Phase 1 Clinical Trial of NPI-0052 in Patients With Advanced Malignancies

A Phase 1 Clinical Trial of NPI-0052 in Patients With Advanced Malignancies

This is a Phase 1 clinical trial examining the safety, pharmacokinetics and pharmacodynamics of escalating doses of the proteasome inhibitor NPI-0052 in patients with advanced malignancies including solid tumors, lymphomas, leukemias and multiple myeloma. By inhibiting proteasomes NPI-0052 prevents the breakdown of proteins involved in signal transduction, which blocks growth and survival in cancer cells.

Patients were enrolled in 1 of 2 study arms. Arm AM (weekly doses of NPI-0052) consisted of patients with solid and hematological malignancies excluding multiple myeloma (MM), and these patients received NPI-0051 once weekly for 3 weeks of every 4 weeks. Arm MM (twice-weekly doses of NPI-0052) consisted of patients with MM and other hematological malignancies, and these patients received NPI-0052 twice weekly for 2 weeks of every 3 weeks. All patients received NPI-0052 administered IV over approximately 1 to 120 minutes. Patients with MM (Arm MM) also received 20 mg dexamethasone per orally or IV on the day before and the day of NPI-0052 dosing.

Patients were initially enrolled in dose-escalating cohorts to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of NPI-0052. Once the RP2D was determined for each arm of the study, the RP2D was evaluated in the dose-expansion stage of the study.

Inclusion Criteria:

• Karnofsky Performance Status (KPS) > 70%.
• Histologically-confirmed advanced malignancy for which a standard, approved therapy is not available.
• Adequate renal, liver, pancreatic and hematologic function
• Signed informed consent (sample IC form is provided in Appendix A).

Exclusion Criteria

• Administration of chemotherapy, biological, immunotherapy or investigational agent (therapeutic or diagnostic) within 28 days
• Patients that require G-CSF and/or platelet support during screening and are likely to require G-CSF and/or platelet support for the duration of the clinical trial.
• Patients with ongoing coagulopathies and/or taking anticoagulants
• Patients receiving intrathecal therapy.
• Known brain metastases.
• Pre-existing adrenal insufficiency; concomitant therapy with replacement corticosteroids. Pre-existing acute or chronic pancreatitis.
• Significant cardiac disease.
• Pregnant or breast-feeding women.
• Concurrent, active secondary malignancy for which the patient is receiving therapy. (Lymphoma patients with a diagnosis of a potentially hormone-sensitive tumor who are without evidence of disease for this second malignancy may continue to receive hormonal therapy).
• Patients with proteinuria Grade 2 or greater
• Active uncontrolled bacterial or fungal infection requiring systemic therapy; infection requiring parenteral antibiotics.
• Patients who are known to be HIV positive or have active Hepatitis A, B, or C infection.