Hodgkin Lymphoma
Conditions
Keywords
HL, idelalisib, CAL-101, GS-1101, PI3K
Brief summary
This study will evaluate the efficacy and safety of idelalisib in participants with relapsed of refractory Hodgkin Lymphoma (HL). The primary objective will be to assess the overall response rate. Eligible participants will initiate oral therapy with idelalisib at a starting dose of 150 mg twice daily. Treatment with idelalisib will continue until tumor progression or unacceptable toxicity.
Interventions
DRUGIdelalisib
Idelalisib tablets administered orally
Sponsors
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 12 years * Karnofsky performance score of ≥ 60 (Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2) * Histologically confirmed diagnosis of classic HL (ie, nodular sclerosis, mixed cellularity, lymphocyte depleted, and or lymphocyte rich types) * Nodal HL that shows fluorodeoxyglucose (FDG) avidity (defined as focal or diffuse FDG uptake above background in a location incompatible with normal anatomy or physiology), and is measurable (defined as the presence of ≥ 1 nodal lesion that measures ≥ 2 cm in a single dimension as assessed by CT, PET/CT, or magnetic resonance imaging (MRI)) * Relapsed or refractory HL after prior myeloablative therapy with autologous stem cell transplantation (ASCT) or after ≥ 2 prior chemotherapy-containing regimens and no curative option with conventional therapy * Discontinuation of all radiotherapy or chemotherapy for the treatment of HL greater than or equal to 3 weeks before initiation of study treatment and discontinuation of all radioimmunotherapy for HL (Visit 2) * All acute toxic effects (excluding alopecia, neurotoxicity, or anemia) of any prior antitumor therapy resolved to Grade ≤ 2 before initiation of study treatment (Visit 2) * For men and women of childbearing potential willingness to abstain from sexual intercourse or employ an effective method of contraception during the study drug administration and follow-up periods * Willingness and ability to provide written informed consent and to comply with protocol requirements
Exclusion criteria
* Known active central nervous system or leptomeningeal lymphoma * History of a non-lymphoma malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, localized prostate cancer, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 5 years * Evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment (Visit 2) * Pregnancy or breastfeeding * Ongoing alcohol or drug addiction * Known history of drug-induced liver injury, chronic active hepatitis C virus (HCV), chronic active hepatitis B virus (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver or portal hypertension * History of prior allogeneic bone marrow progenitor cell or solid organ transplantation * Ongoing immunosuppressive therapy, including systemic corticosteroids. * Prior therapy with idelalisib * Exposure to another investigational drug within 3 weeks prior to start of study treatment * Concurrent participation in another therapeutic treatment trial * Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results * Prior therapy with any drug that inhibits Akt, Bruton tyrosine kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3 kinase (PI3K) (including idelalisib), or spleen tyrosine kinase (SYK)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to Week 110 | Overall response rate (ORR) was assessed based on the International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007), and was defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as assessed by the investigator. * CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. * PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of Target Lymph Nodes as Documented Radiographically | Baseline, Week 8, Week 48, and up to Week 110 | — |
| Change From Baseline in Fluorodeoxyglucose (FDG) Uptake in Lymph Nodes as Assessed by Positron-emission Tomography (PET) | Up to Week 110 | — |
| Time to Response | Up to Week 110 | Time to response (TTR) was defined as the interval from the start of idelalisib treatment to the first documentation of CR or PR. |
| Overall Survival | Up to Week 110 | Overall survival was defined as the time from start of idelalisib treatment to death from any cause. |
| Progression Free Survival | Up to Week 110 | Progression free survival (PFS) was defined as the interval from the start of idelalisib treatment to the earlier of the first documentation of disease progression or death from any cause. |
| Time to Treatment Failure | Up to Week 110 | Time to treatment failure (TTF) was defined as the interval from the start of idelalisib treatment to the earlier of the first documentation of disease progression, the permanent cessation of idelalisib therapy due to an adverse event, or death from any cause. |
| Duration of Response | Up to Week 110 | Duration of response (DOR) was defined as the interval from the first documentation of PR or CR to the earlier of the first documentation of disease progression or death from any cause. |
| Changes in Performance Status as Documented Using the Karnofsky Performance Criteria for Participants ≥ 16 Years of Age and the Lansky Performance Criteria for Participants < 16 Years of Age | Baseline and up to Week 110 | Changes in performance status were assessed using the Karnofsky performance criteria for participants ≥ 16 years of age and the Lansky performance criteria for participants \< 16 years of age. Since there were no participants \< 16 years of age, only the Karnofsky performance criteria were used. The change in Karnofsky performance status was reported as the best (highest change score) and worst (lowest change score) change from baseline using the Karnofsky performance criteria. The Karnofsky score classifies patients according to their functional impairment. Scores are on a scale from 0-100, the lower the score, the worse the survival for most serious illnesses. |
| Changes in the Plasma Concentrations of Disease-associated Chemokines and Cytokines | Up to Week 110 | — |
| Overall Safety Profile of Idelalisib | Up to Week 110 | The overall safety of idelalisib was assessed as the percentage of participants experiencing adverse events (AEs; Serious AEs, Grade ≥ 3 AEs, AEs related to idelalisib, and AEs leading to discontinuation of idelalisib), clinically significant abnormal electrocardiograms (ECG), and laboratory abnormalities. Clinically significant abnormalities in ECG were as determined by the investigator. |
| Compliance With Study Drug Dosing as Assessed by Accounting for Used and Unused Drug | Up to Week 110 | — |
| Idelalisib Trough and Peak Plasma Concentration at Week 4 | Predose and 1.5 hours postdose at Week 4 | Plasma samples were collected predose (trough) and 1.5 hours postdose (peak). The minimum and maximum value among participants sampled at each time point are presented. Results of less than the lower limit of quantitation (ie, 5 ng/mL) were treated as zero prior to the achievement of the first quantifiable concentration and as missing otherwise. |
| Changes in Health-related Quality of Life as Reported Using the Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) Questionnaire | Baseline and up to Week 110 | Change in health-related quality of life was reported by participants using the FACT-Lym questionnaire assessment tool. Results are presented as the mean (SD) best change from baseline in FACT-Lym total score, which was defined as the highest change score (improvement) after baseline. The FACT-Lym total score is on a scale from 0-168, with higher scores associated with a better quality of life. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 15 September 2011. The last study visit occurred on 28 August 2014.
