| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b:
- To determine the maximum tolerated dose (MTD) of oprozomib given orally, once daily, on 2 different schedules: 5 consecutive days every 14 days (bimonthly) or 2 consecutive days every 7 days (weekly) for a 14-day treatment cycle, both schedules given in combination with dexamethasone.
- To evaluate safety and tolerability.
Phase 2:
- To estimate the overall response rate (ORR), defined as the proportion of subjects with the best overall response of stringent complete response (sCR), complete response (CR), near complete response (nCR), very good partial response (VGPR), and partial response (PR) as defined by the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) and modified European Group for Blood and Marrow Transplantation (EBMT) criteria.
- To evaluate safety and tolerability. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate pharmacokinetics (PK).
- To estimate clinical benefit rate (CBR), defined as ORR plus minimal response (MR), as defined by the EBMT criteria.
- To estimate the duration of response (DOR).
- To estimate progression-free survival (PFS).
- To estimate time to progression (TTP). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 hour.
c. 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 consist of at least 1 regimen that included lenalidomide and/or bortezomib. Patients should be considered to be an appropriate candidate for a clinical trial by their treating physician. Relapsed patients must have previously achieved ≥ 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 (ECOG) Performance Status 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- 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.
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) rate of ≥ 30 mL/min calculated using the formula of Cockcroft and Gault [(140 – age) × mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female.
8. Patients must sign written informed consent form (ICF) in accordance with federal, local, and institutional guidelines.
9. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to receiving the first dose 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. |
|
| E.4 | Principal 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 is required and alkylator therapy, where 3 weeks is 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. Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent.
4. Participation in an investigational therapeutic study within 3 weeks prior to first dose.
5. Patients who failed to respond to carfilzomib defined as not having achieved ≥ PR during therapy.
6. Carfilzomib exposure within 6 months prior to first dose
7. Prior oprozomib exposure.
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. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose.
15. 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 6 or less with stable prostate specific antigen levels, or cancer considered cured by surgical resection.
16. Plasma cell leukemia.
17. Female patients who are pregnant or nursing.
18. Any clinically significant psychiatric or medical condition that in the opinion of the investigator could increase patient risk, interfere with protocol adherence or a patient’s ability to give informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
- Dose-limiting toxicities identified to determine the MTD, defined as the highest dose at which < 33% of subjects experience DLTs after 1 cycle (14 days) of treatment.
- Safety and tolerability.
Phase 2:
- Overall response status, to determine whether a subject has a best response of sCR, CR, nCR, VGPR, or PR, as defined by IMWG-URC and EBMT criteria.
- Safety and tolerability. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease response will be assessed every 8 weeks (4 cycles) after 1 year on therapy. |
|
| E.5.2 | Secondary end point(s) |
-Phase 1b/2:
- Pharmacokinetics of oprozomib.
Phase 2:
- Clinical benefit response status, to determine whether a subject has a best response of sCR, CR, VGPR, or PR, as defined by IMWG-URC and MR or nCR per EBMT criteria.
- Duration of response.
- Progression-free survival.
- Time to response.
- Time to progression |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Disease response will be assessed every 8 weeks (4 cycles) after 1 year on therapy. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of the trial is defined as the 30 days follow-up visit after the last dose of oprozomib.
(Subjects will be treated in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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