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

Sponsor
Amgen (Industry)
Overall Status
Terminated
CT.gov ID
NCT01832727
Collaborator
(none)
65
Enrollment
13
Locations
9
Arms
71.8
Actual Duration (Months)
5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

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).

Study Design

Study Type:
Interventional
Actual Enrollment :
65 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma
Actual Study Start Date :
Jul 2, 2013
Actual Primary Completion Date :
Jun 25, 2019
Actual Study Completion Date :
Jun 25, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 180 mg 5/14 Schedule (Phase 1b)

Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib
Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 210 mg 5/14 Schedule (Phase 1b)

    Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 150/180 mg 5/14 Schedule (Phase 1b)

    Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 210 mg 2/7 Schedule (Phase 1b)

    Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 240 mg 2/7 Schedule (Phase 1b)

    Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 270 mg 2/7 Schedule (Phase 1b)

    Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 300 mg 2/7 Schedule (Phase 1b)

    Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Cohort 330 mg 2/7 Schedule (Phase 1b)

    Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.
    Experimental: Phase 2 300 mg 2/7 Schedule

    The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Drug: Oprozomib
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.
    Other Names:
  • OPZ
  • ONX 0912
  • oprozomib ER

    • Drug: Dexamethasone
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Outcome Measures

    Primary Outcome Measures

    1. Participants With Dose-Limiting Toxicities (DLT) [Day 1 to Day 14 (Cycle 1) for continous dosing and Day 15 to Day 28 (Cycle 2) for step-up dosing]

      Toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.03) were considered DLTs if judged by the investigator to be related to oprozomib and occurred in the first 14 days of treatment, with treatment at the dose to be studied (i.e., Cycle 1 for continuous dosing or Cycle 2 for step-up dosing). A DLT was categorized as nonhematologic or hematologic. Examples include: Any ≥ Grade 3 nonhematologic AE, with exceptions or qualifications such as Grade 3 nausea, vomiting, diarrhea, or constipation were considered a DLT only if lasting for > 7 days despite optimal supportive care Grade 3 fatigue lasting > 14 days Grade 4 neutropenia: absolute neutrophil count (ANC) < 500 cells/mcL lasting ≥ 7 days Febrile neutropenia: Any single temperature ≥ 38.3°C or a sustained temperature of ≥ 38.0°C for over 1 hour with ≥ Grade 3 neutropenia (ANC < 1000 cells/mcL) Grade 3/4 thrombocytopenia Others specified in the protocol

    2. Participants With Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2 [Day 1 up to Week 282]

      AE defined as any untoward medical occurrence in a clinical trial participant. Treatment-emergent adverse events were defined as adverse events that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An adverse event that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered to be treatment-emergent. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product

    3. Participants With Treatment-Related, Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2 [Day 1 up to Week 282]

      AE defined as any untoward medical occurrence in a clinical trial participant. TEAEs were defined as AEs that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An AE that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered a TEAE. Investigator assessed AEs for relatedness to study drug. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product

    4. Best Overall Response in Phase 2 as Assessed by Investigator [Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months]

      Disease response and progression were determined using the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC), except for minimal response (MR) and near complete response (nCR) which was based on the European Group for Blood and Marrow Transplantation (EBMT) criteria. Evaluations reported were assessed by the investigator for participants in Phase 2.

    5. Percentage of Participants Who Achieved an Overall Response As Assessed by Investigator During Phase 2 [Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months]

      The overall response rate (ORR) was defined as the percentage of participants 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.

    Secondary Outcome Measures

    1. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Time to Maximum Serum Concentration (Tmax) on Cycle 1, Day 1 [Day 1]

      PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    2. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Maximum Serum Concentration (Cmax) on Cycle 1, Day 1 [Day 1]

      PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    3. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve at the Last Measurable Time Point (AUClast) on Cycle 1, Day 1 [Day 1]

      The area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    4. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve From Time 0 to Time Infinity (AUCinf) on Cycle 1, Day 1 [Day 1]

      The area under the plasma concentration-curve from time 0 to time infinity (AUCinf) was estimated using the linear trapezoidal method PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    5. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Terminal Half-Life (t1/2,z) on Cycle 1, Day 1 [Day 1]

      PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    6. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Apparent Drug Clearance After Oral Administration (CL/F) on Cycle 1, Day 1 [Day 1]

      The apparent drug clearance after oral administration (CL/F) was calculated as the dose divided by AUCinf. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    7. Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Apparent Volume of Distribution After Oral Administration (Vz/F) on Cycle 1, Day 1 [Day 1]

      The apparent volume of distribution after oral administration (Vz/F) calculated as the dose divided by AUCinf times ƒz, where ƒz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2

    8. Percentage of Participants Who Achieved a Clinical Benefit Response As Assessed by Investigator During Phase 2 [Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months]

      The clinical benefit rate (CBR) was defined as Overall Response Rate (ORR) plus Minimal Response (MR) as defined by the European Group for Blood and Marrow Transplantation (EBMT) criteria.

