Indolent Non-Hodgkin Lymphoma
Conditions
Keywords
PI3K Inhibitor
Brief summary
This study examined the effects of predefined 2-week duvelisib dose holidays on tumor responses and safety/tolerability.
Detailed description
This was a Phase 2, randomized, open-label, 2-arm study designed to evaluate the efficacy and safety of prescribed drug holidays of duvelisib treatment in participants with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) who have received at least 1 prior systemic therapy.
Interventions
DRUGDuvelisib
Phosphoinositide 3-kinase (PI3K) inhibitor
Sponsors
SecuraBio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eastern Cooperative Oncology Group performance status ≤ 2 * Histologically confirmed diagnosis of iNHL (subtypes include follicular lymphoma \[FL\] Grades 1 to 3a), marginal zone lymphoma (splenic, nodal, or extranodal), or small lymphocytic lymphoma * Must have received 1 prior systemic regimen for iNHL * Must have documented radiologic evidence of disease progression, at least 1 bi-dimensionally measurable lesion ≥ 1.5 centimeters (which has not been previously irradiated), according to 2007 revised International Working Group criteria, and be a candidate for a subsequent line of therapy. * Must have adequate organ function defined by the following laboratory parameters: * Absolute neutrophil count ≥ 1.0 × 10\^9/liter (L) * Platelet count ≥ 75 × 10\^9/L * Hemoglobin ≥ 8 grams/deciliter * Estimated creatinine clearance ≥ 60 milliliters/minute, as determined by the Cockcroft-Gault method * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (exception: participants with Gilbert's Syndrome may have a bilirubin \> 1.5 × ULN) * Aspartate transaminase/serum glutamic-oxaloacetic transaminase and alanine aminotransferase/serum pyruvic transaminase ≤ 3.0 × ULN
Exclusion criteria
* Anticancer treatment, major surgery, or use of any investigational drug within 28 days before the start of study intervention; palliative radiation therapy is allowed if \> 7 days before planned first dose of study interventions, and any toxicity is Grade ≤ 1 * Clinical or histological evidence of transformation to a more aggressive subtype of lymphoma or grade 3b FL or Richters' transformation or chronic lymphocytic leukemia * Prior allogeneic hematopoietic stem cell transplant; prior treatment with a PI3K inhibitor * History of drug-induced colitis or pneumonitis; tuberculosis treatment ≤ 2 years prior to randomization; administration of a live or live attenuated vaccine within 6 weeks of randomization * Ongoing treatment with chronic immunosuppressants or systemic steroids or treatment for systemic bacterial, fungal, or viral infection * Active cytomegalovirus or Epstein-Barr virus infection * Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus, or herpes zoster at screening * Concurrent administration of medications or foods that are strong inhibitors or inducers of cytochrome P450 3A. No prior use within 2 weeks before the start of study intervention. * Baseline QT interval corrected with Fridericia's method \> 500 milliseconds * Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix, bladder cancer, or prostate cancer not requiring treatment. Participants with previous malignancies are eligible if they have been disease-free for 2 years or more. * Unstable or severe uncontrolled medical condition that would, in the Investigator's judgment, increase the participant's risk to participating in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) According to the 2007 Revised International Working Group (IWG) Criteria | Up to 14 months | ORR was defined as the percentage of participants achieving a complete response (CR) or partial response (PR) and assessed using the 2007 revised IWG criteria. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease and PR as the regression of measurable disease and no new sites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 2 years | PFS was defined as the time from first dose to first progressive disease (PD) or death (progression date/death date - treatment start date + 1) or, for participants without PD or documented death, as the time from first dose to censoring date (censoring date - treatment start date + 1). The 2007 revised IWG criteria defined PD as any new lesion or increase by ≥50% of previously involved sites from nadir. The 2014 Lugano criteria defined PD as a progressive metabolic response (according to positron emission tomography-computed tomography \[PET-CT\]) and progressive disease (according to computed tomography \[CT\]). Results reported as months. |
| ORR At Specific Timepoints | 6, 12, 18, and 24 months after first dose of study intervention | ORR at 6, 12, 18, and 24 months after first dose of study intervention was defined as the percentage of participants achieving CR or PR at each timepoint and was assessed using both the 2007 revised IWG criteria and the 2014 Lugano criteria. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease and PR as the regression of measurable disease and no new sites. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT) and PR as partial metabolic response (according to PET-CT) and partial remission (according to CT). The response was cumulative for each timepoint; a participant was considered a responder if their first response occurred up to the end of that timepoint. |
