An Open-Label, Multi-Center, Global Study to Evaluate Long Term Safety and Efficacy in Patients Who are Receiving or Who Previously Received Durvalumab in Other Protocols (WAVE)

2.1 Study rationale
This is a multicenter, open-label, global study that will enroll patients who
are currently receiving durvalumab monotherapy, or have previously received
durvalumab as monotherapy or in combination with any other approved or
investigational anticancer agents, in an eligible
AstraZeneca/MedImmune-sponsored clinical study (herein referred to as a parent
clinical study).
The aims of the study are the following:
• To collect long-term safety and survival data from patients who received
durvalumab monotherapy and/or durvalumab in combination with any other approved
or investigational anticancer agents.
• To provide continued access to durvalumab monotherapy until confirmed
progressive disease (PD) to patients currently receiving treatment.
• To allow for future retreatment with durvalumab monotherapy upon disease
progression in patients who previously benefited from treatment with durvalumab
as monotherapy, and/or durvalumab in combination with any other approved or
investigational anticancer agents and experienced disease progression after
completion of planned treatment.
The primary aim of this study is to monitor the long-term safety of durvalumab.
Extensive safety-related data are being collected throughout the course of drug
development, and knowledge about a drug*s safety profile continually evolves as
safety data accumulate. This study is aligned with the growing interest in
larger, simpler trials to obtain outcome data,
including long-term effects of drugs and comparative effectiveness and safety.

2.2 Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of
durvalumab is provided in the Investigator*s Brochure (IB).
2.2.1 Immunotherapies
It is increasingly understood that cancers are recognized by the immune system,
and under some circumstances, the immune system may control or even eliminate
tumors (Dunn et al 2004).
Programmed death ligand 1 (PD-L1) is part of a complex system of receptors and
ligands that are involved in controlling T cell activation. The programmed cell
death protein 1 (PD-1) receptor (CD279) is expressed on the surface of
activated T cells (Keir et al 2008). It has 2 known
ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) (Okazaki and Honjo
2007). PD-1 and PD-L1/PD-L2 belong to a family of immune checkpoint proteins
that act as co-inhibitory factors, which can halt or limit the development of T
cell response. When PD-L1 binds to PD-1, an inhibitory signal is transmitted
into the T cell, which reduces cytokine production and suppresses T cell
proliferation. Tumor cells exploit this immune checkpoint pathway as a
mechanism to evade detection and inhibit immune response.
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages
(Qin et al 2016).
Importantly, PD-L1 is commonly over-expressed on tumor cells or on
non-transformed cells in the tumor microenvironment (Pardoll 2012). PD-L1
expressed on the tumor cells binds to PD-1 receptors on the activated T cells,
leading to the inhibition of cytotoxic T cells. These deactivated
T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 pathway
represents an adaptive immune resistance mechanism that is exerted by tumor
cells in response to endogenous antitumor activity.
The inhibitory mechanism described above is co-opted by tumors that express
PD-L1 as a way of evading immune detection and elimination. The binding of an
anti-PD-L1 agent to the PD-L1 receptor inhibits the interaction of PD-L1 with
the PD-1 and CD80 receptors expressed on immune cells (IC). This activity
overcomes PD-L1-mediated inhibition of antitumor immunity.
While functional blockade of PD-L1 results in T cell reactivation, this
mechanism of action (MOA) is different from direct agonism of a stimulatory
receptor such as CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an
anti-PD-L1 antibody could be used therapeutically to enhance antitumor immune
responses in patients with cancer.
Results of preclinical and clinical studies of monoclonal antibodies (mAbs)
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a
manageable safety profile,
supporting the hypothesis that an anti-PD-L1 antibody could be used to
therapeutically enhance antitumor immune response in cancer patients (Brahmer
et al 2012, Hirano et al 2005,
Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008)
with responses that tend to be more pronounced in patients with tumors that
express PD-L1 (Powles et al 2014, Rizvi et al 2015, Segal et al 2015). In
addition, high mutational burden (eg, in bladder carcinoma; Alexandrov et al
2013) may contribute to the responses seen with immune therapy.
Preclinical data has now been added to a wealth of clinical data showing that
blockade of negative regulatory signals to T cells such as cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) and PD-L1 has promising clinical
activity. Ipilimumab was first granted United States
(US) Food and Drug Administration (FDA) approval for the treatment of
metastatic melanoma and is currently under investigation for several other
malignancies. Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and
atezolizumab, an anti-PD-L1 agent, have been granted approvals by agencies for
the treatment of a number of malignancies, including metastatic
melanoma, squamous and non-squamous cell non-small cell lung cancer (NSCLC),
squamous cell carcinoma of the head and neck, and urothelial carcinoma. In
addition, there are data from agents in the anti-PD-1/PD-L1 class showing
clinical activity in a wide range of tumor types.

