A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination with Gemcitabine in Patients with Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer deaths in the United
States (Landis et al. 1999). In 2007, it was predicted that approximately
33,370 people will die of pancreatic cancer in the United States (NCCN 2007).
Despite available treatment modalities, only 1% to 4% of all patients with
pancreatic cancer will survive 5 years. Hence, incidence and mortality rates
are nearly identical (Evans et al. 1997). Long-term survival is limited to
those patients with resectable disease who undergo pancreaticoduodenectomy.
Recently the incorporation of adjuvant treatment with gemcitabine after radical
resection has proven to increase survival in this subset of patients (Oettle et
al, 2007). Unfortunately, because symptoms usually develop late, more than 80%
of patients present with unresectable locally advanced or metastatic disease.

Gemcitabine is currently the standard of care for locally advanced and
metastaticpancreatic cancer in the United States and Europe. For the
registration trial it used a doseof 1,000 mg/m2 weekly for up to 7 weeks
followed by Day 1, 8 and 15 infusions every 4weeks. In the clinical practice
gemcitabine is administered once weekly for 3 weeks,followed by a week of rest,
at each cycle throughout the study, without the up to 7-weekinitial treatment
(Tandem 2000).
Gemcitabine is now used as the reference therapy for almost all randomized
clinical trialsfor the treatment of pancreas cancer, including those conducted
by competitorpharmaceutical companies and cooperative groups worldwide. There
are examples oflarge Phase 3 trials where gemcitabine in the control arm is
administered on Days 1, 8,and 15 every 28 days as it is the proposed control
arm in the Phase 2 of JMMC. Oneexample is the Eastern Cooperative Oncology
Group (ECOG) randomized Phase 3 studyof gemcitabine plus 5-FU versus
gemcitabine in 327 patients with advanced pancreas cancer (163 in the
combination arm and 164 in the monotherapy arm) (Berlin et al. 2001).In this
study, gemcitabine was also administered once weekly for 3 weeks, followed by a
week of rest, at each cycle throughout the study. Median survival were 6.7
months for patients on the combination arm and 5.4 months for patients on the
monotherapy arm (p=0.11, log-rank test). In another recent study patients with
advanced adenocarcinoma of the pancreas were randomly assigned to receive
either gemcitabine 1,000 mg/m2 and cisplatin 50 mg/m2 given on Days 1 and 15 of
a 4-week cycle or gemcitabine alone at a dose of 1,000 mg/m2 on Days 1, 8, and
15 of a 4-week regimen. The efficacy and
toxicity of the control arm was similar to those reported in the pivotal trial
with weekly gemcitabine for 7 weeks (Heinemann et al. 2006).

The primary objective of the Phase 2 part of the study is to determine if
overall survival(OS) in patients with Stage II-IV unresectable pancreatic
cancer administered LY2603618 and gemcitabine combination therapy exceeds
gemcitabine monotherapy OS.

The secondary objectives of the Phase 2 are:
* To characterize further the safety and toxicity profile of LY2603618 when
administered after gemcitabine and to compare it to the safety profile of
gemcitabine monotherapy in the advanced pancreatic cancer population.
* To estimate other time-to-event variables, such as PFS and duration of
response.To explore the percentage change in tumor size at 8 weeks and the
relationship with OS.
* To document response rate per Response Evaluation Criteria in Solid Tumors
(RECIST).
* To evaluate the pharmacokinetics of gemcitabine, deoxydifluorouridine
* (dFdU) and LY2603618 in combination.
* To assess biomarker responses associated with LY2603618 and gemcitabine
combination:
* Incorporation of nucleoside analogs (for example, gemcitabine) into the DNA
of peripheral blood cells.
* Detection of p53 in tumor tissue.
* Detection of fragmented cytokeratin 18 cleaved at Asp396 (M30 neoantigen).
* To explore the evolution of CA19.9 in patients with pancreatic cancer for
each treatment group and its relation with efficacy parameters.
* To explore the pharmacogenetic of drug metabolism enzyme and transporter
(DMET) polymorphisms and its relation with the PK profile, safety and efficacy.
* To perform an exploratory assessment of QTc.

