Cohorts 1, 2, 3, and A.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 AZD1775 225 mg bid. 5 doses over 3 days (Days 1, 2, and 3 of a 21- Day Cycle)/Pemetrexed 500 mg/Carboplatin AUC 6 | 3 |
| Cohort 2 AZD1775 225 mg bid. 5 doses over 3 days (Days 3, 4, and 5 of a 21-Day Cycle)/Pemetrexed 500 mg/Carboplatin AUC 6. | 3 |
| Cohort 3 AZD1775 175 mg bid. 5 doses over 3 days (Days 3, 4, and 5 of a 21-Day Cycle)/Pemetrexed 500 mg/Carboplatin AUC 6 | 1 |
| Cohort A AZD1775 125 mg bid. 5 doses over 3 days (Days 1, 2, and 3 of a 21- Day Cycle)/Pemetrexed 400 mg/Carboplatin AUC 5 | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 2 | 1 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 2 | 0 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 3 | Cohort 1 | Cohort A | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61.0 Years | 81.0 Years | 66.0 Years | 64.0 Years | 63.0 Years |
| Age, Customized < 65 | 3 Participants | 0 Participants | 1 Participants | 4 Participants | 8 Participants |
| Age, Customized >= 65 | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| ECOG Performance Status ECOG Performance Status = 0 | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants |
| ECOG Performance Status ECOG Performance Status = 1 | 2 Participants | 0 Participants | 2 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 3 Participants | 6 Participants | 13 Participants |
| Region of Enrollment United States | 3 Participants | 1 Participants | 3 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 2 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Tobacco Use Non-Smoker | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tobacco Use Smoker | 3 Participants | 1 Participants | 3 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 1 / 1 | 7 / 7 |
| serious Total, serious adverse events | 1 / 3 | 3 / 3 | 1 / 1 | 3 / 7 |
Outcome results
Primary
Progression Free Survival
Progression free survival is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.
Time frame: 6 months
Population: Progression-Free Survival data were not collected.
Secondary
Assess Overall Survival in Each Treatment Arm
Overall survival is defined as the time from the date of randomization until death due to any cause.
Time frame: Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
Population: Overall Survival (OS) data were not collected.
Secondary
Assess the Disease Control Rate in Each Treatment Arm
the disease control rate is defined as the percentage of FAS subjects with a best overall response of CR, PR or SD).
Time frame: Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Assess the Disease Control Rate in Each Treatment Arm | 66.7 Percentage of Participants |
| Cohort 2 | Assess the Disease Control Rate in Each Treatment Arm | 66.7 Percentage of Participants |
| Cohort 3 | Assess the Disease Control Rate in Each Treatment Arm | 0 Percentage of Participants |
| Cohort A | Assess the Disease Control Rate in Each Treatment Arm | 85.7 Percentage of Participants |
Secondary
Assess the Duration of Response in Each Treatment Arm
Duration of response is defined as the time from the date of first documented response until the date of documented progression or any cause death.
Time frame: Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
Population: Duration of response data were not collected.
Secondary
Assess the Objective Response Rates in Each Arm
The objective response rate is defined as the number of the subjects with a confirmed best overall response of CR or PR divided by the number of subjects in the Full Analysis Set (FAS) for whom measureable disease is present at baseline
Time frame: Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Assess the Objective Response Rates in Each Arm | 66.7 Percentage of Participants |
| Cohort 2 | Assess the Objective Response Rates in Each Arm | 33.3 Percentage of Participants |
| Cohort 3 | Assess the Objective Response Rates in Each Arm | 0 Percentage of Participants |
| Cohort A | Assess the Objective Response Rates in Each Arm | 14.3 Percentage of Participants |