Follicular Lymphoma
Conditions
Keywords
MLN9708, Lymphoma, IXAZOMIB
Brief summary
The primary purpose of this study is to evaluate the anti-tumor activity of oral Ixazomib as measured by overall response rate (ORR) in adult participants with relapsed and/or refractory follicular lymphoma (FL).
Interventions
DRUGIXAZOMIB
Each 28-day treatment cycle will include oral administration of IXAZOMIB on Days 1, 8, and 15 followed by a rest period of 13 days.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants 18 years or older. * Participants must have a pathologically confirmed diagnosis of non-Hodgkin lymphoma (NHL) (for the lead-in dose-finding phase) and FL (for phase 2). * Participants must have radiographically or clinically measurable disease. * Participants must be relapsed and/or refractory after at least 1 prior therapy (excluding radiation) with documented progressive disease at the time of enrollment. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. * Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence. * Male participants who agree to practice effective barrier contraception or agree to practice true abstinence. * Voluntary written consent. * Suitable venous access. * Appropriate clinical laboratory values as defined in the protocol. * Recovered from toxicities of prior anticancer therapy. * If the trial proceeds to the second step on the basis of the tandem 2-step design, participants must be confirmed PSMB1 positive at the central laboratory before treatment.
Exclusion criteria
* Peripheral neuropathy that is greater or equal to Grade 2 or Grade 1 with pain. * Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. * Autologous stem cell transplant within 6 months before Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time. * Major surgery within 14 days before the first dose of study drug. * Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study drug. * Comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the participants inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. * Evidence of current uncontrolled cardiovascular conditions including uncontrolled hypertension, severe uncontrolled ventricular arrhythmias, unstable angina, New York Heart Association (NYHA) Class III or IV cardiac disease, or myocardial infarction within the past 6 months. * Diarrhea greater than (\>) Grade 1 on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) categorization. * Systemic antineoplastic (including glucocorticoids \> the equivalent of 15 mg of prednisone daily), experimental, or radiation therapy within 21 days before the first dose of study drug. * Prior treatment with rituximab or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease or immediate treatment is mandated). * Treatment with radioimmunoconjugates or toxin immunoconjugates within 12 weeks before the first dosing of study treatment. * Systemic treatment with strong inhibitors of Cytochrome P450 1A2 (CYP1A2) or Cytochrome P450 3A (CYP3A), or strong CYP3A inducers within 14 days before the first dose of IXAZOMIB - Ongoing systemic therapy with corticosteroids. * Central nervous system (CNS) involvement that is clinically uncontrolled or newly diagnosed in the last 4 months. * Ongoing or active systemic viral infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus or known active hepatitis C virus. * Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ. * Platelet transfusions within 3 days before the 1st dose of study drug. * Inability to swallow capsules, or inability or unwillingness to avoid taking anything by mouth except for water and prescribed medication for 2 hours before and 1 hour after dose of IXAZOMIB - Known allergy to boron or excipients in the formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response Rate (ORR) | Baseline up to Day 15 Cycle 29 (approximately up to Day 802) or until PD or the start of alternate therapies | ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator using the international Working Group criteria for participants CR: disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Time from the date of first dose of study treatment to the date of first documented PD or death (approximately up to Day 802) | PFS is defined as the time from the date of first dose of study treatment to the date of first documented PD or death. Participants without documentation of PD will be censored at the date of last response assessment that is SD or better. Participants without response assessment will be censored at the date of first dose. |
| Phase 2: Rate of Disease Control | Baseline or until occurrence of disease progression, unacceptable toxicities, or discontinuation of study due to any other reasons (approximately up to Day 805) | Rate of disease control is defined as percentage of participants who achieved a SD or better for greater than or equal to (\>=) 6 months. |
| Time to Response (TTR) | Time from the date of first dose of study treatment to the date of first documented PR or better response or death (approximately up to Day 802) | TTR is defined as the time from the date of first dose of study treatment to the date of the first documentation of a PR or better response in a participant who responded. |
| Duration of Response (DOR) | Time from the date of first documentation of a response to the date of first documented PD (approximately up to Day 802) | The DOR is defined as the time from the date of first documentation of a response to the date of first documented PD. Responders without documentation of PD will be censored at the date of last response assessment. DOR was categorized as CR+PR and CR. |
| Lead-in Dose Finding Phase: Recommended Phase 2 Dose (RP2D) | Baseline up to Cycle 1 Day 28 | — |
| Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Baseline up to 30 days after last dose of study drug (approximately up to Day 832) | — |
| Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose | — |
| Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose | — |
| Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose | — |
| Phase 2: Number of Participants With Response Rates in PSMB1 Positive and PSMB1 Negative | Baseline up to occurrence of disease progression, unacceptable toxicities, or discontinuation of study due to any other reasons (approximately up to Day 802) | — |
Countries
Belgium, Canada, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 11 investigative sites in the United States, Belgium, Canada, United Kingdom and Italy from 31 October 2013 to 23 March 2017.
