TIGER-2: A Phase 2, Open-Label, Multicenter, Safety and Efficacy Study of Oral CO 1686 as 2nd Line EGFR-Directed TKI in Patients with Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)

In mid-2015, Clovis submitted a New Drug Application for the use of rociletinib
in patients with T790M-positive NSCLC. In June 2016, the FDA issued a Complete
Response Letter to Clovis stating that more data is required to approve
rociletinib for use outside of a clinical trial. Based on this outcome, Clovis
decided to discontinue development of CO 1686 for NSCLC. Patients will be
informed of this change in the development plans in an update to the informed
consent form for this study. Those patients who continue to derive clinical
benefit from study treatment, will be allowed to continue on study at the
discretion of the Principal Investigator in an extension phase.
The purpose of this protocol amendment (Amendment 5) is to add a new Extension
Phase to allow patients to continue on study but to avoid unnecessary
collection of data that will no longer be analyzed or required for regulatory
purposes, whilst maintaining an appropriate level of safety monitoring. A new
schedule of assessments for the Extension Phase as well as a complete
description of procedures is provided in Appendix C. This schedule replaces
all schedules of assessments in Section 9 and should be followed for all
patients.

In addition, Amendment 5 (Appendix C) also introduces the availability of NAT2
testing for patients , an indirect indicator of the likelihood of developing
hyperglycemia or QTc prolongation. The availability and disclosure of this
information to the patients*s treating physician will not affect the monitoring
and associated treatment guidelines for these adverse events.

For patients who wish to continue rociletinib treatment post progression, it is
important that a full exploration of alternative treatment options between
patients and their treating physicians takes place.
Investigators and their staff are directed to the current Investigator*s
Brochure for the most current efficacy and safety data, in which integrated
summaries of the latest available data can be found and supersedes all safety
and efficacy data in this protocol.

CO-1686 is a novel, potent, small molecule irreversible tyrosine kinase
inhibitor (TKI) that selectively targets mutant forms of the epidermal growth
factor receptor (EGFR) while sparing wild-type (WT) EGFR.
Activating EGFR mutations are key drivers of NSCLC malignancy in 10% to 15% of
patients of European descent and approximately 30% of patients of East Asian
descent. Patients with the most common EGFR activating mutations, exon 21 L858R
and deletions in exon 19, typically have good responses to therapy with first
generation EGFR inhibitors such as erlotinib or gefitinib and also with the
second generation inhibitor afatinib. Toxicity associated with erlotinib,
gefitinib, and afatinib includes skin rash and diarrhea related to inhibition
of the WT EGFR in skin and intestine, respectively.

Despite an impressive initial response to treatment, progression generally
occurs after 9-14 months of erlotinib, gefitinib, or afatinib therapy, driven
in approximately 60% of cases by a second-site EGFR mutation in exon 20 called
T790M (the *gatekeeper* mutation) which mediates resistance to first- and
second-generation EGFR inhibitors. There are no approved therapies that target
T790M specifically, and standard of care remains cytotoxic chemotherapy. Yu et
al reported that T790M positive disease is fatal, with a median overall
survival (OS) of less than 2 years.10

Nonclinical data demonstrate that CO-1686 inhibits T790M as well as the common
activating mutations (L858R, del19) and has minimal inhibitory activity towards
WT EGFR at therapeutic doses. It is anticipated that CO-1686 will promote cell
death in tumor cells with the T790M mutation, thus driving objective tumor
responses and providing therapeutic benefit in patients who have acquired T790M
mediated resistance to first generation EGFR inhibitors. In the first in human
study, CO-1686-008, in patients with advanced EGFR mutation positive NSCLC and
previous treatment with an EGFR inhibitor, no maximum tolerated dose (MTD) was
observed and 3 doses levels, 500 mg twice daily (BID), 625 mg BID, and 750 mg
BID, were selected for further clinical evaluation of safety, tolerability and
efficacy in the expansion cohorts. Maturing data from this study suggest that
patients treated with rociletinib at 500 mg BID and 625 mg BID experience
responses that are comparable in frequency, depth and duration, with an overall
acceptable safety profile for this advanced cancer patient population. To
further describe the risk/benefit profile of the CO 1686 500 mg BID dose,
additional patients will be enrolled at a starting dose of 500 mg BID in this
study (Cohort B). Response Evaluation Criteria In Solid Tumors (RECIST)
responses have been observed across the range of doses studied in Phase 1 with
CO-1686, and the current objective response rate (ORR) in patients with T790M
positive NSCLC is > 60%. The most common toxicity observed is hyperglycemia,
occurring in approximately 30% of patients, which can usually be readily
managed with PO anti hyperglycemic therapy. Adverse events (AEs) typical of WT
EGFR inhibition (the combination of rash and chronic diarrhea) have not been
observed with CO-1686.

