Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
Phase 3, CLL/SLL, Pi3K
Brief summary
A Phase 3 clinical trial to examine the efficacy of duvelisib monotherapy versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
Detailed description
This is an open-label, two- arm, randomized phase 3, superiority trial designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab administered to patients who have been diagnosed with CLL/SLL whose disease is relapsed or refractory. Approximately 150 subjects will receive a starting dose of 25 mg duvelisib BID initially over the course of 21-day treatment cycle followed by 28-day treatment cycles for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). After 18 complete cycles of treatment, subjects may receive additional cycles of duvelisib until disease progression or unacceptable toxicity if they, in the judgment of the Investigator, may derive benefit from continued treatment, and if the subject meets the criteria for additional treatment at Cycle 19 Day 1. Approximately 150 subjects will receive a starting dose of 300 mg ofatumumab on Day 1 followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg ofatumumab once every month for four months. Administration of ofatumumab will not exceed the 12 doses (within 7 cycles).
Interventions
DRUGDuvelisib
PI3K Inhibitor
DRUGOfatumumab
monoclonal antibody
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
* Diagnosis of active CLL or SLL that meets at least one of the IWCLL 2008 criteria for requiring treatment (Binet Stage ≥ B and/or Rai Stage ≥ I) * Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy * Not appropriate for treatment with a purine-based analogue regimen (per National Comprehensive Cancer Network \[NCCN\] or European Society for Medical Oncology \[ESMO\] guidelines), including relapse ≤ 36 months from a purine-based chemoimmunotherapy regimen or relapse ≤ 24 months from a purine-based monotherapy regimen * A cytogenetics or fluorescence in situ hybridization (FISH) analysis of the leukemic cells within 24 months of randomization is required to document the presence or absence of del(17p). Note: if a sample from within 24 months is not available, it should be evaluated as part of the screening laboratory evaluation to inform stratification * Measurable disease with a lymph node or tumor mass \> 1.5 cm in at least one dimension as assessed by computed tomography (CT) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (corresponds to Karnofsky Performance Status \[KPS\] ≥ 60%) * Willingness by subject to be randomized to receive either ofatumumab or duvelisib at the dose and schedule defined in the protocol * Must meet the following laboratory parameters: 1. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≤ 3 x upper limit of normal (ULN) 2. Total bilirubin ≤ 1.5 x ULN 3. Serum creatinine ≤ 2.0 x ULN 4. Hemoglobin ≥ 8.0 g/dL with or without transfusion support 5. Platelet count ≥ 10,000 μL with or without transfusion support * For women of childbearing potential (WCBP): negative serum β-human chorionic gonadotropin (βhCG) pregnancy test within 1 week before randomization (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 24 consecutive months \[women ≤ 55 years\] or 12 consecutive months \[women \> 55 years\]) * Willingness of male and female subjects who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control from the first dose of study drug to 30 days after the last dose of duvelisib and for 12 months after last dose of ofatumumab. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception * Ability to voluntarily sign consent for and adhere to the entire study visit schedule and all protocol requirements * Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form (ICF) before any study specific screening procedures are performed
Exclusion criteria
* History of Richter's transformation or prolymphocytic leukemia * Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP) that is uncontrolled or requiring \> 20 mg once daily (QD) of prednisone (or equivalent) to maintain hemoglobin \> 8.0 g/dL or platelets \> 10,000 μL without transfusion support * Refractory to ofatumumab (progression or relapse \<12 months of receiving ofatumumab therapy or \<24 months of receiving an ofatumumab- containing regimen) * Prior allogeneic transplant (prior autologous stem cell transplant \>6 months prior to study entry is permitted) * Known central nervous system lymphoma or leukemia; subjects with symptoms of CNS disease must have a negative CT scan or negative diagnostic lumbar puncture prior to randomization * Use of any of the following medications or procedures within the specified timeframe: * Use of live or live attenuated vaccines within 30 days prior to randomization * Chemotherapy, radiation therapy, or