Pre-assignment details
Participants with follicular lymphoma (FL) prior to treatment were enrolled in this 2 phase study: Lead in dose finding phase in which maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ixazomib was evaluated and Phase 2 proteasome subunit beta type-1 (PSMB1) was done to evaluate the safety, efficacy, tolerability of ixazomib.
Participants by arm
| Arm | Count |
|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in non-hodgkin lymphoma (NHL) participants. | 3 |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL participants. | 7 |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL participants. | 6 |
| Phase 2: PSMB1 Positive Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in relapsed Or refractory follicular lymphoma (RRFL) participants. | 12 |
| Phase 2: PSMB1 Negative Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL participants. | 1 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Lead-in Dose Finding Phase | Death | 0 | 3 | 1 | 0 | 0 |
| Lead-in Dose Finding Phase | Disease Progression | 2 | 4 | 3 | 0 | 0 |
| Lead-in Dose Finding Phase | Other | 0 | 0 | 1 | 0 | 0 |
| Phase 2 | Disease Progression | 0 | 0 | 0 | 9 | 1 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Phase 2: PSMB1 Positive | Phase 2: PSMB1 Negative | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 72.0 years STANDARD_DEVIATION 6.56 | 57.9 years STANDARD_DEVIATION 11.13 | 64.3 years STANDARD_DEVIATION 7.71 | 64.7 years STANDARD_DEVIATION 11.73 | 79.0 years | 64.2 years STANDARD_DEVIATION 10.9 |
| Height | 170.0 centimeter (cm) STANDARD_DEVIATION 7.04 | 175.0 centimeter (cm) STANDARD_DEVIATION 11.5 | 169.2 centimeter (cm) STANDARD_DEVIATION 9.11 | 168.8 centimeter (cm) STANDARD_DEVIATION 6.7 | 157.5 centimeter (cm) | 170.1 centimeter (cm) STANDARD_DEVIATION 8.77 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 7 Participants | 6 Participants | 12 Participants | 0 Participants | 28 Participants |
| Region of Enrollment Belgium | 1 participants | 2 participants | 3 participants | 3 participants | 0 participants | 9 participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 2 participants | 0 participants | 0 participants | 3 participants |
| Region of Enrollment Italy | 0 participants | 0 participants | 0 participants | 5 participants | 0 participants | 5 participants |
| Region of Enrollment United Kingdom | 0 participants | 3 participants | 1 participants | 2 participants | 0 participants | 6 participants |
| Region of Enrollment United States | 2 participants | 1 participants | 0 participants | 2 participants | 1 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 5 Participants | 8 Participants | 0 Participants | 21 Participants |
| Smoking classification Current smoker | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Smoking classification Ex-smoker | 1 Participants | 1 Participants | 1 Participants | 5 Participants | 0 Participants | 8 Participants |
| Smoking classification Never smoked | 2 Participants | 4 Participants | 5 Participants | 7 Participants | 1 Participants | 19 Participants |
| Weight | 76.1 kilogram (kg) STANDARD_DEVIATION 11.27 | 85.8 kilogram (kg) STANDARD_DEVIATION 20.72 | 85.3 kilogram (kg) STANDARD_DEVIATION 10.95 | 78.7 kilogram (kg) STANDARD_DEVIATION 13.54 | 82.4 kilogram (kg) | 81.6 kilogram (kg) STANDARD_DEVIATION 14.45 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 3 / 7 | 1 / 6 | 0 / 12 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 6 / 6 | 11 / 12 | 1 / 1 |
| serious Total, serious adverse events | 1 / 3 | 3 / 7 | 4 / 6 | 4 / 12 | 1 / 1 |
Outcome results
Primary
Number of Participants With Overall Response Rate (ORR)
ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator using the international Working Group criteria for participants CR: disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Time frame: Baseline up to Day 15 Cycle 29 (approximately up to Day 802) or until PD or the start of alternate therapies
Population: The response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Number of Participants With Overall Response Rate (ORR) | CR | 0 participants |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Number of Participants With Overall Response Rate (ORR) | PR | 0 participants |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Number of Participants With Overall Response Rate (ORR) | Stable Disease (SD) | 1 participants |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Number of Participants With Overall Response Rate (ORR) | PD | 2 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Number of Participants With Overall Response Rate (ORR) | CR | 0 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Number of Participants With Overall Response Rate (ORR) | PD | 3 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Number of Participants With Overall Response Rate (ORR) | PR | 0 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Number of Participants With Overall Response Rate (ORR) | Stable Disease (SD) | 2 participants |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Number of Participants With Overall Response Rate (ORR) | PD | 3 participants |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Number of Participants With Overall Response Rate (ORR) | PR | 0 participants |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Number of Participants With Overall Response Rate (ORR) | Stable Disease (SD) | 2 participants |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Number of Participants With Overall Response Rate (ORR) | CR | 0 participants |