    9. Kaplan-Meier Estimates for Duration of Response (DOR) as Assessed by Investigator During Phase 2 [Day 1 up to 13.16 months]

      Duration of response was defined as the time from first evidence of partial response (PR) or better (i.e. best overall response) to confirmation of disease progression or death due to any cause. Durations were calculated for responders only. Medians and percentiles were estimated using the Kaplan-Meier method. 95% confidence intervals for medians and percentiles were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.

    10. Kaplan-Meier Estimates for Progression-free Survival (PFS) as Assessed by Investigator During Phase 2 [Day 1 up to 14.1 months]

      Progression-free survival (PFS) was defined as number of months between start of treatment and first evidence of documented disease progression or death (due to any cause), whichever occurs first. Disease progression was determined using IMWG-URC per investigator. The duration of PFS was right-censored for participants who met 1 of the following conditions: 1) starting a new anticancer therapy before documentation of disease progression or death; 2) death or disease progression immediately after more than 1 consecutively missed disease assessment visit or; 3) alive without documentation of disease progression before the data cutoff date. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.

    11. Kaplan-Meier Estimate for Time to Progression (TTP) as Assessed by Investigator During Phase 2 [Day 1 up to 14.1 months]

      Time to progression (TTP) was defined as the number of months between the start of treatment to the first documentation of disease progression. Disease progression was determined using IMWG-URC as assessed by the investigator. The same censoring rules, except for death, as in analysis of PFS were applied in the calculation of TTP. Participants who died prior to progressive disease were censored at the date of last evaluable response assessment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:
    1. Diagnosis of multiple myeloma with measureable disease as indicated by 1 or more of the following:
      1. Serum M-protein ≥ 500 mg/dL
      1. Urine M-protein ≥ 200 mg/24 hours
      1. 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

    1. 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.

    2. Males and females ≥ 18 years of age

    3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2

    4. 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

    5. Absolute neutrophil count (ANC) ≥ 1000 cells/mcL, hemoglobin ≥ 7.0 g/dL, and platelet count ≥ 30,000 cells/mcL:

      1. Patients must not have received platelet transfusions for at least 1 week prior to Screening.
      1. 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.

      1. Patients may receive red blood cell (RBC) transfusions or receive supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines.

    1. 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.

    2. Uric acid, if elevated, must be corrected to within laboratory normal range before dosing.

    3. Patients must sign a written informed consent form in accordance with federal, local, and institutional guidelines.

    4. 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.

    5. 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:

      1. Had at least a partial response to prior carfilzomib therapy
      1. Was not removed from carfilzomib therapy due to toxicity, unless approved by the medical monitor
      1. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 USC/Norris Comprehensive Cancer Center Los Angeles California United States
    2 H. Lee Moffitt Cancer Center & Research Institute Tampa Florida United States
    3 University of Kansas Cancer Center and Medical Pavilion Westwood Kansas United States
    4 Center for Cancer and Blood Disorders Bethesda Maryland United States
    5 Dana-Farber Cancer Institute Boston Massachusetts United States
    6 Massachusetts General Hospital Boston Massachusetts United States
    7 Karmanos Cancer Institute Detroit Michigan United States
    8 Division of Hematology/ Oncology, UNC at Chapel Hill Chapel Hill North Carolina United States
    9 Gabrail Cancer Center Research Canton Ohio United States
    10 Froedtert Hospital and the Medical College of Wisconsin Milwaukee Wisconsin United States
    11 CHRU, Hopital Huriez - Department of Hematology Lille CEDEX France
    12 CHU Hotel Dieu - Service d'Hematologie Clinique NANTES Cedex France
    13 CHU de NANCY - Hopital de BRABOlS Vandoeuvre Les Nancy France

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT01832727
    Other Study ID Numbers:
    • 2012-001
    • 20130408
    • 2013-001169-18
    First Posted:
    Apr 16, 2013
    Last Update Posted:
    Jul 13, 2020
    Last Verified:
    Jun 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Amgen
    multiple myeloma
    oprozomib
    OPZ
    ONX 0912
    Onyx
    proteasome inhibitor
    oprozomib tablets
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Dexamethasone

    Study Results

    Participant Flow

    Recruitment Details This study was conducted at 18 centers in the United States and France.
    Pre-assignment Detail Eighty-one subjects were screened; sixteen were not enrolled due to entry criteria violations.
    Arm/Group Title Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Arm/Group Description Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Period Title: Overall Study
    STARTED 9 7 3 4 4 6 8 6 18
    COMPLETED 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 9 7 3 4 4 6 8 6 18