For definitions of *enter* and *enroll,* refer to the Abbreviations and
Definitions table at the beginning of this protocol. Study I2I-MC-JMMC is an
open-label, multicenter, no placebo controlled Phase 1 followed by a randomized
Phase 2 study of IV administration of LY2603618 in combination with gemcitabine
versus gemcitabine monotherapy. The Phase 1 will include patients with solid
malignancy that are unlikely to benefit from approved therapies, and are
amenable to gemcitabine therapy. For Phase 2 the trial can be offered only to
patients with advanced or metastatic pancreatic adenocarcinoma at first
presentation or after relapse, who are considered eligible for chemotherapy
with gemcitabine.

The Phase 2 part is a 2:1 randomized, open label, 2-arm study of LY2603618 in
combination with gemcitabine vs. gemcitabine alone (See Figure JMMC.2). JMMC
will have a total of approximately 125 patients with approximately 26 patients
enrolled in Phase 1 and 99 patients enrolled in Phase 2.
All patients are intended to receive 2 cycles of therapy (8 weeks) and then be
assessed for disease progression. The investigator and Lilly physician will
jointly allow those patients whom have not progressed on treatment to continue
on study as long as the patient is benefiting, or until one of the criteria for
study discontinuation is fulfilled (see Section 4.3). Patients must be
evaluated at the completion of every 2 cycles to determine whether the patient
continues to benefit from treatment prior to receiving additional cycles of
therapy.
All patients enrolled in the study (Phases 1 and 2) will receive gemcitabine
1000 mg/m2 as a 30-minute IV infusion, once weekly (Days 1, 8, and 15) for 3
consecutive weeks followed by 1 week of rest; repeating every 28 days (3
administrations per cycle).
Patients enrolled to the experimental arm (Arm A) in Phase 2 will receive the
dose of LY2603618 as determined in the Phase 1 and in the same sequence.
Patients enrolled to the control arm (Arm B) in Phase 2 will receive only
gemcitabine at 1000 mg/m2 with the same weekly schedule

All participating patients in this trial will receive gemcitabine intravenously
over
approximately 30 minutes (maximum 60 minutes) at a dose of 1000 mg/m2 on Days
1, 8,and 15 followed by a week of rest (28 day cycle).For those patients
enrolled in Phase 1 portion or randomized to Arm A in the Phase 2 portion,
LY2603618 will be administered intravenously over 1 hour approximately 24 hours
after the administration of gemcitabine (range 20 to 33 hours after the
initiation of the gemcitabine infusion).

