A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL)

Advances in the treatment of mCRC have led to an improvement in survival from
12 months with fluorouracil monotherapy to approximately 2.5 years with current
combination regimens. However, there are significant molecular differences
between tumours and between tumour microenvironments that can affect both
prognosis and response to treatment. Many new cancer drugs target specific
molecular aberrations or cell-signalling pathways, but these drugs are only
active in a subset of patients due to molecular differences between tumours.
Personalized medicine has made some major advances in CRC, with RAS testing to
guide treatment with the anti-EGFR monoclonal antibodies cetuximab and
panitumumab now being part of routine clinical practice. However, not all
patients who are RASwt respond to anti-EGFR therapy and, despite extensive
research into other biomarkers for anti-angiogenic drugs, chemotherapy and
other targeted agents, these are not yet established in clinical practice, and
a validated biomarker for anti-angiogenic therapy is still lacking. Therefore,
there is a clear need for both molecular screening approaches to understand the
disease better and to fully characterize tumours and identify patients who are
most likely to benefit from targeted treatments, as well as for new biomarkers
to assist with predicting response to both existing drugs as well as to drugs
currently under investigation.

On June 3rd 2016 Roche submitted a temporary halt to recruitment notification.
The study was a year ahead of its planned enrolment schedule. The aim of our
halt was to amend the design of the trial to allow future enrolment of screened
`no-biomarker patients* into new treatment arms. Cohort 2 (no *biomarker
cohort) is fully recruited. The planned protocol amendment (version 6) to add a
new `no-biomarker* cohort is being submitted and Roche would like to re-start
recruitment into the trial as soon as this protocol amendment is approved.
The following substantial changes are introduced with this amendment; two new
treatment cohorts have been added including three new IMPs: trastuzumab,
pertuzumab and cobimetinib . Patients in the experimental treatment arm of
Cohort 3 will receive capecitabine, trastuzumab and pertuzumab, and those in
Cohort 4 will receive cobimetinib and atezolizumab. For a full rational for the
addition of the new IMPs please refer to the protocol version 6, section 1.3.

EFFICACY OBJECTIVES
Within each cohort, the study has the following co-primary efficacy objectives:
· Assessing early efficacy during the Maintenance Treatment Phase based on a 20%
reduction in tumour size after 2 months of treatment
· Evaluating PFS
The secondary efficacy objectives include the evaluation of efficacy through
other endpoints:
· OS
· ORR
· Disease control rate (DCR)
· Time to treatment response (TTR)
· Duration of response (DoR)
· ECOG performance status

SAFETY OBJECTIVES
The safety of this study are to assess the safety of each treatment including:
· Incidence, nature and severity of adverse events (AEs)
· Incidence and reasons for any dose reductions, interruptions or premature
discontinuation of any component of study treatment
· Clinically significant laboratory values
AEs refer to all treatment-emergent adverse events occurring after the
initiation of study
medication (i.e. on or after Day 1, Cycle 1 of the Induction Treatment Phase).
AEs will
continue to be collected during the Maintenance Treatment Phase and
Post-Treatment
Follow-up Phase as applicable.

EXPLORATORY OBJECTIVES
The exploratory efficacy objective of this study is:
· To evaluate PFS measured according to mRECIST in patients treated with
MPDL3280A
(anti-PD-L1 antibody)
The exploratory biomarker objectives of this study are as follows:
· To explore whether there is differential benefit from treatment in patient
subgroups
defined by different biomarkers, e.g. but not limited to biomarker panels
(mutation and
expression profiles), immune panels etc.
· If applicable, to assess correlations between biomarkers/marker panels and
safety
· Where possible, to investigate if changes in expression/mutation panels of
biomarkers
during treatment correlate with treatment efficacy or failure i.e. to explore
potential
resistance/escape mechanisms to (targeted) treatment
· Explore prognostic and potentially predictive effects of markers/marker
profiles
· Explore prevalence of specific markers at Baseline and/or salvage/resistance
markers to
guide targeted therapy approaches beyond MODUL, e.g. but not limited to
programmed
cell death-1 (PD-L1)

This is a randomised, multi-centre, active-controlled, open-label,
parallel-group clinical trial of biomarker-driven maintenance treatment for
first-line metastatic colorectal cancer (mCRC). Patients with mCRC are eligible
for entry, and cannot have received any prior chemotherapy
in the metastatic setting.