    Baseline Characteristics

    Arm/Group Title Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule Total
    Arm/Group Description Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Total of all reporting groups
    Overall Participants 9 7 3 4 4 6 8 6 18 65
    Age, Customized (Count of Participants)
    <65 years
    5
    55.6%
    4
    57.1%
    2
    66.7%
    1
    25%
    4
    100%
    2
    33.3%
    4
    50%
    5
    83.3%
    6
    33.3%
    33
    50.8%
    65 - <75 years
    2
    22.2%
    3
    42.9%
    0
    0%
    2
    50%
    0
    0%
    3
    50%
    3
    37.5%
    0
    0%
    7
    38.9%
    20
    30.8%
    >=75 years
    2
    22.2%
    0
    0%
    1
    33.3%
    1
    25%
    0
    0%
    1
    16.7%
    1
    12.5%
    1
    16.7%
    5
    27.8%
    12
    18.5%
    Sex: Female, Male (Count of Participants)
    Female
    3
    33.3%
    4
    57.1%
    1
    33.3%
    2
    50%
    1
    25%
    2
    33.3%
    3
    37.5%
    2
    33.3%
    9
    50%
    27
    41.5%
    Male
    6
    66.7%
    3
    42.9%
    2
    66.7%
    2
    50%
    3
    75%
    4
    66.7%
    5
    62.5%
    4
    66.7%
    9
    50%
    38
    58.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    2
    3.1%
    Not Hispanic or Latino
    9
    100%
    7
    100%
    3
    100%
    4
    100%
    2
    50%
    6
    100%
    8
    100%
    5
    83.3%
    11
    61.1%
    55
    84.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    7
    38.9%
    8
    12.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    11.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    1
    33.3%
    1
    25%
    1
    25%
    2
    33.3%
    1
    12.5%
    1
    16.7%
    1
    5.6%
    8
    12.3%
    White
    8
    88.9%
    7
    100%
    2
    66.7%
    3
    75%
    2
    50%
    4
    66.7%
    7
    87.5%
    4
    66.7%
    10
    55.6%
    47
    72.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    1
    16.7%
    7
    38.9%
    9
    13.8%

    Outcome Measures

    1. Primary Outcome
    Title Participants With Dose-Limiting Toxicities (DLT)
    Description Toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.03) were considered DLTs if judged by the investigator to be related to oprozomib and occurred in the first 14 days of treatment, with treatment at the dose to be studied (i.e., Cycle 1 for continuous dosing or Cycle 2 for step-up dosing). A DLT was categorized as nonhematologic or hematologic. Examples include: Any ≥ Grade 3 nonhematologic AE, with exceptions or qualifications such as Grade 3 nausea, vomiting, diarrhea, or constipation were considered a DLT only if lasting for > 7 days despite optimal supportive care Grade 3 fatigue lasting > 14 days Grade 4 neutropenia: absolute neutrophil count (ANC) < 500 cells/mcL lasting ≥ 7 days Febrile neutropenia: Any single temperature ≥ 38.3°C or a sustained temperature of ≥ 38.0°C for over 1 hour with ≥ Grade 3 neutropenia (ANC < 1000 cells/mcL) Grade 3/4 thrombocytopenia Others specified in the protocol
    Time Frame Day 1 to Day 14 (Cycle 1) for continous dosing and Day 15 to Day 28 (Cycle 2) for step-up dosing

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Arm/Group Description Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 9 7 3 4 4 6 8 6 18
    Participants reporting >=1 DLT
    0
    0%
    3
    42.9%
    1
    33.3%
    0
    0%
    0
    0%
    2
    33.3%
    0
    0%
    2
    33.3%
    1
    5.6%
    Mental status changes
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alanine aminotransferase increased
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Aspartate aminotransferase increased
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypertension
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Subarachnoid haemorrhage
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Thrombocytopenia
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    Anemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    5.6%
    Nausea
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    Upper respiratory tract infection
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    Vomiting
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    Pain in jaw
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Participants With Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2
    Description AE defined as any untoward medical occurrence in a clinical trial participant. Treatment-emergent adverse events were defined as adverse events that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An adverse event that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered to be treatment-emergent. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product
    Time Frame Day 1 up to Week 282

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Arm/Group Description Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 9 7 3 4 4 6 8 6 18
    >=1 TEAE
    9
    100%
    7
    100%
    3
    100%
    4
    100%
    4
    100%
    6
    100%
    8
    100%
    6
    100%
    18
    100%
    Grade >=3 (severe)
    8
    88.9%
    5
    71.4%
    2
    66.7%
    3
    75%
    3
    75%
    5
    83.3%
    6
    75%
    5
    83.3%
    16
    88.9%
    Serious AE
    4
    44.4%
    2
    28.6%
    2
    66.7%
    2
    50%
    1
    25%
    1
    16.7%
    3
    37.5%
    0
    0%
    9
    50%
    Leading to discontinuation of IP
    4
    44.4%
    6
    85.7%
    1
    33.3%
    0
    0%
    1
    25%
    1
    16.7%
    2
    25%
    1
    16.7%
    11
    61.1%
    Fatal AE
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3. Primary Outcome
    Title Participants With Treatment-Related, Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2
    Description AE defined as any untoward medical occurrence in a clinical trial participant. TEAEs were defined as AEs that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An AE that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered a TEAE. Investigator assessed AEs for relatedness to study drug. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product
    Time Frame Day 1 up to Week 282

