The primary objective of this study is to assess the efficacy of MEDI4736 treatment compared with placebo in terms of overall survival (OS) and progression free survival (PFS; (per RECIST 1.1 as assessed by the investigator).
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the efficacy of MEDI4736 treatment compared with placebo in terms of
OS and PFS.
PFS using investigator site assessments according to RECIST 1.1.
Secondary outcome
To further assess the efficacy of MEDI4736 compared with placebo in terms of:
OS24, ORR, DoR, APF12, APF18, PFS2 and TTDM.
To assess the safety and tolerability profile of MEDI4736 compared with placebo.
To assess the PK of MEDI4736.
To investigate the immunogenicity of MEDI4736.
To assess symptoms and health-related quality of life in patients treated with
MEDI4736 compared with placebo using EORTC QLQ-C30 v3 and LC13.
Background summary
Non-small cell lung cancer (NSCLC) represents approximately 80% to 85% of all
lung cancers and 30% of patients present with Stage III disease. Standard
treatment for patients with a good performance status and unresectable Stage
III NSCLC is platinum-based doublet chemotherapy and radiotherapy administered
with curative intent. A meta-analysis of concurrent versus sequential
chemoradiotherapy showed better outcomes with concurrent therapy, but even with
concurrent chemoradiotherapy 5-year overall survival (OS) is only approximately
15% (Butts et al 2014). Therefore, sequential/maintenance (consolidation)
therapy has been and continues to be explored in an attempt to prolong a
favourable clinical state after delivery of definitive chemoradiotherapy.
The immune system can identify tumour-associated antigens and eliminate the
cancerous cells expressing them and thus plays an important role in preventing
and combating the growth of tumours. Blockade of negative regulatory signals to
T-cells such as cytotoxic T-lymphocyte antigen 4
(CTLA-4) and programmed death ligand 1 (PD-L1) has shown promising clinical
activity. PD-L1 is expressed in a broad range of cancers with a high frequency,
up to 88% in some types of cancer.
In vitro, an antibody that blocks the interaction between PD-L1 and its
receptors can relieve PD-L1-dependent immunosuppressive effects and enhance the
cytotoxic activity of anti-tumour T-cells (Blank et al 2006). Based on these
findings, an anti-PD-L1 antibody could be used therapeutically to enhance
anti-tumour immune responses in patients with cancer. Results of several
preclinical studies using mouse tumour models support this hypothesis, where
antibodies directed against PD-L1, or its receptor PD-1, showed anti-tumour
activity (Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Zhang et al
2008).
For more details please also refer to chapter 1. INTRODUCTION, page 21-34 of
Clinical Study Protocol D4191C00001 Version 1 19 February 2014.
Study objective
The primary objective of this study is to assess the efficacy of MEDI4736
treatment compared with placebo in terms of overall survival (OS) and
progression free survival (PFS; (per RECIST 1.1 as assessed by the
investigator).
Study design
This is a Phase III, randomised, double-blind, placebo-controlled, multi-centre
study assessing the efficacy and safety of MEDI4736 compared with placebo, as
sequential therapy in male and female patients with locally advanced,
unresectable NSCLC (Stage III), who have not progressed following definitive,
platinum-based, concurrent chemoradiation therapy.
Approximately 880 patients will be enrolled and 702 patients randomised
(patients will be in CR, PR or have SD following definitive, platinum-based,
concurrent chemoradiation therapy) at 310 to 370 sites worldwide, in a 2:1
ratio (MEDI4736 to placebo) to 1 of 2 arms:
• MEDI4736 (10 mg/kg every 2 weeks [Q2W] intravenous [iv] for up to 12 months)
• Placebo (matching placebo for infusion Q2W iv for up to 12 months).
Randomisation will be stratified by: age at randomisation (<65 versus >=65 years
of age), sex (male versus female), and smoking history (smoker versus
non-smoker). Patients must complete their last dose of radiation therapy
within 5 to 10 days prior to randomisation in the study (the last dose of
radiation therapy is defined as the day of the last radiation treatment
session). For patients who are recovering from toxicities associated with
prior treatment, randomisation may be delayed by up to 14 days from the end of
the chemoradiation therapy. For those patients randomised to the placebo arm
no cross-in to the MEDI4736 arm is permitted and similarly those patients
randomised to the MEDI4736 arm no cross-in to the placebo arm is permitted.
