Phase 2 Clinical Trial of NPI-0052 in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

This is a Phase 2, open-label, multicenter study examining the safety, pharmacokinetics and pharmacodynamics, and best overall response to escalating doses of the proteasome inhibitor NPI-0052 (also known as marizomib) in patients with relapsed or relapsed/refractory multiple myeloma. NPI-0052 is a novel, second generation proteasome inhibitor that prevents the breakdown of proteins involved in signal transduction which blocks growth and survival in cancer cells. The study is a Phase 2 study and is a 2-stage efficacy design in a selected subgroup of patients (Arm C) treated with the recommended phase 2 dose of NPI-0052, as determined in a previously completed Phase 1 study. The study is to evaluate the safety and any preliminary evidence of efficacy of NPI-0052 in multiple myeloma patients who have previously received carfilzomib (PR-171, Kyprolis™) and subsequently had disease progression.


Eligibility Criteria:
Inclusion Criteria: Prior to Amendment 13:

* Age 18 years.
* Karnofsky Performance Status (KPS) score 70%.
* All patients must have histologic evidence of multiple myeloma. Evidence of relapsed or relapsed/refractory disease for which no other approved treatment is available and clinically indicated. In addition, patients may have undergone prior bone marrow transplantation. For patients treated at the Recommended Phase 2 Dose patients are required to have measurable relapsed or relapsed/refractory disease. Disease must be assessed within 28 days prior to treatment initiation.

  1. Measurable disease is defined as one of the following:

     * Serum M-protein ≥0.5 g/dL
     * Urine M-protein ≥200 mg/24 hours
     * Involved serum free light chain (FLC) level ≥10 mg/dL, provided the serum FLC ratio is abnormal
  2. Relapsed and Refractory are defined as:

     * Must have received at least 2 prior treatment regimens.
     * Must have received prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of bortezomib (either in separate regimens or within the same regimen).
     * Must have received a cytotoxic chemotherapy agent (eg, alkylating agent).
     * Relapsed Disease: Must have progressive disease after having achieved at least stable disease for at least one cycle of treatment during at least one prior regimen.
     * Refractory Disease: Must have documented evidence of progressive disease during or within 60 days (measured from the end of the last cycle) of completing the most recently received anti-myeloma drug regimen prior to study entry
* All AEs resulting from prior chemotherapy, surgery, or radiotherapy must have resolved to NCI-CTCAE Grade 1 (except for hematologic parameters outlined below).
* The following laboratory results, within 7 days prior to NPI-0052 administration (transfusions and/or growth factor support may be used with discretion by the Investigator during Screening):

  * Hemoglobin 8 g/dL
  * Absolute neutrophil count 0.5 × 109/L
  * Platelet count 30 × 109/L
  * Serum bilirubin 1.5 × ULN
  * AST 2.5 × ULN
  * Serum creatinine 1.5 × ULN
  * Creatinine clearance ≥40 mL/min
* Signed informed consent.
* Must have previously received at least 2 cycles of carfilzomib (as a single agent or in combination with other agents) and subsequently had disease progression during or within 60 days of carfilzomib therapy. Carfilzomib does not have to be the most recent therapy that the patient has received, but patients must have documented disease progression during or within 60 days of their last anti-myeloma therapy

Inclusion Criteria Amendment 13:

* Age 18 years.
* Karnofsky Performance Status score 70%.
* All patients must have histologic evidence of multiple myeloma and evidence of relapsed or relapsed/refractory disease as defined below Patients are required to have measurable relapsed or relapsed/refractory disease. Disease must be assessed within 28 days prior to treatment initiation.

  1. Measurable disease defined as one of the following:

     * Serum M-protein ≥0.5 g/dL
     * Urine M-protein ≥200 mg/24 hours
     * Involved serum free light chain (FLC) level ≥10 mg/dL provided the serum FLC ratio is abnormal
  2. Relapsed and Refractory are defined as:

     * Must have received at least 2 prior treatment regimens.
     * Must have received prior treatment with at least 2 cycles of an immunomodulator (lenalidomide or pomalidomide or thalidomide).
     * Must have previously received at least 2 cycles of carfilzomib (as a single agent or in combination with other agents) and subsequently had disease progression during or within 60 days of carfilzomib therapy. Carfilzomib does not have to be the most recent therapy that the patient has received, but patients must have documented disease progression during or within 60 days of their last anti-myeloma therapy. Patients may also have received bortezomib.

In addition, patients may have undergone prior cytotoxic chemotherapy, bone marrow transplantation and previously participated in other clinical trials.

* Relapsed Disease: Must have progressive disease after having achieved at least stable disease for at least one cycle of treatment during at least one prior regimen.
* Refractory Disease: Must have documented evidence of progressive disease during or within 60 days (measured from the end of the last cycle) of completing the most recently received anti-myeloma drug regimen prior to study entry.

  * All Adverse Events resulting from prior chemotherapy, surgery, or radiotherapy, must have resolved to CTCAE Grade 1 (except for hematologic parameters outlined below).
  * The following laboratory results, within 7 days of NPI-0052 administration (transfusions and/or growth factor support may be used with discretion by the Investigator during the screening period):
* Hemoglobin 8 g/dL
* Absolute neutrophil count 0.5 x 109/L
* Platelet count 30 x 109/L
* Serum bilirubin 1.5 x ULN
* AST 2.5 x ULN
* Serum creatinine 1.5 x ULN
* Creatinine clearance ≥40 mL/min -Signed informed consent.

Exclusion Criteria:

* Administration of chemotherapy, biological, immunotherapy, or investigational agent (therapeutic or diagnostic) within 14 days prior to receipt of study medication (this washout period can be reduced to 7 days for biologically targeted therapies (eg, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, and dexamethasone or equivalent), provided the patient has recovered from the toxicity from these regimens per Inclusion Criterion #4). Patients must be 6 weeks from last dose of nitrosourea and 12 weeks from BMT. Patients must be 2 weeks from last dose of radiation.
* Patients with Grade \>1 proteinuria (1 g/24 hour excluding M proteins = urine paraprotein subtracted from total urine protein), untreated urinary tract infection, as well as any pre existing kidney disease (acute or chronic) that in the Investigator's assessment would impose excessive risk to the patient.
* Patients with evidence of mucosal or internal bleeding and/or platelet refractory (ie, unable to maintain platelet count 30 × 109/L).
* Significant cardiac disease defined as:

  * Patients with congenital long QT syndrome;
  * Congestive heart failure of Class III or IV of the NYHA classification;
  * History of myocardial infarction or ischemia within 12 months of study enrollment.
* Abnormal left ventricular ejection fraction (LVEF) (\< lower limit of normal as defined by the study site for a patient of that age) by echocardiogram (ECHO) or multiple-gated angiography (MUGA).
* 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 or surgically sterile, or they must agree to use acceptable methods of birth control (ie, a hormonal contraceptive with barrier method, intra-uterine device, diaphragm with spermicidal or condom with spermicide, or abstinence) for the duration of the study and for one month following study completion. Female patients with childbearing potential must have a negative serum pregnancy test within the 7 days before the first NPI-0052 administration. Male patients must be surgically sterile or agree to use an acceptable method of contraception.
* Active uncontrolled bacterial or fungal infection requiring systemic therapy; infection requiring parenteral antibiotics.
* Known to be HIV positive or positive and active for hepatitis A, B, or C.
* Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient. Examples of such conditions include infection requiring parenteral or oral anti-infective treatment or any altered mental status or psychiatric condition that would interfere with an understanding of the informed consent.
* Unwilling or unable to comply with procedures required in this protocol.