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Arm/Group Description Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 9 7 3 4 4 6 8 6 18
    >=1 related TEAE
    9
    100%
    7
    100%
    3
    100%
    4
    100%
    4
    100%
    6
    100%
    8
    100%
    6
    100%
    18
    100%
    Grade >=3 (severe)
    8
    88.9%
    5
    71.4%
    2
    66.7%
    2
    50%
    2
    50%
    2
    33.3%
    4
    50%
    3
    50%
    14
    77.8%
    Serious AE
    3
    33.3%
    2
    28.6%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    2
    25%
    0
    0%
    3
    16.7%
    Leading to discontinuation of IP
    3
    33.3%
    6
    85.7%
    0
    0%
    0
    0%
    1
    25%
    1
    16.7%
    1
    12.5%
    1
    16.7%
    7
    38.9%
    Fatal AE
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4. Primary Outcome
    Title Best Overall Response in Phase 2 as Assessed by Investigator
    Description Disease response and progression were determined using the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC), except for minimal response (MR) and near complete response (nCR) which was based on the European Group for Blood and Marrow Transplantation (EBMT) criteria. Evaluations reported were assessed by the investigator for participants in Phase 2.
    Time Frame Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months

    Outcome Measure Data

    Analysis Population Description
    Safety Population
    Arm/Group Title Phase 2 300 mg 2/7 Schedule
    Arm/Group Description The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 18
    Stringent Complete Response (sCR)
    0
    0%
    Complete Response (CR)
    1
    11.1%
    Near Complete Response (nCR)
    0
    0%
    Very Good Partial Response (VGPR)
    2
    22.2%
    Partial Response (PR)
    9
    100%
    Minimal Response (MR)
    1
    11.1%
    Stable Disease (SD)
    2
    22.2%
    Progressive Disease (PD)
    1
    11.1%
    Not Evaluable (NE)
    2
    22.2%
    Unknown
    0
    0%
    5. Primary Outcome
    Title Percentage of Participants Who Achieved an Overall Response As Assessed by Investigator During Phase 2
    Description The overall response rate (ORR) was defined as the percentage of participants 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.
    Time Frame Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months

    Outcome Measure Data

    Analysis Population Description
    Safety Population
    Arm/Group Title Phase 2 300 mg 2/7 Schedule
    Arm/Group Description The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 18
    Number (95% Confidence Interval) [percentage of participants]
    66.7
    741.1%
    6. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Time to Maximum Serum Concentration (Tmax) on Cycle 1, Day 1
    Description PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 9 9 4 6 5 3 19 6
    Median (Full Range) [hours]
    1.0
    1.1
    1.0
    1.0
    2.0
    2.0
    1.0
    1.5
    7. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Maximum Serum Concentration (Cmax) on Cycle 1, Day 1
    Description PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 9 9 4 6 5 3 19 6
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    633
    (192.1)
    754
    (91.7)
    841
    (73.8)
    906
    (69.3)
    881
    (37.8)
    672
    (54.5)
    785
    (63.7)
    578
    (80.1)
    8. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve at the Last Measurable Time Point (AUClast) on Cycle 1, Day 1
    Description The area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 9 9 4 6 5 3 19 6
    Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL]
    1140
    (197.4)
    1770
    (104.7)
    2170
    (51.8)
    1900
    (68.9)
    2530
    (63.4)
    1690
    (16.1)
    1740
    (70.3)
    1690
    (70.8)
    9. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve From Time 0 to Time Infinity (AUCinf) on Cycle 1, Day 1
    Description The area under the plasma concentration-curve from time 0 to time infinity (AUCinf) was estimated using the linear trapezoidal method PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 7 6 4 4 5 1 15 4
    Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL]
    947
    (229.7)
    1600
    (127.2)
    2180
    (51.6)
    1970
    (88.8)
    2550
    (63.5)
    NA
    (NA)
    1900
    (77.7)
    2150
    (27.6)
    10. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Terminal Half-Life (t1/2,z) on Cycle 1, Day 1
    Description PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 7 6 4 4 5 1 15 4
    Geometric Mean (Geometric Coefficient of Variation) [hr]
    0.962
    (40.6)
    0.573
    (29.4)
    0.970
    (79.2)
    0.850
    (29.5)
    1.36
    (80.1)
    NA
    (NA)
    0.710
    (40.7)
    0.805
    (40.1)
    11. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Apparent Drug Clearance After Oral Administration (CL/F) on Cycle 1, Day 1
    Description The apparent drug clearance after oral administration (CL/F) was calculated as the dose divided by AUCinf. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 7 6 4 4 5 1 15 4
    Geometric Mean (Geometric Coefficient of Variation) [mL/hr]
    190000
    (229.7)
    131000
    (127.2)
    110000
    (51.6)
    137000
    (88.8)
    118000
    (63.5)
    NA
    (NA)
    157000
    (77.7)
    153000
    (27.6)
    12. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Apparent Volume of Distribution After Oral Administration (Vz/F) on Cycle 1, Day 1
    Description The apparent volume of distribution after oral administration (Vz/F) calculated as the dose divided by AUCinf times ƒz, where ƒz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Arm/Group Description Participants who were administered 180 mg oprozomib tablets. Participants who were administered 210 mg oprozomib tablets. Participants who were administered 240 mg oprozomib tablets. Participants who were administered 270 mg oprozomib tablets. Participants who were administered 300 mg oprozomib tablets. Participants who were administered 150 mg extended release oprozomib tablets. Participants who were administered 300 mg extended release oprozomib tablets. Participants who were administered 330 mg extended release oprozomib tablets.
    Measure Participants 7 6 4 4 5 1 15 4
    Geometric Mean (Geometric Coefficient of Variation) [mL]
    264000
    (235.6)
    108000
    (106.7)
    154000
    (79.5)
    168000
    (138.9)
    231000
    (54.7)
    NA
    (NA)
    161000
    (69.0)
    178000
    (44.3)
    13. Secondary Outcome
    Title Percentage of Participants Who Achieved a Clinical Benefit Response As Assessed by Investigator During Phase 2
    Description The clinical benefit rate (CBR) was defined as Overall Response Rate (ORR) plus Minimal Response (MR) as defined by the European Group for Blood and Marrow Transplantation (EBMT) criteria.
    Time Frame Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months