Pre-assignment details
32 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib Idelalisib up to 300 mg (75, 100, or 150 mg tablets) administered orally twice daily until tumor progression or development of unacceptable toxicity. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Idelalisib |
|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 16.1 |
| Classical Hodgkin Lymphoma Pathologic Subtype Lymphocyte Rich | 2 participants |
| Classical Hodgkin Lymphoma Pathologic Subtype Nodular Sclerosis | 23 participants |
| Disease Stage at Screening Stage I | 1 participants |
| Disease Stage at Screening Stage II | 8 participants |
| Disease Stage at Screening Stage III | 6 participants |
| Disease Stage at Screening Stage IV | 10 participants |
| Karnofsky Performance Status | 83 units on a scale STANDARD_DEVIATION 7.1 |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 22 participants |
| Race/Ethnicity, Customized Other | 3 participants |
| Race/Ethnicity, Customized White | 19 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 11 Participants |
| Time Since Diagnosis (years) | 3.9 years STANDARD_DEVIATION 4.26 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 25 |
| serious Total, serious adverse events | 9 / 25 |
Outcome results
Primary
Overall Response Rate
Overall response rate (ORR) was assessed based on the International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007), and was defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as assessed by the investigator. * CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. * PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions.
Time frame: Up to Week 110
Population: Intent-to-treat (ITT) Analysis Set: participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib | Overall Response Rate | 20.0 percentage of participants |
Secondary
Change From Baseline in Fluorodeoxyglucose (FDG) Uptake in Lymph Nodes as Assessed by Positron-emission Tomography (PET)
Time frame: Up to Week 110
Population: An analysis of changes in FDG uptake by the tumor was not conducted due to unavailability of lymph node biopsy samples.
Secondary
Changes in Health-related Quality of Life as Reported Using the Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) Questionnaire
Change in health-related quality of life was reported by participants using the FACT-Lym questionnaire assessment tool. Results are presented as the mean (SD) best change from baseline in FACT-Lym total score, which was defined as the highest change score (improvement) after baseline. The FACT-Lym total score is on a scale from 0-168, with higher scores associated with a better quality of life.
Time frame: Baseline and up to Week 110
Population: FACT-Lym Evaluable Analysis Set: participants who had sufficient baseline and on-study measurements to provide interpretable results for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idelalisib | Changes in Health-related Quality of Life as Reported Using the Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) Questionnaire | 5.1 units on a scale | Standard Deviation 7.24 |
Secondary
Changes in Performance Status as Documented Using the Karnofsky Performance Criteria for Participants ≥ 16 Years of Age and the Lansky Performance Criteria for Participants < 16 Years of Age
Changes in performance status were assessed using the Karnofsky performance criteria for participants ≥ 16 years of age and the Lansky performance criteria for participants \< 16 years of age. Since there were no participants \< 16 years of age, only the Karnofsky performance criteria were used. The change in Karnofsky performance status was reported as the best (highest change score) and worst (lowest change score) change from baseline using the Karnofsky performance criteria. The Karnofsky score classifies patients according to their functional impairment. Scores are on a scale from 0-100, the lower the score, the worse the survival for most serious illnesses.