ablative therapy within 3 weeks of randomization * Tyrosine kinase inhibitor within 7 days of randomization * Other investigational therapy (not included above) within 3 weeks of randomization * Previous treatment with a PI3K inhibitor or BTK inhibitor * Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic steroids \> 20 mg prednisone (or equivalent) QD * History of tuberculosis treatment within the preceding two years * Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of study treatment (defined as requiring IV antimicrobial, antifungal or antiviral agents) * Subjects on antimicrobial, antifungal or antiviral prophylaxis are not specifically excluded if all other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | The primary efficacy endpoint for the study was PFS, defined as time from randomization to the first documentation of PD as determined by blinded independent review or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Hematologic Improvements | 3 years | Subjects with hematologic improvement included those subjects with abnormally high values for neutrophil count, hemoglobin, or platelet count at Baseline determined to have consistently met the criteria of an improvement for those parameters for a period of at least 60 days during which the subject did not have a transfusion or exogenous cytokines. |
| Overall Survival | Every 6 months for up to 3 years after first dose | A stratified Cox regression analysis was used to test for any treatment effect. |
| Lymph Node Response Rate | 3 years | Lymph node response defined as greater than or equal to 50% decrease in the SPD of target lymph nodes |
| Overall Response Rate (ORR) | Until disease progression or unacceptable toxicity assessed up to 6 years | ORR is a key secondary efficacy endpoint with overall response defined as best response of CR, CRi, PR, or PRwL, according to the modified IWCLL/IWG Response Criteria, with modification for treatment-related lymphocytosis as defined in the protocol. |
| Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values | From 04 Feb 2014 till 19 June 2018 | An analysis of TEAEs with an onset within the first 24 weeks of treatment was performed to examine and compare the incidence of events across an equal period for each treatment arm.Twenty-four weeks was anticipated to be the median exposure to ofatumumab. |
| Number of Subjects With Samples Available for Duvelisib Pharmacokinetics (PK) | Cycle 2, Cycle 3, and Cycle 7 | Number of subjects with samples available for duvelisib Pharmacokinetics (PK) |
| Duration of Response (DOR) | Time from the first documentation of response to first documentation of progressive disease or death due to any cause | Duration of response is defined only for subjects demonstrating a response (eg, CR, CRi, PR, PRwL), with the response and progression statuses both determined by the blinded, central independent review. The analysis will be descriptive for each treatment group only. |
Countries
Australia, Austria, Belgium, France, Germany, Hungary, Italy, New Zealand, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Duvelisib Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules. | 160 |
| Ofatumumab Ofatumumab is administered as an IV infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL. | 159 |
| Total | 319 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 55 | 6 |
| Overall Study | Completed Treatment Cycles Per Protocol | 1 | 103 |
| Overall Study | Death | 12 | 3 |
| Overall Study | Disease Progression | 35 | 31 |
| Overall Study | Never Dosed | 2 | 4 |
| Overall Study | Other is reason listed by PI | 4 | 1 |
| Overall Study | Physician Decision | 3 | 4 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 13 | 7 |
Baseline characteristics
| Characteristic | Duvelisib | Ofatumumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 112 Participants | 105 Participants | 217 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants | 54 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 130 Participants | 133 Participants | 263 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 22 Participants | 19 Participants | 41 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 9 Participants | 16 Participants | 25 Participants |
| Race (NIH/OMB) White | 150 Participants | 142 Participants | 292 Participants |
| Region of Enrollment Australia | 9 participants | 12 participants | 21 participants |
| Region of Enrollment Austria | 3 participants | 8 participants | 11 participants |
| Region of Enrollment Belgium | 13 participants | 14 participants | 27 participants |
| Region of Enrollment France | 12 participants | 18 participants | 30 participants |
| Region of Enrollment Germany | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Hungary | 35 participants | 30 participants | 65 participants |