    Outcome Measure Data

    Analysis Population Description
    Safety Population
    Arm/Group Title Phase 2 300 mg 2/7 Schedule
    Arm/Group Description The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 18
    Number (95% Confidence Interval) [percentage of participants]
    72.2
    802.2%
    14. Secondary Outcome
    Title Kaplan-Meier Estimates for Duration of Response (DOR) as Assessed by Investigator During Phase 2
    Description Duration of response was defined as the time from first evidence of partial response (PR) or better (i.e. best overall response) to confirmation of disease progression or death due to any cause. Durations were calculated for responders only. Medians and percentiles were estimated using the Kaplan-Meier method. 95% confidence intervals for medians and percentiles were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
    Time Frame Day 1 up to 13.16 months

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2 300 mg 2/7 Schedule
    Arm/Group Description The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 18
    Median (95% Confidence Interval) [months]
    NA
    15. Secondary Outcome
    Title Kaplan-Meier Estimates for Progression-free Survival (PFS) as Assessed by Investigator During Phase 2
    Description Progression-free survival (PFS) was defined as number of months between start of treatment and first evidence of documented disease progression or death (due to any cause), whichever occurs first. Disease progression was determined using IMWG-URC per investigator. The duration of PFS was right-censored for participants who met 1 of the following conditions: 1) starting a new anticancer therapy before documentation of disease progression or death; 2) death or disease progression immediately after more than 1 consecutively missed disease assessment visit or; 3) alive without documentation of disease progression before the data cutoff date. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
    Time Frame Day 1 up to 14.1 months

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2 300 mg 2/7 Schedule
    Arm/Group Description The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 18
    Median (95% Confidence Interval) [months]
    12.2
    16. Secondary Outcome
    Title Kaplan-Meier Estimate for Time to Progression (TTP) as Assessed by Investigator During Phase 2
    Description Time to progression (TTP) was defined as the number of months between the start of treatment to the first documentation of disease progression. Disease progression was determined using IMWG-URC as assessed by the investigator. The same censoring rules, except for death, as in analysis of PFS were applied in the calculation of TTP. Participants who died prior to progressive disease were censored at the date of last evaluable response assessment.
    Time Frame Day 1 up to 14.1 months

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2 300 mg 2/7 Schedule
    Arm/Group Description The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Measure Participants 18
    Median (95% Confidence Interval) [months]
    12.2