The goals of protocol CO-1686-019 are to evaluate the antitumor efficacy,
safety and population pharmacokinetic (POPPK)/pharmacodynamic relationships of
PO single agent CO-1686, when administered at the therapeutically active doses
of 625 mg BID and 500 mg BID to patients with EGFR mutated, advanced/metastatic
NSCLC after failure of 1 previous EGFR directed TKI.
CO-1686 was being developed with a companion diagnostic (Qiagen, United
Kingdom) to identify patients whose tumors express activating EGFR mutations as
well as the T790M resistance mutation.

Primary Objective
* To evaluate the antitumor efficacy of PO single agent CO-1686, as measured by
ORR, when administered to patients with EGFR mutated, centrally confirmed T790M
positive and T790M negative advanced NSCLC after tumor progression on 1
previous EGFR directed TKI

Secondary Objectives
* To assess clinical efficacy in patients with centrally confirmed T790M
positive NSCLC: disease control rate (DCR), duration of response (DR), PFS, and
OS following CO-1686 treatment
* To assess quality of life (QoL) by patient reported outcomes (PRO) following
CO-1686 treatment
* To evaluate the safety and tolerability of CO-1686
* To determine the pharmacokinetics (PK) of CO 1686 using POPPK methods and
explore correlations between PK, exposure, response, and/or safety findings

Exploratory Objectives
* To evaluate clinical benefit of continued CO-1686 treatment following disease
progression
* To evaluate concordance of mutant EGFR detection between tissue and plasma
and assess CO-1686 mediated alterations in mutant EGFR levels over time using
circulating tumor deoxyribonucleic acid (ctDNA) obtained from plasma
* To explore tissue and blood based biomarkers that may be predictive of
response or primary resistance to CO-1686 and investigate mechanisms of
acquired resistance in the tissue and blood of patients who experience clinical
progression during treatment with CO-1686

This is a Phase 2, single arm, open label, dual cohort, multicenter study
evaluating the safety and efficacy of CO 1686 administered PO BID to patients
with previously treated mutant EGFR NSCLC.
Patients will be enrolled into 2 cohorts. Cohort A will enroll approximately
125 eligible patients who are centrally confirmed T790M positive and will be
treated at 625 mg BID. Cohort B will be a continuation of the study and will
enroll up to approximately 100 eligible patients who will be either centrally
confirmed T790M positive or T790M negative. All patients in Cohort B will be
treated at a starting dose of 500 mg BID. The priority for study enrollment
will be for all T790M positive patients to be enrolled into Cohort A first.
Once Cohort A is complete, eligible T790M positive patients will then be
enrolled into Cohort B. All eligible T790M negative patients will be enrolled
into Cohort B.

The study (Cohorts A and B) will consist of a Screening Phase to establish
study eligibility and document baseline measurements; an open label Treatment
Phase, in which the patient will receive CO- 686 to ascertain efficacy and
safety until disease progression as defined by RECIST Version 1.1, clinical
tumor progression, or unacceptable toxicity as assessed by the investigator.
For patients with clinical progression, radiographic assessment should be
performed to document evidence of radiographic progression.