| Phase 2: PSMB1 Positive | Number of Participants With Overall Response Rate (ORR) | CR | 0 participants |
| Phase 2: PSMB1 Positive | Number of Participants With Overall Response Rate (ORR) | PR | 1 participants |
| Phase 2: PSMB1 Positive | Number of Participants With Overall Response Rate (ORR) | PD | 7 participants |
| Phase 2: PSMB1 Positive | Number of Participants With Overall Response Rate (ORR) | Stable Disease (SD) | 4 participants |
| Phase 2: PSMB1 Negative | Number of Participants With Overall Response Rate (ORR) | PD | 1 participants |
| Phase 2: PSMB1 Negative | Number of Participants With Overall Response Rate (ORR) | Stable Disease (SD) | 0 participants |
| Phase 2: PSMB1 Negative | Number of Participants With Overall Response Rate (ORR) | PR | 0 participants |
| Phase 2: PSMB1 Negative | Number of Participants With Overall Response Rate (ORR) | CR | 0 participants |
Secondary
Duration of Response (DOR)
The DOR is defined as the time from the date of first documentation of a response to the date of first documented PD. Responders without documentation of PD will be censored at the date of last response assessment. DOR was categorized as CR+PR and CR.
Time frame: Time from the date of first documentation of a response to the date of first documented PD (approximately up to Day 802)
Population: The response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: PSMB1 Positive | Duration of Response (DOR) | 0.0328542094 months |
Secondary
Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib
Time frame: Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose
Population: The PK analysis set where Cycle 1 Day 1 and 15 assessment were available. The PK analysis population included all participants enrolled in the lead-in dose finding phase that had sufficient dosing data and ixazomib concentration-time data. The PK analysis population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1 Day 15 | 2440.0000 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 272.21315 |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1 Day 1 | 1265.0000 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 332.34019 |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1 Day 1 | 1030.1429 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 367.90326 |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1 Day 15 | 2007.0000 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 986.30117 |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1 Day 1 | 1680.3333 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 656.0124 |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for Ixazomib | Cycle 1 Day 15 | 3120.0000 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 2503.83706 |
Secondary
Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose
Population: The plasma pharmacokinetic (PK) analysis population included all participants enrolled in the lead-in dose finding phase that had sufficient dosing data and ixazomib concentration-time data. The PK analysis population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1 Day 1 | 141.3333 nanogram per milliliter (ng/mL) | Standard Deviation 52.27173 |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1 Day 15 | 124.2667 nanogram per milliliter (ng/mL) | Standard Deviation 71.0184 |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1 Day 1 | 103.4717 nanogram per milliliter (ng/mL) | Standard Deviation 57.53181 |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1 Day 15 | 144.0667 nanogram per milliliter (ng/mL) | Standard Deviation 105.15884 |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1 Day 1 | 121.1167 nanogram per milliliter (ng/mL) | Standard Deviation 69.07212 |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1 Day 15 | 152.0667 nanogram per milliliter (ng/mL) | Standard Deviation 102.71131 |
Secondary
Lead-in Dose Finding Phase: Recommended Phase 2 Dose (RP2D)
Time frame: Baseline up to Cycle 1 Day 28
Population: The dose limiting toxicity (DLT)- evaluable population included all participants who received all Cycle 1 doses of ixazomib and had completed Cycle 1 safety procedures, or experience a DLT in Cycle 1 in the lead-in dose finding phase of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: Recommended Phase 2 Dose (RP2D) | 5.3 mg |
