A Phase 2 study of SAR245409 in patients with relapsed or refractory mantle cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia/small lymphocytic lymphoma

The treatment of relapsed and refractory (R/R) MCL, FL, and CLL/SLL remains an
important unmet medical need. Despite advances in treatment options, prognosis
remains poor. There is good clinical evidence the inhibition of the
PI3K/mTor/Akt pathway is an effective approach in R/R MCL, FL, and CLL/SLL as
described in Section 4.1.3. SAR245409 is a novel dual PI3 kinase/mTor inhibitor
which has been well tolerated in at least 10 patients with NHL.

This study uses the single-agent maximum tolerated dose of 50 mg bid. This is
the maximum tolerated dose determined in the solid tumor cohort of the Phase 1
single-agent study, XL765-001. A cohort of patients with lymphoma is currently
enrolling at 50 mg bid in the ongoing Phase 1 study. Ten patients with lymphoma
have enrolled to date with none experiencing dose-limiting toxicities.

Primary
* To evaluate the efficacy of SAR245409 as determined by the objective response
rate (ORR) in patients with 1 of the following relapsed or refractory lymphoma
or leukemia subtypes: mantle cell lymphoma (MCL), follicular lymphoma (FL), or
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
Secondary
* To assess duration of response, progression free survival (PFS), and
proportion of patients with PFS at 6 months (24 weeks) in patients with either
MCL, FL, or CLL/SLL treated with SAR245409
* To evaluate the safety and tolerability of SAR245409 in patients with MCL,
FL, or CLL/SLL
* To further characterize the plasma pharmacokinetics (PK) of SAR245409 in
patients with MCL, FL, or CLL/SLL
Exploratory
* To assess the pharmacodynamic effects of SAR245409 in patients with MCL, FL,
or CLL/SLL
* To define predictive markers of response and/or resistance to SAR245409 based
on molecular profiling of cancer tissue

This is a multicenter, multinational, nonrandomized, open-label, 2-stage, Phase
2 clinical trial of SAR245409 at 50 mg orally twice daily (bid) for a 28-day
cycle in patients with relapsed or refractory (R/R) MCL, FL, or CLL/SLL having
failed at least 2 standard treatment regimens. Patients will enroll into 1 of 3
groups based on disease:
Group 1: R/R MCL
Group 2: R/R Grade 1, 2, or 3a FL
Group 3: R/R CLL or SLL
Simon*s minimax 2-stage design will be used to determine whether the drug is
potentially efficacious to warrant further study in 1 or more of the disease
groups studied. Objective responses will be assessed by the Investigator
according to the International Working Group for Lymphoma (IWL) and
International Working Group on Chronic Lymphocytic Leukemia (IWCLL) criteria.

A cycle is defined as 28 days of dosing with SAR245409.
Telephone safety assessments will be performed at specified intervals in
between site visits. Safety assessments (AEs, vital signs, electrocardiogram
[ECG], ophthalmologic examinations, laboratory tests, and concomitant
medications) will be performed prior to the start of the investigational
medicinal product (IMP) on Cycle1, Day1 and according to the study flowchart.
Tumor assessments will be performed at the end of Cycle 2 and then every 3
cycles for a period of 2 years or until disease progression or withdrawal from
study. Patients who continue on study beyond 2 years will have tumor
assessments at a minimum of every 6 cycles.
SAR245409 plasma concentration analysis will be performed separately for
patients with MCL, FL and CLL/SLL. Blood samples will be obtained at scheduled
time points and if possible, whenever there is an IMP-related SAE.
Blood or processed blood, hair and tumor tissue samples will be obtained for
analyses of a variety of established and exploratory pharmacodynamic biomarkers
on a defined schedule (see Section 1.2 and Section 9.4). When possible, PD
sample collection will coincide with scheduled PK time points.
Optional on study tumor biopsies maybe collected from consented patients at the
time points specified in Section 1.2 of the study protocol. The maximum
sampling is 3 biopsy time points, including baseline. The tumor tissues will
be analyzed for biomarkers related to SAR245409 mechanism of action. Matched
blood and hair sampling are required when optional biopsies are collected.
A blood sample will be obtained prior to the first dose of SAR245409 from
patients who signed the optional pharmacogenetic (PGx) informed consent form.
The PGx blood sample will be collected to investigate allelic variants of drug
metabolizing enzyme (DME) and/or drug transporters as intrinsic factors
associated with pharmacokinetic or pharmacodynamic variability of SAR245409.
For CLL patients, additional buccal swabs will be obtained from consented
patients for genotyping analyses. PGx blood and buccal swap may also be used
for genotyping and/or tumor genome sequencing analyses.

See paragraph "Intervention" for extent of the burden.
The average expected participation period per patient is 4-12 months.

The patient may experience (any) discomfort undergoing the required procedures.
The risks of taking blood may include fainting, pain, and/or bruising.
There might only be a little discomfort, but not risk when the
electrocardiogram electrodes are applied to the skin.
Having a biopsy taken may cause some pain, inflammation, bleeding, swelling, or
infection at the site of the biopsy.
When having a CT scan, the patient will receive small doses of radiation. All
radiation adds up over a lifetime. Some people may feel a closed-in feeling
while lying in the scanner. The patient may receive intravenous contrast
material to better visualize the sites of tumor. If the patient is having a CT
scan of the abdomen, he/she may be asked to drink a contrast fluid that may
cause nausea.

The disease of patients participating in this study is resistent or refractory.
It is possible that SAR245409 may be effective in this disease; It is hoped
that the information obtained in this study may provide valuable information to
assist future patients.