Patients may opt to continue to receive treatment with CO-1686 following
radiographic progression, as outlined in the National Comprehensive Cancer
Network (NCCN) guidelines for treatment of NSCLC with EGFR TKIs, if the
patient provides additional consent, the investigator believes it is in the
best interest of the patient, and the sponsor approves. In general, eligible
patients may include those with asymptomatic systemic progression or locally
symptomatic progression, such as brain metastases amenable to local treatment,
with concomitant asymptomatic systemic progression or continued systemic
disease control.

Each 28 day period of treatment will represent 1 cycle, with dosing initiated
on Cycle 1 Day 1 (C1D1).
Dosing will be delayed or reduced according to protocol specified toxicity
criteria. As mentioned above, patients who provide additional consent may
continue to receive treatment with CO 1686 post progression if, in the opinion
of the investigator and approved by the sponsor, the patient is still
benefitting.

Sparse blood sampling for population PK analyses will be conducted in all
patients treated with CO-1686. Serial blood sampling for longitudinal
quantitative assessment of ctDNA will be conducted. A central laboratory will
confirm presence or absence of the T790M mutation in formalin fixed paraffin
embedded (FFPE) tumor tissue prior to study enrollment. Following disease
progression on CO-1686, patients who provide additional consent will undergo
tumor biopsy before subsequent line therapy is initiated.

AEs will be collected from the time the first dose of CO-1686 is administered
through 28 days after the last dose. Study procedure related AEs that occur
after signing of the Informed Consent Form (ICF) and before administration of
CO-1686 will also be captured. All patients will be followed at approximately 2
monthly intervals to determine disease progression (if patient discontinues
treatment before progression), survival status and subsequent NSCLC therapy
until death or sponsor decision, whichever comes first. After discontinuation
of protocol specified treatment, subsequent anticancer therapy use will be
recorded.

In mid-2015, Clovis submitted a New Drug Application for the use of rociletinib
in patients with T790M-positive NSCLC. In June 2016, the FDA issued a Complete
Response Letter to Clovis stating that more data is required to approve
rociletinib for use outside of a clinical trial. Based on this outcome, Clovis
decided to discontinue development of CO 1686 for NSCLC. Patients will be
informed of this change in the development plans in an update to the informed
consent form for this study. Those patients who continue to derive clinical
benefit from study treatment, will be allowed to continue on study at the
discretion of the Principal Investigator in an extension phase.
The purpose of this protocol amendment (Amendment 5) is to add a new Extension
Phase to allow patients to continue on study but to avoid unnecessary
collection of data that will no longer be analyzed or required for regulatory
purposes, whilst maintaining an appropriate level of safety monitoring. A new
schedule of assessments for the Extension Phase as well as a complete
description of procedures is provided in Appendix C. This schedule replaces
all schedules of assessments in Section 9 and should be followed for all
patients.

In addition, Amendment 5 (Appendix C) also introduces the availability of NAT2
testing for patients, an indirect indicator of the likelihood of developing
hyperglycemia or QTc prolongation. The availability and disclosure of this
information to the patients*s treating physician will not affect the monitoring
and associated treatment guidelines for these adverse events.

For patients who wish to continue rociletinib treatment post progression, it is
important that a full exploration of alternative treatment options between
patients and their treating physicians takes place.
Investigators and their staff are directed to the current Investigator*s
Brochure for the most current efficacy and safety data, in which integrated
summaries of the latest available data can be found and supersedes all safety
and efficacy data in this protocol.

To date, over 500 patients with NSCLC have received at least one dose of
CO-1686. Commonly reported side effects in these patients, which may have been
due to taking the study drug are listed below. However, as CO-1686 is an
investigational product, not all side effects are known, and there is a risk
that rare or previously unknown side effects may occur.

