Peripheral T-cell Lymphoma
Conditions
Keywords
Lymphoma, T-cell Lymphoma, Relapse, Refractory, PI3K-δ,γ
Brief summary
This is a multi-center, parallel cohort, open-label, Phase 2 study of duvelisib, an oral dual inhibitor of phosphoinositide-3-kinase-delta, gamma (PI3K-δ,γ), in participants with relapsed/refractory peripheral T-cell lymphoma (PTCL).
Detailed description
The study had 2 phases, a Dose Optimization Phase and an Expansion Phase. In the Dose Optimization Phase, participants were randomly assigned to 1 of 2 study cohorts, as follows: * Cohort 1: Duvelisib per oral (PO) twice daily (BID) at a starting dose of 25 milligrams (mg), with potential escalation on a per-participant basis to 50 mg and then 75 mg, based on the participant's response to and tolerance of therapy, in 28-day cycles. * Cohort 2: Duvelisib 75 mg PO BID, administered in 28-day cycles. A total of 20 participants were to be enrolled in the Dose Optimization Phase, with 10 participants per cohort. Based on the safety and activity data obtained in the Dose Optimization Phase of the study, the Expansion Phase dose of duvelisib was to be determined. In the Expansion Phase, approximately 100-130 participants were to be enrolled and receive duvelisib dose in 28-day cycles as determined in Dose Optimization Phase.
Interventions
DRUGDuvelisib
Duvelisib PO 25 mg BID or 50 mg BID or 75 mg BID in 28-day cycles.
Sponsors
SecuraBio
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years of age 2. Diagnosis of one of the following histologic subtypes of PTCL, pathologically confirmed, as defined by the World Health Organization: 1. Peripheral T-cell lymphoma-not otherwise specified; 2. Angioimmunoblastic T-cell lymphomas; 3. Anaplastic large cell lymphoma (ALCL); or 4. Natural-killer/T-cell lymphoma 3. Received at least 2 cycles of one standard regimen for newly diagnosed advanced PTCL, and one of the following: 1. failed to achieve at least a PR after 2 or more cycles of standard therapy; 2. failed to achieve a CR after completion of standard therapy; and/or 3. persistent or progressive disease after an initial response 4. For participants with CD30+ ALCL, failed or are ineligible or intolerant to brentuximab vedotin 5. Measurable disease as defined by Lugano for PTCL, that is, at least 1 measurable disease lesion \> 1.5 centimeters in at least one dimension by conventional techniques (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography \[CT\], CT with contrast, magnetic imaging resonance)
Exclusion criteria
1. Primary leukemic PTCL subtypes (that is, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma and aggressive NK-cell leukemia) or transformed mycosis fungoides 2. Received prior allogeneic transplant 3. Received prior treatment with a PI3K inhibitor 4. Known central nervous system involvement by PTCL 5. Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic steroids \> 20 mg of prednisone (or equivalent) once daily 6. Ongoing treatment for systemic bacterial, fungal, or viral infection at Screening 7. Known hypersensitivity to duvelisib and/or its excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) as Assessed by the Investigator Using the Lugano Criteria | 56 days (2 cycles; 28-day cycles) | ORR was defined as the percentage of participants with CR + PR, as assessed by the investigator using the Lugano criteria, for participants receiving the optimal dose of duvelisib for at least one cycle of study therapy. |
| ORR as Assessed by the Independent Review Committee (IRC) Using the Lugano Criteria | 56 days (2 cycles; 28-day cycles) | ORR was defined as the percentage of participants with CR + PR, as assessed by the IRC using the Lugano criteria, for participants receiving the optimal dose of duvelisib for at least one cycle of study therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) As Assessed by the Investigator Using the Lugano Criteria | Up to 8 weeks | DCR was defined as the percentage of participants with a best overall response of CR or PR or with a best overall response of stable disease (SD) sustained for at least 8 weeks. |
| DOR as Assessed by the IRC Using the Lugano Criteria | Up to 70 months | DOR was defined for participants with CR or PR as the time from the date of the first documentation of response (CR or PR) to the date of the first documentation of PD or death due to any cause. Participants who withdrew from the study for any reason prior to PD and participants who had ongoing response at the time of the data cut were censored at the date of their last response assessment. |
| PFS as Assessed by the IRC Using the Lugano Criteria | Up to 70 months | PFS was defined as the time from the date of first treatment to the date of the first radiographic disease progression or death due to any cause, whichever occurred first. |
