Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Dexamethasone acetate

Proteasome Inhibitors

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

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.

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.

Oprozomib

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.

The primary objectives are:

Phase 1b:

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

Phase 2:

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

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

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

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

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

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

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.

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.

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

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

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

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

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

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.

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.

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 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.

Amgen

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.

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.

Cohort 180 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.

Cohort 210 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.

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)

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.

Phase 2 300 mg 2/7 Schedule

Total

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Safety population: all subjects who receive at least 1 dose of study treatment

Study Director

Participants reporting >=1 DLT

Mental status changes

Alanine aminotransferase increased

Aspartate aminotransferase increased

Hypertension

Subarachnoid haemorrhage

Thrombocytopenia

Anemia

Nausea

Upper respiratory tract infection

Vomiting

Pain in jaw

Participants With Dose-Limiting Toxicities (DLT)

>=1 TEAE

Grade >=3 (severe)

Serious AE

Leading to discontinuation of IP

Fatal AE

Participants With Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2

>=1 related TEAE

Participants With Treatment-Related, Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2

Best Overall Response in Phase 2 as Assessed by Investigator

Percentage of Participants Who Achieved an Overall Response As Assessed by Investigator During Phase 2

Participants who were administered 180 mg oprozomib tablets.

180 mg Oprozomib Tablet

Participants who were administered 210 mg oprozomib tablets.

210 mg Oprozomib Tablet

Participants who were administered 240 mg oprozomib tablets.

240 mg Oprozomib Tablet

Participants who were administered 270 mg oprozomib tablets.

270 mg Oprozomib Tablet

Participants who were administered 300 mg oprozomib tablets.

300 mg Oprozomib Tablet

Participants who were administered 150 mg extended release oprozomib tablets.

150 mg Oprozomib ER Tablet

Participants who were administered 300 mg extended release oprozomib tablets.

300 mg Oprozomib ER Tablet

Participants who were administered 330 mg extended release oprozomib tablets.

330 mg Oprozomib ER Tablet

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

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

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

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

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

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

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

Percentage of Participants Who Achieved a Clinical Benefit Response As Assessed by Investigator During Phase 2

Kaplan-Meier Estimates for Duration of Response (DOR) as Assessed by Investigator During Phase 2

Kaplan-Meier Estimates for Progression-free Survival (PFS) as Assessed by Investigator During Phase 2

Kaplan-Meier Estimate for Time to Progression (TTP) as Assessed by Investigator During Phase 2

Overall Study

Symptoms and General Pathology

Recurrence

Phase I, Dose Escalation, Single Arm, Open Label

Oral administration of Oprozomib on Days 1-5 of a 14 day cycle

To evaluate the safety and tolerability of Oprozomib in patients with advanced refractory or recurrent solid tumors including determination of its Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) To determine the pharmacokinetics (PK) of Oprozomib To explore the anti-tumor activity of Oprozomib in this patient population including the overall response rate (ORR), the duration of responses (DOR), the progression-free survival (PFS) and time to progression (TTP) To define the pharmacodynamics (PDn) of Oprozomib.

This is a Phase 1, open label, dose-escalation study to determine the safety, MTD, and PK/PDn of Oprozomib when administered orally (PO) on Days 1, 2, 3, 4, and 5 of a 14 day cycle in patients with advanced refractory or recurrent solid tumor malignancies for which standard curative measures do not exist or are no longer effective.

Phase 1 Study of Oprozomib Administered Orally in Patients With Advanced Refractory or Recurrent Solid Tumors

A Phase 1, Open-label, Dose Escalation Study of Oprozomib Administered Orally in Patients With Advanced Refractory or Recurrent Solid Tumors

* To evaluate the safety and tolerability of Oprozomib in patients with advanced refractory or recurrent solid tumors including determination of its Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)
* To determine the pharmacokinetics (PK) of Oprozomib

* To explore the anti-tumor activity of Oprozomib in this patient population including the overall response rate (ORR), the duration of responses (DOR), the progression-free survival (PFS) and time to progression (TTP)
* To define the pharmacodynamics (PDn) of Oprozomib.

