Open-label single arm phase II study on pembrolizumab for recurrent primary central nervous sytem lymphoma

Primary central nervous system lymphoma (PCNSL) is a malignant lymphoma, most
commonly of the diffuse large B-cell lymphoma (DLBCL) type, that is confined to
the central nervous system (CNS) at time of diagnosis.

The median progression-free survival time is around 12 months from the initial
diagnosis and the median overall survival is approximately 3 years in most
series. The standard therapy at diagnosis is based on high-dose methotrexate
(MTX) chemotherapy, which may be combined with other chemotherapeutics (e.g.
cytarabine) and followed by consolidation therapies such as whole-brain
radiotherapy (WBRT), intensified chemotherapy or autologous stem cell
transplantation (ASCT). Therapeutic options for recurrent/progressive PCNSL
after MTX-based first-line therapy are poorly defined and novel treatment
concepts based on biological insights are urgently needed to improve patient
outcomes.

Activating the immune system against PCNSL might be a promising therapeutic
strategy. In this regard, the development and clinical availability of immune
checkpoint blockers that interfere with immune-inhibiting signals represents a
novel and promising therapeutic option. Among the most promising compounds are
drugs that inhibit the interaction between the receptor, PD-1, and its ligands.
The administration of antibodies which block PD-1 such as pembrolizumab has
provided very promising results in patients with metastatic melanoma and other
advanced cancers including lymphomas and was overall well tolerated
.Pembrolizumab was approved by the US health authority FDA for therapy of
metastatic melanoma. Several clinical trials are evaluating pembrolizumab in
lymphomas, however, CNS involvement is an exclusion criterion in these studies.

In summary, there is a high medical need for patients suffering from
recurrent/progressive PCNSL. Targeting the PD-1 pathway may represent a very
promising novel approach for the treatment of these patients.

Primary objective
To evaluate the Overall Response Rate (CR/PRrate) in patients treated
with pembrolizumab for recurrent or progressive PCNSL after
MTX-based first-line therapy
To evaluate the safety of pembrolizumab in subjects diagnosed with
recurrent PCNSL

Secondary objectives
To describe Best Overall Response categories (CR, PR, SD, PD) in
patients treated with pembrolizumab for relapsed PCNSL after MTX-based
first-line therapy
To describe individual duration of response over time
To assess median progression-free survival in this patient population
To assess median overall survival in this patient population

Exploratory objectives
To assess PD-L1 as a predictive marker for response to pembrolizumab
Examination of PD-L1 expression in tumor tissue, including infiltrating
immune cells, obtained during biopsy of primary tumor (and recurrent
tumor if available)
To investigate neuro-radiological response patterns

Prospective, single-arm, phase II

Pembrolizumab 200 mg every 3 weeks until disease progression, unacceptable
toxicity or withdrawal of consent.

Before inclusion into the study standard blood tests need to be performed
including tests for liver infections (hepatitis B and C) and HIV. Additionally,
an ECG, tumor evaluation by MRI scan of the brain and, in women of
reproductive potential, a pregnancy test will be performed. Patients will also
need to be examined by a neurologist and an ophthalmologist. This does not
entail a significant risk. Pembrolizumab is administered as an 30-minute
infusion in out-patient setting. Generally, pembrolizumab is usually
well-tolerated with mostly treatable and reversible side-effects such as
diarroea, nausea, itching, skin rash, painful joints and fatigue. Occasionally
auto-immune disease occur such as inflammation of kidneys, lung, thyroid or
pituitary gland. These are a result of the mechanism of action of pembrolizumab
(enhancement of immunity) and are rare (less than 2/100) but may be severe.
Pembrolizumab is administered once every 3 weeks as long as it is tolerated and
no tumor progression occurs. Prior to each cycle standard blood tests and a
physical examination are performed. Every 8 weeks an MRI scan will be made to
evaluate the effect of treatment and every 3 weeks a pregnancy test will be
done in women of reproductive potential.