Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (Stage IIIB-IV)
Conditions
Keywords
Lung cancer; NSCLC
Brief summary
Primary objective: To assess the efficacy of various sequences of either a small molecule or an IMT (IMT-A) followed by a IMT-B (MEDI4736) .
Detailed description
This is a multi-arm, multi-cohort, Phase IIa, open-label study of selected small molecules (gefitinib, AZD9291, or selumetinib + docetaxel) or 1st IMT (hereafter referred to as IMT-A; tremelimumab) followed by sequential switch to a 2nd IMT (hereafter referred to as IMT-B; MEDI4736) in locally advanced or metastatic NSCLC (Stage IIIB-IV). Patients will be enrolled concurrently into multiple cohorts.
Interventions
DRUGGefitinib
Gefitinib once daily followed by MEDI4736
DRUGAZD9291
AZD9291 once daily followed by MEDI4736
DRUGSelumetinib+Docetaxel
Selumetinib twice daily + docetaxel, followed by MEDI4736
DRUGTremelimumab
Tremelimumab every 4 weeks followed by MEDI4736
Sponsors
Quintiles, Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Provision of archived tumor tissue sample and mandatory tissue biopsy * Patients must have either histologically or cytologically documented NSCLC who present with locally advanced or metastatic stage IIIB-IV disease * Life expectancy ≥12 weeks * Patients must have measurable disease and at least 1 lesion not previously irradiated * World Health Organization (WHO) performance status of 0 or 1
Exclusion criteria
* Mixed small cell and NSCLC histology * Prior exposure to any anti-PD-1 or anti-PD-L1 antibody
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Complete Response (CR) Rate | Up to 2 years | To assess the efficacy of various sequences. CR (per RECIST 1.1 as assessed by the local/site Investigator) is defined as the disappearance of all target and non-target lesions. Confirmed complete response rate (CR rate) is defined as the number (%) of patients with a confirmed overall response of CR and was based on the evaluable analysis set. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to 2 years | To further assess the efficacy of various sequences. Objective response rate (ORR; per RECIST 1.1 as assessed by the site Investigator) is defined as the number (%) of patients with a confirmed overall response of CR or PR and was based on the evaluable analysis set. Per RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Progression-free Survival | Up to 2 years | Progression-free survival (per RECIST 1.1 as assessed by Investigator) is defined as the date of 1st dose of MEDI4736 until the date of objective disease progression or death. Progression of disease (PD) At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Duration of Response | Within 12 months | Duration of response (DoR; per RECIST 1.1 as assessed by the site Investigator) will be defined as the time from the date of 1st documented response (which is subsequently confirmed) until the 1st date of documented progression or death in the absence of disease progression. |
| Overall Survival | Up to 2 years | To assess the efficacy of various sequences. In survival follow up at data cut off. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 10 study centers in United States. The first subject was enrolled on 25 July 2014.
Pre-assignment details
Due to the small numbers of patients treated in Cohorts A through C (gefitinib, AZD9291, or selumetinib + docetaxel), statistical analyses were only done and summary tables prepared for the 28 patients randomised to Cohort D (tremelimumab, either 1-cycle or 2-cycles).