    Adverse Events

    Time Frame All-cause Mortality - Death that occurred from the date of enrollment until the data cutoff of 30 July 2019. Treatment-emergent adverse events - Day 1 up to Week 282
    Adverse Event Reporting Description All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
    Arm/Group Title Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Arm/Group Description Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14- day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    All Cause Mortality
    Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Serious Adverse Events
    Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/9 (44.4%) 2/7 (28.6%) 2/3 (66.7%) 2/4 (50%) 1/4 (25%) 1/6 (16.7%) 3/8 (37.5%) 0/6 (0%) 9/18 (50%)
    Blood and lymphatic system disorders
    Neutropenia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Thrombocytopenia 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Gastrointestinal disorders
    Diarrhoea 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Gastrointestinal haemorrhage 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Nausea 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Oesophagitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    General disorders
    Non-cardiac chest pain 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Infections and infestations
    Clostridium difficile infection 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Influenza 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Meningitis aseptic 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Pneumonia 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 3/18 (16.7%)
    Sepsis 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Septic shock 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Spinal cord infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Urinary tract infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Injury, poisoning and procedural complications
    Subarachnoid haemorrhage 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Metabolism and nutrition disorders
    Dehydration 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Tumour lysis syndrome 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Musculoskeletal and connective tissue disorders
    Bone lesion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Psychiatric disorders
    Delirium 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Renal and urinary disorders
    Acute kidney injury 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Vascular disorders
    Hypertension 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Other (Not Including Serious) Adverse Events
    Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/9 (100%) 7/7 (100%) 3/3 (100%) 4/4 (100%) 4/4 (100%) 6/6 (100%) 8/8 (100%) 6/6 (100%) 18/18 (100%)
    Blood and lymphatic system disorders
    Anaemia 3/9 (33.3%) 2/7 (28.6%) 1/3 (33.3%) 1/4 (25%) 1/4 (25%) 0/6 (0%) 5/8 (62.5%) 3/6 (50%) 8/18 (44.4%)
    Leukopenia 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Lymphopenia 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Microcytic anaemia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Neutropenia 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Thrombocytopenia 1/9 (11.1%) 2/7 (28.6%) 1/3 (33.3%) 1/4 (25%) 1/4 (25%) 2/6 (33.3%) 3/8 (37.5%) 2/6 (33.3%) 4/18 (22.2%)
    Cardiac disorders
    Angina unstable 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Arrhythmia 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Atrial fibrillation 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Bundle branch block right 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Diastolic dysfunction 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Palpitations 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Pericardial effusion 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Sinus tachycardia 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Tachycardia 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Ventricular extrasystoles 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Ear and labyrinth disorders
    Cerumen impaction 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Ear congestion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Ear discomfort 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Middle ear effusion 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Otorrhoea 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Tinnitus 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Vertigo 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 3/18 (16.7%)
    Eye disorders
    Cataract 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Vision blurred 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 2/6 (33.3%) 2/18 (11.1%)
    Visual impairment 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Vitreous floaters 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Gastrointestinal disorders
    Abdominal discomfort 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 2/18 (11.1%)
    Abdominal distension 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 2/6 (33.3%) 7/18 (38.9%)
    Abdominal pain 2/9 (22.2%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 6/18 (33.3%)
    Abdominal pain upper 3/9 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 4/18 (22.2%)
    Abdominal rigidity 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Anal incontinence 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Constipation 2/9 (22.2%) 2/7 (28.6%) 1/3 (33.3%) 2/4 (50%) 1/4 (25%) 1/6 (16.7%) 4/8 (50%) 5/6 (83.3%) 10/18 (55.6%)
    Dental caries 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Diarrhoea 8/9 (88.9%) 6/7 (85.7%) 2/3 (66.7%) 4/4 (100%) 3/4 (75%) 6/6 (100%) 7/8 (87.5%) 5/6 (83.3%) 14/18 (77.8%)
    Diverticulum 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Dry mouth 2/9 (22.2%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Dyspepsia 3/9 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 2/4 (50%) 1/6 (16.7%) 2/8 (25%) 0/6 (0%) 6/18 (33.3%)
    Eructation 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Faeces soft 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Flatulence 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Functional gastrointestinal disorder 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Gastrointestinal motility disorder 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Gastrointestinal sounds abnormal 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Gastrooesophageal reflux disease 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 3/8 (37.5%) 2/6 (33.3%) 2/18 (11.1%)
    Gingival bleeding 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Glossodynia 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Haematochezia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Haemorrhoids 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Hypoaesthesia oral 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Ileus 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Large intestine polyp 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Lip haematoma 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Nausea 8/9 (88.9%) 7/7 (100%) 3/3 (100%) 4/4 (100%) 3/4 (75%) 5/6 (83.3%) 7/8 (87.5%) 6/6 (100%) 12/18 (66.7%)
    Oral disorder 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Periodontal disease 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Retching 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Salivary hypersecretion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Stomatitis 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Toothache 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Vomiting 6/9 (66.7%) 5/7 (71.4%) 3/3 (100%) 4/4 (100%) 3/4 (75%) 2/6 (33.3%) 2/8 (25%) 5/6 (83.3%) 8/18 (44.4%)
    General disorders
    Asthenia 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 8/18 (44.4%)
    Chest discomfort 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Chest pain 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/18 (0%)
    Chills 2/9 (22.2%) 0/7 (0%) 2/3 (66.7%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 2/6 (33.3%) 3/18 (16.7%)
