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

Subjects will receive carfilzomib 20 mg/m2 as an intravenous bolus over 2 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. A maximum of 12 cycles will be administered.

carfilzomib

Subjects will receive carfilzomib intravenously over up to 10 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. In cycle 1, the dose is 20 mg/m2. If all doses are administered and well-tolerated over Cycle 1, beginning with Cycle 2 the dose will escalate to 27 mg/m2 cycle. A maximum of 12 cycles will be administered.

To evaluate the overall response rate and safety and tolerability of carfilzomib in subjects with relapsed and refractory multiple myeloma.

Patients must have received prior treatment with bortezomib and either thalidomide or lenalidomide and be refractory to their last treatment.

Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma

An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma

For both A0 and A1, to evaluate the best overall response rate (stringent complete response \[sCR\]+ complete response \[CR\]+ very good partial response \[VGPR\]+ partial response \[PR\]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy

sCR, CR, VGPR, PR, and minimal response (MR)

Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.

Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.

The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.

The time from start of treatment to death due to any cause OS was to be censored on the date the subject was last known to be alive for those who were alive or lost to follow-up as of a data analysis cutoff date.

Amgen

Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle

Carfilzomib (A0)

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16.If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.

Carfilzomib (A1)

Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycle

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.

Total

Age, Categorical

Sex: Female, Male

Safety population: The safety population consists of all enrolled patients who received at least 1 dose of carfilzomib.

Onyx Medical Information

Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle

Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16.If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.

Response-Evaluable Population:

1. had measurable disease at Baseline
2. received at least 1 dose of carfilzomib
3. underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib

Analysis population described in reporting groups below

Best Overall Response Rate (ORR)

Clinical Benefit Response (sCR+CR+VGPR+PR+MR)

Complete Response

Very Good Partial Response

Partial Response

Minimal Response

Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycle.

Assessed by principal investigator.

Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.

Clinical Benefit Response (CBR) (A0 Only)

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.

Assessed by Independent Review Committee

Response-Evaluable Population:

1. had measurable disease at Baseline
2. received at least 1 dose of carfilzomib
3. underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib

Clinical Benefit Response (CBR) (A1 Only)

Carfilzomib (A0) for (ORR)

Subjects with overall response within the response-evaluable population were included in the analysis of DOR. See analysis population description of response-evaluable population above.

Duration of Response (A0 Only)

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. For subjects with ORR.

Carfilzomib (A1) for (ORR)

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. For subjects with CBR.

Carfilzomib (A1) for (CBR)

Subjects with overall response within the response-evaluable population were included in the analysis of DOR. See overall analysis population description of response-evaluable population above.

Duration of Response (A1 Only)

Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle.

Assesed by principal investigator.

Time to Progression (A0 Only)

Time to Progression (A1 Only)

Progression-free Survival (A0 Only)

Progression-free Survival (A1 Only)

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.

Safety population: The safety population was used for the analysis of safety data in this study. The safety population consists of all enrolled patients who received at least 1 dose of carfilzomib. However, for some safety analyses, at least 1 laboratory, neurological, electrocardiogram, or vital sign measurement obtained subsequent to at least 1 dose of carfilzomib was required for inclusion in the analysis of a safety specific parameter. To assess change from baseline, a baseline measurement was also required.

Carfilzomib (A1) - Safety Population

In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.

Response-Evaluable Population(the primary analysis population) was defined as all patients who

* had measurable disease at Baseline by either M-protein (serum and/or urine) or by quantitative serum Ig for certain patients with IgA myeloma
* received at least 1 dose of carfilzomib
* underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or patients who discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib-irrespective of availability of baseline and post-baseline assessment

Carfilzomib (A1) - Response-evaluable Population

Overall Survival (A1 Only)

Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles

Overall Study

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.

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

Age, Customized

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

Diseases and Abnormalities at or Before Birth

Congenital Abnormalities

Arteriovenous Malformations

Hemangioma

Vascular Malformations

Cardiovascular Abnormalities

Neoplasms, Vascular Tissue

Onyx

TRUFILL

Gary Duckwiler, MD

Test whether AVMs treated with Onyx is equivalent to treatment with n-BCA. Success is defined as an AVM size reduction greater than 50%

Recent advances in the endovascular treatment of arteriovenous malformations (AVMs) have increased the number of patients with brain AVMs for whom embolization therapy may be appropriate. The permanency of obliterated nidi and occurrence of procedural complications are thought to be at least partially influenced by the characteristics of the material used, with liquid agents more likely to reach and occlude the AVM nidus compared to particulate embolic agents.

The only liquid embolic agent approved in the U.S. for the presurgical embolization of AVMs is TRUFILL®. TRUFILL n-butyl cyanoacrylate (n-BCA) is a liquid adhesive that polymerizes into a solid material upon contact with blood fluids or tissue, via an anionic mechanism. TRUFILL Ethiodized Oil is mixed into the n-BCA monomer as a radiopaque polymerizing retardant. TRUFILL Tantalum Powder may also be added for radiopacity. The TRUFILL n-BCA Liquid Embolic System received U.S. FDA premarket approval on September 25, 2000 (P990040) for use in the embolization of cerebral AVMs, when presurgical devascularization is desired.

Onyx™ is a non-adhesive liquid embolic agent comprised of ethylene vinyl alcohol (EVOH) copolymer dissolved in dimethyl sulfoxide (DMSO), and of micronized tantalum powder. Onyx precipitates into a solid on contact with blood fluids, due to rapid diffusion of the DMSO solvent. The Onyx Liquid Embolic System received the European "CE mark" in July 1999, and has been available outside of the U.S. since September 1999 for use in the embolization of AVMs.

The purpose of this randomized-controlled study is to obtain prospective clinical data on the performance of Onyx (investigational device) and TRUFILL (control device) in the presurgical embolization of brain AVMs. Device safety will be assessed by comparing overall and device-related morbidity and mortality. The primary efficacy endpoint is the angiographic reduction in AVM size (volume) achieved. The objective is to demonstrate that Onyx is no worse than TRUFILL within a specified clinical tolerance. Study results will be used to support a premarket approval application for Onyx in the presurgical embolization of brain AVMs.

Study Comparing Onyx and TRUFILL in Brain Arteriovenous Malformations (AVMs)

U.S. Multicenter, Randomized Controlled Study Comparing the Performance fo Onyx(EVOH) and TRUFILL® (n-BCA)in Presurgical Embolization of Brain Arteriovenous Malformations (BAVMs)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma	NCT00511238	Multiple Myelom...	carfilzomib carfilzomib	18 Years -	Amgen
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 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma	NCT00511238	Multiple Myelom...	carfilzomib carfilzomib	18 Years -	Amgen
Study Comparing Onyx and TRUFILL in Brain Arteriovenous Malformations (AVMs)	NCT00857662	Brain Arteriove...	Onyx TRUFILL	-	Medtronic Neurovascular Clinical Affairs
Study Comparing Onyx and TRUFILL in Brain Arteriovenous Malformations (AVMs)	NCT00857662	Brain Arteriove...	Onyx TRUFILL	-	Medtronic Neurovascular Clinical Affairs
Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma	NCT00511238	Multiple Myelom...	carfilzomib carfilzomib	18 Years -	Amgen

Spots Global Cancer Trial Database for onyx

Every month we try and update this database with for onyx 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 onyx

Every month we try and update this database with for onyx 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 onyx 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.