| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Chronic Lymphocytic Leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008978 |
| E.1.2 | Term | Chronic lymphocytic leukemia refractory |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 efficacy of acalabrutinib monotherapy (Arm A) compared with idelalisib/rituximab or bendamustine/rituximab (Arm B) based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Hallek 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012)—hereafter referred to as IWCLL 2008 criteria in subjects with relapsed/ or refractory (R/R) chronic lymphocytic leukemia (CLL). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate Arm A (acalabrutinib) compared with Arm B (idelalisib/rituximab or bendamustine/rituximab) in terms of:
• Investigator (INV)-assessed PFS per IWCLL 2008 criteria.
• INV- and IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria.
• Overall survival (OS).
• Patient-reported outcomes (PROs) by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue) (will no longer be collected as of Amendment 6.0).
• INV- and IRC-assessed duration of response (DOR).
• Time to next treatment (TTNT).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men and women ≥ 18 years of age.
2. ECOG performance status of 0 to 2.
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008):
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.
b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
c. Presence of ≥ 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any point since initial diagnosis).
4.Must have documented CD20-positive CLL.
5.Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL).
b. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
c. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a LDT of < 6 months. LDT may be obtained by linear regression extrapolation of ALC obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 x 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
f. Constitutional symptoms documented in the subject’s chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease- related symptoms or signs:
i. Unintentional weight loss ≥ 10% within the previous 6 months before screening.
ii. Significant fatigue (ECOG performance score 2; inability to work or perform usual activities).
iii. Fevers higher than 100.5°F or 38.0°C for ≥ 2 weeks before screening without evidence of infection.
iv. Night sweats for > 1 month before screening without evidence of infection.
6. Meet the following laboratory parameters:
a. Absolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.
b. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL
(30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. If an Investigator has chosen bendamustine/rituximab as the Arm B treatment, platelets must be ≥ 75,000 cells/μL (75 x 109/L).
c. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 x upper limit of normal (ULN).
d. Total bilirubin ≤ 1.5 x ULN.
e. Estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female].
7.Must have received ≥ 1 prior systemic therapies for CLL. Note: Single-agent steroids or localized radiation are not considered a prior line of therapy. If a single- agent anti-CD20 antibody was previously administered, subjects must have received ≥ 2 doses.
8.Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib, 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. Highly effective forms of contraception are defined in Section 9.2.5.
9. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. Highly effective forms of contraception are defined in Section 9.2.5.
10.Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
11.Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules without difficulty.
12.Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). |
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| E.4 | Principal exclusion criteria |
1.Known CNS lymphoma or leukemia.
2.Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome. 3.Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone or equivalent).
4.Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199) or a BCR inhibitor (e.g, Btk inhibitors or PI3K inhibitors).
5.Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
6.Corticosteroid use > 20 mg daily prednisone equivalent within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for admin of study drug or contrast. For example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded.
7.Prior radio- or toxin-conjugated antibody therapy.
8.Prior allogeneic stem cell transplant or prior autologous transplant within 6 months of first dose of study drug(s) or presence of graft-vs-host disease or receiving treatment for graft-vs-host disease.
9.Major surgical procedure within 30 days of first dose of study drug.
10.History of prior malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician.
b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.
c. Adequately treated carcinoma in situ without current evidence of disease.
11.Significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec (calculated using Fridericia’s formula: QT/RR0.33) at screening.
12.Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass
13.Received a live virus vaccination within 28 days of first dose of study drug.
14.Known history of infection with HIV or any uncontrolled active systemic infection (e. g, bacterial, viral or fungal). For sites in Germany: active HIV infection(seropositivity for HIV-1 or HIV-2 antibodies, and if positive, reactivity against the HIV specific p24 antigen).
15.Active CMV infection (active viremia as evidenced by positive polymerase chain reaction [PCR] result for CMV DNA).
16.Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative PCR result before randomization.
b.Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization.
17.Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension. 18.History of or ongoing drug-induced pneumonitis.
19.History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis. 20.History of stroke or intracranial hemorrhage within 6 months before first dose of study drug. 21.History of bleeding diathesis (e.g, hemophilia, von Willebrand disease).
22.Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g, phenprocoumon) within 7 days of first dose of study drug.
23.Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 24.Requires treatment with a strong CYP3A inhibitor/inducer.
25.Requires treatment with proton-pump inhibitors (e.g, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
26.Breast feeding or pregnant.
27.Concurrent participation in another therapeutic clinical trial.
28.Prothrombin time/international normalized ratio (INR) or activated partial thromboplastin time (aPTT; in the absence of a Lupus anticoagulant) > 2.0 x ULN.
29. History of confirmed progressive multifocal leukoencephalopathy (PML) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is PFS (defined as the time from randomization until disease progression or death from any cause) as assessed by the IRC per IWCLL 2008 criteria. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• INV-assessed PFS per IWCLL 2008 criteria.
• INV-assessed ORR (defined as the proportion of patients who achieve a best response of complete remission [CR], complete remission with incomplete bone marrow recovery [CRi], nodular partial remission [nPR], or partial remission [PR]) per IWCLL 2008 criteria.
• IRC-assessed ORR per IWCLL 2008 criteria.
• OS (defined as the time from randomization to the date of death due to any cause)
• PROs as measured by change in scores from baseline to each assessment in the FACIT-Fatigue (will no longer be collected as of Amendment 6.0).
• INV- and IRC-assessed DOR (defined as the time from the first documentation of objective response to the earlier time of disease progression [assessed by the IRC per IWCLL 2008 criteria] or death from any cause)
• TTNT (defined as the time from randomization to institution of nonprotocol-specified treatment for CLL)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| 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) | 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 113 |
| 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 |
| Canada |
| Hong Kong |
| Israel |
| Korea, Republic of |
| New Zealand |
| Singapore |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Sweden |
| Bulgaria |
| Romania |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Croatia |
| Denmark |
| Hungary |
| Russian Federation |
| Slovakia |
| Turkey |
| Ukraine |
| United Kingdom |
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| 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
|
| Last visit of the last subject (LSLV). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| 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 | 9 |
| 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 |
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