2.2.2 Durvalumab
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that
blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with
PD-1 on T cells and CD80 (B7.1) on IC. It is being developed by
AstraZeneca/MedImmune, for use in the treatment of cancer. (MedImmune is a
wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred
to as AstraZeneca throughout this document.) The propose MOA for durvalumab
is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade
of PD-L1/PD- 1 and PD-L1/CD80 interactions releases the inhibition of immune
responses, including those that may result in tumor elimination. In vitro
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1
on primary human T cells resulting in the restored proliferation of
interferon gamma (IFN-γ) (Stewart et al 2015). In vivo studies have shown that
durvalumab inhibits tumor growth in xenograft models via a T cell-dependent
mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to
stimulate the patient*s antitumor immune response by binding to PD-L1 and by
shifting the balance toward an antitumor response. Durvalumab has been
engineered to reduce antibody-dependent cellular cytotoxicity and
complement-dependent cytotoxicity.
To date, durvalumab has been given to more than 6000 patients as part of
ongoing studies, either as monotherapy or in combination with any other
approved or investigational anticancer agents.
Details on the safety profile of durvalumab monotherapy are summarized in
Section 4.3.1.1 and Section 8.3.13. Refer to the current durvalumab IB for a
complete summary of preclinical and clinical information including safety,
efficacy, and pharmacokinetics (PK).
Durvalumab administered either as a single agent or in combination continues to
be evaluated in multiple immuno-oncology clinical studies. To date, several
different doses and schedules have been evaluated in multiple indications,
including administration for a fixed duration.
Durvalumab has been administered intravenously (IV) in multiple clinical
studies for up to 12 months or until PD, whichever occurs earlier. After the
completion of therapy in these ongoing clinical studies, patients are followed
with regular tumor assessments to continue monitoring the clinical activity of
durvalumab. Emerging data from these ongoing studies
suggest that some patients lose clinical benefit after completing 12 months of
therapy, eg, HAWK (NCT02207530) and ATLANTIC (NCT02087423) studies.
Patients treated with chemotherapy alone are generally unlikely to respond to
re-challenge with the same agent upon progression. In contrast, responses have
been observed upon retreatment with immunotherapies (Santini 2018). Several
potential mechanisms of resistance to immunotherapy exist, including loss of T
cell *memory* or recurrence of immune escape, which suggest that retreatment
for patients who initially respond or demonstrate stable disease (SD)
merits further study. Preliminary data in patients previously treated with
immunotherapies suggest that responses are similar to those observed following
initial treatment (Forde et al 2014, Hodi et al 2010).
Therefore, AstraZeneca has modified the durvalumab treatment regimen in
specific indications, to allow patients to continue treatment until confirmed
PD, rather than requiring treatment discontinuation at 12 months. Treatment
until progression is consistent with the approved agents with a similar MOA to
durvalumab, such as PD-1 targeting antibodies nivolumab and pembrolizumab,
which are used to treat patients in a number of indications, including but not
limited to melanoma, NSCLC, urothelial cancer, and renal cell carcinoma.

Primary Objective: To monitor long-term safety of durvalumab (all
cohorts)

Secondary Objectives: To assess the efficacy of durvalumab in terms of ORR and
DOR in patients who undergo
retreatment with durvalumab (Cohort 2 only)


Secondary Objectives
To assess the OS of patients (all cohorts)

This is a multicenter, open-label, global study that will enroll patients who
are currently receiving durvalumab monotherapy, or have previously received
durvalumab as monotherapy or in combination with any other approved or
investigational anticancer agents, in an eligible parent clinical study. The
study initially aims to enroll approximately 600 patients; study size may
increase as new parent clinical studies are incorporated into this study. Some
of these patients will no longer be eligible to receive treatment or
retreatment with durvalumab, and will be followed for overall survival (OS).
For patients who are eligible to continue treatment or restart
durvalumab, treatment will be administered every 4 weeks (q4w; ±3 days) until
PD, unless there is unacceptable toxicity, withdrawal of consent, death, or
another discontinuation criterion is met. All patients in the study will be
followed for safety for 90 days after the last dose of durvalumab, and every 3
months (±2 weeks) beginning 90 days after the last dose of study drug
for OS. For an overview of the study design, see Section 1.3. For details on
treatments given during the study, see Section 6.1.
4.2 Scientific rationale for study design
4.2.1 Rationale for retreatment option
In contrast to patients treated with chemotherapy, who are unlikely to respond
to re-challenge with the same agent upon progression, responses have been
observed upon retreatment with immunotherapies. Several potential mechanisms of
resistance to immunotherapy exist, including loss of T cell *memory* or
recurrence of immune escape, which suggests that retreatment for patients who
initially respond or demonstrate SD is reasonable. Preliminary data in patients
previously treated with immunotherapies suggest that responses are similar to
those observed
following initial treatment (Forde et al 2014, Hodi et al 2010).
Durvalumab has been administered IV in multiple clinical studies up to 12
months. After the completion of therapy in these ongoing clinical studies,
patients are followed with regular tumor assessments to continue monitoring the
clinical activity of durvalumab. Emerging data from these ongoing studies
suggest that some patients lose clinical benefit after completing 12 months of
therapy.