    Discomfort 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Facial pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Fatigue 6/9 (66.7%) 4/7 (57.1%) 2/3 (66.7%) 2/4 (50%) 2/4 (50%) 4/6 (66.7%) 7/8 (87.5%) 6/6 (100%) 7/18 (38.9%)
    Feeling abnormal 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 0/6 (0%) 1/18 (5.6%)
    Feeling jittery 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Gait disturbance 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Influenza like illness 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Malaise 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Mucosal inflammation 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Nodule 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Oedema 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 2/6 (33.3%) 0/18 (0%)
    Oedema peripheral 1/9 (11.1%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 2/6 (33.3%) 5/18 (27.8%)
    Pain 0/9 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Pyrexia 2/9 (22.2%) 0/7 (0%) 2/3 (66.7%) 0/4 (0%) 2/4 (50%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 5/18 (27.8%)
    Hepatobiliary disorders
    Hepatitis cholestatic 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Immune system disorders
    Seasonal allergy 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Infections and infestations
    Bronchitis 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Candida infection 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Cellulitis 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Clostridium difficile infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Conjunctivitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Diverticulitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Fungal skin infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Gastroenteritis 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Genital herpes 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Haemophilus infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Herpes virus infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Herpes zoster 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Hordeolum 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Influenza 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Nasopharyngitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Pneumonia 1/9 (11.1%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Sepsis 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Sinusitis 2/9 (22.2%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Tinea cruris 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Tooth abscess 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Tooth infection 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Upper respiratory tract infection 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 3/6 (50%) 3/8 (37.5%) 5/6 (83.3%) 1/18 (5.6%)
    Urinary tract infection 2/9 (22.2%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Urinary tract infection enterococcal 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Viral upper respiratory tract infection 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Injury, poisoning and procedural complications
    Animal bite 1/9 (11.1%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Animal scratch 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Concussion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Contusion 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Fall 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Infusion related reaction 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Laceration 1/9 (11.1%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Muscle strain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Skin abrasion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Thermal burn 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Wound 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Investigations
    Alanine aminotransferase increased 0/9 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 1/8 (12.5%) 2/6 (33.3%) 0/18 (0%)
    Aspartate aminotransferase decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Aspartate aminotransferase increased 0/9 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 2/6 (33.3%) 0/18 (0%)
    Blood alkaline phosphatase decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Blood alkaline phosphatase increased 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Blood creatinine decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Blood creatinine increased 3/9 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 2/8 (25%) 0/6 (0%) 1/18 (5.6%)
    Blood lactate dehydrogenase increased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Blood phosphorus increased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Blood pressure abnormal 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Blood urea decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Blood uric acid decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Cardiac murmur 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Ejection fraction decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    International normalised ratio increased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Lymphocyte count decreased 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Neutrophil count decreased 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Platelet count decreased 2/9 (22.2%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Protein total increased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Weight decreased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 3/18 (16.7%)
    White blood cell count decreased 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    White blood cell count increased 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Metabolism and nutrition disorders
    Cell death 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Decreased appetite 5/9 (55.6%) 1/7 (14.3%) 2/3 (66.7%) 0/4 (0%) 3/4 (75%) 0/6 (0%) 2/8 (25%) 2/6 (33.3%) 5/18 (27.8%)
    Dehydration 0/9 (0%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Diabetes mellitus 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Fluid overload 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Hypercalcaemia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Hyperglycaemia 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 2/4 (50%) 1/6 (16.7%) 2/8 (25%) 0/6 (0%) 1/18 (5.6%)
    Hyperkalaemia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Hypermagnesaemia 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Hyperphosphataemia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Hyperuricaemia 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Hypoalbuminaemia 2/9 (22.2%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 2/18 (11.1%)
    Hypocalcaemia 3/9 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 2/6 (33.3%) 0/18 (0%)
    Hypoglycaemia 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 2/4 (50%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Hypokalaemia 4/9 (44.4%) 1/7 (14.3%) 1/3 (33.3%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 2/18 (11.1%)
    Hypomagnesaemia 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 2/6 (33.3%) 0/8 (0%) 2/6 (33.3%) 2/18 (11.1%)
    Hyponatraemia 2/9 (22.2%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 2/6 (33.3%) 2/18 (11.1%)
    Hypophosphataemia 1/9 (11.1%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 2/6 (33.3%) 1/18 (5.6%)
    Hypovolaemia 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Iron deficiency 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Lactic acidosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Malnutrition 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 3/6 (50%) 0/18 (0%)
    Arthritis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Back pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 1/18 (5.6%)
    Bone pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Exostosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Joint stiffness 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Joint swelling 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Limb discomfort 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Muscle spasms 1/9 (11.1%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 0/6 (0%) 6/18 (33.3%)
