The primary efficacy objective for this study is to evaluate the efficacy of MPDL3280Ain patients with PD-L1*positive locally advanced or metastatic NSCLC, as measuredby investigator-assessed ORR according to modified RECIST.SECONDARY OBJECTIVESThe…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy outcome measure is investigator-assessed objective response
(confirmed PR or confirmed CR) according to modified RECIST.
Secondary outcome
Objective response (confirmed PR or confirmed CR) per RECIST v1.1 as
determined by the investigator
• DOR, defined as the time from the first occurrence of a documented objective
response to the time of radiographic progression per RECIST v1.1 as determined
by
the investigator, or death from any cause on study
• PFS, defined as the time from first dose of MPDL3280A to the time of
radiographic
progression per RECIST v1.1 as determined by the investigator, or death from any
cause on study
• PFS per modified RECIST, defined as follows:
For patients who discontinue at first documented radiographic progression or
who die on study: the time from first dose of MPDL3280A to the time of
progression or death
For patients who continue beyond first documented radiographic progression
and have confirmed progression at the follow-up tumor assessment or who die
on study: the time from first dose of MPDL3280A to the time of first
documented progression or death
For patients who continue beyond first documented progression and do not
have confirmed progression at the follow-up tumor assessment: the time from
first dose of MPDL3280A to the time of subsequent radiographic progression
(i.e., after the first instance) or death
• DOR, defined as the time from the first occurrence of a documented objective
response to the time of radiographic progression per modified RECIST as
determined by the investigator, or death from any cause on study
• OS, defined as the time from the first dose of MPDL3280A to the time of death
from any cause on study
Safety Outcome Measures
The safety outcome measures for this study are as follows:
• Incidence, nature, and severity of AEs, graded according to the NCI CTCAE v4.0
• Changes in vital signs, physical findings, and clinical laboratory results
• Incidence of ATA response to MPDL3280A and potential correlation with
pharmacokinetic
(PK), pharmacodynamic, safety, and efficacy parameters
Biomarker Outcome Measure
The biomarker outcome measure for this study is as follows:
• PD-L1 expression status defined according to IHC and qPCR criteria
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:
• MPDL3280A maximum serum concentration (Cmax) after infusion on Day 1 of Cycle
1
• MPDL3280A minimum serum concentration (Cmin) prior to the infusion on Day 1
of Cycles 2,
4, and 8 and at study termination
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:
• Status of PD-L1, immune- and NSCLC-related and other exploratory biomarkers
in archival
and/or freshly obtained tumor tissues and blood collected before, during, or
after treatment
with MPDL3280A or at progression
• Status of exploratory biomarkers in blood, plasma, or serum (including but
not limited to
cytokines such as IFN-γ)
• Status of tumor-infiltrating immune cells and biomarkers in biopsy specimens
and blood
collected at the first evidence of radiographic disease progression
• Status of FDG-PET scans performed at the first evidence of radiographic
disease
progression compared with baseline and early on-treatment scans
• Global health status/quality of life as measured by the EORTC QLQ-C30 and
QLQ-LC13
Background summary
Despite recent improvements in treatment, the prognosis for patients with
advanced
NSCLC remains dismal, with median OS of approximately 12.5 months
(Sandler et al. 2006). Patients who receive second-line treatment for their
disease have
an even more limited prognosis, with a median survival duration of approximately
8*9 months (Stinchcombe et al. 2008). Approved therapies are associated with
significant toxicities (e.g., neuropathy, febrile neutropenia,
myelosuppression, and
alopecia) that negatively impact quality of life. Therefore, there is a
continuing need
for more efficacious, better-tolerated treatments.
Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses
in
some patients, and expression of PD-L1 by tumor cells in several tumor types
(including NSCLC) correlates with response to therapy (Topalian et al. 2012).
Early unpublished data from the Phase Ia Study PCD4989g suggest that tumor PD-L1
status as determined by IHC in patients with NSCLC correlates with response
to MPDL3280A. Four of 4 patients with PD-L1*positive NSCLC achieved a partial
response (PR; clinical partial response or unconfirmed partial response). Only
4 of
26 (15%) patients with PD-L1*negative NSCLC achieved an objective response.
A potential benefit in terms of OS or durable disease control remains to be
tested in
controlled studies.
No targeted therapy currently exists for NSCLC patients with PD-L1*positive
tumors.