Time frame: Baseline and up to Week 110
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idelalisib | Changes in Performance Status as Documented Using the Karnofsky Performance Criteria for Participants ≥ 16 Years of Age and the Lansky Performance Criteria for Participants < 16 Years of Age | Best Change | 6 units on a scale | Standard Deviation 5.3 |
| Idelalisib | Changes in Performance Status as Documented Using the Karnofsky Performance Criteria for Participants ≥ 16 Years of Age and the Lansky Performance Criteria for Participants < 16 Years of Age | Worst Change | -1 units on a scale | Standard Deviation 6.9 |
Secondary
Changes in the Plasma Concentrations of Disease-associated Chemokines and Cytokines
Time frame: Up to Week 110
Population: This analysis was not conducted due to discrepancies with the transfer of samples.
Secondary
Compliance With Study Drug Dosing as Assessed by Accounting for Used and Unused Drug
Time frame: Up to Week 110
Population: ITT Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idelalisib | Compliance With Study Drug Dosing as Assessed by Accounting for Used and Unused Drug | Number of doses dispensed | 463 number of doses | Standard Deviation 462.3 |
| Idelalisib | Compliance With Study Drug Dosing as Assessed by Accounting for Used and Unused Drug | Number of doses taken | 329 number of doses | Standard Deviation 321.1 |
Secondary
Duration of Response
Duration of response (DOR) was defined as the interval from the first documentation of PR or CR to the earlier of the first documentation of disease progression or death from any cause.
Time frame: Up to Week 110
Population: Responding Analysis Set: participants who achieved a best response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib | Duration of Response | 8.4 months |
Secondary
Idelalisib Trough and Peak Plasma Concentration at Week 4
Plasma samples were collected predose (trough) and 1.5 hours postdose (peak). The minimum and maximum value among participants sampled at each time point are presented. Results of less than the lower limit of quantitation (ie, 5 ng/mL) were treated as zero prior to the achievement of the first quantifiable concentration and as missing otherwise.
Time frame: Predose and 1.5 hours postdose at Week 4
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Idelalisib | Idelalisib Trough and Peak Plasma Concentration at Week 4 | Trough - minimum (n = 20) | 142 ng/mL |
| Idelalisib | Idelalisib Trough and Peak Plasma Concentration at Week 4 | Trough - maximum (n = 20) | 2120.0 ng/mL |
| Idelalisib | Idelalisib Trough and Peak Plasma Concentration at Week 4 | Peak - minimum (n = 22) | 90.2 ng/mL |
| Idelalisib | Idelalisib Trough and Peak Plasma Concentration at Week 4 | Peak - maximum (n = 22) | 8570.0 ng/mL |
Secondary
Overall Safety Profile of Idelalisib
The overall safety of idelalisib was assessed as the percentage of participants experiencing adverse events (AEs; Serious AEs, Grade ≥ 3 AEs, AEs related to idelalisib, and AEs leading to discontinuation of idelalisib), clinically significant abnormal electrocardiograms (ECG), and laboratory abnormalities. Clinically significant abnormalities in ECG were as determined by the investigator.
Time frame: Up to Week 110
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Idelalisib | Overall Safety Profile of Idelalisib | Any AE | 96.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Serious AE | 36.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Grade ≥ 3 AE | 48.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | AE related to idelalisib | 76.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | AE leading to permanent drug discontinuation | 8.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Clinically significant abnormal ECG at Week 16 | 0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Grade 3 or 4 hemoglobin | 4.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Grade 3 or 4 neutrophils | 8.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Grade 3 or 4 platelets | 4.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Grade 3 or 4 alanine aminotransferase | 20.0 percentage of participants |
| Idelalisib | Overall Safety Profile of Idelalisib | Grade 3 or 4 aspartate aminotransferase | 16.0 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the time from start of idelalisib treatment to death from any cause.
Time frame: Up to Week 110
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib | Overall Survival | 19.8 months |
Secondary
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of Target Lymph Nodes as Documented Radiographically
Time frame: Baseline, Week 8, Week 48, and up to Week 110
Population: ITT Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idelalisib | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of Target Lymph Nodes as Documented Radiographically | Percent Change at Week 8 (n = 24) | -14.1 percent change in SPD |
| Idelalisib | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of Target Lymph Nodes as Documented Radiographically | Percent Change at Week 48 (n = 5) | -45.9 percent change in SPD |
| Idelalisib | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of Target Lymph Nodes as Documented Radiographically | Best Percent Change from Baseline (n = 24) | -24.1 percent change in SPD |
Secondary
Progression Free Survival
Progression free survival (PFS) was defined as the interval from the start of idelalisib treatment to the earlier of the first documentation of disease progression or death from any cause.
Time frame: Up to Week 110
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib | Progression Free Survival | 2.3 months |
Secondary
Time to Response
Time to response (TTR) was defined as the interval from the start of idelalisib treatment to the first documentation of CR or PR.
Time frame: Up to Week 110
Population: Responding Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib | Time to Response | 2.0 months |
Secondary
Time to Treatment Failure
Time to treatment failure (TTF) was defined as the interval from the start of idelalisib treatment to the earlier of the first documentation of disease progression, the permanent cessation of idelalisib therapy due to an adverse event, or death from any cause.
Time frame: Up to Week 110
Population: No data are presented because time to treatment failure data were not collected.