| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068919 |
| E.1.2 | Term | B-cell 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 evaluate the effect of the combination of idelalisib (IDELA) and obinutuzumab vs the combination of chlorambucil and obinutuzumab on progression-free survival (PFS) in subjects with previously untreated CLL |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of the combination of IDELA and obinutuzumab as compared to the combination of chlorambucil and obinutuzumab on the magnitude of response and overall survival
- To evaluate the effect of the combination of IDELA and obinutuzumab, as compared to the combination of chlorambucil and obinutuzumab, on minimal residual disease (MRD)
- To describe the safety profile observed with the addition of IDELA to obinutuzumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female ≥18 years of age.
2) Diagnosis of B-cell CLL, according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and documented within medical records.
3) Not a candidate for fludarabine therapy based on either:
a) creatinine clearance < 70 ml/min, or
b) CIRS score > 6, by the assessment of the investigator.
4) No prior therapy for CLL other than corticosteroids for disease complications.
5) CLL that warrants treatment based on pre-defined criteria.
6) Presence of measurable lymphadenopathy (defined as the presence of ≥1 nodal lesion that measures ≥2.0 cm in the longest dimension [LD] and ≥1.0 cm in the longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or magnetic resonance imaging [MRI] and confirmed by the Independent Review Committee).
7) ECOG performance status of ≤2.
8) Required baseline laboratory data (within 28 days prior to randomization) as shown in the protocol.
9) For female subjects of childbearing potential, willing to use a protocol-recommended method of contraception during heterosexual intercourse from signing of informed consent throughout the study treatment period and up to 30 days from the last dose of IDELA or chlorambucil, or 18 months from the last dose of obinutuzumab, whichever is later.
10) For male subjects of reproductive potential, having intercourse with females of childbearing potential, willing to use a protocol-recommended method of contraception during heterosexual intercourse from the randomization visit throughout the study treatment period and up to 3 months from the last dose of IDELA or chlorambucil or 18 months from the last dose of obinutuzumab (whichever is later) and refrain from sperm donation from the randomization visit throughout the study treatment period and up to 3 months from the last dose of IDELA or chlorambucil or 18 months from the last dose of obinutuzumab (whichever is later).
11) Lactating females must agree to discontinue nursing before study drug administration.
12) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current CLL disease status, medical condition, and the potential benefits and risks of alternative treatments for CLL.
13) Willing and able to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions.
14) Evidence of a signed informed consent. |
|
| E.4 | Principal exclusion criteria |
1) Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation).
2) Known presence of myelodysplastic syndrome.
3) History of a non-CLL malignancy with the following exceptions:
a) the malignancy has been in remission without treatment for ≥ 5 years prior to randomization, or
b) carcinoma in situ of the cervix, or
c) adequately treated basal or squamous cell skin cancer or other localized non-melanoma skin cancer, or
d) asymptomatic prostate cancer without known metastatic disease and with no current requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to enrollment, or
e) DCIS of the breast treated with lumpectomy alone, or
f) Other adequately treated Stage 1 or 2 cancer currently in complete remission.
4) Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for IDELA, obinutuzumab, or chlorambucil.
5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of randomization.
6) Ongoing drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension.
7) History of non-infectious pneumonitis.
8) Ongoing inflammatory bowel disease.
9) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
10) Ongoing immunosuppressive therapy other than corticosteroids.
11) Received last dose of study drug on another therapeutic clinical trial within 30 days prior to randomization.
12) Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results.
13) Undergone major surgery within 30 days prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) - defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria excluding lymphocytosis alone. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A formal interim efficacy analysis will be conducted by the DMC after approximately 67% of the expected number of 138 events (definitive CLL progressions per IRC or deaths) have occurred. The primary efficacy analysis will be conducted after approximately the 138th event (definitive CLL progression per IRC or death). |
|
| E.5.2 | Secondary end point(s) |
- CR rate – defined as the proportion of subjects who achieve a confirmed CR
- MRD negativity rate – defined as the proportion of subjects with MRD <10^-4, assessed by flow cytometry in bone marrow at Week 36 (±3 weeks) after therapy initiation. For subjects receiving the final dose of obinutuzumab after the original scheduled date, the MRD assessment will be performed no less than 12 weeks after the last dose of obinutuzumab.
- Overall response rate (ORR) – defined as the proportion of subjects who achieve a confirmed complete response (CR) or confirmed partial response (PR)
- Nodal response rate – defined as the proportion of subjects who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions
- Overall survival (OS) – defined as the interval from randomization to death from any cause |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy analysis will be conducted after approximately the 138th event (definitive CLL progression per IRC or death) |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 110 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Croatia |
| Czech Republic |
| France |
| Hungary |
| Italy |
| Poland |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