| Region of Enrollment Italy | 23 participants | 18 participants | 41 participants |
| Region of Enrollment New Zealand | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Spain | 21 participants | 19 participants | 40 participants |
| Region of Enrollment United Kingdom | 7 participants | 10 participants | 17 participants |
| Region of Enrollment United States | 30 participants | 21 participants | 51 participants |
| Sex: Female, Male Female | 64 Participants | 64 Participants | 128 Participants |
| Sex: Female, Male Male | 96 Participants | 95 Participants | 191 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 78 / 158 | 70 / 155 |
| other Total, other adverse events | 149 / 158 | 130 / 155 |
| serious Total, serious adverse events | 124 / 158 | 50 / 155 |
Outcome results
Primary
Progression-free Survival (PFS)
The primary efficacy endpoint for the study was PFS, defined as time from randomization to the first documentation of PD as determined by blinded independent review or death due to any cause.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Progression-free Survival (PFS) | 13.3 Months |
| Ofatumumab | Progression-free Survival (PFS) | 9.9 Months |
Secondary
Duration of Response (DOR)
Duration of response is defined only for subjects demonstrating a response (eg, CR, CRi, PR, PRwL), with the response and progression statuses both determined by the blinded, central independent review. The analysis will be descriptive for each treatment group only.
Time frame: Time from the first documentation of response to first documentation of progressive disease or death due to any cause
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Duration of Response (DOR) | 11.1 Months |
| Ofatumumab | Duration of Response (DOR) | 9.3 Months |
Secondary
Lymph Node Response Rate
Lymph node response defined as greater than or equal to 50% decrease in the SPD of target lymph nodes
Time frame: 3 years
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Duvelisib | Lymph Node Response Rate | 136 Participants |
| Ofatumumab | Lymph Node Response Rate | 25 Participants |
Secondary
Number of Subjects With Hematologic Improvements
Subjects with hematologic improvement included those subjects with abnormally high values for neutrophil count, hemoglobin, or platelet count at Baseline determined to have consistently met the criteria of an improvement for those parameters for a period of at least 60 days during which the subject did not have a transfusion or exogenous cytokines.
Time frame: 3 years
Population: Subjects With Abnormal Hematologic Values at Baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Duvelisib | Number of Subjects With Hematologic Improvements | 56 Participants |
| Ofatumumab | Number of Subjects With Hematologic Improvements | 51 Participants |
Secondary
Number of Subjects With Samples Available for Duvelisib Pharmacokinetics (PK)
Number of subjects with samples available for duvelisib Pharmacokinetics (PK)
Time frame: Cycle 2, Cycle 3, and Cycle 7
Population: Intent to Treat for duvelisib patients, no PK samples were collected for ofatumumab patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duvelisib | Number of Subjects With Samples Available for Duvelisib Pharmacokinetics (PK) | 158 participants |
Secondary
Overall Response Rate (ORR)
ORR is a key secondary efficacy endpoint with overall response defined as best response of CR, CRi, PR, or PRwL, according to the modified IWCLL/IWG Response Criteria, with modification for treatment-related lymphocytosis as defined in the protocol.
Time frame: Until disease progression or unacceptable toxicity assessed up to 6 years
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Duvelisib | Overall Response Rate (ORR) | 118 Participants |
| Ofatumumab | Overall Response Rate (ORR) | 72 Participants |
Secondary
Overall Survival
A stratified Cox regression analysis was used to test for any treatment effect.
Time frame: Every 6 months for up to 3 years after first dose
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Duvelisib | Overall Survival | 54.94 Months |
| Ofatumumab | Overall Survival | 63.25 Months |
Secondary
Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values
An analysis of TEAEs with an onset within the first 24 weeks of treatment was performed to examine and compare the incidence of events across an equal period for each treatment arm.Twenty-four weeks was anticipated to be the median exposure to ofatumumab.
Time frame: From 04 Feb 2014 till 19 June 2018
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Duvelisib | Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values | 150 Participants |
| Ofatumumab | Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values | 143 Participants |