Risk Profile for LY2603618
Approval Date 2009 December 16

As of 17 November 2009, LY2603618 has been administered to 50 patients with
cancer with adverse event data available from 44 patients through 02 October
2009; therefore, there is very limited safety information available for
LY2603618 in humans, and the majority of the risks are based on studies in
animals.
Risks and Discomforts Associated with LY2603618
LY2603618 is a drug designed to work with other chemotherapeutic (anti-cancer)
agents that damage DNA (part of the cell that has all of the genetic
information. LY2603618 interrupts the tumor cell*s ability to repair the
damage of DNA or altered cell growth after being treated with another
anti-cancer drug. When LY2603618 is administered with other anti-cancer drugs,
the effect of the anti-cancer drug is expected to be enhanced. It is also
possible that the toxicity of the other anti-cancer drug will be increased when
LY2603618 is administered with it.
Of the 50 patients who were given LY2603618, thirty-one patients have received
LY2603618 in combination with pemetrexed. Nineteen patients received LY2603618
in combination with gemcitabine.
Through 17 November 2009, twenty-one patients had events that met serious
criteria (hospitalization, life-threatening, or other serious reason). Of the
21 patients, 17 patients were treated with LY2603618 in combination with
pemetrexed. In 6 of the 17 patients treated with the combination of LY2603618
and pemetrexed, the events were considered possibly related to LY2603618 and
pemetrexed by their study doctor. In the combination of LY2603618 with
pemetrexed,1patient experienced a lung infection (pneumonia). A second patient
experienced a decrease in white and red blood cells and feeling tired. The
third patient experienced an allergic-type reaction while receiving LY2603618,
which produced a feeling of not being able to get air into the lungs and a rise
in the blood pressure and the heart rate. A fourth patient experienced
diarrhea which lasted 2 weeks. The fifth patient experienced fever and a
decrease in red cells and platelets. The sixth patient was hospitalized with
bleeding from the lower intestine. This patient also presented a decrease in
white and red blood cells and platelets.As of 02 October 2009, all 31 patients
experienced 1 or more discomforts while receiving LY2603618 and pemetrexed. The
discomforts reported in more than 10% of the patients who have received at
least one dose of LY2603618 are below. These adverse events might be related
to LY2603618 and/or pemetrexed, the disease, other medications taken by the
patient, or a combination of some or all these factors.
12 to 17 patients reported:
* Low white blood cell counts that could increase the probability of infections
* Nausea
* Feeling tired.
8 to 11 patients reported:
* Low red blood cell counts that could make you feel tired
* Constipation
* Diarrhea or loose stools
* Vomiting
* Low potassium level in blood that could cause cramps or problems with the
heart
* Fever
4 to 7 patients reported:
* Low platelet count that could cause bleeding and/or bruising
* Feeling sick or discomfort in your stomach
* Swelling or water retention in the arms or legs
* Chills or feeling cold
* Fungal infection in the mouth that may cause a burning feeling or irritation
in the mouth or throat
* Increased in a blood test called alkaline phosphatase which may indicate
damage to your liver by treatment
* Dehydration or excessive water loss in the body
* Increased sugar in your blood
* Low magnesium in your blood which may produce weakness in your muscles
* Musculoskeletal chest pain that is not associated with cardiac pain or
disorder
* Back pain
* Bad taste in mouth that may alter the taste of food or drinks
* Tremor
* Feeling short of breath
* An accumulation of fluid in the lungs
* Rash
Rare, but serious events reported in at least 1 patient; not previously listed
(<10%):
* Infusion reaction that may cause shortness of breath, an increase heart rate,
and/or an increase in blood pressure
* Bleeding in the intestines
Four patients treated with LY2603618 in combination with gemcitabine
experienced serious adverse events; all were considered possibly related to
study treatment (LY2603618 and/or gemcitabine) by the study doctor. One of the
3 patients treated with LY2603618 and gemcitabine experienced an
infusion-related reaction while receiving LY2603618 with cold sweats and low
blood pressure. The second patient experienced worsening in her kidney
function after several infusions of LY2603618 and gemcitabine. The third
patient experienced a decrease in white blood cells which did not require any
therapy. A fourth patient experienced discomfort, inflammation and clots in
the vein at the infusion site after receiving LY2603618.
As of 17 November 2009, nineteen patients have been treated with LY2603618 and
gemcitabine with data available from 13 patients through 02 October 2009.
These patients experienced 1 or more discomforts. The discomforts reported in
>10% of the patients who have received at least 1 dose of LY2603618 are below.
These adverse events might be related to LY2603618, gemcitabine, the disease,
other medications taken by the patient, or a combination of some or all these
factors.
4 to 8 patients reported:
* Low red blood cell counts that could make you feel tired
* Nausea
* Feeling tired
* Vomiting
2 to 3 patients reported:
* Low white blood cell counts that could increase the probability of infections
* Low neutrophil cell counts that could increase the probability of infection
* Low platelet count that could cause bleeding and/or bruising
* Changes in heart rhythm that may make you feel palpitations or feelings of
fainting.
* Diarrhea or loose stools
* Constipation
* Uncomfortable feeling in the stomach such as abdominal pain, upset stomach,
bloating, or indigestion
* Swelling or water retention in the arms or legs
* Chills or feeling cold
* Infusion site pain
* Musculoskeletal chest pain that is not associated with cardiac pain or
disorder
* Fever
* Changes in some blood tests that may reflect the drug damaging your liver.
* Increased creatinine in blood
* Lack or decrease in your appetite
* Back pain
* Headache
* Worsening of kidney function
* Cough
* Feeling short of breath
* Flushing
Rare, but serious events reported in at least 1 patient; not previously listed
(<10%):
* Infusion reaction that may cause low blood pressure, and or cold sweating,
and/or feeling dizzy
* Inflammation, irritation, and/or clotting of a vein just under the skin near
the infusion site
Information on adverse events in animals can indicate a possible risk to
people. It may be useful in your decision as to whether to participate in this
study.
Animals that received LY2603618 showed harmful effects in the following parts
of the body:
* Stomach and intestines, where microscopic tissue damage was seen
* Damage to the cells in the testes that form sperm
* Bone marrow (which makes red and white blood cells), where there were fewer
cells present that form blood cells.
* Reversible increases in heart rate
The harmful effects seen in animals occurred with higher doses of LY2603618
than will be given to humans.
In addition, LY2603618 caused infusion or injection site injuries, where injury
was noted to the blood vessel and surrounding tissues in animal studies. This
infusion site injury or lesion appeared in large veins where the catheter was
placed. The lesion occurred also when the compound was injected using small
veins in the animal legs. In another experiment, LY2603618 also caused
irritation at the skin and the tissue under the skin when LY2603618 was
purposely injected under the skin outside the vein.
In humans, LY2603618 could be administered using a vein in your arm or a
central catheter that may already be surgically placed in a large vein in your
body. When LY2603618 is administered to humans, the infusion will be followed
by a flush of fluid that does not have any drug. This will reduce the
possibility of LY2603618 irritation and avoid accidental skin contact with
LY2603618 that could spill while removing the needle from your arm. It is
possible that you may experience discomfort, blood clot formation, bleeding,
skin irritation, or other side effects related to the infusion. You should
tell immediately your doctor or the nurse taking care of the infusion if you
notice any discomfort around the site of the injection.
Risks in Men
While you take LY2603618:
* Do not father a child (if you are a male). If you do father a child during
the study, you should immediately call the study doctor.
Risks in Women
While you take LY2603618:
* For women who could become pregnant, methods to avoid pregnancy should be
taken. Tests in the lab show that LY2603618 can change DNA, and therefore
LY2603618 could harm an unborn baby. You will be asked to have a pregnancy
test before you are given the study drugs. You must use an effective avoidance
of pregnancy method during the study. If you become pregnant, you will no
longer be allowed to take part in the study.
* Stop breastfeeding (if you are nursing a baby). It is not known if LY2603618
passes to a baby through breast milk.