| Duration of Response (DOR) | Up to 2 years | DOR was defined for participants with CR or PR as the time from the date of first documentation of response (CR or PR) to date of the first documentation of PD or death. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease, PR as the regression of measurable disease and no new sites, and PD as any new lesion or increase by ≥50% of previously involved sites from nadir. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT), PR as partial metabolic response (according to PET-CT) and partial remission (according to CT), and PD as a progressive metabolic response (according to PET-CT) and progressive disease (according to CT). Results are reported as months. |
| Lymph Node Response Rate (LNRR) | 14 months | LNRR was calculated as the percentage of participants achieving ≥50% decrease in the sum of the product of the diameters of target lymph nodes. The confidence interval for LNRR was calculated only for participants who had at least 1 nodal target lesion, using the Clopper-Pearson exact method for binomial proportions. Participants whose target lesions were all extranodal were excluded from this analysis. |
| Time To First Response (TTFR) | Up to 14 months | For participants with CR or PR, TTFR was defined as the time from first dose of study intervention to time of first CR or PR and was calculated as: the date of first CR or PR - randomization date + 1. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease and PR as the regression of measurable disease and no new sites. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT) and PR as partial metabolic response (according to PET-CT) and partial remission (according to CT). Results are reported as months. |
| Time To Treatment Failure (TTF) | Up to 2 years | TTF was calculated as the time from first dose of study treatment to discontinuation for any reason (discontinuation date - treatment start date + 1). Participants who were still ongoing treatment at time of data cut were censored (last dose date - treatment start date + 1). Results reported as months. |
| ORR According to 2014 Lugano Criteria | Up to 14 months | ORR was defined as the percentage of participants achieving a CR or PR and was assessed using the 2014 Lugano criteria. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT) and PR as partial metabolic response (according to PET-CT) and partial remission (according to CT). |
| Overall Survival (OS) | Up to 2 years | OS was the time from first dose to death (death date - treatment start date + 1). Participants without documented death were censored at their last known alive date (last known alive date - treatment start date + 1). Results reported as months. |
Countries
Czechia, Germany, Italy, Poland, Russia, South Korea, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Duvelisib, Continuous and Intermittent Dosing Duvelisib 25 mg BID continuously for 10 weeks, followed by 25 mg BID dosed 2 weeks off and 2 weeks on of each subsequent 4-week cycle. | 51 |
| Duvelisib, Intermittent Dosing Duvelisib 25 mg BID dosed 2 weeks on and 2 weeks off. | 51 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Consent Withdrawn Prior to Receiving Study Drug | 1 | 0 |
| Overall Study | Death | 8 | 7 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Participant Moved | 1 | 0 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Progressive Disease | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Duvelisib, Intermittent Dosing | Total | Duvelisib, Continuous and Intermittent Dosing |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 11.4 | 62.2 years STANDARD_DEVIATION 11.85 | 60.5 years STANDARD_DEVIATION 12.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 98 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 23 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 78 Participants | 36 Participants |
| Sex: Female, Male Female | 27 Participants | 55 Participants | 28 Participants |
| Sex: Female, Male Male | 24 Participants | 47 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 51 | 7 / 51 |
| other Total, other adverse events | 49 / 51 | 50 / 51 |
| serious Total, serious adverse events | 13 / 51 | 16 / 51 |
Outcome results
Primary
Overall Response Rate (ORR) According to the 2007 Revised International Working Group (IWG) Criteria
ORR was defined as the percentage of participants achieving a complete response (CR) or partial response (PR) and assessed using the 2007 revised IWG criteria. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease and PR as the regression of measurable disease and no new sites.
