Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

The primary objectives are:

Phase 1b:

* To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oprozomib given orally, once daily, on 2 different schedules.
* To evaluate safety and tolerability

Phase 2:

* To estimate the overall response rate (ORR).
* To evaluate safety and tolerability

The purpose of the Phase 1b portion of the study was to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), safety, and pharmacokinetics (PK) of oprozomib administered orally once daily in combination with dexamethasone, in participants with relapsed and/or refractory multiple myeloma, using a 3 + 3 dose-escalation scheme with and without step-up dosing. The MTD was defined as the highest dose level at which fewer than 33% of participants had a dose-limiting toxicity (DLT).

Eligibility Criteria:
Key Inclusion Criteria:

1. Diagnosis of multiple myeloma with measureable disease as indicated by 1 or more of the following:

   * a. Serum M-protein ≥ 500 mg/dL
   * b. Urine M-protein ≥ 200 mg/24 hours
   * c. Only for subjects without measurable serum and urine M-protein, serum free light chain: Involved free light chain (FLC) level ≥ 10 mg/dL, provided serum FLC ratio is abnormal
2. Patients requiring therapy who have relapsed and/or are refractory to their last therapy and have been treated with at least 1, but not more than 5, lines of multiple myeloma therapy. Prior therapy must have consisted of at least 1 regimen that included lenalidomide and/or bortezomib. Patients should be considered to be appropriate candidates for a clinical study by their treating physicians. Relapsed patients must have previously achieved ≥ minimal response (MR) on at least 1 line of therapy, as assessed by the treating physician. Refractory patients are allowed, but it is not required that patients be refractory to their last therapy. Primary refractory patients are allowed in the Phase 1b portion of the study only.
3. Males and females ≥ 18 years of age
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2
5. Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal (ULN) in the absence of Gilbert's disease or hemolysis, aspartate aminotransferase (AST) ≤ 3 times ULN, and alanine aminotransferase (ALT) ≤ 3 times ULN
6. Absolute neutrophil count (ANC) ≥ 1000 cells/mcL, hemoglobin ≥ 7.0 g/dL, and platelet count ≥ 30,000 cells/mcL:

   * a. Patients must not have received platelet transfusions for at least 1 week prior to Screening.
   * b. Screening ANC must be independent of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for

     ≥ 2 weeks prior to first dose.
   * c. Patients may receive red blood cell (RBC) transfusions or receive supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines.
7. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault (\[140 - Age\] \* Mass (kg) / \[72 \* creatinine mg/mL\]). Multiply result by 0.85 if female.
8. Uric acid, if elevated, must be corrected to within laboratory normal range before dosing.
9. Patients must sign a written informed consent form in accordance with federal, local, and institutional guidelines.
10. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to receiving the first dose of study drug and agree to use effective methods of contraception during the study and for 3 months following the last dose of study drug. Postmenopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.
11. Prior carfilzomib is not required but is allowed if a patient had at least 2 cycles of carfilzomib alone or in combination with a dose of at least 20/27 mg/m\^2, as long as the patient:

    * a. Had at least a partial response to prior carfilzomib therapy
    * b. Was not removed from carfilzomib therapy due to toxicity, unless approved by the medical monitor
    * c. Was not removed from carfilzomib therapy for progressive disease nor experienced progressive disease within 6 months after any prior carfilzomib therapy.

Key Exclusion Criteria:

1. Radiation therapy within 2 weeks prior to first dose; localized radiation therapy within 1 week prior to first dose
2. Immunotherapy/standard myeloma therapy within 2 weeks prior to first dose (except for antibody therapy, where 6 weeks are required, and alkylator therapy, where 3 weeks are required); prior stem cell transplant (SCT) therapy (autologous SCT within the prior 8 weeks; allogeneic SCT within the prior 16 weeks). Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (GvHD).
3. Plasmapheresis is not permitted at any time during the Screening period or while the subject is receiving study treatment. If a subject has started screening procedures requiring plasmapheresis, or is anticipated to require plasmapheresis during or after the Screening period, this patient will be considered ineligible and should not be enrolled.
4. Glucocorticoid therapy within 14 days prior to enrollment that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent
5. Participation in an investigational therapeutic study within 3 weeks prior to first dose
6. Prior oprozomib exposure
7. Known hypersensitivity/toxicity or intolerance to dexamethasone
8. Major surgery within 3 weeks prior to first dose
9. Congestive heart failure (\[CHF\] New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to first dose
10. Uncontrolled hypertension or uncontrolled diabetes
11. Active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose
12. Known or suspected human immunodeficiency virus (HIV) infection or patients who are HIV seropositive
13. Active hepatitis A, B, or C infection
14. History of previous clinically significant GI bleed in the last 6 months prior to first dose
15. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose
16. Other malignancy within the past 3 years, with the exception of adequately treated basal cell carcinoma of the skin, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate cancer of Gleason Score of 6 or less with stable prostate specific antigen levels, or cancer considered cured by surgical resection
17. Plasma cell leukemia
18. Female patients who are pregnant or nursing
19. Inability to swallow medication, inability or unwillingness to comply with the drug administration requirements, or GI condition that could interfere with the oral absorption or tolerance of treatment
20. Any contraindication to oral hydration (e.g., significant preexisting comorbidity or fluid restriction)
21. Any clinically significant psychiatric or medical condition that in the opinion of the investigator could increase patient risk or interfere with protocol adherence or a patient's ability to give informed consent.