An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies

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 a member of the B7 family of ligands that
inhibit T-cell activity through binding to the PD-1 receptor (Keir et al 2008)
and to CD80 (Butte et al 2007). PD-L1 expression is an adaptive response that
helps tumors evade detection and elimination by the immune system. In contrast,
cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively
expressed by regulatory T cells and upregulated on activated T cells. Binding
of CTLA-4 to CD80 or CD86 on IC leads to inhibition of T-cell activation (Fife
and Bluestone, 2008). Expression of PD-L1 protein is induced by inflammatory
signals that are typically associated with an adaptive immune response (eg,
IFNγ) and can be found on both tumor cells (TC) and tumor infiltrating immune
cells. The binding of PD-L1 to PD-1 on activated T cells delivers an inhibitory
signal to the T cells, preventing them from killing target TC, and protecting
the tumor from immune elimination (Zou and Chen 2008). PD-L1 may also inhibit T
cells through binding to CD80, although the exact mechanism is still not
elucidated (Butte et al 2007; Paterson et al 2011).
In vivo studies have shown that durvalumab inhibits tumor growth in xenograft
models via a T cell-dependent mechanism (Stewart et al 2015).
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88%
in some types 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 non-clinical 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 e.g., in bladder carcinoma (Alexandrov et al 2013) may
contribute to the responses seen with immune therapy.
In contrast to PD-L1, CTLA-4 is constitutively expressed by regulatory T cells
and upregulated on activated T cells. CTLA-4 delivers a negative regulatory
signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on
antigen-presenting cells. In addition, blockade of CTLA-4 binding to CD80/86 by
anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and
antitumor activity in animal models, including killing of established murine
solid tumors and induction of protective antitumor immunity. Therefore, it is
expected that treatment with an anti-CTLA-4 antibody will lead to increased
activation of the human immune system, increasing antitumor activity in
patients with solid tumors.
Pre-clinical data has now been added to with a wealth of clinical data showing
that blockade of negative regulatory signals to T-cells such as CTLA-4 and
PD-L1 has promising clinical activity. Ipilimumab was 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 whilst nivolumab and pembrolizumab, two anti-PD-1 agents and
atezolizumab, an anti PD-L1 agent have been granted approvals by agencies such
as the United States of America Food and Drug Administration and the European
Medicines Agency approval for the treatment of a number of malignancies
including metastatic melanoma, squamous and non-squamous cell non-small-cell
lung cancer, squamous cell carcinoma of the head and neck, and urothelial
carcinoma. In addition there is data from agents in the anti-PD-1/PD-L1class
showing clinical activity in a wide range of tumor types.

There remains a significant unmet medical need for additional treatment options
for advanced solid tumors, including bladder, lung, and head and neck.
Treatment with agents targeting PD-1/PD-L1 (such as durvalumab) or CTLA-4 (such
as tremelimumab) has shown activity in several tumor types in a subset of
patients deriving meaningful and durable benefit. Efficacy data for patients
treated with durvalumab monotherapy in the bladder cancer, lung cancer, and
head and neck squamous cell carcinoma (HNSCC) cohorts have shown some clinical
activity. Preliminary data generated from patients with NSCLC treated with
durvalumab + tremelimumab combination therapy have shown early signs of
clinical activity, and data from competitors indicate that the combination may
act synergistically (Wolchok et al 2013). Thus, these agents may potentially
offer benefit to this patient population. The study design aims to minimize
potential risks and intensive monitoring, including early safety assessment, is
in place for those risks deemed to be most likely based on prior experience
with the investigational products (IPs; including durvalumab, tremelimumab, and
SoC).

Main protocol:
To assess the incidence, severity, nature, seriousness, intervention/treatment,
outcome, and causality, including immune-relatedness, of adverse events of
special interest (AESIs) in patients who are treated with durvalumab and
tremelimumab combination therapy or durvalumab monotherapy, using fixed dosing.