Participants by arm
| Arm | Count |
|---|---|
| Gefitinib With a Seq. Switch to a MEDI4736 Gefitinib once daily followed by MEDI4736 - analyses not done due to low n | 1 |
| Selumetinib+Docetaxel With a Seq. Switch to a MEDI4736 Selumetinib twice daily + docetaxel, followed by MEDI4736 - analyses not done due to low n | 2 |
| Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 Tremelimumab every 4 weeks (1 cycle) followed by MEDI4736 | 14 |
| Tremelimumab (2 Cycles) With a Seq. Switch to MEDI4736 TREMELIMUMAB 10MG/KG Q4W 8WEEKS/MEDI4736 10MG/KG Q2W 12MONTHS | 13 |
| AZD9291 With a Seq. Switch to a MEDI4736 The 1 patient in the AZD9291 cohort was not dosed and no baseline data were recorded in the database. | 0 |
| Total | 30 |
Baseline characteristics
| Characteristic | Gefitinib With a Seq. Switch to a MEDI4736 | Selumetinib+Docetaxel With a Seq. Switch to a MEDI4736 | Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 | Tremelimumab (2 Cycles) With a Seq. Switch to MEDI4736 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 79.0 Years STANDARD_DEVIATION 0 | 65.0 Years STANDARD_DEVIATION 12.73 | 57.8 Years STANDARD_DEVIATION 12.05 | 64.3 Years STANDARD_DEVIATION 7.85 | 61.8 Years STANDARD_DEVIATION 10.85 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 2 Participants | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 6 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 8 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 2 / 2 | 0 / 0 | 13 / 14 | 13 / 13 |
| serious Total, serious adverse events | 0 / 1 | 1 / 2 | 0 / 0 | 5 / 14 | 8 / 13 |
Outcome results
Primary
Confirmed Complete Response (CR) Rate
To assess the efficacy of various sequences. CR (per RECIST 1.1 as assessed by the local/site Investigator) is defined as the disappearance of all target and non-target lesions. Confirmed complete response rate (CR rate) is defined as the number (%) of patients with a confirmed overall response of CR and was based on the evaluable analysis set.
Time frame: Up to 2 years
Population: Per the analysis plan, efficacy would not be analyzed for treatment groups that did not have a sufficient number of enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 | Confirmed Complete Response (CR) Rate | 0 patients (%) |
| Tremelimumab (2 Cycles) With a Seq. Switch to MEDI4736 | Confirmed Complete Response (CR) Rate | 0 patients (%) |
Secondary
Duration of Response
Duration of response (DoR; per RECIST 1.1 as assessed by the site Investigator) will be defined as the time from the date of 1st documented response (which is subsequently confirmed) until the 1st date of documented progression or death in the absence of disease progression.
Time frame: Within 12 months
Population: Per the analysis plan, efficacy would not be analyzed for treatment groups that did not have a sufficient number of enrolled patients. Response was observed for 1 patient in the Tremelimumab 1-cycle arm for up to and including 6 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 | Duration of Response | NA Months |
Secondary
Objective Response Rate (ORR)
To further assess the efficacy of various sequences. Objective response rate (ORR; per RECIST 1.1 as assessed by the site Investigator) is defined as the number (%) of patients with a confirmed overall response of CR or PR and was based on the evaluable analysis set. Per RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 2 years
Population: Per the analysis plan, efficacy would not be analyzed for treatment groups that did not have a sufficient number of enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 | Objective Response Rate (ORR) | 11.1 patients (%) |
| Tremelimumab (2 Cycles) With a Seq. Switch to MEDI4736 | Objective Response Rate (ORR) | 0 patients (%) |
Secondary
Overall Survival
To assess the efficacy of various sequences. In survival follow up at data cut off.
Time frame: Up to 2 years
Population: Per the analysis plan, efficacy would not be analyzed for treatment groups that did not have a sufficient number of enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 | Overall Survival | 0 patients |
| Tremelimumab (2 Cycles) With a Seq. Switch to MEDI4736 | Overall Survival | 0 patients |
Secondary
Progression-free Survival
Progression-free survival (per RECIST 1.1 as assessed by Investigator) is defined as the date of 1st dose of MEDI4736 until the date of objective disease progression or death. Progression of disease (PD) At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Up to 2 years
Population: Per the analysis plan, efficacy would not be analyzed for treatment groups that did not have a sufficient number of enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tremelimumab (1 Cycle) With a Seq. Switch to a MEDI4736 | Progression-free Survival | 1 patients |
| Tremelimumab (2 Cycles) With a Seq. Switch to MEDI4736 | Progression-free Survival | 0 patients |