| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults with relapsed or refractory chronic lymphocytic leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adults with relapsed or refractory chronic lymphocytic leukemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the preliminary efficacy of finite therapy with the combination of tirabrutinib, entospletinib with obinutuzumab in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of the combination of tirabrutinib and entospletinib with and without obinutuzumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Documentation of relapsed or refractory CLL
2) Have an indication for treatment per modified IWCLL 2008 criteria; subjects without radiographically measureable disease (defined as ≥ 1 lesion > 1.5cm in diameter as assessed by computer tomography (CT) or magnetic resonance imaging [MRI]) must have bone marrow evaluation at screening
3) Adequate hematologic function as indicated by a platelet count ≥ 50 x 10^9/L, a neutrophil count ≥ 1 x 10^9/L and a hemoglobin ≥ 8g/dL unless lower values are directly attributable to documented bone marrow burden of CLL
4) Adequate renal function as indicated by a CrCl ≥ 50 mL/min calculated by the modified Cockroft-Gault formula or from a 24h urine collection
5) Adequate liver function as indicated by total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless attributed to Gilbert’s syndrome and AST/ALT ≤ 2.5×ULN
6) Male or female ≥ 18 years of age
7) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
8) Absence of active HBV infection (serological testing within 6 weeks prior to randomization or enrollment with the following results: HBsAg negative AND anti-HBcAb negative, or if anti-HBcAb positive, HBV DNA PCR negative)
9) HCV Ab negative or if Ab positive, negative HCV RNA PCR within 6 weeks prior to randomization or enrollment
10) Negative testing for HIV within 6 weeks prior to randomization or enrollment
11) Satisfies the following criteria:
a) For female subjects of childbearing potential, willingness to abstain from sexual intercourse or use a protocol-specified method of contraception
b) Male subjects of reproductive potential who engage in sexual intercourse must agree to use protocol specified method(s) of contraception
12) Ability and willingness to provide written informed consent and adhere to protocol requirements including study visit schedule, drug administration plan, imaging studies, laboratory testing, other study procedures and restrictions |
|
| E.4 | Principal exclusion criteria |
1) Known transformation of CLL (ie, Richter’s transformation, prolymphocytic leukemia)
2) Known CNS involvement
3) Progression on treatment with any inhibitor of BTK, SYK, PI3K, BCL-2, or obinutuzumab. The treatment and disease response history of subjects with prior treatment with agents in these classes should be reviewed by the sponsor or the GCLLSG study office prior to enrollment to clarify sensitivity to these treatments
4) Any treatment for CLL other than corticosteroids for symptomatic management within 28 days of the start of study treatment
5) Participation in a concurrent therapeutic clinical trial unless all treatment is complete with only ongoing surveillance
6) Diagnosis of or concern for progressive multifocal leukoencephalopathy
7) History of myelodysplastic syndrome or another malignancy other than CLL, except for the following: any malignancy that has been in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to start of study therapy.
8) Active infection requiring systemic therapy
9) Pregnant or nursing women (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment and monthly during therapy)
10) Active autoimmune disease including autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura requiring a higher corticosteroid equivalent than prednisone 10 mg daily. Higher doses of corticosteroids prescribed for any indication must be stopped > 14 days prior to randomization or enrollment; exceptions may be made for corticosteroids prescribed specifically for management of CLL symptoms after discussion with the study medical monitor.
11) Diagnosis of inflammatory bowel disease or ongoing symptomatic pneumonitis
12) History of stroke or intracranial hemorrhage within 12 months of randomization or enrollment; subjects requiring therapeutic anticoagulation for any indication should be discussed with the GCLLSG coordinating physician and/or medical monitor prior to screening.
13) Legal incapacity, prisoners or subjects institutionalized by regulatory or court order, or any individual in dependence to study sponsor or any investigator
14) Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, moderate CYP2C9 inducers, or strong P-gp inducers while on study; use within 2 weeks of first dose of study treatment should be avoided
15) Requirement for proton pump inhibitor (PPI) therapy
16) Demonstration of QTc interval >450 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
17) Known hypersensitivity to obinutuzumab, entospletinib, tirabrutinib, or any of the excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the rate of complete remission (CR) per modified International Workshop on CLL (IWCLL 2008) criteria at Week 25 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Clinical/Laboratory visits will occur on Day 1 of Week 1 to Week 5, then every 4 weeks until Week 25. Qualitative treatment response assessment based on physical exam, laboratory parameters, and presence of B-symptoms will be performed every 4 weeks from Week 5 to Week 25. Assessment of response per modified IWCLL 2008 criteria should also be recorded at Week 25 and subsequent to any CT and/or bone marrow biopsy that is repeated while on study. Peripheral blood MRD will be assessed on Day 1 of Weeks 1, 13, and 25, 33. |
|
| E.5.2 | Secondary end point(s) |
- Rate of complete response (CR) with bone marrow minimal residual disease (MRD) negativity (CR/BM MRD-) at Week 25
- Rate of CR with MRD negativity (<10^-4) in peripheral blood (CR/PB MRD-) at Week 25
- Overall response rate (ORR) at Week 25 with duration of Response (DOR) including CR, CR with incomplete bone marrow recovery (CRi), partial remission (PR), and PR with lymphocytosis
- Type, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Clinical/Laboratory visits will occur on Day 1 of Week 1 to Week 5, then every 4 weeks until Week 25, Week 29, then every 12 weeks from Week 33 until Week 105. Qualitative treatment response based on physical exam, laboratory parameters, and presence of B-symptoms will be performed every 4 weeks from Week 5 to Week 29, and then every 12 weeks starting at Week 33 and then at all scheduled visits thereafter. Assessment of response per modified IWCLL 2008 criteria should also be recorded at Week 25 and subsequent to any CT and/or bone marrow biopsy that is repeated while on study. Peripheral blood MRD will be assessed on Day 1 of Weeks 1, 13, 25, 33, 45, 105, and EOT. AEs will be assessed at each visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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