Risk Profile for Gemcitabine (LY188011)
Approval Date 2007 October 24

As of 31 August 2007, 2,159,090 patients are estimated to have been treated
with gemcitabine worldwide based on sales data. Over 7000 patients were
treated in Lilly-sponsored clinical trials for which data are stored in the
corporate database.
Risks and Discomforts Associated with Gemcitabine
Very common side effects reported by more than 10% of patients receiving
gemcitabine include:
* Nausea and vomiting (feeling or being sick). These effects rarely prevent
further treatment with gemcitabine and can be managed using medication.
* Decrease in white blood cells, red blood cells, and platelets. A decrease in
white blood cells increases the chance of developing an infection. A decrease
in red blood cells (anemia) may cause feelings of being tired. A decreased
platelet count may increase the chance of bruising and bleeding after injury.
* Changes in liver function tests (tests that show how your liver is working).
These changes are usually mild and non-progressive and rarely require stopping
treatment with gemcitabine.
* Flu-like symptoms, including fever, headaches, chills, muscle soreness,
fatigue, weakness, lethargy, loss of appetite, cough, runny nose, and sweating.
* Mild effects on the kidneys (blood or protein in the urine); diarrhoea;
allergic skin rash frequently associated with itching; mild hair loss;
shortness of breath; and fluid retention (usually seen as swelling of the
hands, feet, or face).
Common side effects reported by between 1% and 10% of patients receiving
gemcitabine include inflammation of the mucous membranes of the mouth and
throat, and decreased white blood cells with fever.
Uncommon side effects reported by between 0.1% and 1% of patients receiving
gemcitabine (that is, between 1 in 1000 and 1 in 100 patients) include wheezing.
Rare side effects reported by between 0.01% and 0.1% of patients receiving
gemcitabine (that is, between 1 in 10,000 and 1 in 1000 patients) include a
fast or irregular heart beat, decreased blood pressure, severe changes in liver
function tests (including changes that may cause jaundice), severe effects on
the lungs including respiratory distress (severe difficulty breathing), and
severe effects on the kidneys, sometimes leading to kidney failure.
Very rare side effects reported by less than 0.01% of patients (that is, less
than 1 in 10,000 patients) receiving gemcitabine include:
* Heart failure.
* Severe allergic reactions. The symptoms may include rash, changes in blood
pressure, swelling and increased fluid in the tissues, increased heart rate,
difficultly in breathing, and collapse.
* Blood vessel inflammation and gangrene (death of soft tissue due to lack of
blood supply).
* Severe skin reactions, including peeling of the skin.
Patients who have received radiotherapy before, during, or after receiving
gemcitabine may sometimes experience side effects at the site of the
radiotherapy.
Many of the side effects described above may be experienced by patients
receiving other chemotherapy drugs. As with most other cancer therapies, there
have been infrequent instances of death due to chemotherapy-related
complications in patients who received gemcitabine.
Studies in experimental animals have shown that gemcitabine can harm the
development of the embryo or fetus. This means that the use of gemcitabine
should be avoided in pregnant and nursing women because of the potential of
harm to the fetus.