A randomized, controlled Phase III study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic renal cell-carcinoma.

RCC accounts for approximately 3% of adult malignancies and is characterised by
the lack of early warning signs, diverse symptoms and resistance to radiation
and chemotherapy. The longterm survival for patients with metastatic RCC
remains modest with the current therapies available. In addition there are a
number of toxicities associated with the current therapies. Thus the management
of patients with mRCC remains a challenge and there is still high medical need
for better treatment options.
IMA901 is a vaccine with a new mechanism of action which involves stimulating
an immune response that is directed towards specific targets that are
functionally important for the tumour. Studies so far with IMA901 have shown
promising survival data and a favourable safety profile. In order to strengthen
and maintain the immune response,
IMA901 will be given along with the immunomodulators GMCSF and lowdose
cyclophosphamide. The coadministration with these immunomodulators has shown
encouraging results and a good tolerability in previous studies.
Combining existing therapies is difficult due to their toxicities. However
given the good safety profile of IMA901, combining IMA901 with an existing
therapy could be a new therapy option. Preclinical studies investigating IMA901
in combination with sunitinib show that the combined therapy is feasible and
the effects of IMA901 might be further enhanced by the stimulation of the
immune system that results from sunitinib treatment.
This study will investigate the efficacy and safety of IMA901 given on top of
sunitinib in patients with RCC, with the hope that it will lead to an increase
in overall survival of these patients.

The primary objective of the present phase III study is to investigate whether
IMA901 can prolong overall survival in patients with metastatic and/or locally
advanced renal cell carcinoma (RCC) when added to standard first-line therapy
with sunitinib.
Secondary objectives include a subgroup analysis of overall survival in
patients who are positive for a prospectively defined primary biomarker
signature, the investigation of progression-free survival, best tumor response,
safety, and immunological parameters (in a subset of patients).
Further objectives are additional biomarker analyses.

This is a multicenter, open-label, randomized phase III study to investigate
whether IMA901 can prolong overall survival in patients with metastatic and/or
locally advanced RCC when added to standard first-line therapy with sunitinib
(primary endpoint).

* Screening (Visits A and B):
Informed consent will be obtained from patients for HLA typing (screening 1,
Visit A). HLA-A*02-positive patients will then again be requested to give a
separate informed consent to the remaining screening examinations (Screening 2,
Visit B) and participation in the study. All screening examinations (screening
1 and 2) must be completed (i.e. the results of the screening examinations
[except for biomarker and immunomonitoring analysis] must be available) before
start of sunitinib therapy.

* Start of sunitinib therapy:
Patients fulfilling all eligibility criteria will enter study IMA901-301 and
start sunitinib first-line therapy according to the label (50 mg orally once
daily, 4 weeks on treatment followed by 2 weeks off). One complete sunitinib
cycle is defined as 42 days.
Patients eligible for continued sunitinib treatment (i.e. no clinical disease
progression, no adverse events preventing further treatment after the first 4
weeks on sunitinib) will be randomized at Visit C which must take place 3 to 10
days before Visit D (see below).

* Randomization (Visit C):
At Visit C patients will be randomized at a ratio of 3:2 to the vaccination arm
(Arm 1) and the control arm (Arm 2) and will receive further treatment as
follows:
o Arm 1 (vaccination arm): 10 vaccinations with IMA901 plus GM-CSF.
Cyclophosphamide will be administered once prior to the first vaccination.
Continued sunitinib therapy.
o Arm 2 (control arm): Continued sunitinib therapy.
Randomization will be stratified according to risk group (favorable vs.
intermediate), region (US vs. CEE vs. WEE vs. Asia) and prior nephrectomy (yes
vs. no).

* Low-dose CY administration (Visit D):
At Visit D a single i.v. infusion of 300 mg/m2 cyclophosphamide (CY) will be
given to patients in Arm 1 (vaccination arm). Visit D must be performed between
days 31 and 36 of the first sunitinib cycle (i.e. within days 3 and 8 of the
off-phase of the first sunitinib cycle) and 3 ± 1 days before the first
vaccination (Visit 1) based on the following rationale: Vaccinations 1 to 3 (to
be administered on 3 consecutive days = Visits 1 to 3) are considered to be
highly relevant for immunological priming and are thus given during days with
presumed low systemic concentrations of sunitinib in order to minimize the risk
of interference with the initial T cell expansion, which is between days 33 and
42 of the first sunitinib cycle (i.e. between days 5 and 14 of the sunitinib
off-phase). The first vaccination shall not be given before day 33 of the first
sunitinib cycle (i.e. day 5 of the sunitinib off-phase) because by then the
sunitinib plasma levels have decreased to approx. 25% of steady state
concentration (t1/2=40 to 60h).

* Vaccination schedule (starting with Visit 1):
Patients in Arm 1 (vaccination arm) will start vaccination therapy 3 ± 1 days
after Visit D with an intradermal (i.d.) injection of GM-CSF followed by an
i.d. injection of IMA901. Patients will receive 6 vaccinations in the first 3
weeks (induction period, Visits 1 to 6) and then 4 more vaccinations at 3
weekly intervals (maintenance period, Visits 7 to 10).