Potential patients will undergo screening assessments to determine study
eligibility within 28 days prior to starting study induction treatment. The
primary tumour tissue block prepared at the time of the initial diagnosis will
be used for biomarker assessment for maintenance treatment cohort assignment.
An optional core biopsy of metastatic tumour will also be collected from all
patients during Screening. Biopsies already done as part of routine practice
within two months of the 28-day. Screening Phase are also acceptable.
Eligible patients will enter a 4-month Induction Treatment Phase. Treatment
during this phase, based on Investigator*s choice, will be either:
· Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin
(FOLFOX) in combination with bevacizumab
or
· Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two
2-week cycles of 5-FU/LV with bevacizumab
Patients will be assessed for AEs at every cycle, and remaining safety
parameters (such as concomitant medications, physical examination and clinical
laboratory assessments) will be assessed every 4 weeks (two treatment cycles)
during the Induction Treatment Phase.
Tumour assessments will be evaluated according to the Response Evaluation
Criteria in Solid Tumors version 1.1 (RECIST 1.1) during the Induction
Treatment Phase. Tumour assessments during treatment will be based on local
standard of care, but are required at the
end of the Induction Treatment Phase (see Appendix 1).
Patients who do not have progressive disease and who have completed the
Induction Treatment Phase can then proceed to the Maintenance Treatment Phase.
Each cohort will consist of a cohort-specific experimental treatment arm and a
standard control arm of fluoropyrimidine (5-FU or capecitabine) and
bevacizumab.
For details of the experimental treatment arms, refer tot protocol section
3.1.2. The study will follow an adaptive design, where additional cohorts can
be added or existing cohorts may be modified over the course of the study via
protocol amendment.

Efficacy, safety and tolerability will be assessed during the entire
Maintenance Treatment Phase.
All patients will undergo a Study Treatment Discontinuation visit within 30
days following their last study treatment and will enter the Post-Treatment
Follow-up Phase of the study. During the Post-Treatment Follow-up Phase,
patients will be followed every 3 months for subsequent
anti-cancer therapies, survival, and AEs including therapy-specific safety
assessments. Patients who discontinue study treatment in either the Induction
or Maintenance Treatment Phases prior to disease progression will also enter
the Post-Treatment Follow-up Phase but will also continue to be followed for
progression, with disease status followed according to local practice until
progression or the end of the study, whichever
comes first. All patients will remain in the Post-Treatment Follow-up Phase
until death or the end of the study, whichever comes first.

Patients eligible for participation in this study are treated in the induction
treatment pahse with a standard treatment of:
5-fluorouracil (5-FU), leucovorine (LV), oxaliplatine and bevacizumab during 16
weeks or
5-FU, LV, oxaliplatine en bevacizumab during 12 weeks, followed by 5-FU, LV
eand bevacizumab during 4 weeks.

Each cohort exists of a cohort-specific experimental arm and a standard control
arm of fluoropyrimidine (5-FU of capecitabine) en bevacizumab. For details of
the experimental treatment arms, see protocol section 3.1.2. (figure 2 page 69
protocol).The allocation will be done according to the study specific schedule
as described in figure 2.

The test procedures and treatments may entail risks and cause discomfort. There
is a slight chance of pain or a bruise when blood is collected. Some people may
faint when blood is collected. During this study, with patient approval,
biopsies may be performed. The following risks are associated with a biopsy:
bruising, bleeding, infection and side-effects of the numbing medication
(anaesthetic) that may be given for the procedure. In rare cases, these risks
may be life-threatening and make hospitalization necessary. In order to reduce
the risks, the site of the biopsy will be numbed and sterile techniques will be
used. Undergoing an MRI or PET / CT scan may entail additional discomfort,
specifically, a sense of claustrophobia (being *locked in*) or suffering from
the noise during the scan. The disadvantages of participating in this study
are: time investment to undergo various procedures for this study, additional
or prolonged hospitalization(s), additional blood collection, additional
examinations, biopsies and any side effects of the study medications.

An allergic reaction to one of the study medications may be mild (skin rash,
fever, chills, headache, nausea or vomiting) or severe (low blood pressure,
elevated heart rate, anxiety and / or difficulty swallowing or breathing).
These side-effects are most common during the first few doses, but may occur
during any administration. The research physician may prescribe medication and
other supportive care in order to reduce or prevent the severity of these
side-effects. In rare cases, these symptoms can be so severe that they possibly
require the administration of the study medications to be stopped permanently.
Sometimes, side-effects develop and get worse over time due to the development
of antibodies against the study medication. Usually these side-effects involve
skin rashes, joint and muscle pain, fever and fatigue. Medication may be
prescribed to reduce the effect of these symptoms. If these side-effects are
serious or persist for a very long time, it may be necessary to permanently
stop administration of the study medications.

Risk of drug interactions:
It is possible that treatment with the study medications may affect the
activity of other medication.
Patient may experience one or more of these side-effects, or currently unknown
side effects, and they may be mild, moderate, severe, or (in very rare cases)
life-threatening or even fatal. If side-effects do occur, the study physician
must be notified immediately. He / she may prescribe medication to combat any
discomfort. Furthermore, in the event of a serious reaction, the study
physician may decide to suspend or permanently terminate treatment with the
study medications.