Tumour assessments will be performed using computed tomography/magnetic
resonance imaging. The baseline assessment should be performed within 28 days
of randomisation and within 5 to 10 days post the end of chemoradiation
therapy, and ideally as close as possible before the start of study drug.
Efficacy for all patients will be assessed by objective tumour assessments
every 8 weeks (relative to the date of randomisation) for the first 12 months,
then every 12 weeks thereafter, until confirmed objective disease progression
as defined by Response Evaluation Criteria In Solid Tumours (RECIST) 1.1
(irrespective of the reason for stopping study drug/or subsequent therapy). If
an unscheduled assessment is performed, and the patient has not progressed,
every attempt should be made to perform the subsequent assessments at their
scheduled visits. Blinded Independent Central Review (BICR) of a random sample
of scans, from approximately 250 evaluable patients (with both progressive and
non-progressive disease by investigator assessment) will be conducted and
sensitivity analyses performed.
Following completion or discontinuation of study drug, patients will enter a
follow-up period.
Once a patient has had objective progression recorded and has discontinued
study drug, the patient will be followed up for survival status every 2 months
until death, withdrawal of consent or the end of the study.
There will be 2 analyses of the study. The first analysis data cut off will
occur at 35.5 months when it is expected that 491 PFS events have occurred (70%
maturity). The second analysis data cut-off will occur at 62 months when it is
expected that 491 OS events have occurred (70% maturity).
If the study achieves statistical significance for the co-primary
endpoints of PFS and/or OS at one of the planned interim analyses, then that
will be
considered the final analysis for that endpoint. Further analyses for that
particular endpoint
may occur based on the needs for long term follow-up with more mature data.
At the time of Amendment 07 finalisation, the study endpoints had been met and
the planned
analysis portion of the study had been concluded. The study will continue until
all analyses for long term PFS / OS benefit are complete and those patients who
have been in OS and PFS follow-up for approximately 5 years will be considered
to have completed the study. Additional details on long-term follow up,
including data collection for patients in follow-up or in re-treatment, are
provided in the Long-term follow up section (9.5) of the protocol.
Intervention
Patients enrolled to the MEDI4736 arm will receive MEDI4736 10 mg/kg via a
60-minute iv infusion Q2W ± 3 days for up to 12 months.
Patients enrolled to the placebo arm will receive matching placebo via a
60-minute iv infusion Q2W ± 3 days for up to 12 months.
Study burden and risks
Chemoradiotherapy often induces initial tumour shrinkage followed by eventual
PD as the tumours find mechanisms to bypass the chemoradiotherapy-induced
growth inhibition. Triggering or augmenting an antigenic antitumour response
with chemoradiotherapy and combining or following this treatment with
anti-PD-L1 therapy, which acts to preserve ongoing immune responses by blocking
an immunosuppressive signal
theoretically may result in enhanced antitumour activity by improving local
control and decreasing systemic spread.
Agents that act via antagonism of an inhibitory pathway modulate an existing
antigen-specific T-cell receptor signal and have a limited potential to drive
systemic, nonspecific activation of T cells. MEDI4736 antagonizes an inhibitory
receptor (PD-L1) and as such, in the absence
of an antigen-specific T-cell receptor signal, inhibition of function of PD-L1
is not anticipated to elicit any response. MEDI4736 did not induce release of
any cytokine from any donor at any concentration tested. Experience with
MEDI4736 is limited, but for the 20 patients treated to date with available
safety data (in the dose-escalation phase of the study on a Q2W schedule),
there have been no DLTs. The majority of AEs (in 15 of the 20 patients) have
been CTCAE Grade 1 or Grade 2. There have been no Grade 3 or higher
treatment-related AEs. Six patients have had a total of 11 treatment-emergent
SAEs. Four patients have died due to AEs but none of these events were
considered by the reporting investigator to be related to treatment with
MEDI4736.