| Duration of Response (DOR) as Assessed by the Investigator Using the Lugano Criteria | Up to 70 months | DOR was defined for participants with CR or PR as the time from the date of the first documentation of response (CR or PR) to the date of the first documentation of progressive disease (PD) or death due to any cause. Participants who withdraw from the study for any reason prior to PD and participants who had ongoing response at the time of the data cut were censored at the date of their last response assessment. |
| Overall Survival (OS) | Up to 70 months | OS was defined as the time from the date of first treatment to the date of death due to any cause. Participants without documented death were censored at last alive date. |
| Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Day 15 of Cycles 1 and 2 (4 hours postdose) (28-day cycles) | Blood samples were taken for the analyses of duvelisib and IPI-656 in plasma at designated time points. Results are reported as nanograms/milliliter (ng/mL). |
| DCR as Assessed by the IRC Using the Lugano Criteria | Up to 8 weeks | DCR was defined as the percentage of participants with a best overall response of CR or PR or with a best overall response of SD sustained for at least 8 weeks. |
| Progression-free Survival (PFS) as Assessed by the Investigator Using the Lugano Criteria | Up to 70 months | PFS was defined as the time from the date of first treatment to the date of the first radiographic disease progression or death due to any cause, whichever occurred first. |
Countries
Germany, Italy, Japan, United Kingdom, United States
Participant flow
Recruitment details
Regardless of study phase, all participants underwent screening assessments up to 30 days before the first study drug dose.
Participants by arm
| Arm | Count |
|---|---|
| Dose Optimization Phase: Cohort 1 Duvelisib PO BID at a starting dose of 25 mg, with potential escalation on a per-participant basis to 50 mg and then 75 mg, based on the participant's response to and tolerance of therapy, in 28-day cycles. | 20 |
| Dose Optimization Phase: Cohort 2 Duvelisib 75 mg PO BID, administered in 28-day cycles. | 13 |
| Expansion Phase Duvelisib PO BID at a starting dose of 75 mg for the first 2 cycles, followed by a mandatory reduction to 25 mg BID thereafter for those participants with CR, PR or SD, in 28-day cycles (dose determined in Optimization Phase). | 123 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Dose Optimization Phase | Closure Of The Study By The Sponsor | 3 | 1 | 0 |
| Dose Optimization Phase | Death | 16 | 11 | 0 |
| Dose Optimization Phase | Withdrawal by Subject | 1 | 1 | 0 |
| Expansion Phase | Adverse Event | 0 | 0 | 1 |
| Expansion Phase | Closure Of The Study By The Sponsor | 0 | 0 | 39 |
| Expansion Phase | Death | 0 | 0 | 78 |
| Expansion Phase | Progressive Disease | 0 | 0 | 1 |
| Expansion Phase | Withdrawal by Subject | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Expansion Phase | Dose Optimization Phase: Cohort 2 | Dose Optimization Phase: Cohort 1 |
|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 13.29 | 62.9 years STANDARD_DEVIATION 13.59 | 65.0 years STANDARD_DEVIATION 7.22 | 64.0 years STANDARD_DEVIATION 14.81 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 62 participants | 49 participants | 5 participants | 8 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 79 participants | 64 participants | 7 participants | 8 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 14 participants | 10 participants | 1 participants | 3 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 3 | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 4 | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 5 | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 1 participants | 0 participants | 0 participants | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 12 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 111 Participants | 12 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 18 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 9 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 120 Participants | 92 Participants | 12 Participants | 16 Participants |
| Sex: Female, Male Female | 66 Participants | 56 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 90 Participants | 67 Participants | 9 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 16 / 20 | 11 / 13 | 78 / 123 |
| other Total, other adverse events | 19 / 20 | 13 / 13 | 121 / 123 |
| serious Total, serious adverse events | 14 / 20 | 9 / 13 | 60 / 123 |
Outcome results
Primary
ORR as Assessed by the Independent Review Committee (IRC) Using the Lugano Criteria
ORR was defined as the percentage of participants with CR + PR, as assessed by the IRC using the Lugano criteria, for participants receiving the optimal dose of duvelisib for at least one cycle of study therapy.
