PEMbrolizumab Plus Lenvatinib In Second Line And Third Line Malignant Pleural MEsotheLiomA Patients.

There is no standard second line treatment in malignant pleural mesothelioma
(MPM). Pembrolizumab has shown to be active in in small phase II studies in
MPM. Its activity however, is limited, with a response rate up to 20%. So,
there is a need for new treatment combinations with drugs that might exhibit a
synergistic interaction with pembrolizumab. The mechanisms of actions of
lenvatinib, which has a broad spectrum of activities, predicts many synergistic
interactions with PD-1 blocking. Since the arrival of nivolumab plus ipilimumab
as first line standard of care treatment in mesothelioma, no treatment options
are investigated in this group of patients in the second line. The aim of this
study is to characterize the potential clinical activity, toxicity and
biomarkers of outcome of pembrolizumab - lenvatinib in patients with recurrent
MPM.

Primary:
1. To determine the objective response rate (ORR), defined by Modified
(i)RECIST criteria for pleural mesothelioma, of the combination of
pembrolizumab - lenvatinib in pre-treated patients with MPM.

Secondary:
1. To describe the safety of pembrolizumab- lenvatinib in patients with MPM.
2. To describe the disease control rate (DCR) at 3 and 6 months, clinical
benefit, progression free survival (PFS), overall survival (OS), duration of
response (DOR) and time to progression (TTP).
3. To describe ORR and PFS by independent radiological review.

Exploratory objectives
1. The immunological status in the tumors before study and after 6 weeks of
treatment with pembrolizumab+ lenvatinib. This research will include PD-L1
status, mutational load and other potential biomarkers (e.g. micro vessel
density count).
2. To explore the value of exhaled breath analyses.
3. The ORR, PFS and OS of pembrolizumab and lenvatinib in the second course
setting (see second course)

PEMMELA is a Dutch prospective single center, single arm, open label,
investigator-initiated phase II trial for patients with unresectable malignant
pleural mesothelioma who have disease progression or recurrence after 1 or 2
lines of chemotherapy.
The primary endpoint is ORR defined by Modified RECIST 1.1 for pleural
malignant mesothelioma. For details about the endpoints, see chapter 9,
statistical considerations.

All subjects will receive continious daily treatment with lenvatinib 20mg once
daily and 200mg pembrolizumab iv tri-weekly intil disease progression of
unacceptable toxicity for a maximum of 2 years.

Although single agent PD-1 blocking, with pembrolizumab or nivolumab resulted
in an ORR around 20% in pre-treated MPM patients, the progression free survival
was limited to 2.6 -6.1 months. New therapeutic strategies are needed to
improve for patients with recurrent MPM.
The combination of angiogenesis blocking (by lenvatinib) and PD-1 blocking
(pembrolizumab) seemed promising in both pre-clinical models and other solid
tumours (see section 1.5). Up to 7 studies have been presented with safety data
(see appendix F). Although patients are at risk of greater toxicity when they
receive combination therapy (see section 1.6), all previous studies with
lenvatinib-pembrolizumab concluded that the toxicity was manageable and it
outweighs the large activity of the combination therapy.
We integrated both safety data of single agent lenvatinib and pembrolizumab and
the data of the combination therapy in our treatment schedule. For example;
telephonic contact after 24-48 hours after the first gift of study medication
and visit at day 8 of cycle 1, an urine dipstick every 3 weeks and strict rules
for controlled blood pressure as inclusion criteria. In general, it appears
that the incidence of TRAEs increases with increasing doses. We have provided
rules for dose interruption and dose reduction for both lenvatinib and
pembrolizumab (section 5.2.). AEs of special interest are mention in section
5.2.3. We will perform continue safety monitoring (see section 9.5). The
accrual can be halted if excessive numbers of dose reductions and/or stopping
with trial medication because of toxicity is seen, that is, more than expected
based on previous phase I/II data (see appendix F). A lung function test will
be performed every six weeks, as surrogate for quality of live as recommended
by a patient advocate.
Currently all MPM patients are treated with platinum-pemetrexed in the first
line. Although MPM is known for inter-tumor heterogeneity, no personalized
medicine is available yet. Small phase II studies with PD(L)-1 blocking could
not reveal a relationship between PD-L1 expression and response. The PEMMALA
study will determine both the clinical activity and safety of
lenvatinib-pembrolizumab and will search for mechanism of action in blood and
biopsies. We will take a biopsy of the pleura before start of treatment, after
signing of informed consent. A second, optional, biopsy will be taken of pleura
after 6 weeks of treatment. These samples can provide import information about
the nature of MPM, can give signs of activity on a pathologic level and
hopefully provide information which can be used to develop biomarkers for MPM.
Blood samples for research purposes will be taken at baseline and at day 1 of
cycle 2, 3 and 6. *