Common (>20% of patients)
* Nausea
* Hyperglycemia (high blood glucose wich is the same as high levels of sugar in
the blood): High blood glucose can cause symptoms such as nausea, vomiting and
feeling tired. The patient must tell the doctor if he/she notices any of these
symptoms as it could be a sign the blood glucose is increasing. The patient
may be asked to take another medicine to control high blood glucose levels.
* Feeling tired
* Loose stools (diarrhea)
* Abnormal heart rhythms, visible on ECG (tracing of the heart rythm), called
increase in QT. In severe cases, this can cause changes to the rhythm of the
heart; and in rare instances, could result in death. The patient will be
carefully monitored in the study for any changes to his/her ECG.

Less Common (5-19% of patients)
* Decrease in appetite
* Muscle spasms
* Vomiting
* Weight loss
* Joint or muscle pain
* Dizziness
* Changes in blood tests that measure how well your kidney and liver are
functioning.
* Low blood counts (red blood cells, white blood cells, and platelets).
o A low red blood cell count may make you feel tired or dizzy
o A low white blood cell count puts you at higher risk for infection.
o A low platelet count affects the ability of your blood to clot and could lead
to bleeding events

Rare (<5% of patients)
* Constipation
* Headache
* Rash
* Change in sense of taste
* Insomnia (difficulty sleeping)
* Lung inflammation (pneumonitis). Patients taking CO-1686 who developed
pneumonitis have recovered, but this event could be very serious and could
result in death
* Pancreatitis (inflammation of your pancreas, which in one patient resulted in
death)

Some patients who have been taking CO-1686 for an extended period of time have
experienced decreased vision due to clouding of the lens of the eye (cataracts).

In addition to physical examinations including, checking vital signs and the
rhythm and rate of the heart, other possible side effects will be regularly
monitored for by the study staff when they check the results of the blood tests.

CO-1686 is an experimental drug that may have other side effects that are not
known and cannot be predicted at this time. These side effects may be serious.
It is important that the patient tells the study staff about any side effects
he/she is experiencing, even if he/she does not think they are due to taking
the study drug.

Allergic Reactions
Rare or unknown side effects could possibly occur, including life-threatening
reactions. As with any drug, it is possible that could have an allergic
reaction to CO-1686, such as itching, skin rash, facial swelling, and a severe
or sudden drop in blood pressure. The sudden drop in blood pressure may lead
to shock with loss of consciousness and/or possible seizures, including the
possibility of death.

Blood Sampling
Having blood drawn from a vein in your body may cause some pain, redness, or
bruising where the needle is inserted. An infection is also possible, but
rare. If the patient feel faint while having your blood drawn, he should sit
or lie down to avoid falling.

Procedure(s) to Remove Tumor Tissue
Each type of procedure has some risks and may cause discomfort.

Electrocardiogram (ECG)
The skin may react to the sticky patches that attach the detectors (electrodes)
to the chest, wrist and ankles for the ECG. This skin irritation usually
disappears when the patches are removed.

CT and MRI Scans
Computed tomography (CT) scans use x-ray radiation. The amount of radiation
the patient will receive during a CT scan is small, but the more radiation he
receives over the course of his life, the more likely it is that the cells in
your body may change or that he develops a new cancer. Some CT scans require
the patient to drink a *contrast solution*. It is possible that the contrast
solution may cause him to have nausea, vomiting, itching, or skin rash. In
rare cases, it may cause the throat to swell and make it hard to breathe.
These may be signs of an allergic reaction so tell the study doctor right away
if you have any of these side effects. You may have some discomfort from lying
still in an enclosed space for a prolonged period of time.
Sometimes a magnetic resonance imaging (MRI) scan is done in patients with
allergies to the contrast solution used in a CT scan. An MRI does not use
x-ray radiation, but it takes a little longer and patients sometimes have to
lie in a more enclosed space. A contrast agent may be injected into your vein
before the scan is done to help the doctor see the tumor more clearly.
X-ray
There is a small possibility that you may require an X- ray during the course
of the study.

Pregnancy
Treatment with CO-1686 may involve risks to a fetus, embryo, or unborn child
that are currently unknown. The patient cannot participate in this study if
she is pregnant or thinking about becoming pregnant. The patient should not
nurse (breast feed) a baby while in this study because the study drug may enter
breast milk and may possibly harm your child.