Study Phase III Randomized Study to Investigate the Use of Acalabrutinib in the Treatment of Patients with Early Stage CLL With High Risk of Early Disease Progression.

The study will consist of a screening phase, a treat¬ment/observation phase until progression, and a follow-up phase for progression in patients who discontinue treatment with Acalabrutinib without confirmed progression. Patients who progress will be followed for survival and initiation of subsequent antileukemic therapy. In the study, 130 patients from 20 centers in Spain with intermediate, high or very high risk will be randomized (1:1) to receive Acalabrutinib (n=65) or clinical observation (n=65). Acalabrutinib will be administered orally 100 mg twice daily on a continuous schedule.

Even though the majority of patients with CLL are currently diagnosed at early stages of the disease, there is a consensus that the standard of care in these patients is clinical observation (watch & wait) despite of the presence of risk factors for premature disease progression. Early treatment in patients with adverse prognostic parameters could prevent a disease evolving to a more advanced stage, and therefore more difficult to treat. So far, conventional chemotherapy did not show any benefit in terms of overall survival in patients with early stage CLL. (Dighiero 1998, Hoechstetter Leukemia 2017) Alongside this, treatment with chemotherapy may provoke two undesired effects: first, the occurrence of bone marrow toxicity that may hamper the subsequent administration of other treatments during the course of the disease; second, but not less relevant, genotoxic drug delivery may elicit a phenomenon of clonal selection leading to the appearance of CLL cells with genetic aberrations associated with refractoriness and aggressive outcome (i.e., TP53).

Against this background, it is of interest to investigate the role of new non-genotoxic drugs in the treatment of patients with CLL in early stages. Among different scores for selecting cases that are likely to progress rapidly, the German CLL Study Group (GCLLSG) risk score that includes 8 independent predictors for OS and PFS, differentiates patients with low-risk PFS vs. those with risk of early disease progression (median PFS 87 months vs. less than 27 months), allowing for a risk-adapted treatment approach in early stage CLL. (Pflug 2014, Langerbeins 2015).

Acalabrutinib, a second-generation, selective inhibitor of BTK, has shown substantial activity in patients with CLL. Acalabrutinib is a non-genotoxic drug active in cases with genetic lesions associated with chemorefratoriness and adverse outcome, including patients with alterations of TP53. Therefore, acalabrutinib represents a suitable compound for the treatment of patients with CLL in early stages with risk of early disease progression, including the high-risk CLL patient population with TP53 alterations.

Randomized, open-label, parallel-group, multicenter, phase III trial with two arms, one with acalabrutinib (Arm A) and the other with the standard of care for the management of early Binet stage A patients "clinical observation (watch & wait)" (Arm B) in patients with untreated early stage CLL and risk factors for early disease progression. Early risk of disease progression will be defined by the GCLLSG prognostic index: intermediate (3-5), high (6-10) or very high (11-14) risk scores are required to be included in the study. Randomization will be managed through an IRT system:

• Arm A (65 patients): Patients assigned to arm A, will receive acalabrutinib as one capsule of 100 mg orally twice daily on a continuos schedule until disease progression, unacceptable toxicity or early withdrawal.
• Arm B (65 patients): Patients assigned to arm B, will remain on the w&w approach until disease progression or early withdrawal.

The enrolment period is estimated in 24 months. A treatment cycle is defined as lasting 28 days.

The duration of the study will be of 60 months from the inclusion of the first patient to the last patient has completed the last follow up visit.

1. Periods of patient participation in the study

   • Screening Phase: After providing the written Informed Consent Form (ICF) to participate in the study, patients will be evaluated for eligibility, baseline characteristics and risk factors, during a screening period up to 28 days prior to randomization.
   • Treatment/Observation Phase: The treatment/observation Phase extends from randomization until symptomatic disease progression, unacceptable toxicity or early withdrawal. A treatment cycle is defined as lasting 28 days.
   • Suspected Disease Progression Visit: A visit should be performed at any time when disease progression is suspected. If progression is confirmed, the patient will be followed every 6 months to assess survival status and receipt of subsequent antileukemic therapy until death, patient withdrawal, loss to follow-up, or study termination, whichever comes first. The subsequent treatment decision will be up to the investigator and should generally follow the routine practice.
   • End-of-Treatment/Observation Visit: For patients receiving acalabrutinib, the End-of-Treatment Visit will be performed within 30 days (± 3 days) after the last dose of treatment administration or progression. For patients remaining in the w&w approach, the End-of- Observation Visit will be performed within 30 days of progression.
   • Follow-up for Progression (Pre-PD FU): Patients who discontinue the study treatment without confirmed progression (according to iwCLL guidelines) will continue to be followed for progression every 4 months (±7 days) for the first 24 months of study, then every 6 months (±7 days) until progression or study closure.