Time frame: 56 days (2 cycles; 28-day cycles)
Population: Modified Intent-to-treat (mITT): all participants who received at least one dose of study drug. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using IRC assessment reported for the Expansion Phase only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | ORR as Assessed by the Independent Review Committee (IRC) Using the Lugano Criteria | 48.0 percentage of participants |
Primary
Overall Response Rate (ORR) as Assessed by the Investigator Using the Lugano Criteria
ORR was defined as the percentage of participants with CR + PR, as assessed by the investigator using the Lugano criteria, for participants receiving the optimal dose of duvelisib for at least one cycle of study therapy.
Time frame: 56 days (2 cycles; 28-day cycles)
Population: Dose Optimization Efficacy Set: All participants who received at least one dose of study drug, completed at least one cycle of treatment, and had at least one scan to assess disease response after completion of one cycle of treatment. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using investigator assessment reported for the Dose Optimization Phase only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | Overall Response Rate (ORR) as Assessed by the Investigator Using the Lugano Criteria | 53.8 percentage of participants |
| Dose Optimization Phase: Cohort 2 | Overall Response Rate (ORR) as Assessed by the Investigator Using the Lugano Criteria | 53.8 percentage of participants |
Secondary
DCR as Assessed by the IRC Using the Lugano Criteria
DCR was defined as the percentage of participants with a best overall response of CR or PR or with a best overall response of SD sustained for at least 8 weeks.
Time frame: Up to 8 weeks
Population: Modified Intent-to-treat (mITT): all participants who received at least one dose of study drug. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using IRC assessment reported for the Expansion Phase only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | DCR as Assessed by the IRC Using the Lugano Criteria | 49.6 percentage of participants |
Secondary
Disease Control Rate (DCR) As Assessed by the Investigator Using the Lugano Criteria
DCR was defined as the percentage of participants with a best overall response of CR or PR or with a best overall response of stable disease (SD) sustained for at least 8 weeks.
Time frame: Up to 8 weeks
Population: Dose Optimization Efficacy Set: All participants who received at least one dose of study drug, completed at least one cycle of treatment, and had at least one scan to assess disease response after completion of one cycle of treatment. As pre-specified, efficacy analysis using investigator assessment reported for the Dose Optimization Phase only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | Disease Control Rate (DCR) As Assessed by the Investigator Using the Lugano Criteria | 61.5 percentage of participants |
| Dose Optimization Phase: Cohort 2 | Disease Control Rate (DCR) As Assessed by the Investigator Using the Lugano Criteria | 61.5 percentage of participants |
Secondary
DOR as Assessed by the IRC Using the Lugano Criteria
DOR was defined for participants with CR or PR as the time from the date of the first documentation of response (CR or PR) to the date of the first documentation of PD or death due to any cause. Participants who withdrew from the study for any reason prior to PD and participants who had ongoing response at the time of the data cut were censored at the date of their last response assessment.
Time frame: Up to 70 months
Population: Modified Intent-to-treat (mITT): all participants who receive at least one dose of study drug. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using IRC assessment reported for the Expansion Phase only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | DOR as Assessed by the IRC Using the Lugano Criteria | 7.9 month |
Secondary
Duration of Response (DOR) as Assessed by the Investigator Using the Lugano Criteria
DOR was defined for participants with CR or PR as the time from the date of the first documentation of response (CR or PR) to the date of the first documentation of progressive disease (PD) or death due to any cause. Participants who withdraw from the study for any reason prior to PD and participants who had ongoing response at the time of the data cut were censored at the date of their last response assessment.
Time frame: Up to 70 months
Population: Dose Optimization Efficacy Set: All participants who received at least one dose of study drug, completed at least one cycle of treatment, and had at least one scan to assess disease response after completion of one cycle of treatment. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using investigator assessment reported for the Dose Optimization Phase only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | Duration of Response (DOR) as Assessed by the Investigator Using the Lugano Criteria | 4.22 month |
| Dose Optimization Phase: Cohort 2 | Duration of Response (DOR) as Assessed by the Investigator Using the Lugano Criteria | 3.32 month |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first treatment to the date of death due to any cause. Participants without documented death were censored at last alive date.