Secondary
Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose
Population: The PK analysis population included all participants enrolled in the lead-in dose finding phase that had sufficient dosing data and ixazomib concentration-time data. The PK analysis population where data at specified time points was available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1 Day 1 | 1.0000 hour |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1 Day 15 | 1.0000 hour |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1 Day 1 | 1.0000 hour |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1 Day 15 | 0.7500 hour |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1 Day 1 | 1.0500 hour |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1 Day 15 | 1.0000 hour |
Secondary
Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to 30 days after last dose of study drug (approximately up to Day 832)
Population: The safety population included all enrolled participants who had received at least 1 dose of ixazomib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 3 participants |
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 1 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 7 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 3 participants |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 6 participants |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 4 participants |
| Phase 2: PSMB1 Positive | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 4 participants |
| Phase 2: PSMB1 Positive | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 11 participants |
| Phase 2: PSMB1 Negative | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 1 participants |
| Phase 2: PSMB1 Negative | Number of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 1 participants |
Secondary
Phase 2: Number of Participants With Response Rates in PSMB1 Positive and PSMB1 Negative
Time frame: Baseline up to occurrence of disease progression, unacceptable toxicities, or discontinuation of study due to any other reasons (approximately up to Day 802)
Population: The biomarker population included all participants positive or negative for the PSMB1 biomarker and where the assay has passed quality control. Data will be derived from a baseline blood sample.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Phase 2: Number of Participants With Response Rates in PSMB1 Positive and PSMB1 Negative | 12 participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Phase 2: Number of Participants With Response Rates in PSMB1 Positive and PSMB1 Negative | 1 participants |
Secondary
Phase 2: Rate of Disease Control
Rate of disease control is defined as percentage of participants who achieved a SD or better for greater than or equal to (\>=) 6 months.
Time frame: Baseline or until occurrence of disease progression, unacceptable toxicities, or discontinuation of study due to any other reasons (approximately up to Day 805)
Population: The response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Phase 2: Rate of Disease Control | 16.7 percentage of participants |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Phase 2: Rate of Disease Control | NA percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from the date of first dose of study treatment to the date of first documented PD or death. Participants without documentation of PD will be censored at the date of last response assessment that is SD or better. Participants without response assessment will be censored at the date of first dose.
Time frame: Time from the date of first dose of study treatment to the date of first documented PD or death (approximately up to Day 802)
Population: The modified intent-to-treat (mITT) population included all participants who received at least 1 dose of ixazomib in the phase 2 portion of the study or who received at least 1 dose of ixazomib and are treated at the RP2D in the lead-in dose finding phase of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Dose Finding Phase: Ixazomib 4 mg | Progression Free Survival (PFS) | 1.9 months |
| Lead-in Dose Finding Phase: Ixazomib 5.3 mg | Progression Free Survival (PFS) | 2.4 months |
| Lead-in Dose Finding Phase: Ixazomib 7.0 mg | Progression Free Survival (PFS) | NA months |
Secondary
Time to Response (TTR)
TTR is defined as the time from the date of first dose of study treatment to the date of the first documentation of a PR or better response in a participant who responded.
Time frame: Time from the date of first dose of study treatment to the date of first documented PR or better response or death (approximately up to Day 802)
Population: The response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: PSMB1 Positive | Time to Response (TTR) | 560 days |