* Study completion:
An individual patient is considered to have "completed" the study, if
• He/she has completed all scheduled visits.
• He/she experiences documented disease progression (as per RECIST 1.1. and/or
clinical progression) or dies.
• He/she experiences adverse event(s) that in the opinion of the investigator
require a permanent stop of sunitinib first-line therapy or a transient stop
for more than 6 weeks.

Patients who for other reasons leave the study are considered as "prematurely
withdrawn".
In any of the above mentioned cases, the investigator should aim to perform a
formal End of Study (EOS) Visit.

Patients will be randomized at a ratio of 3:2 to the vaccination arm (Arm 1)
and the control arm (Arm 2) and will receive further treatment as follows:
o Arm 1 (vaccination arm): 10 vaccinations with IMA901 plus GM-CSF.
Cyclophosphamide (single i.v. infusion of 300 mg/m2 ) will be administered once
prior to the first vaccination. Continued sunitinib therapy.
o Arm 2 (control arm): Continued sunitinib therapy.

It is anticipated that patients be in the study for a maximum period of about
25 months which includes the following periods:
Screening period - maximum of 4 weeks - 2 visits
Pre-vaccination period - 5 weeks - 1 visit
Treatment (vaccination) period - 4 months - Vaccination group: 11 visits;
Control group 6 visits
Follow-up period for tumor assessment - maximum of 19 months

Tumor assessments:
CT or MRI of the chest, abdomen and pelvis are scheduled in both study arms at
screening (Visit B), at Visit 7 (within the off-phase of the second sunitinib
cycle) and then at day 28 of every second sunitinib cycle, i.e. every 12 weeks
(Visits 11 to 18/EOS) until all patients had the chance to complete Visit 14
(i.e., no remaining patient is non-progressive and still on-study before Visit
14).
CT or MRI of the brain is mandatory at screening (Visit B) and thereafter will
only be performed if clinically indicated.
In patients with known or suspected bone metastases, imaging of bone lesions
(e.g., bone scan or X-ray or CT or MRI) will be performed at screening and if
clinically indicated thereafter.

Safety assessments:
Safety assessments will be performed on a regular basis in both study arms and
will comprise continuous AE reporting, physical examinations and assessment of
vital signs, hematology, clinical chemistry and urinalysis. Up to the end of
the vaccination period safety assessments will be done at screening (Visit B),
at Visit D, then at 3-weekly intervals (Visits 6 and 7) followed by a 6-weeks
interval (Visits 9) and a 5-weeks interval (Visit 11). During the follow-up
period for PFS, safety will be assessed every 12 weeks (Visits 12 to 18/EOS).
A thyroid function test (TFT) will be performed at screening (Visit B), at
Visit D, at Visits 7 and 11 and then every 12 weeks (Visits 12 to 18/EOS). AE
reporting will continue during the follow-up period for PFS (Visits 12 to
18/EOS).
A 12-lead ECG will be performed in both study arms at screening (Visit B) and
Visit 18/EOS.
Pregnancy testing will be performed according to applicable legislation. At the
very least, women of child bearing potential must undergo a pregnancy test
during screening, after the vaccination period (Visit 11) and at Visit 18/EOS.
The Karnofsky performance status will be documented in both study arms at
screening (Visit B) and then at Visits D, 7 and 11 to 18/EOS.
Concomitant medication (documentation starting with Visit B) and details of
sunitinib therapy will be documented in both study arms at all study visits.

Biomarker analysis:
Serum biomarkers will be analyzed in all patients in both study arms. Blood
samples for biomarker assessment will be collected at screening (Visit B) and
during the study (Visits D as well as 7, 9, 11 and 18/EOS).
In addition, tumor biomarkers will be analyzed in a purely exploratory fashion
in both study arms, where paraffin sections or blocks from tumor tissue are
available. For the collection of paraffin sections or blocks separate informed
consents will be requested as this analysis is optional.

Immunomonitoring (subset of patients only):
In a subset of patients recruited at pre-selected centers specialized cellular
immunomonitoring will be performed (T-cell responses to peptides contained in
IMA901 and analysis of other immune cell populations that may influence T-cell
responses such as Tregs, myeloid-derived suppressor cells etc.). Pre-sunitinib
baseline blood samples to analyze cellular biomarkers, the potential influence
of sunitinib on immune parameters and to allow immunological baseline
comparison between the study arms will be taken at Visit B from patients in
both study arms. Further blood samples for immunogenicity analysis will be
taken only from patients in the vaccination arm (Arm 1) at Visits D, 5, 6, 7
and 9 (3 ± 1 days before and 2, 3, 6 and 12 weeks after the first vaccination).
One additional blood sample for hematology analysis (needed for
immunomonitoring) will be taken from patients in the vaccination arm (Arm 1) at
Visit 5 at preselected sites where immunomonitoring is performed. The goal is
to have evaluable immune data from approximately 80 patients randomized to the
vaccination arm (Arm 1).

Follow-up for overall survival
After the interventional study period (including e.g. blood drawings, study
medication, tumor assessments) all patients (including pre-maturely withdrawn
patients unless they have withdrawn consent for overall survival follow-up)
will be followed for survival (primary endpoint), subsequent anti-tumor therapy
(or continued sunitinib therapy if applicable) and signs of autoimmunity every
3 months for a maximum of 8 years.

Risks in connection with this study are possible side effects of IMA901, GM-CSF
or Cyclophosphamide, those of taking blood and radiation exposure due to CT
imaging