Time frame: Up to 70 months
Population: Dose Optimization Efficacy Set: All participants who received at least one dose of study drug, completed at least one cycle of treatment, and had at least one scan to assess disease response after completion of one cycle of treatment. Modified Intent-to-treat (mITT): all participants who receive at least one dose of study drug. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | Overall Survival (OS) | 6.70 month |
| Dose Optimization Phase: Cohort 2 | Overall Survival (OS) | 10.58 month |
| Expansion Phase | Overall Survival (OS) | 12.4 month |
Secondary
PFS as Assessed by the IRC Using the Lugano Criteria
PFS was defined as the time from the date of first treatment to the date of the first radiographic disease progression or death due to any cause, whichever occurred first.
Time frame: Up to 70 months
Population: Modified Intent-to-treat (mITT): all participants who received at least one dose of study drug. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using IRC assessment reported for the Expansion Phase only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | PFS as Assessed by the IRC Using the Lugano Criteria | 3.4 months |
Secondary
Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite)
Blood samples were taken for the analyses of duvelisib and IPI-656 in plasma at designated time points. Results are reported as nanograms/milliliter (ng/mL).
Time frame: Day 15 of Cycles 1 and 2 (4 hours postdose) (28-day cycles)
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Here, 'Overall Number of Participants Analyzed' signifies those who were evaluable for this outcome measure, and 'Number Analyzed' signifies those participants who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Optimization Phase: Cohort 1 | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Duvelisib: Cycle 1, Day 15 | 1238.1 ng/mL | Standard Deviation 787.53 |
| Dose Optimization Phase: Cohort 1 | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Duvelisib: Cycle 2, Day 15 | 1492.5 ng/mL | Standard Deviation 1019.1 |
| Dose Optimization Phase: Cohort 1 | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Metabolite (IPI-156): Cycle 1, Day 15 | 1310.4 ng/mL | Standard Deviation 1408.99 |
| Dose Optimization Phase: Cohort 1 | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Metabolite (IPI-156): Cycle 2, Day 15 | 894.8 ng/mL | Standard Deviation 441.55 |
| Dose Optimization Phase: Cohort 2 | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Metabolite (IPI-156): Cycle 1, Day 15 | 1580.9 ng/mL | Standard Deviation 772.13 |
| Dose Optimization Phase: Cohort 2 | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Duvelisib: Cycle 1, Day 15 | 2070.0 ng/mL | Standard Deviation 889.39 |
| Expansion Phase | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Duvelisib: Cycle 2, Day 15 | 2648.2 ng/mL | Standard Deviation 1336.94 |
| Expansion Phase | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Metabolite (IPI-156): Cycle 2, Day 15 | 2427.0 ng/mL | Standard Deviation 1655.89 |
| Expansion Phase | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Duvelisib: Cycle 1, Day 15 | 2873.7 ng/mL | Standard Deviation 1709.15 |
| Expansion Phase | Plasma Concentration of IPI-145 (Duvelisib) and IPI-656 (Metabolite) | Metabolite (IPI-156): Cycle 1, Day 15 | 2387.5 ng/mL | Standard Deviation 1919.33 |
Secondary
Progression-free Survival (PFS) as Assessed by the Investigator Using the Lugano Criteria
PFS was defined as the time from the date of first treatment to the date of the first radiographic disease progression or death due to any cause, whichever occurred first.
Time frame: Up to 70 months
Population: Dose Optimization Efficacy Set: All participants who received at least one dose of study drug, completed at least one cycle of treatment, and had at least one scan to assess disease response after completion of one cycle of treatment. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. As pre-specified, efficacy analysis using investigator assessment reported for the Dose Optimization Phase only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Optimization Phase: Cohort 1 | Progression-free Survival (PFS) as Assessed by the Investigator Using the Lugano Criteria | 3.55 month |
| Dose Optimization Phase: Cohort 2 | Progression-free Survival (PFS) as Assessed by the Investigator Using the Lugano Criteria | 3.55 month |