Antirheumatic Agents

Cyclophosphamide

Lenalidomide

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Angiogenesis Inhibitors

Growth Inhibitors

Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Participants received oprozomib 180 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Participants received oprozomib 210 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Participants received oprozomib 240 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with oral cyclophosphamide 300 mg/m² on days 1, 8, and 15 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 8 cycles, whichever occurred first. After completing 8 cycles of treatment, participants with stable disease or better were to continue on oprozomib with dexamethasone premedication for a total of 24 cycles or until progression of disease or unacceptable toxicity. After completing 24 cycles of treatment, participants without evidence of disease progression could have continued on oprozomib with or without dexamethasone pretreatment.

Extended release (ER) tablets administered orally

Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.

Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants \> 75 years of age, at the discretion of the investigator.

Administered orally at 300 mg/m² (up to a maximum of 600 mg) on days 1, 8, and 15 of each 28-day cycle for a maximum of 8 cycles of therapy (approximately 8 months).

The primary objectives of this study included the following:

Phase 1b:

* To establish the maximum tolerated dose (MTD) of oprozomib given in combination with lenalidomide and dexamethasone (ORd) or with cyclophosphamide and dexamethasone (OCyd)
* To evaluate the safety and tolerability of oprozomib and dexamethasone administered in combination with lenalidomide or oral cyclophosphamide

Phase 2:

* To estimate the antitumor activity of each combination regimen, as measured by overall response rate (ORR) and complete response rate (CRR)
* To evaluate the safety and tolerability of each combination regimens, as assessed by the type, incidence, severity and seriousness of adverse events, and abnormalities in selected laboratory analytes

Phase 1b used a standard 3 + 3 dose-escalation scheme to determine the MTD. For each combination regimen, oprozomib doses were to be escalated in sequential cohorts of 3 participants with expansion to up to 6 participants if a dose-limiting toxicity (DLT) was observed in 1 of the first 3 participants. The doses of lenalidomide, cyclophosphamide, and dexamethasone were to remain fixed in all dose cohorts.

The phase 2 portion of the study was to include up to 35 additional participants in each of the 2 combination regimens, treated at the recommended phase 2 dose (RP2D) of oprozomib that was identified during the phase 1b portion of the study in order to better characterize safety and tolerability, and antimyeloma activity.

This study was stopped by sponsor decision during the dose escalation in phase 1b prior to initiation of phase 2.

Oprozomib and Dexamethasone,in Combination With Lenalidomide or Oral Cyclophosphamide to Treat Newly Diagnosed Multiple Myeloma

Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone, in Combination With Lenalidomide or Oral Cyclophosphamide in Patients With Newly Diagnosed Multiple Myeloma

DLTs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. A DLT is defined as any of the following treatment-related events:

* Any ≥ Grade 3 nonhematologic toxicity with the following conditions:

  * ≥ Grade 3 nausea, vomiting, diarrhea, or constipation only if for \> 7 days despite optimal supportive care
  * Asymptomatic Grade 3 hypophosphatemia, Grade 3 hyperglycemia or toxicity solely due to dexamethasone, ≥ Grade 3 rash attributed to lenalidomide, and Grade 3 fatigue for \< 14 days were not considered DLTs
* Grade 4 neutropenia: absolute neutrophil count (ANC) \< 0.5 × 10\^9/L lasting ≥ 7 days, despite myeloid growth factor support
* Febrile neutropenia
* Grade 4 thrombocytopenia for ≥ 7 days or \< 7 days with ≥ Grade 2 clinically significant bleeding or \< 10,000 platelets requiring platelet transfusion, or Grade ≥ 3 with clinically significant bleeding or requiring platelet transfusion.

Adverse events (AEs) were graded using NCI-CTCAE (version 4.03) and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE.

A serious AE is an event that met 1 or more of the following criteria:

* Death
* Life-threatening experience
* Required inpatient hospitalization or prolongation of an existing hospitalization
* Resulted in persistent or significant disability/incapacity
* A congenital anomaly birth defect in the offspring of an exposed female subject or offspring of a female partner of a male subject
* Important medical events that, based upon appropriate medical judgment, jeopardized the participant and may have required medical or surgical intervention to prevent an outcome listed above.

Treatment-related AEs are those considered related to at least 1 study drug by the investigator.

Plasma samples for oprozomib concentration assays were only collected for participants in the 5/14 dosing schedule groups.

Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry.

ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria.

PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline.

VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC).

CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \<5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC.

sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM).