   Study visits will no longer be carried out for patients who have withdrawn their informed consent, have died or have been lost to follow-up.

2. Study drug - dosage and administration:

   Acalabrutinib is orally administered and is suitable for formulating in capsules. Acalabrutinib will be supplied by ASTRAZENECA FARMACÉUTICA SPAIN, S.A., on behalf of the Sponsor, as hard gelatin capsules of 100 mg for oral administration. Acalabrutinib can be taken with or without food. As acalabrutinib is metabolized by CYP3A, subjects should be cautioned against using herbal remedies or dietary supplements (in particular, St John's wort, which is a potent CYP3A inducer). Otherwise, subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, nausea or vomiting.

3. Description of Procedures

   • Confirmation of Eligibility: Perform all necessary procedures and evaluations to document that the patient meets each eligibility criterion.
   • Medical History: will include concurrent medical signs and symptoms based upon available documents and patient history.
   • Adverse Events: All medical occurrences that meet the accepted regulatory definition of AE must be recorded from the time the informed consent form is signed until 30 days after the last dose of study drug (in Arm A) or progression (in both arms).
   • Physical Examination, Vital Signs, Height and Weight, ECOG. This will include the lymphatic system, spleen and liver examination as well. will be performed at every visit during the study.
   • Clinical Stage Rai/Binet: A Binet or Rai staging system will be used at every study visit (except on Day 15 Cycle 1 and Day 15 Cycle 2) to stratify patients according to the disease risk.
   • Disease-related symptoms will be assessed and collected at every study visit.
   • Electrocardiogram (ECG) done only at Screening.
   • Concomitant Medication: All medications from 14 days before the start of study drug administration through 30 days after the last dose of study drug or progression.
   • German CLL Study Group (GCLLSG) prognostic index will be determined for each patient only at screening.
   • Cumulative Illness Rating Scale is a measure of comorbid medical conditions that help to characterize patients with concomitant morbidity and fit.
   • Hepatitis Serologies: Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B surface antibody, and Hepatitis B core antibody.
   • Hematology: will be performed at every visit by local laboratory and will include a complete blood cell count.
   • Coagulation Panel: Measurement of prothrombin time /INR, and activated partial thromboplastin time will be performed at Screening.
   • Serum chemistry will be locally performed at every visit (except on Day 15 of Cycles 1 and 2)
   • Creatinine clearance (Cockcroft-Gault) will be evaluated (only at screening) by local laboratory.
   • Cytogenetic, CLL FISH Panel within 90 days prior to the inclusion in the study to detect abnormalities in chromosomes 13q, 12, 11q, and 17p must be evaluated.
   • Blood for immunophenotyping (for diagnosis), IGVH mutation status, and serum markers (B2-microglobulin and thymidine kinase) will be centralized in the department of Hematology of the University Hospital of Vall d'Hebron. Blood samples will be collected for all patients at Screening.
   • Serum quantitative immunoglobulin (IgG, IgM, IgA) levels will be evaluated by local laboratory at screening, on Day 1 of every odd cycle from Cycles 3 through 12, on Day 1 of every odd cycle (for Cycles 13, 15, 17, 19, 21 and 23), and then every 3 cycles until progression or study closure.
   • Coombs test will be performed (only at screening) by local laboratory.
   • CT scans of the neck, chest, abdomen, and pelvis.
   • Bone Marrow Aspirate and/or Biopsy should be obtained to confirm CR, or confirm cytopenic progression and distinguish autoimmune versus treatment-related causes. In addition, a further marrow assessment should be performed at any time during follow-up when the patient has cleared MRD from the peripheral blood. Marrow aspirate to confirm CR should have a flow-cytometry-based MRD; MRD should be also analysed in peripheral blood .
   • Overall response assessment will include evaluation of physical exams, recording of symptoms, and hematological evaluations. OR will be assessed on Day 1 Cycle 2, on Day 1 of Cycles 3 to 12, and on Day 1 of Cycles 13, 15, 17, 19, 21, and 23, and then every 3 cycles to disease progression or study closure. For patients in Arm B, response assessment will be performed on Day 1 of every 3 cycles to progression or study termination.
   • Overall Survival: After progression, patients will be followed every 6 months to assess survival status and the start of subsequent cancer therapies until death, patient withdrawal, loss to follow-up, or study termination, whichever comes first.
   • Biomarkers: Blood samples will be collected for an exploratory biomarker assessment at baseline and at progression. Samples at month 3, 6 and 12 will be optional and will collected in patients who have accepted in the inform consent form.

