Indolent Non-Hodgkin Lymphoma
Conditions
Keywords
PI3K Inhibitor
Brief summary
This was a Phase 2 clinical trial to evaluate the safety and efficacy of duvelisib as a monotherapy in participants with indolent non-Hodgkin lymphoma (iNHL) (follicular lymphoma \[FL\], marginal zone lymphoma, or small lymphocytic lymphoma) that was refractory to rituximab and to either chemotherapy or radioimmunotherapy (RIT).
Detailed description
This was an open-label, single-arm safety and efficacy study of duvelisib administered orally to participants who had been diagnosed with iNHL whose disease was refractory to rituximab and to either chemotherapy or RIT. Approximately 120 participants received 25 milligrams of duvelisib twice daily over the course of 28-day treatment cycles for up to 13 cycles. After completing 13 treatment cycles of duvelisib, participants continued to receive additional cycles of duvelisib until disease progression or unacceptable toxicity. However, to receive additional cycles of duvelisib beyond 13 cycles, participants must have had evidence of response (complete response \[CR\] or partial response \[PR\]) or stable disease according to the International Working Group criteria by the end of Cycle 13.
Interventions
DRUGDuvelisib
Phosphoinositide-3-kinase (PI3K) inhibitor
Sponsors
SecuraBio
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
* Participants who had been diagnosed with iNHL that had progressed. * Participants must have exhibited lack of CR or progressive disease (PR) or progression within 6 months after the last dose of a chemotherapy induction regimen or RIT. * Participants must have had rituximab-refractory disease, defined as lack of CR or PR or PD within 6 months of last dose. * Measurable disease with a lymph node or tumor mass ≥1.5 centimeters in at least one dimension by computed tomography (CT), positron emission tomography/CT or magnetic resonance imaging. * Adequate renal and hepatic function.
Exclusion criteria
* Candidate for potentially curative therapies in the opinion of the investigator. * Previous treatment with a PI3K inhibitor or Bruton's tyrosine kinase inhibitor. * Prior history of allogeneic hematopoietic stem cell transplant. * Prior chemotherapy, cancer immunosuppressive therapy, or other investigational agents within 4 weeks before first dose of study drug. * Grade 3B FL and/or clinical evidence of transformation to a more aggressive subtype of lymphoma. * Symptomatic central nervous system NHL. * Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of study treatment. * Prior, current, or chronic hepatitis B or hepatitis C infection, positive result for hepatitis C virus antibodies, hepatitis B surface antigen, or hepatitis B core antibodies. * History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Every 8-16 weeks while on treatment with duvelisib for up to 72 months | ORR, defined as the total percentage of participants who had a best overall response of either complete response (CR) or partial response (PR), was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma. ORR is reported with a 2-sided 95% exact confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Every 8-16 weeks for up to 72 months | DOR, defined as the time from the first documentation of response to either progressive disease (PD) or death due to any cause, was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma. |
| Progression-free Survival (PFS) | Every 8-16 weeks for up to 72 months | PFS, defined as the time from the first dose of study treatment to the first documentation of either Investigator-assessed PD or death resulting from any cause, was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Every 2-8 weeks for up to 73 months | An adverse event was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as any adverse event that emerged or worsened in the period from the first dose of study treatment to 30 days after the last dose of study treatment. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
| Plasma Concentration of Duvelisib and IPI-656 | Every 4 weeks for 12 weeks (C1D15: predose, 1 and 4 hours post dose; C2D1 and C3D1: anytime during study visit) | The serum concentration of duvelisib and its main metabolite, IPI-656, are reported for Day 15 of Cycle 1 (C1D15) and Day 1 of Cycle 2 (C2D1) and Day 1 of Cycle 3 (C3D1). Results are reported in nanograms/milliliter (ng/mL). |
| Time to Response (TTR) | First dose to first documentation of complete or partial response (up to 6 months) | TTR, defined as the time from the first dose of study treatment to the first documentation of response, was evaluated by an independent, third-party panel of radiologists and oncologists (Independent Review Committee \[IRC\]) according to the revised IWG Response Criteria for Malignant Lymphoma. |
| Overall Survival (OS) | Every 16 weeks for up to 72 months | OS, defined as the time from the first dose of study treatment to the date of death, was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma. |
Countries
Belarus, Belgium, Bulgaria, Canada, Czechia, France, Georgia, Hungary, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
This multicenter, multinational study enrolled participants at 56 medical clinics across 12 countries.