Duration of response was defined as the time from first evidence of partial response (PR) or better to confirmation of disease progression or death due to any cause.

Median DOR was estimated using Kaplan-Meier methods. Participants who started a new anticancer therapy before documentation of disease progression or death, or who were alive without documentation of disease progression before the data cut-off date or who died or had disease progression immediately after more than 1 consecutively missed disease assessment visit were censored at the date of last disease assessment.

Progression-free survival is defined as the time from the start of treatment to disease progression or death (due to any cause), whichever occurred first. Median PFS was estimated using Kaplan-Meier methods. Participants who started a new anticancer therapy before documentation of disease progression or death, or who were alive without documentation of disease progression before the data cut-off date or who died or had disease progression immediately after more than 1 consecutively missed disease assessment visit were censored at the date of last disease assessment.

Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first.

After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Oprozomib 150 mg 5/14 + Lenalidomide + Dexamethasone

Participants received oprozomib 180 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first.

After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Oprozomib 180 mg 5/14 + Lenalidomide + Dexamethasone

Participants received oprozomib 210 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first.

Oprozomib 210 mg 5/14 + Lenalidomide + Dexamethasone

Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first.

After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Oprozomib 210 mg 2/7 + Lenalidomide + Dexamethasone

Participants received oprozomib 240 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first.

After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Oprozomib 240 mg 2/7 + Lenalidomide + Dexamethasone

Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with oral cyclophosphamide 300 mg/m² on days 1, 8, and 15 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 8 cycles, whichever occurred first.

After completing 8 cycles of treatment, participants with stable disease or better were to continue on oprozomib with dexamethasone premedication for a total of 24 cycles or until progression of disease or unacceptable toxicity. After completing 24 cycles of treatment, participants without evidence of disease progression could have continued on oprozomib with or without dexamethasone pretreatment.

Oprozomib 210 mg 2/7 + Cyclophosphamide + Dexamethasone

Age, Continuous

Race/Ethnicity, Customized

A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction;

1. = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature;
2. = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about \> 50% of waking hours;
3. = Capable of only limited self-care, confined to bed or chair \> 50% of waking hours;
4. = Completely disabled, confined to bed or chair;
5. = Dead.

Eastern Cooperative Oncology Group (ECOG) Performance Status

Participants received oprozomib 210 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first.

After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma	NCT01832727	Multiple Myelom...	Oprozomib Dexamethasone	18 Years -	Amgen
Phase 1 Study of Oprozomib Administered Orally in Patients With Advanced Refractory or Recurrent Solid Tumors	NCT01129349	Solid Tumors	Oprozomib	18 Years -	Amgen
Oprozomib and Dexamethasone,in Combination With Lenalidomide or Oral Cyclophosphamide to Treat Newly Diagnosed Multiple Myeloma	NCT01881789	Multiple Myelom...	Oprozomib Lenalidomide Dexamethasone Cyclophosphamid...	18 Years -	Amgen
Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma	NCT02227914	Advanced Hepato...	Oprozomib Sorafenib	18 Years -	Amgen
Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma	NCT02227914	Advanced Hepato...	Oprozomib Sorafenib	18 Years -	Amgen
Phase 1 Study of Oprozomib Administered Orally in Patients With Advanced Refractory or Recurrent Solid Tumors	NCT01129349	Solid Tumors	Oprozomib	18 Years -	Amgen
Oprozomib and Dexamethasone,in Combination With Lenalidomide or Oral Cyclophosphamide to Treat Newly Diagnosed Multiple Myeloma	NCT01881789	Multiple Myelom...	Oprozomib Lenalidomide Dexamethasone Cyclophosphamid...	18 Years -	Amgen
A Phase 1 Study of Oprozomib to Assess Food Effect, Drug-Drug Interaction With Midazolam, and Safety and Tolerability in Patients With Advanced Malignancies	NCT02244112	Advanced Non-Ce...	Oprozomib Midazolam	18 Years -	Amgen
Open-label Study of the Safety and Activity of Oprozomib in Patients With Hematologic Malignancies	NCT01416428	Multiple Myelom... Waldenstrom Mac...	oprozomib	18 Years -	Amgen

Spots Global Cancer Trial Database for oprozomib

Every month we try and update this database with for oprozomib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for oprozomib

Every month we try and update this database with for oprozomib cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for oprozomib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.