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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: NPI-0052 on Days 1, 8, 15 every 28 days
* Drug: NPI-0052 on Days 1, 4, 8, 11 every 21 days
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm AM: advanced malignancies<br>Dose Escalation - 9 dose cohorts NPI-0052 on Days 1, 8, 15 every 28 days NPI-0052 doses ranging from 0.1 to 0.9 mg/m2 | Drug: NPI-0052 on Days 1, 8, 15 every 28 days<br>* NPI-0052 dose ranging from 0.1 to 0.9 mg/m2 NPI-0052 IV injection over 1 to 120 minutes on Days 1, 8, and 15 of 4-week cycles<br>* Other names: proteasome inhibitor;|
| Experimental: Arm MM: multiple myeloma<br>Dose Escalation - 8 dose cohorts NPI-0052 on Days 1, 4, 8, 11 every 21 days NPI-0052 doses ranging from 0.075 to 0.6 mg/m2 Dexamethasone 20 mg oral or IV day before and day after NPI-0052 dosing. | Drug: NPI-0052 on Days 1, 4, 8, 11 every 21 days<br>* NPI-0052 dose ranging from 0.075 to 0.6 mg/m2 NPI-0052 IV injection over 1 to 120 minutes on Days 1, 4, 8, and 11 of 3-week cycles<br>* Other names: proteasome inhibitor;Drug: Dexamethasone<br>* 20 mg oral or IV day before and day after NPI-0052 dosing.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of NPI-0052 | Assess dose-limiting toxicities during Cycle 1 for each treatment arm | Cycle 1 (Arm AM: 28-days, Arm MM: 21-days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the pharmacokinetics activity of NPI-0052 | the assess the time course of NPI-0052 in the body | Baseline, Days 1 and 15 (before injection and 1 hour post injection) of Cycle 1 | 
| To evaluate the safety and tolerability of NPI-0052 | Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Treatment period through 28-days after the last dose of study drug | 
| To evaluate the pharmacodynamics of NPI-0052 | proteasome inhibition in blood samples | Baseline, Days 1 and 15 (before injection and 1 hour post injection) of Cycles 1 and 2 and of every other cycle thereafter through study completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, leukemias (inc. CLL), lymphomas, cutaneous lymphoma, marginal zone lymphoma, advanced malignancies without standard treatment options