A Randomized, Open-Label, Multinational Phase 3 Trial Comparing Amrubicin Versus Topotecan in Patients With Extensive or Limited and Sensitive or Refractory Small Cell Lung Cancer After Failure of First-Line Chemotherapy

Japanese clinical trials in relapsed SCLC patients have demonstrated
encouraging response and survival data for this population. It appears that
treatment with amrubicin leads to a survival advantage when compared with
historical data on treatment with standard topotecan therapy in relapsed SCLC
patients. The current trial is designed to test the hypothesis that in a
Western population, treatment with amrubicin leads to a survival benefit when
compared with treatment with topotecan in patients with SCLC after failure of
first-line chemotherapy.

The primary objective is to demonstrate superiority in overall survival of
amrubicin (40 mg/m2 administered as a 5-minute infusion once daily for 3
consecutive days starting on Day 1 of a 21-day course) compared with topotecan
hydrochloride (topotecan) (1.5 mg/m2 administered as a 30 minute infusion once
daily for 5 consecutive days starting on Day 1 of a 21-day course) in patients
with extensive or limited and sensitive or refractory small cell lung cancer
(SCLC) after failure of first-line chemotherapy.
The important secondary objectives are to further characterize the clinical
benefit of amrubicin compared with topotecan in terms of the following:
• Objective response rate (ORR) using Response Evaluation Criteria in Solid
Tumors (RECIST); and
• Progression-free survival (PFS).
Additional secondary objectives are to assess or compare the effect of
amrubicin relative to topotecan in terms of the following:
• Duration of response;
• Time to tumor progression (TTP);
• Quality of life (assessed using EuroQol [EQ-5D] and the Lung Cancer Symptom
Scale [LCSS]);
• Safety; and
• Pharmacokinetics (plasma and whole blood concentrations) in amrubicin-treated
patients only.

This is a Phase 3, randomized, open-label, multinational study to determine the
superiority in overall survival of amrubicin compared with topotecan when
administered to patients with extensive or limited and sensitive or refractory
SCLC after failure of first-line chemotherapy. Sensitive will be defined as a
best response to first-line platinum-based chemotherapy of complete response,
partial response, or stable disease, with subsequent progression * 90 days
after completing first-line chemotherapy; refractory will be defined as
progressive disease as best response to first-line platinum-based chemotherapy
or progression < 90 days after completing first-line chemotherapy.
Patients randomized prior to the effective date of Amendment 5 (03October2008)
were stratified by type of response to first-line therapy (sensitive versus
refractory), Eastern Cooperative Oncology Group (ECOG) score, and disease
stage. Effective with the implementation of Amendment 5, randomized patients
are stratified by type of response to first-line therapy (sensitive versus
refractory), and the disease stage (limited versus extensive). Patients
randomized to the amrubicin study arm (Arm A) will receive 40 mg/m2 amrubicin
as a 5-minute intravenous infusion once daily for 3 consecutive days starting
on Day 1 of a 21-day course. Patients randomized to the topotecan study arm
(Arm B) will receive 1.5 mg/m2 topotecan as a 30-minute intravenous infusion
once daily for 5 consecutive days starting on Day 1 of a 21-day course.
Patients in both treatment arms will be treated for up to 6 cycles, unless
there is disease progression, unacceptable toxicity, the patient withdraws
consent for further treatment, or the physician decides to discontinue
treatment. Patients who continue to experience stable disease or better at
Cycle 6 may receive 6 additional cycles, for a total of 12 cycles over a
duration of approximately 8 months, using the same study events schedule (see
Table 1), after discussion with the sponsor. Once a patient completes
treatment, the patient will enter the follow-up period. Follow-up will continue
until the patient dies, withdraws consent for further follow-up or is lost to
follow-up.
A data monitoring committee (DMC) will assess the ongoing conduct of the study
with a frequency sufficient to monitor patient safety as described in the DMC
charter. CT scans or MRI will be collected and archived by the sponsor or their
representative in the event that an independent review is needed to verify
response to treatment. All 12 lead electrocardiograms (ECGs) will be collected
and archived by the sponsor or their representative and centrally reviewed.
ECHO/MUGA scans for patients showing confirmed significant LVEF reductions will
be collected for later central independent review. Details will be provided in
the Statistical Analysis Plan (SAP).
In addition to efficacy and safety assessments, quality-of-life (all patients)
and medical resource-use (subset of patients) data will be gathered prior to
dosing at Cycle 1, during treatment (even cycles), and at follow-up for both
treatment arms. Sparse blood sampling will be performed on amrubicin patients
for whole blood and plasma pharmacokinetic analyses. One blood sample will be
collected from each patient for pharmacogenomic research to evaluate variants
in genes involved in metabolism and transport of amrubicin. Blood samples for
pharmacogenomic research are optional and are collected from both amrubicin and
topotecan patients to help distinguish between the predictive and prognostic
value of any genetic variants.
One interim analysis of the efficacy variables is planned during the study. The
DMC will review data as part of the interim analysis. The interim analysis is
to occur when the total number of patient deaths reaches 294. The final
analysis is planned after 490 deaths have occurred.