4.3 Justification for dose
4.3.1 Durvalumab dose and treatment regimen justification
4.3.1.1 Durvalumab monotherapy dose rationale
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, preclinical
activity, clinical PK/pharmacodynamics, biomarkers, and activity data from
Study CD-ON-MEDI4736-1108 (hereafter referred to as Study 1108) in patients
with advanced solid tumors and from a Phase I study performed in Japanese
patients with advanced solid tumor (D4190C00002).
Pharmacokinetic/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with dose
ranging from 0.1 to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks
(q3w), durvalumab exhibited nonlinear (dose-dependent) PK consistent with
target-mediated drug disposition. The PK approached linearity at >=3 mg/kg q2w,
suggesting near complete target saturation (membranebound and soluble PD-L1),
and further showed that the durvalumab dosing frequency can be adapted to a
particular regimen given the linearity seen at doses higher than 3 mg/kg. The
expected half-life with doses >=3 mg/kg q2w is approximately 21 days. A
dose-dependent suppression in peripheral soluble PD-L1 was observed over the
dose range studied, consistent with engagement of durvalumab with PD-L1. A low
level of immunogenicity has been observed.
No patients have experienced immune-complex disease following exposure to
durvalumab. (For further information on immunogenicity, please see the current
durvalumab IB.)
A population PK model was developed using the data from Study 1108 (doses=0.1
to 10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations
indicate that a similar overallexposure is expected following both 10 mg/kg q2w
and 20 mg/kg q4w regimens, as represented by AUCss (4 weeks). Median Cmax,ss is
expected to be higher with 20 mg/kg q4w (~1.5 fold) and median Ctrough,ss is
expected to be higher with 10 mg/kg q2w (~1.25 fold). Clinical activity with
the 20 mg/kg q4w dosing regimen is anticipated to be consistent with 10 mg/kg
q2w with the proposed similar dose of 20 mg/kg q4w expected to (a) achieve
complete target saturation in the majority of patients; (b) account for
anticipated variability in PK, pharmacodynamics, and clinical activity in
diverse cancer populations; (c) maintain sufficient PK exposure in case of
antidrug antibodies impact; and (d) achieve PK exposure that yielded maximal
antitumor activity in animal models.
Given the similar area under the serum drug concentration-time curve and modest
differences in median peak and trough levels at steady state, the observation
that both regimens maintain complete soluble PD-L1 suppression at trough, and
the available clinical data, the 20 mg/kg q4w
and 10 mg/kg q2w regimens are expected to have similar efficacy and safety
profiles, supporting further development with a dose of 20 mg/kg q4w.
Clinical data
Refer to the current durvalumab IB for a complete summary of clinical
information including safety, efficacy, and PK at the 20 mg/kg q4w regimen. The
IB reflects the current regimen that is used across the program when durvalumab
monotherapy is dosed q4w.
4.3.1.2 Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from
Study 1108 (N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors).
Population PK analysis indicated only a minor impact of body weight (WT) on the
PK of durvalumab (coefficient of <=0.5). The impact of body weight (WT)-based
(10 mg/kg q2w) and fixed dosing (750 mg q2w) of durvalumab was evaluated by
comparing predicted steady state PK concentrations (5th, median, and 95th
percentiles) using the population PK model. A fixed dose of 750 mg was selected
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000
patients were simulated using body WT distribution of 40 to 120 kg. Simulation
results demonstrate that body WT-based and fixed dosing regimens yield similar
median steady state PK concentrations with slightly less overall
between-patient variability with fixed dosing regimen.
Similar findings have been reported by others (Narwal et al 2013, Ng et al
2006, Wang et al 2009, Zhang et al 2012). Wang and colleagues investigated 12
mAbs and found that fixed and body weight-based dosing perform similarly, with
fixed dosing being better for 7 of
12 antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic
proteins and peptides, and showed that fixed dosing performed better for 12 of
18 in terms of reducing the between-patient variability in PK/pharmacodynamic
parameters (Zhang et al 2012).