The potential for clinical benefit associated with inhibition of the PD-1/PD-L1
pathway, supported by objective responses observed in earlier studies in
patients with NSCLC, outweighs the known and potential risks based on the AEs
reported in patients treated with MEDI4736 and other PD-1/PD-L1 inhibitors.
Thus, the benefit/risk assessment, favours the conduct of this proposed study.
Södertälje Södertälje
Södertälje SE 151 85
SE
Södertälje Södertälje
Södertälje SE 151 85
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Listed location countries
Age
Inclusion criteria
1. Provision of signed, written and dated informed consent prior to any study
specific procedures
2. Male or female aged 18 years or older
3. Patients must have histologically- or cytologically-documented NSCLC who
present with locally advanced, unresectable (Stage III) disease
4. Patients must have received at least 2 cycles of platinum-based chemotherapy
concurrent with radiation therapy.
5. Patients must have not progressed following definitive, platinumbased,
concurrent chemoradiation therapy.
6. Provision of an archived tumour tissue block where such samples exist in a
quantity sufficient to allow for analysis.
7. Life expectancy >=12 weeks
8. World Health Organization (WHO) Performance Status of 0 or 1
9. Evidence of post-menopausal status, or negative urinary or serum pregnancy
test for female pre-menopausal patients.
10. Adequate organ and marrow function.
Exclusion criteria
1. Either Previous drug assignment in the present study or Prior randomisation
or treatment in a previous durvalumab (MEDI4736) and/or tremelimumab clinical
study regardless of treatment arm assignment.
2. Participation in another clinical study with an investigational product
during the last 4 weeks
3. Concurrent enrolment in another clinical study, unless it is an
observational (non-interventional) clinical study or the follow-up period of an
interventional study
4. Mixed small cell and non-small cell lung cancer histology
5. Receipt of sequential chemoradiation therapy for locally advanced NSCLC
6. Patients with locally advanced NSCLC who have progressed whilst receiving
definitive platinum based, concurrent chemoradiation therapy
7. Receipt of any immunotherapy, or investigational drug within 4 weeks prior
to the first dose of study drug
8. Current or prior use of immunosuppressive medication within 28 days before
the first dose of study drug, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are
not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
Systemic steroid administration required as prophylaxis against or to manage
toxicities arising from chemotherapy and/or radiation therapy delivered as part
of the chemoradiation therapy for locally advanced NSCLC is allowed.
9. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody
10. Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation
therapy.
11. Patients with irreversible toxicity that is not reasonably expected to be
exacerbated by study drug may be included (eg, hearing loss) after consultation
with the AstraZeneca/MedImmune medical monitor.
12. Patients with >= grade 2 pneumonitis from prior chemoradiation therapy
13. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
for cancer treatment.
14. Recent major surgery within 4 weeks
15. Active or prior documented autoimmune disease within the past 2 years,
except for: Vitiligo, Grave's disease, or psoriasis not requiring systemic
treatment
16. Active or prior documented inflammatory bowel disease (eg, Crohn's disease,
ulcerative colitis)
17. History of primary immunodeficiency
18. History of organ transplant that requires therapeutic immunosuppression
19. History of hypersensitivity to MEDI4736 or any excipient
20. Uncontrolled intercurrent illness
21. Receipt of live attenuated vaccination within 30 days prior to study entry
or within 30 days of receiving study drug.
22. History of another primary malignancy within 5 years prior to starting
study drug, except for adequately treated in situ malignancies such as basal or
squamous cell carcinoma of the skin or cancer of the cervix in situ and the
disease under study
23. Female patients who are pregnant, breast-feeding or male or female patients
of reproductive potential who are not employing an effective method of birth
control
24. Any condition that, in the opinion of the investigator, would interfere
with evaluation of the study drug or interpretation of patient safety or study
results.
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 | EUCTR2014-000336-42-NL |
| ClinicalTrials.gov | NCT02125461 |
| CCMO | NL49365.060.14 |