Module A:
To collect additional data and assess the incidence, severity, nature,
seriousness, intervention/treatment, outcome, and causality, including
immune-relatedness, of adverse events of special interest (AESIs) in patients
with locally advanced or metastatic urothelial or non-urothelial carcinoma of
the urinary tract (including the urinary bladder, ureter, urethra and renal
pelvis) treated with a fixed dose of durvalumab monotherapy

Main protocol:
This is an open-label, multi-center, study to determine the short and long term
safety of fixed doses of durvalumab 1500 mg + tremelimumab 75 mg combination
therapy or durvalumab 1500 mg monotherapy in patients with advanced solid
malignancies.
This study is modular in design, each tumor specific Module allowing evaluation
of the safety, tolerability, and anti-tumor activity of the combination of
durvalumab + tremelimumab or durvalumab alone in different solid tumors.
The modules are developed as separate components appended to this protocol.
Additional modules may be added as part of this protocol as decisions on
additional tumor types and/or exploratory sub-studies are made.
One or more of these modules will be opened in a given country / region based
on local patient population prevalence, and results of feasibility studies.
The main protocol (and each tumor specific module) consists of a screening
period, a treatment period, a 90 day safety follow-up period*, and a survival
follow-up period.
Patients will attend a safety follow-up visit 90 days after study treatment
discontinuation. Thereafter, patients will be contacted by phone or electronic
communication every 3 months for survival status up to 5 years following date
of first patient treatment initiation. All patients will be followed for a
minimum of 6 months following enrollment of last patient.
*Any immune-mediated adverse events (imAEs) that are unresolved at the
patient*s last visit in the study are followed up by the Investigator for as
long as medically indicated and up to 12 months post onset. Non-imAEs are
followed to the 90 day visit post treatment discontinuation.

Module A:
This is an open-label, multi-center, study to determine the short and long term
safety of fixed dose of durvalumab 1,500 mg in adult patients (age >=18 years)
with urothelial and nonurothelial carcinoma of the urinary tract (all
histologies e.g.: transitional cell, adenocarcinoma, squamous cell carcinoma,
small cell carcinoma, etc.) that has progressed during or after previous
platinum based chemotherapy, either for metastatic disease or progressive
disease less than 12 months after adjuvant or neo-adjuvant chemotherapy.
The study consists of a screening period, a treatment period, a 90 day safety
follow-up period*, and a survival follow-up period.
Patients will attend a safety follow-up visit 90 days after study treatment
discontinuation. Thereafter, patients will be contacted by phone or electronic
communication every 3 months for survival status up to 5 years following date
of first patient treatment initiation. All patients will be followed for a
minimum of 6 months following enrollment of last patient.
*Any imAEs that are unresolved at the patient*s last visit in the study are
followed up by the Investigator for as long as medically indicated and up to 12
months post onset. Non-imAEs are followed to the 90-day visit post treatment
discontinuation.

Durvalumab + tremelimumab combination therapy
• Durvalumab 1,500 mg plus tremelimumab 75mg via IV infusion once every 4 weeks
(Q4W), starting on Week 0, for up to a maximum of
4 doses (or cycles) followed by:
• Durvalumab monotherapy 1,500 mg via IV infusion Q4W, starting 4 weeks after
the last infusion of the combination or discontinuation of tremelimumab.

OR

Durvalumab monotherapy
• Durvalumab 1,500 mg via IV infusion Q4W, starting on Week 0.
Each tumor specific module will specify combination therapy or monotherapy, and
will
provide details of infusion duration.

Module A:
Durvalumab monotherapy.

Based upon the available non-clinical and clinical safety data, the limited
survival benefit provided by the currently available treatment options to
patients, the limited life expectancy due to malignant disease, the activity
seen with durvalumab in this tumor type, and the strength of the scientific
hypotheses under evaluation, the durvalumab monotherapy and durvalumab +
tremelimumab combination therapy proposed in this study may have the potential
to provide meaningful clinical benefit with a manageable safety and
tolerability profile by generating durable clinical responses, thereby
improving quality of life (QoL) and potentially extending survival.
Furthermore, preclinical and clinical evidence indicate that the combination of
PD 1/PD-L1 and CTLA-4 targeting agents may provide antitumor activity, with
additional synergy from the combination (Wolchok et al 2013). Therefore, the
investigation of the potential therapeutic efficacy of durvalumab monotherapy
and durvalumab + tremelimumab combination therapy in patients with PD-L1-High
and PD-L1 Low/Neg tumors is acceptable, and the overall benefit/risk assessment
supports the proposed study design.