4. Main Efficacy Evaluations Suspected Disease Progression: should be confirmed with a CT scan (or MRI, if CT is contraindicated).

   Disease Evaluation: Objective response will be categorized as CR, CR with incomplete bone marrow recovery (CRi), nodular partial remission (nPR), partial response (PR), stable disease, or progressive disease-all based upon IWCLL criteria (Hallek 2018). Patients who achieve PR in all parameters except lymphocyte count will be considered a PR with lymphocytosis, for the purposes of the Protocol. CRs must be confirmed by bone marrow biopsy/aspirate.

   Given the known mechanism of action of BCR-inhibiting agents, including acalabrutinib, and the treatment-related lymphocytosis frequently observed during treatment with acalabrutinib, isolated treatment-related lymphocytosis (in absence of other clinical, CT, or laboratory evidence of disease progression) will not be considered progressive disease. This approach is supported by the IWCLL guidelines (Hallek 2018).

5. Safety, Monitoring and Reporting: An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

   PETHEMA Foundation has delegated Pharmacovigilance functions to the Pharmacovigilance Department of the CRO Dynamic Science S.L.

6. Warnings, Precautions, and Adverse Effects: Acalabrutinib is contraindicated in subjects with clinically significant hypersensitivity to the compound itself or to the excipients in its formulation.

   Hemorrhagic events, including CNS, respiratory, and gastrointestinal hemorrhage, have been reported in clinical trials with acalabrutinib. The mechanism for hemorrhage is not well understood.

   Serious infections, including fatal events, have been reported in clinical studies with acalabrutinib. The most frequently reported Grade 3 or 4 infection was pneumonia. Cases of hepatitis B virus reactivation (resulting in liver failure and death in 1 case) and cases of progressive multifocal leukoencephalopathy have occurred in subjects with hematologic malignancies.

   Cytopenias: treatment-emergent Grade 3 or 4 cytopenias including neutropenia, anemia, and thrombocytopenia have occurred in clinical studies with acalabrutinib.

   Events of second primary malignancies, including non-skin carcinomas, have been reported in clinical studies with acalabrutinib. The most frequently reported was skin cancer.

   Events of atrial fibrillation/flutter have been reported in clinical studies with acalabrutinib, particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute infections, and a previous history of atrial fibrillation. The mechanism for atrial fibrillation is not well understood.

   Subjects should be managed per institutional guidelines with supportive care and diagnostic evaluations as clinically indicated.

7. Drug-drug Interactions: Acalabrutinib is partially metabolized by CYP3A; its exposure is affected when coadministered with strong CYP3A inducers or inhibitors. Consequently, the concomitant use of strong inhibitors/inducers of CYP3A should be avoided when possible. Subjects who require therapy with strong inhibitors of CYP3A should not be enrolled into the study.

   Subjects should avoid the use of calcium carbonate containing drugs or supplements for a period of at least 2 hours before and 2 hours after taking acalabrutinib. Use of omeprazole, esomeprazole, lansoprazole or any other proton pump inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study drug exposure. For subjects who require H2 antagonists, the recommendation is that acalabrutinib is taken at least 2 hours before the H2 antagonist.

8. Treatment-related lymphocytosis, for the purposes of this Protocol, is defined as an elevation in blood lymphocyte count of ≥50% compared to baseline. Acalabrutinib associated treatment-related lymphocytosis generally occurs within the first weeks of therapy, peaks within the first few months, and resolves slowly. Patients with treatment-related lymphocytosis should remain on study treatment and continue with all study-related procedures.

9. Once the complete study is explained, written Informed Consent will be obtained from the patient, legal guardian or representative before starting participation in the study.

10. In order to respect patient privacy, patients will be identified by patient number in all case report forms, study drug accountability logs, study reports and communications. Confidentiality of patients will be kept and their identity will not be disclosed as far as permitted by the law and relevant regulations. Regulation (EU) 2016/679 of the European Parliament and of the Council, of 27 April 2016, on the protection of natural persons with regard to the processing of personal data and the free movement of such data, and Organic Law 3/2018 of December 5, on the Protection or Personal Data and guarantee of digital rights.