A fixed dosing approach is preferred by the prescribing community, due to ease
of use and reduced dosing errors. Given the expectation of similar PK exposure
and variability, AstraZeneca considered it feasible to switch to fixed dosing
regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg q4w
durvalumab (equivalent to 20 mg/kg q4w) is included in the current study.

4.3.1.3 Rationale for duration of treatment
In this study, the duration of treatment was selected to allow eligible
patients to continue treatment with durvalumab monotherapy until confirmed PD.
Additionally, patients who completed the defined duration of treatment with
durvalumab or durvalumab plus any other approved or investigational anticancer
agents in a parent clinical study and subsequently experienced confirmed PD,
will be permitted

2.3 Benefit/risk assessment
More detailed information about the known and expected benefits and risks, and
reasonably expected adverse events (AEs) of durvalumab may be found in the IB.

2.3.1 Overall benefits
As is commonly the case for clinical trials with a fixed treatment or study
duration, long-term safety and efficacy endpoints often lack feasibility within
the time frame permitted by design.
The benefit of this study, which identifies potentially eligible patients from
parent clinical studies, allows for the continued access of durvalumab and
observation of patients treated with durvalumab. Durvalumab will be provided to
eligible, treatment-experienced patients who have been treated for months under
parent clinical studies and have demonstrated a response and
tolerability to treatment. They will be treated as long as they continue to
receive benefit for treatment with durvalumab.
Conducting this study serves the important purpose to better understand the
long-term patient safety and survival outcomes across a diverse group of
patient population exposed to durvalumab.

2.3.1.1 Benefits of durvalumab as monotherapy
The majority of the safety and efficacy data currently available for durvalumab
are based on 5 monotherapy studies (CD-ON-MEDI47361108, ATLANTIC, HAWK,
PACIFIC, and D4190C00007) for which efficacy data are available. Data from
these studies have demonstrated clinical activity of durvalumab therapy in
patients with NSCLC. PACIFIC has shown significant improvements in median
progression-free survival with durvalumab treatment compared with placebo for
patients with NSCLC (16.8 months [95% confidence interval {CI}: 13.0, 18.1]
versus 5.6 months [95% CI: 4.6, 7.8]; stratified hazard ratio for disease
progression or death, 0.52; 95% CI: 0.42, 0.65; p<0.001). Similar findings in
favor of durvalumab compared with placebo were found for duration of response
(DOR; 72.8% versus 46.8% of patients had ongoing response at 18 months,
respectively) and median time to death or distant metastasis (23.2 months
versus 14.6 months, respectively; p<0.001).

2.3.2 Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as
PD-L1 as well as those directed against PD-1 or CTLA-4, aim to boost endogenous
immune responses directed against tumor cells. By stimulating the immune
system, however, there is the potential for adverse effects on normal tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of
agents are thought to be due to the effects of inflammatory cells on specific
tissues. These risks are generally events with a potential inflammatory or
immune-mediated mechanism and that may require more frequent monitoring and/or
unique interventions, such as immunosuppressants and/or endocrine therapy.
These immune-mediated effects can occur in nearly any organ system
and are most commonly seen as gastrointestinal (GI) AEs such as colitis and
diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as
liver enzyme elevations, skin events such as rash and dermatitis, and
endocrinopathies including hypo- and hyperthyroidism.

2.3.2.1 Potential risks of durvalumab monotherapy
Risks with durvalumab include, but are not limited to, diarrhea/colitis,
pneumonitis/ILD, endocrinopathies (ie, events of hypophysitis/hypopituitarism,
adrenal insufficiency, hyper- and hypothyroidism, and type I diabetes mellitus
[DM]), hepatitis/increases in transaminases, nephritis/increases in creatinine,
pancreatitis/increases in amylase and lipase, rash/dermatitis,
myocarditis, myositis/polymyositis, other rare or less frequent inflammatory
events including neuromuscular toxicities, infusion-related reactions,
hypersensitivity reactions, and infections/serious infections.
For information on all identified and potential risks with durvalumab, please
always refer to the current version of the durvalumab IB.
In monotherapy clinical studies, AEs reported an incidence of >=20%, this
included events such as fatigue, cough, decreased appetite, dyspnea, and
nausea. A total of 5% to 10% of patients discontinued the drug due to an AE.
Please see the current version of the IB for a detailed summary of the
monotherapy data including AEs, serious adverse events (SAEs), and Common
Terminology Criteria Grade 3 to 5 events reported across the durvalumab
program. The majority of treatment-related AEs were manageable with dose
delays, symptomatic treatment, and in the case of events suspected to have an
immune basis, the use of established treatment guidelines for immune-mediated
toxicity (see Section 8.4.4).
A detailed summary of durvalumab monotherapy AE data can be found in the
current version of the durvalumab IB