These data provide a rationale for evaluating the efficacy of MPDL3280A in
patients
with NSCLC selected on the basis of tumor PD-L1 expression.
Study objective
The primary efficacy objective for this study is to evaluate the efficacy of
MPDL3280A
in patients with PD-L1*positive locally advanced or metastatic NSCLC, as
measured
by investigator-assessed ORR according to modified RECIST.
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:
• To evaluate PFS and DOR according to modified RECIST
• To evaluate the efficacy of MPDL3280A, as measured by investigator-assessed
ORR, DOR, and PFS, where all response endpoints are determined according to
RECIST v1.1
• To evaluate OS
• To evaluate PFS in patients who experience a confirmed PR or confirmed CR per
modified RECIST at any time on study treatment
• To evaluate the safety and tolerability of MPDL3280A
• To characterize the pharmacokinetics of MPDL3280A
• To evaluate the incidence and titers of ATAs against MPDL3280A and to explore
the potential relationship of the immunogenicity response with pharmacokinetics,
safety, and efficacy
Study design
This is a Phase II, global, multicenter, single-arm trial designed to evaluate
the efficacy
and safety of MPDL3280A in patients with PD-L1*positive locally advanced or
metastatic NSCLC.
Approximately 130 patients in total will be enrolled; approximately 45 study
participants will be patients who have not received prior chemotherapy for
advanced
disease (Cohort 1) and approximately 75 will be patients who have progressed
during or
following a prior platinum-based chemotherapy regimen for advanced disease
(Cohort 2;
the maximum number of prior therapies for patients in Cohort 2 is
unrestricted). A
separate cohort (Cohort 3) will enroll approximately 10 selected second-line
(or greater)
patients with previously treated brain metastases
Intervention
MPDL3280A IV (fixed dose of 1200 mg) will be administered on Day 1 of 21-day
cycles.
Study burden and risks
treatment with MPDL3280A offers the potential for clinical benefit in NSCLC
patients selected on the basis of tumor PD-L1 expression. Because most
MPDL3280A-related toxicities observed to date have been mild and transient in
nature
and do not overlap with the adverse effects of chemotherapy, patients who do not
respond to study treatment are considered likely to be able to subsequently
receive
standard therapies for which they would otherwise have been eligible. Patients
will be
fully informed of the risk of continuing study treatment in spite of apparent
radiographic
progression (applies only to patients in Cohorts 2 and 3; does not apply to
first-line
patients enrolled in Cohort 1), and investigators should make a careful
assessment of
the potential benefit of doing so, considering radiographic data, biopsy
results, and the
clinical status of the patient.
1 DNA WAY MS 241 B
South San Francisco, CA 94080-4990
US
1 DNA WAY MS 241 B
South San Francisco, CA 94080-4990
US
Listed location countries
Age
Inclusion criteria
• Age >= 18 years
• Histologically or cytologically documented Stage IIIB (not eligible for definitive
chemoradiotherapy), Stage IV, or recurrent NSCLC
• PD-L1*positive status as determined by an IHC assay performed by a central
laboratory
• ECOG performance status of 0 or 1
• Measurable disease as defined by RECIST v1.1
• For female patients of childbearing potential, agreement (by patient) to remain abstinent (refrain from heterosexual intercourse) or to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) during the treatment period and to continue its use for 5 months after the last dose of atezolizumab;Inclusion Criteria Unique to Cohort 1
• No prior chemotherapy for locally advanced or metastatic (i.e., Stage IIIB not eligible
for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC;Inclusion Criteria Unique to Cohorts 2 and 3
• Disease progression during or following prior platinum-based chemotherapy
for locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive
chemoradiotherapy, Stage IV, or recurrent) NSCLC;Inclusion Criteria Unique to Cohort 3
• Diagnosis of brain metastases by brain MRI or contrast-enhanced CT;For more detailed information please refer to protocol section 4.1
Exclusion criteria
Cancer-Specific Exclusions
• Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy
within 3 weeks prior to initiation of study treatment
• Treatment with any other investigational agent or participation in another clinical trial
with therapeutic intent within 28 days prior to enrollment
• Known CNS disease, including treated brain metastases: Cohorts 1 and 2
• Leptomeningeal disease;For more detailed information please refer to protocol section 4.1
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-000177-69-NL |
| ClinicalTrials.gov | NCT01846416 |
| CCMO | NL45044.031.13 |