Time frame: Up to 14 months
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Per-protocol (PP) Analysis Set: all participants in the mITT analysis set who did not violate the protocol in a way that would significantly affect the study outcome. Here, 'Number Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Overall Response Rate (ORR) According to the 2007 Revised International Working Group (IWG) Criteria | PP | 62.2 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | Overall Response Rate (ORR) According to the 2007 Revised International Working Group (IWG) Criteria | mITT | 65.3 percentage of participants |
| Duvelisib, Intermittent Dosing | Overall Response Rate (ORR) According to the 2007 Revised International Working Group (IWG) Criteria | mITT | 52.9 percentage of participants |
| Duvelisib, Intermittent Dosing | Overall Response Rate (ORR) According to the 2007 Revised International Working Group (IWG) Criteria | PP | 54.3 percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined for participants with CR or PR as the time from the date of first documentation of response (CR or PR) to date of the first documentation of PD or death. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease, PR as the regression of measurable disease and no new sites, and PD as any new lesion or increase by ≥50% of previously involved sites from nadir. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT), PR as partial metabolic response (according to PET-CT) and partial remission (according to CT), and PD as a progressive metabolic response (according to PET-CT) and progressive disease (according to CT). Results are reported as months.
Time frame: Up to 2 years
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Duration of Response (DOR) | 2007 Revised IWG Criteria | 21.4 months |
| Duvelisib, Continuous and Intermittent Dosing | Duration of Response (DOR) | 2014 Lugano Criteria | 21.4 months |
| Duvelisib, Intermittent Dosing | Duration of Response (DOR) | 2007 Revised IWG Criteria | 32.2 months |
| Duvelisib, Intermittent Dosing | Duration of Response (DOR) | 2014 Lugano Criteria | 32.2 months |
Secondary
Lymph Node Response Rate (LNRR)
LNRR was calculated as the percentage of participants achieving ≥50% decrease in the sum of the product of the diameters of target lymph nodes. The confidence interval for LNRR was calculated only for participants who had at least 1 nodal target lesion, using the Clopper-Pearson exact method for binomial proportions. Participants whose target lesions were all extranodal were excluded from this analysis.
Time frame: 14 months
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Lymph Node Response Rate (LNRR) | 64.3 percentage of participants |
| Duvelisib, Intermittent Dosing | Lymph Node Response Rate (LNRR) | 60.9 percentage of participants |
Secondary
ORR According to 2014 Lugano Criteria
ORR was defined as the percentage of participants achieving a CR or PR and was assessed using the 2014 Lugano criteria. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT) and PR as partial metabolic response (according to PET-CT) and partial remission (according to CT).
Time frame: Up to 14 months
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Per-protocol (PP) Analysis Set: all participants in the mITT analysis set who did not violate the protocol in a way that would significantly affect the study outcome. Here, 'Number Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | ORR According to 2014 Lugano Criteria | mITT | 65.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR According to 2014 Lugano Criteria | PP | 62.2 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR According to 2014 Lugano Criteria | mITT | 51.0 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR According to 2014 Lugano Criteria | PP | 52.2 percentage of participants |
Secondary
ORR At Specific Timepoints
ORR at 6, 12, 18, and 24 months after first dose of study intervention was defined as the percentage of participants achieving CR or PR at each timepoint and was assessed using both the 2007 revised IWG criteria and the 2014 Lugano criteria. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease and PR as the regression of measurable disease and no new sites. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT) and PR as partial metabolic response (according to PET-CT) and partial remission (according to CT). The response was cumulative for each timepoint; a participant was considered a responder if their first response occurred up to the end of that timepoint.