This is an open-label study. Patients will be randomized to receive one of 2
treatments, amrubicin or topotecan, at a ratio of 2:1 (amrubicin to topotecan).
Treatment should be started within 7 days of randomization; each cycle is 21
days. Patients in both treatment arms will be treated for up to 6 cycles,
unless there is disease progression, unacceptable toxicity, the patient
withdraws consent for further treatment, or the physician decides to
discontinue treatment. Patients who continue to experience stable disease or
better at Cycle 6 may receive 6 additional cycles, using the same study events
schedule (see Table 1), after discussion with the sponsor. Two dose reductions
are permitted for each patient.
Amrubicin for injection is supplied as 50-mg vials. Patients will receive 40
mg/m2 amrubicin as a 5-minute infusion once daily for 3 consecutive days
starting on Day 1 of a 21-day course.
Topotecan for injection is supplied as 4-mg vials. Patients will receive 1.5
mg/m2 as a 30-minute infusion once daily for 5 consecutive days starting on Day
1 of a 21-day course.

Side Effects of Amrubicin
We have learned from the use of Amrubicin in Japan that there are anticipated
side effects. These effects include:
• decrease in white blood cells which can lead to increased chance of
infection, and in rare cases can be serious and could result in death,
• decrease in platelets (blood clotting cells) that could result in a risk of
bleeding, decrease in red blood cells (anemia - which may cause tiredness and
lack of energy)
• Nausea and/or vomiting
• Loss of appetite
• Loss of hair
• Sores on the inside of the mouth
• Diarrhea
• Fever
• vein inflammation
• Changes to the electrical activity of the heart (shown on ECG)
• Red-colored urine
• Elevations in some liver function tests, which may indicate damage to the
liver
• Elevations in kidney function tests, which may indicate damage to the kidneys
• aggravation of a kind of pneumonia has occurred in patients with lung cancer
and lymphoma.
• There have also been rare occurrences of gastrointestinal ulcer or
irritation, which can lead to serious bleeding.

A decrease in the heart*s ability to pump blood to all parts of the body, of
uncertain significance has occurred in some Japanese patients. Therefore, your
heart function status will be monitored closely during your participation in
the study.

When a person receives chemotherapy after having had radiation therapy, skin or
tissue damage from the prior radiation therapy can become damaged again (may
involve redness, peeling, pain, and swelling). This is referred to as radiation
recall. Skin changes have been noted to range from mild redness to tissue
death. Radiation recall may also occur in the lungs and other internal organs.
A variety of chemotherapeutic agents, including anthracyclines, such as
doxorubicin, can cause radiation recall reaction Radiation recall has not been
reported with Amrubicin, however, it is a potential risk with Amrubicin since
other anthracyclines have caused this reaction.

Chemotherapy agents, such as Amrubicin, are often followed by treatment with a
certain type of growth factor (pegylated granulocyte-colony-stimulating factor,
pegylated G CSF, pegfilgrastim). When chemotherapy agents are followed by
treatment with this certain type of growth factor, a reaction called hand-foot
syndrome (HFS) is sometimes seen. Hand-foot syndrome is a condition that may
involve painful swelling, redness and tenderness over the palms and soles that
may result in blistering and shedding of the skin. Growth factors are sometimes
used to increase production of white blood cells. If HFS occurs, your doctor
may change your treatment to use a different type of growth factor.

In addition, when receiving amrubicin, it is very important to let your study
nurse know if
the
medication is causing any redness, swelling, pain or discomfort at the
injection site.

Side Effects of Topotecan
Common side effects for topotecan include:
• Neutropenia or leucopenia - decrease in white blood cells which can lead to
increased chance of infection, and in rare cases be serious and could result in
death. Possibly this may require antibiotics and/or a drug to increase your
white blood cell count
• Thrombocytopenia - decrease in platelets (blood clotting cells) that could
result in a risk of bleeding
• Anaemia - decrease in red blood cells which may cause tiredness and lack of
energy
• Nausea and/or vomiting
• Sores on the inside of the mouth
• Loss of appetite
• Loss of weight
• Feeling unwell
• Loss of hair
• Diarrhoea
• Fever
• Constipation
• abdominal pain
• difficulty breathing
• coughing
• tiredness
• weakness
• rash (allergic reaction)
• headache
• numbness/tingling.
• Yellow skin
• Itching sensation
• Muscle pain
• Rare side effects include sepsis and elevations in some liver function tests,
which may indicate damage to the liver, and elevations in kidney function
tests, which may indicate damage to the kidneys.

Other Possible Risks and side effects.
Low white blood cell counts can lead to an increased chance of infection and
may require antibiotics and/or a drug to increase your white blood cell count.
There is a risk of infection or swelling at the injection/catheter site. The
risks of having blood drawn include pain, bruising, and rarely, infection.
MRI or CT scans can be associated with extremely rare allergic reactions to
contrast agents used to see things during the procedure. When you have this
type of scan, you will be checked carefully by the radiologist for these
allergic reactions and will be treated immediately if one happens.

Duration of Side Effects:
While on study, you can experience the above described side effects. You should
discuss your concerns with your doctor. There also may be other side effects
that we cannot predict. Let your doctor know about the side effects that you
are experiencing. Your doctor may be able to give you other drugs to make side
effects less serious or uncomfortable. Many side effects go away after the
investigational drug is stopped, but in some cases, these side effects may be
serious and/or long lasting. Rarely, side effects could be fatal.