    Muscular weakness 0/9 (0%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 3/6 (50%) 1/18 (5.6%)
    Musculoskeletal chest pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 1/18 (5.6%)
    Musculoskeletal pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 1/6 (16.7%) 0/18 (0%)
    Myalgia 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 3/6 (50%) 2/18 (11.1%)
    Neck pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Osteonecrosis of jaw 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Pain in extremity 0/9 (0%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 1/6 (16.7%) 1/18 (5.6%)
    Pain in jaw 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 2/8 (25%) 0/6 (0%) 0/18 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Squamous cell carcinoma 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Nervous system disorders
    Cognitive disorder 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Dizziness 3/9 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 2/8 (25%) 2/6 (33.3%) 2/18 (11.1%)
    Dysgeusia 1/9 (11.1%) 2/7 (28.6%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 1/6 (16.7%) 3/8 (37.5%) 3/6 (50%) 4/18 (22.2%)
    Head discomfort 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Headache 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 2/4 (50%) 1/4 (25%) 1/6 (16.7%) 3/8 (37.5%) 1/6 (16.7%) 6/18 (33.3%)
    Hypoaesthesia 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 1/6 (16.7%) 0/18 (0%)
    Lethargy 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Memory impairment 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Neuropathy peripheral 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Paraesthesia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/18 (5.6%)
    Peripheral sensory neuropathy 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Presyncope 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Seizure 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Somnolence 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Tremor 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Psychiatric disorders
    Agitation 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Anxiety 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 3/18 (16.7%)
    Bruxism 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Confusional state 0/9 (0%) 1/7 (14.3%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Disorientation 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Insomnia 1/9 (11.1%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 2/8 (25%) 2/6 (33.3%) 4/18 (22.2%)
    Irritability 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 2/18 (11.1%)
    Mental disorder 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Mental status changes 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Thinking abnormal 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Renal and urinary disorders
    Acute kidney injury 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Dysuria 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 1/18 (5.6%)
    Haematuria 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Nocturia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Pollakiuria 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Renal failure 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Urinary hesitation 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Urinary incontinence 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Reproductive system and breast disorders
    Balanoposthitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Breast disorder 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Erectile dysfunction 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Uterine prolapse 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Vaginal haemorrhage 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Vaginal prolapse 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 1/9 (11.1%) 1/7 (14.3%) 1/3 (33.3%) 0/4 (0%) 2/4 (50%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 6/18 (33.3%)
    Dysphonia 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Dyspnoea 2/9 (22.2%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 2/6 (33.3%) 2/18 (11.1%)
    Dyspnoea exertional 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Epistaxis 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Haemoptysis 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Hiccups 2/9 (22.2%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 3/18 (16.7%)
    Hypoxia 0/9 (0%) 1/7 (14.3%) 2/3 (66.7%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Nasal congestion 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Oropharyngeal pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Orthopnoea 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Pleural effusion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Pleuritic pain 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Pulmonary embolism 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Respiratory failure 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Rhinitis allergic 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Rhinorrhoea 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Rhonchi 0/9 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Sinus congestion 0/9 (0%) 0/7 (0%) 0/3 (0%) 2/4 (50%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Sneezing 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Wheezing 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Angioedema 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Blister 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Chronic papillomatous dermatitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Dermatitis allergic 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Drug eruption 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Dry skin 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 2/6 (33.3%) 0/18 (0%)
    Ecchymosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Hair texture abnormal 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Hyperhidrosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 1/18 (5.6%)
    Miliaria 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Nail ridging 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Night sweats 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 1/18 (5.6%)
    Onychomadesis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Pruritus 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Rash 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Rash macular 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Rash maculo-papular 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Skin lesion 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Surgical and medical procedures
    Joint surgery 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Medical device implantation 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Vascular disorders
    Aortic aneurysm 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Deep vein thrombosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Flushing 0/9 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Haematoma 1/9 (11.1%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)
    Hot flush 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/18 (0%)
    Hypertension 3/9 (33.3%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 1/4 (25%) 2/6 (33.3%) 1/8 (12.5%) 2/6 (33.3%) 1/18 (5.6%)
    Hypotension 1/9 (11.1%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/18 (11.1%)
    Orthostatic hypotension 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 2/6 (33.3%) 0/18 (0%)
    Phlebitis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/18 (0%)
    Post thrombotic syndrome 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Thrombosis 0/9 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/18 (5.6%)
    Venous thrombosis 0/9 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/18 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen, Inc
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT01832727
    Other Study ID Numbers:
    • 2012-001
    • 20130408
    • 2013-001169-18
    First Posted:
    Apr 16, 2013
    Last Update Posted:
    Jul 13, 2020
    Last Verified:
    Jun 1, 2020