Time frame: 6, 12, 18, and 24 months after first dose of study intervention
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 6 months: 2007 Revised IWG Criteria | 63.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 12 months: 2007 Revised IWG Criteria | 65.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 18 months: 2007 Revised IWG Criteria | 65.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 24 months: 2007 Revised IWG Criteria | 65.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 6 months: 2014 Lugano Criteria | 63.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 12 months: 2014 Lugano Criteria | 65.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 18 months: 2014 Lugano Criteria | 65.3 percentage of participants |
| Duvelisib, Continuous and Intermittent Dosing | ORR At Specific Timepoints | 24 months: 2014 Lugano Criteria | 65.3 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 24 months: 2014 Lugano Criteria | 51.0 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 6 months: 2007 Revised IWG Criteria | 49.0 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 6 months: 2014 Lugano Criteria | 47.1 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 12 months: 2007 Revised IWG Criteria | 52.9 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 18 months: 2014 Lugano Criteria | 51.0 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 18 months: 2007 Revised IWG Criteria | 52.9 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 12 months: 2014 Lugano Criteria | 51.0 percentage of participants |
| Duvelisib, Intermittent Dosing | ORR At Specific Timepoints | 24 months: 2007 Revised IWG Criteria | 52.9 percentage of participants |
Secondary
Overall Survival (OS)
OS was the time from first dose to death (death date - treatment start date + 1). Participants without documented death were censored at their last known alive date (last known alive date - treatment start date + 1). Results reported as months.
Time frame: Up to 2 years
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Overall Survival (OS) | NA months |
| Duvelisib, Intermittent Dosing | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from first dose to first progressive disease (PD) or death (progression date/death date - treatment start date + 1) or, for participants without PD or documented death, as the time from first dose to censoring date (censoring date - treatment start date + 1). The 2007 revised IWG criteria defined PD as any new lesion or increase by ≥50% of previously involved sites from nadir. The 2014 Lugano criteria defined PD as a progressive metabolic response (according to positron emission tomography-computed tomography \[PET-CT\]) and progressive disease (according to computed tomography \[CT\]). Results reported as months.
Time frame: Up to 2 years
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Progression-free Survival (PFS) | 2007 Revised IWG Criteria | 16.0 months |
| Duvelisib, Continuous and Intermittent Dosing | Progression-free Survival (PFS) | 2014 Lugano Criteria | 16.0 months |
| Duvelisib, Intermittent Dosing | Progression-free Survival (PFS) | 2007 Revised IWG Criteria | 23.0 months |
| Duvelisib, Intermittent Dosing | Progression-free Survival (PFS) | 2014 Lugano Criteria | 23.0 months |
Secondary
Time To First Response (TTFR)
For participants with CR or PR, TTFR was defined as the time from first dose of study intervention to time of first CR or PR and was calculated as: the date of first CR or PR - randomization date + 1. The 2007 revised IWG criteria defined CR as the disappearance of all evidence of disease and PR as the regression of measurable disease and no new sites. The 2014 Lugano criteria defined CR as a complete metabolic response (according to PET-CT) and a complete radiologic response (according to CT) and PR as partial metabolic response (according to PET-CT) and partial remission (according to CT). Results are reported as months.
Time frame: Up to 14 months
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Number Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Time To First Response (TTFR) | 2007 Revised IWG Criteria | 2.30 months |
| Duvelisib, Continuous and Intermittent Dosing | Time To First Response (TTFR) | 2014 Lugano Criteria | 2.30 months |
| Duvelisib, Intermittent Dosing | Time To First Response (TTFR) | 2007 Revised IWG Criteria | 2.30 months |
| Duvelisib, Intermittent Dosing | Time To First Response (TTFR) | 2014 Lugano Criteria | 2.30 months |
Secondary
Time To Treatment Failure (TTF)
TTF was calculated as the time from first dose of study treatment to discontinuation for any reason (discontinuation date - treatment start date + 1). Participants who were still ongoing treatment at time of data cut were censored (last dose date - treatment start date + 1). Results reported as months.
Time frame: Up to 2 years
Population: Modified Intent-to-treat (mITT) analysis set: all participants who receive at least 1 dose of duvelisib. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib, Continuous and Intermittent Dosing | Time To Treatment Failure (TTF) | 12.6 months |
| Duvelisib, Intermittent Dosing | Time To Treatment Failure (TTF) | 14.3 months |