Phase 1 Clinical Trial of NPI-0052 in Patients With Advanced Solid Tumor Malignancies or Refractory Lymphoma

NPI-0052 (also known as marizomab) is a second generation proteasome inhibitor being
developed as an anticancer agent. Proteasomes are responsible for degrading substrates such
as damaged and aged proteins, tumor suppressors, and cell cycle regulators, and for
regulating NF-κB activation by degrading its inhibitor, IκB. Blocking the proteasome pathway
results in accumulation of proteins, which can cause cell death, particularly in tumor cells
(Kisselev, 2001).

The Food and Drug Administration (FDA) approved the first proteasome inhibitor (bortezomib;
Velcade®) in 2003 for the treatment of patients with multiple myeloma (MM) and subsequently
for treatment of patients with mantle cell lymphoma in 2006. Although this compound has
demonstrated efficacy in both of those indications, resistance and toxicity develop with
continued therapy. Resistance may result from a variety of mechanisms. Bortezomib toxicity
(primarily neurological with peripheral neuropathy and neuralgia, and also thrombocytopenia
and neutropenia) can result in treatment discontinuation (about 25% of patients in a clinical
trial conducted in patients at time of first relapse required cessation of therapy due to
adverse events).

NPI-0052 inhibits the chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L)
activity of human erythrocyte-derived 20S proteasomes. Also known as salinosporamide A,
NPI-0052 is a novel chemical entity discovered during the fermentation of Salinispora tropica
NPS021184, a marine actinomycete, and is manufactured by saline fermentation. NPI-0052 was
shown in nonclinical studies to have increased potency and duration of biological effects
compared with bortezomib and may provide a significant therapeutic advantage, particularly if
toxicity is less at therapeutic doses.

This was the first-in-human study of NPI-0052, and was conducted in cancer patients.

Inclusion Criteria:

- Histologically-confirmed solid tumor malignancy (patients must be refractory to or
demonstrate unacceptable toxicity towards effective therapy known to provide clinical
benefit for their condition) OR refractory lymphoma (patients whose disease has
progressed despite standard therapy including at least one-doxorubicin-containing
regimen and one anti-CD20 monoclonal antibody-containing regimen.

- KPS ≥70%.

- All Adverse Events of any prior chemotherapy, surgery, or radiotherapy, must have
resolved to NCI CTCAE (v. 3.0) Grade ≤ 1 (except for hemoglobin).

- Adequate bone marrow, renal, adrenal, pancreatic and liver function.

- Signed informed consent.

Exclusion Criteria:

- Administration of chemotherapy, biological, immunotherapy or investigational agent
(therapeutic or diagnostic) within 28 days prior to receipt of study medication (6
weeks for nitrosoureas or mitomycin C; 12 weeks for radioimmunotherapy). Major
surgery, other than diagnostic surgery, within 4 weeks before first study drug
administration. Radiotherapy within 4 weeks.

- Patients that require G-CSF and/or platelet support.

- Patients with ongoing coagulopathies.

- Patients with prior bone marrow transplant therapy (autologous or allogeneic).

- Patients receiving intrathecal therapy.

- Known brain metastases.

- Significant cardiac disease.

- Patients with a prior hypersensitivity reaction of CTCAE Grade ≥ 3 to therapy
containing propylene glycol or ethanol.

- Pregnant or breast-feeding women. Female patients must be postmenopausal, surgically
sterile or they must agree to use acceptable methods of birth control. Female patients
with childbearing potential must have a negative serum pregnancy test. Male patients
must be surgically sterile or agree to use an acceptable method of contraception.

- Concurrent, active secondary malignancy for which the patient is receiving therapy.

- Active uncontrolled bacterial or fungal infection requiring systemic therapy;
infection requiring parenteral antibiotics.

- Known to be positive for HIV; active hepatitis A, B, or C infection.