Participants by arm
| Arm | Count |
|---|---|
| Duvelisib Participants received a dose of 25 mg duvelisib BID over the course of 28-day treatment cycles until disease progression or unacceptable toxicity. | 129 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 68 |
| Overall Study | Disease Progression | 1 |
| Overall Study | Follow-up Completed | 39 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Study Terminated by the Sponsor | 6 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Duvelisib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 65 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants |
| Age, Continuous | 63.6 years STANDARD_DEVIATION 11.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants |
| Race/Ethnicity, Customized Missing | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants |
| Race/Ethnicity, Customized White | 116 Participants |
| Region of Enrollment Belarus | 10 participants |
| Region of Enrollment Belgium | 2 participants |
| Region of Enrollment Bulgaria | 5 participants |
| Region of Enrollment Canada | 9 participants |
| Region of Enrollment Czechia | 9 participants |
| Region of Enrollment France | 6 participants |
| Region of Enrollment Georgia | 1 participants |
| Region of Enrollment Hungary | 7 participants |
| Region of Enrollment Italy | 21 participants |
| Region of Enrollment Spain | 2 participants |
| Region of Enrollment United Kingdom | 11 participants |
| Region of Enrollment United States | 46 participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 68 / 129 |
| other Total, other adverse events | 122 / 129 |
| serious Total, serious adverse events | 83 / 129 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR, defined as the total percentage of participants who had a best overall response of either complete response (CR) or partial response (PR), was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma. ORR is reported with a 2-sided 95% exact confidence interval.
Time frame: Every 8-16 weeks while on treatment with duvelisib for up to 72 months
Population: Full Analysis Set (FAS): all participants who received at least 1 dose of duvelisib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duvelisib | Overall Response Rate (ORR) | 59.7 percentage of participants |
Comparison: ORR was tested against the null (≤30%) by 1-sided exact binomial test at 0.025 level.p-value: <=0.0001Exact Binomial Test
Secondary
Duration of Response (DOR)
DOR, defined as the time from the first documentation of response to either progressive disease (PD) or death due to any cause, was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma.
Time frame: Every 8-16 weeks for up to 72 months
Population: Full Analysis Set (FAS): all participants who received at least 1 dose of duvelisib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Duration of Response (DOR) | 10.16 months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as any adverse event that emerged or worsened in the period from the first dose of study treatment to 30 days after the last dose of study treatment. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Every 2-8 weeks for up to 73 months
Population: Full Analysis Set (FAS): all participants who received at least 1 dose of duvelisib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Duvelisib | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 128 Participants |
Secondary
Overall Survival (OS)
OS, defined as the time from the first dose of study treatment to the date of death, was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma.
Time frame: Every 16 weeks for up to 72 months
Population: Full Analysis Set (FAS): all participants who received at least 1 dose of duvelisib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Overall Survival (OS) | 28.96 months |
Secondary
Plasma Concentration of Duvelisib and IPI-656
The serum concentration of duvelisib and its main metabolite, IPI-656, are reported for Day 15 of Cycle 1 (C1D15) and Day 1 of Cycle 2 (C2D1) and Day 1 of Cycle 3 (C3D1). Results are reported in nanograms/milliliter (ng/mL).
Time frame: Every 4 weeks for 12 weeks (C1D15: predose, 1 and 4 hours post dose; C2D1 and C3D1: anytime during study visit)
Population: Pharmacokinetics (PK) Set: all participants who received at least 1 dose of duvelisib and with at least 1 adequate post-baseline blood sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Duvelisib | Plasma Concentration of Duvelisib and IPI-656 | C1D15 1 hour post dose | 1175 ng/mL |
| Duvelisib | Plasma Concentration of Duvelisib and IPI-656 | C2D1 | 631 ng/mL |
| Duvelisib | Plasma Concentration of Duvelisib and IPI-656 | C1D15 4 hours post dose | 852 ng/mL |
| Duvelisib | Plasma Concentration of Duvelisib and IPI-656 | C3D1 | 696 ng/mL |
| Duvelisib | Plasma Concentration of Duvelisib and IPI-656 | C1D15 Predose | 414 ng/mL |
| IPI-656 | Plasma Concentration of Duvelisib and IPI-656 | C3D1 | 664 ng/mL |
| IPI-656 | Plasma Concentration of Duvelisib and IPI-656 | C1D15 Predose | 648 ng/mL |
| IPI-656 | Plasma Concentration of Duvelisib and IPI-656 | C1D15 1 hour post dose | 641 ng/mL |
| IPI-656 | Plasma Concentration of Duvelisib and IPI-656 | C1D15 4 hours post dose | 714 ng/mL |
| IPI-656 | Plasma Concentration of Duvelisib and IPI-656 | C2D1 | 704 ng/mL |
Secondary
Progression-free Survival (PFS)
PFS, defined as the time from the first dose of study treatment to the first documentation of either Investigator-assessed PD or death resulting from any cause, was evaluated locally (investigator's assessment) according to the revised IWG Response Criteria for Malignant Lymphoma.
Time frame: Every 8-16 weeks for up to 72 months
Population: Full Analysis Set (FAS): all participants who received at least 1 dose of duvelisib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Progression-free Survival (PFS) | 9.57 months |
Secondary
Time to Response (TTR)
TTR, defined as the time from the first dose of study treatment to the first documentation of response, was evaluated by an independent, third-party panel of radiologists and oncologists (Independent Review Committee \[IRC\]) according to the revised IWG Response Criteria for Malignant Lymphoma.
Time frame: First dose to first documentation of complete or partial response (up to 6 months)
Population: Full Analysis Set (FAS): all participants who received at least 1 dose of duvelisib and who were considered responders (CR or PR) per IRC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Time to Response (TTR) | 1.87 month |