A phase I, open-label, two-stage, randomized, crossover, comparative pharmacokinetic and safety study of two formulations of CO-1.01 for injection in patients with advanced solid tumors.

Gemcitabine-5*-elaidate is a fatty acid derivative of gemcitabine. Gemcitabine
is used alone or in combination with other chemotherapy as a treatment for
several solid tumor types, including pancreatic cancer, NSCLC, breast cancer,
and ovarian cancer. Gemcitabine-5*-elaidate was synthesized to improve the
clinical efficacy of gemcitabine by rendering cellular uptake independent of
nucleoside transporters (which can be highly limiting in cancer cells) and
prolonging the retention of the active metabolites, thus overcoming resistance
mechanisms and schedule dependency that limits the efficacy of gemcitabine.

Nonclinical studies indicate that CO-1.01, a gemcitabine derivative, appears to
be independent of nucleoside transporters (e.g., human equilibrative nucleoside
transporter 1 [hENT1]) to exert its anticancer activity. Therefore, patients
with low or no meaningful expression of hENT1 treated with CO-1.01 are
predicted to show superior clinical outcomes compared with those given
gemcitabine. Furthermore, the PK profiles of CO-1.01 and gemcitabine are
different, and this may also favorably influence the in vivo antiproliferative
effects of CO-1.01.

The formulation of CO-1.01 that is currently in clinical studies contains 15
mg/mL of gemcitabine-5*-elaidate solubilized in purified phospholipids.
Recently, Clovis Oncology developed another formulation of CO-1.01, which
contains 30 mg/mL of gemcitabine-5*-elaidate solubilized in purified
phospholipids.

Primary objective:
•To compare the pharmacokinetic (PK) profiles of gemcitabine-5*-elaidate
(parent compound) of two formulations of CO-1.01 in order to investigate
whether the confidence interval (CI) for the ratio of the AUC0-* of the two
formulations is contained within 80 to 125%

Secondary objectives:
•To assess the PK of CO-1.01 and metabolites in plasma and urine after 1250
mg/m2 CO-1.01 given as a single 30 min intravenous (i.v.) infusion
•To evaluate the effects on the QT/QTc interval of the ECG of each formulation
of CO-1.01
•To explore the relationship between the PK of CO-1.01 and the potential
changes in QT/QTc
•To determine the tolerability and toxicity of CO-1.01

Exploratory:
•To evaluate tumor response of CO-1.01 in patients who enter the optional
Treatment Extension Period of the study

This is a two-stage, open-label, randomized, two treatment period by two
sequence crossover design study.

De study consist of two stages. In the first stage (Stage 1) the PK of CO-1.01
will be investigated. In the second stage of the study (Stage 2) the efficacy
and safety of CO-1.01 will be further investigated. The second stage is
optional.

An interim analysis of the PK data will be performed after completion of Stage
I. A sample size re-estimation will be performed to determine the number of
patients needed to have 80% power to meet the primary objective of the study.
The required additional patients will then be enrolled. Stage I of the trial
will enroll 12 patients and the total number of patients enrolled in both
stages will not exceed 36 patients. The results from both stages will then be
combined for the final analysis. It is anticipated that the detailed ECG
assessments will be performed on patients who participate in Stage I of the
study only; otherwise, the procedures in the two stages will be the same.

Patients will be randomly assigned to one of two following treatment sequences.
Treatment Sequence 1: Day 1 Formulation A, Day 8 Formulation B
Treatment Sequence 2: Day 1 Formulation B, Day 8 Formulation A

Each patient will be treated as follows:

• Pretreatment ECG visit: Triplicate standard ECGs and a 9-hour period of
continuous ECG monitoring (Holter) during the Screening Period

• Pharmacokinetic Period: Patients will receive two different formulations of
CO-1.01 at a dose of 1250 mg/m2 given over 30 min i.v. on Day 1 and Day 8.
Patients will be randomly assigned to one of two treatment sequences. The
randomization will be stratified by gender.

Upon completion of the Pharmacokinetic Period (Stage 1)(i.e., through Day 10),
patients may continue to participate in an optional Treatment-Extension Period
which begins with Cycle 1, Day 15. CO-1.01 will be administered on Days 1, 8,
and 15 of a 28-day cycle during the Treatment Extension Period. For patients
who continue treatment with CO-1.01, the dose may be delayed or decreased for
drug-related toxicity, and treatment may continue until tumor progression or
intolerable toxicity

During the first cycle of treatment (Pharmacokinetic Period), patients will
undergo PK assessments and cardiac assessments (12-lead ECG and Holter monitor)
on Days 1 to 3 and Days 8 to 10. Central/core laboratories will be used for ECG
interpretation and PK assay. Local imaging assessments for antitumor efficacy
(Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) will be
performed at Screening and after completion of every two cycles. AEs will be
assessed from the time informed consent (IC) is obtained through 28 days after
the last dose of CO-1.01. Other safety tests (vital signs, clinical laboratory
tests, Eastern Cooperative Oncology Group [ECOG], and physical exam) will be
collected as scheduled in the protocol.

CO-1.01 will be administered as a 30 ± 3 min i.v. infusion under medical
supervision. All treatment cycles are 28 days long with CO-1.01 doses
administered on Days 1, 8 and 15.

CO-1.01 Formulation A: The current formulation of C0-1.01, which contains 15
mg/mL of gemcitabine-5*-elaidate solubilized in purified phospholipids

CO-1.01 Formulation B: New formulation of CO-1.01, which contains 30 mg/mL of
gemcitabine-5*-elaidate solubilized in purified phospholipids

Patients will be randomized to two different treatment schedules and will
receive each of the CO-1.01 formulations on opposite weeks of treatment as
follows:

•Treatment Sequence 1: 1250 mg/m2/day of CO-1.01 Formulation A on Day 1 and
Formulation B on Day 8
•Treatment Sequence 2: 1250 mg/m2/day of CO-1.01 Formulation B on Day 1 and
Formulation A on Day 8

The optional Treatment Extension Period will start on Day 15 of Cycle 1.
CO-1.01 will be dosed on Days 1, 8, and 15 of a 28-day cycle during the
Treatment Extension Period. Where possible, Formulation B (new formulation)
will be used for the Treatment Extension Period, although Formulation A
(current formulation) may also be used as determined by the sponsor.

Study assessments will be performed at screening, C1D1, C1D2, C1D3, C1D8, C1D9,
C1D10, C1D15, and CXD1, CXD8, CxD15, CxD22 (only the even numbered cycles) of
every consecutive cycle. Treatment duration will continue until disease
progression, Intercurrent illness that prevents administration of CO-1.01,
unacceptable toxicity, patient withdrawal of consent, major noncompliance that
may affect patient safety, pregnancy, death, or discontinuation from the study
for any other reason, whereupon all patients will complete the End of Treatment
visit ± 28 days after last study medication.

Please refer to Table 4, page 46-47 of the protocol.

Risks:
• Toxicity due to the use of CO-1.01
• Reaction to the use of contrast fluid (used for CT scans
• Side effects of blood sampling