Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Tumors

The role of the proteasome in carcinogenesis and cell survival has been well established,
and its inhibition associated with an accumulation of pro-apoptotic proteins and cell death.
Proteasome inhibitors, such has bortezomib, have been extensively studied and are widely
used as effective therapy in the treatment for hematologic malignancies, such as multiple
myeloma where circulating proteasome levels have been correlated with survival. Carfilzomib,
a novel irreversible proteasome inhibitor which specifically targets the chymotryptic site
of the proteasome has shown more potency than bortezomib and may be able to overcome
bortezomib resistance. Response rates between 25-54% were seen in patients with previously
treated myeloma in the phase 2 setting.

Given the effectiveness of proteasome inhibition in multiple myeloma, the role of proteasome
in solid tumors is under active investigation. Previous trials of bortezomib in breast,
prostate, lung, and pancreatic cancer have shown little activity of this agent in these
diseases. Whether the lack of activity may be mechanistically related (bortezomib inhibits
chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH)-like activities of the
proteasome), or a lack of potency in target inhibition, is unknown.

In a phase Ib/II study of 14 patients (phase I) and 51 patients (phase II) with advanced
solid tumors, Rosen and colleagues noted single-agent activity with carfilzomib. Carfilzomib
was dosed on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle to a maximum of 12 cycles, with
20-36 mg/m² noted as the recommended phase 2 dose based on DLT data. A PR in both renal and
small cell lung cancer, and stable disease > 16 weeks in mesothelioma, ovarian, renal, and
non-small cell lung cancer was observed. The treatment was tolerable with the most common
adverse events (AEs) including fatigue, headache, diarrhea, nausea and constipation.

Given the activity of carfilzomib seen in selected solid tumors, and unpublished data to
suggest weekly dosing may result in a similar pharmacokinetic profile including AUC, the
investigators propose to study the safety, tolerability, pharmacokinetics, and anti-tumor
activity of carfilzomib monotherapy given on a weekly dosing schedule. Weekly dosing has the
advantage of patient convenience, and if acceptable toxicity and pharmacokinetics, it allows
for easier integration of this schedule into subsequent combination therapy clinical trials.

Inclusion Criteria:

- Patient aged 18 years or older at the time of enrollment.

- Advanced/metastatic solid tumor refractory to standard therapy.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2.

- Adequate organ function as assessed by the following:

- Bone marrow:

- Hemoglobin greater than or equal to 9.0 g/dL

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mm³

- Platelet count greater than or equal to 100,000/mm³

- Hepatic:

- Total bilirubin less than or equal to 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x
ULN

- Prothrombin time (PT)-international normalized ratio (INR)/partial
thromboplastin time (PTT) < 1.5 x ULN except in patients receiving active
anticoagulation

- Renal:

- Serum creatinine ≤ 1.5 x upper limit of normal or

- Glomerular filtration rate (GFR) of 50 ml/minute or greater (if elevated
serum creatinine level > 1.5 x ULN)

- Willingness to sign informed consent by patient or patient's legal representative.

- Patient with known but adequately treated brain metastases and without central
nervous system (CNS) disease progression as determined by CT or MRI imaging within 4
weeks of the first dose of study drug.

Exclusion Criteria:

- Treatment related residual toxicity > grade 1.

- Prior treatment with a proteasome inhibitor.

- Uncontrolled systemic disease or intercurrent illness.

- Recent history of myocardial infarction (MI) or symptomatic coronary artery disease
within the preceding 6 months.

- History of uncontrolled hypertension (systolic > 150 mmHg or diastolic pressure > 90
mmHG despite optimal medical management).

- Ejection fraction < 50%.

- Known and actively treated infection with human immunodeficiency virus (HIV),
hepatitis B or C.

- Major surgery or significant traumatic injury within 4 weeks of first study treatment
from which the subject has not fully recovered.

- Pregnant or breast feeding women.

- Female patient of child-bearing potential or male patient with partner of
child-bearing potential but unable or unwilling to use effective contraception
(double barrier such as condoms, contraceptive sponge, diaphragm or vaginal ring with
spermicidal jellies or cream; or hormonal method such as oral, parenteral or
transdermal hormonal agents for at least three months prior to study drug
administration).

- Corticosteroid doses greater than equivalent of prednisone 7.5 mg PO daily.

- Recent therapy with any active anticancer agent within 4 weeks of the 1st dose of the
study drugs.

- Any other current malignancy or previous malignancies within 3 years of enrollment
except: curatively treated in situ carcinoma of the cervix uteri; localized basal or
squamous cell carcinoma of the skin, curatively treated in situ breast carcinoma, and
early stage prostate cancer.

- Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize
carfilzomib).

- Contraindication to any of the required concomitant drugs or supportive treatments,
including hypersensitivity to all anticoagulation and antiplatelet options, antiviral
drugs, or intolerance to hydration due to preexisting pulmonary or cardiac
impairment.

- Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to randomization.

- Any other clinically significant medical disease or condition that, in the
Investigator's opinion, may interfere with protocol adherence or a subject's ability
to give informed consent.