11. Early study discontinuation: This study may be discontinued early if, in the Sponsor's opinion, there is sufficient reasonable cause.

12. Data registering and storage: The investigator will keep all study records in compliance with ICH-GCP requirements and current regulations.

13. Responsibility and insurance: The Sponsor has taken out an insurance policy covering, in its terms and conditions, the liability for damages caused to participants and derived from this research, performed fully in compliance with both the scientific Protocol and the applicable law and professional standards.

Inclusion Criteria:

1. Adult patients with previously untreated CLL according to IWCLL criteria (Hallek, 2018).

2. Must understand and voluntarily sign an informed consent form.

3. Age ≥ 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other Protocol requirements.

4. Diagnosis of CLL prior to inclusion in the study.

5. Binet clinical stage A and Rai 0 or 1.

6. Absence of criteria for the initiation of chemotherapy, defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018):

   • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
   • Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
   • Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
   • Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or lymphocyte doubling time (LDT) of less than 6 months.
   • A minimum of any one of the following disease-related symptoms: unintentional weight loss ≥10% within the previous 6 months, significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities), fevers of ≥38.0°C for 2 or more weeks without other evidence of infection, or night sweats for more than 1 month without evidence of infection.
   • Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids.
   • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine).

7. GCLLSG prognostic index with intermediate (3-5), high (6-10) or very high (11-14) risk scores.

8. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1.

9. All sexually active subjects with the capacity to reproduce (male and female) must use high-efficacy contraceptive methods during the course of the study. These restrictions apply for 3 months after the last dose of acalabrutinib. High-efficacy contraceptive methods include:

   • Total abstinence when consistent with the subject's typical and preferred lifestyle (periodic abstinence [e.g. calendar methods, ovulation, symptothermal and post-ovulation methods] and the withdrawal method are not acceptable contraceptive methods).

   • Female sterilisation defined as surgical hysterectomy, bilateral oophorectomy, or tubal ligation at least six weeks prior to the study treatment (a simple oophorectomy does not meet the definition of female sterilisation).

   • Male sterilisation (at least six months before screening). A man who has undergone a vasectomy must be the only partner who is a study subject.

   • Combination of two of the following methods (a+b or a+c or b+c):

     1. Use of oral, injected or implanted hormonal contraceptives, or other hormonal contraceptive methods that have a comparable efficacy (failure rate < 1%), for example, hormonal vaginal ring or transdermal hormonal contraceptive. If an oral contraceptive is used, women must use the same pill for a minimum of three months before taking the study treatment.
     2. Placement of an intrauterine device (IUD) or an intrauterine system (IUS).
     3. Barrier contraceptive methods: condom or cervical cap (cervical/vault diaphragm or cap) with foam/gel/film/spermicidal cream/vaginal suppository.

10. Female subjects of childbearing potential must have a negative serum pregnancy test at screening. Females of child bearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to other causes, including prior chemotherapy, anti-estrogens, or ovarian suppression.

Exclusion Criteria:

1. Prior treatment for CLL.

2. Meets any criteria for the initiation of treatment defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018).

3. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection and/or known history of progressive multifocal leukoencephalopathy (PML). Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.

4. Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤ 40 mL/min/1.73m2.

5. Absolute neutrophil count (ANC) < 1.0 X 109/L.

6. Platelet count < 100 X 109/L.

7. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) >2.5 x upper limit of normal (ULN).

8. Serum total bilirubin >1.5 x ULN, except in cases of Gilbert's syndrome.

9. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) >2 x ULN.

10. Active bleeding, history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).

11. 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 enrolment to this study.

12. Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication.

13. Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 3 months prior to enrolment. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening can enrol on study.

14. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.

15. Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy.

16. Pregnant or lactating females.

17. Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating study therapy.

18. Prior history of malignancies, other than CLL, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:

    • Basal cell carcinoma of the skin
    • Squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)

19. Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia, or a positive direct antiglobulin test result.

20. Chronic use of steroids in excess of prednisone 20mg/day or its equivalent.

21. Major surgery within the last 28 days prior to registration.

22. History of stroke or intracranial hemorrhage within 6 months prior to enrolment.

23. Requires treatment with strong CYP3A4/5 Inhibitors.

24. Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components).

25. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.