A Pivotal Bioequivalence Study of DOXIL/CAELYX (Doxorubicin HCL) in Patients With Advanced or Refractory Solid Malignancies Including Patients With Ovarian Cancer

This is a randomized (individuals will be assigned in a random order to study treatment
sequences), open-label (identity of assigned treatment sequences will be known), single
dose, 2-cycle, crossover (patients will receive both treatments in a random order)
bioequivalence study of DOXIL/CAELYX (doxorubicin HCL) in patients with advanced or
refractory solid malignancies (including patients with ovarian cancer). This study has an
adaptive 2-stage design. Bioequivalence based on encapsulated doxorubicin will be tested at
the end of Stage 1 using data from at least 24 ovarian cancer patients. An interim analysis
of free doxorubicin will be performed at the end of Stage 1 using data from 42 patients of
all cancer types. The study may continue into Stage 2 with additional patients of all cancer
types; and final evaluation of bioequivalence for free doxorubicin will be performed at the
end of Stage 2. The study will include a screening phase followed by an open-label treatment
phase consisting of 2 doxorubicin treatment cycles and an end-of-treatment visit on Cycle 3,
Day 1. Participants may enter an optional extension phase after 2 cycles. Safety will be
monitored throughout the study. Blood samples for pharmacokinetic analysis will be obtained
from all participants at specified times over 29 days after starting each study drug
administration in Cycles 1 and 2 for determination of plasma concentrations of encapsulated
and free doxorubicin.

Inclusion Criteria:

- Diagnosed with advanced or refractory solid malignancies: histologically or
cytologically confirmed advanced ovarian cancer failing platinum-based chemotherapy;
histologically or cytologically confirmed metastatic breast cancer after failing
approved life-prolonging therapies; any histologically or cytologically confirmed
solid malignancy that is metastatic or unresectable, and for which standard treatment
is no longer an option

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Recovered from acute toxicity of any prior treatment (exemptions: alopecia, grade-1
neuropathy)

- Prior doxorubicin (or other anthracyclines) at cumulative dose of <=360 mg/m2 or
cumulative epirubicin dose <=720 mg/m2 (calculated using doxorubicin equivalent
doses: 1 mg doxorubicin = 1 mg DOXIL/CAELYX = 0.3 mg mitoxantrone = 0.25 mg
idarubicin)

- Adequate liver, bone marrow, and renal function according to protocol-defined
parameters

- Left ventricular ejection fraction (LVEF) within normal limits of the institution as
determined by multiple uptake gated acquisition (MUGA) or echocardiography

- Agrees to protocol-defined use of effective contraception

- Negative pregnancy test at screening (applicable to women of child bearing potential)
within 7 days prior to starting treatment

Exclusion Criteria:

- Positive history of known brain metastases or leptomeningeal disease (patients with
brain metastases can only be enrolled if the following conditions are all met:
treated and stable for >4 weeks [>2 weeks after SRS/Cyberknife]; no evidence for
progression or hemorrhage after treatment; steroid treatment discontinued at least 2
weeks prior to first administration of doxorubicin; enzyme inducing anti-epileptic
drugs discontinued at least 4 weeks before first administration of doxorubicin

- History of hypersensitivity reaction to doxorubicin HCl or other components of
DOXIL/CAELYX

- Any major surgery, radiotherapy, or immunotherapy within the last 21 days (limited
palliative radiation allowed >=2 weeks prior to the first dose; >=4 weeks for whole
brain radiotherapy); chemotherapy regimens with delayed toxicity within the last 4
weeks (or within the last 6 weeks for prior nitrosourea or mitomycin C); chemotherapy
regimens given continuously or on a weekly basis with limited potential for delayed
toxicity within the last 2 weeks

- Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of doxorubicin

- Unstable angina or myocardial infarction within the preceding 12 months; congestive
heart failure or any history of uncontrolled cardiac disease >Class II based on New
York Heart Association Criteria

- Has an infection that is either an uncontrolled infection, clinically important
(occurred within 4 weeks prior to first dose of study agent), or requiring current
systemic intravenous treatment

- Uncontrolled concurrent illness including, but not limited to, poorly controlled
hypertension or diabetes, or psychiatric illness/social situation that may
potentially impair patient's compliance with study procedures

- Concomitant use of strong CYP3A4 inhibitors (such as clarithromycin, diltiazem,
erythromycin, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin and
verapamil) and strong CYP3A4 inducers (such as carbamazepine, phenobarbital,
phenytoin, rifampin and St John's wort) from at least 4 weeks before the first dose
of doxorubicin in Cycle 1 and until after completion of all pharmacokinetic sampling
in Cycle 2

- Has any condition that, in the opinion of the investigator, would make participation
not be in the best interest (eg, compromise the well-being) of the patient or that
could prevent, limit, or confound the protocol-specified assessments

- Woman who is pregnant, or breast-feeding, or planning to become pregnant or is a man
who plans to father a child while enrolled in this study or within 3 months after the
last dose of study drug