TAILOR - Multicohort Study to Customize Ibrutinib Treatment Regimens for Patients with Previously Untreated Chronic Lymphocytic Leukemia (54179060CLL2032)

Studio Clinico

Patologia: Neoplasie ematologiche

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: II Randomizzato

Linee di trattamento: Prima linea

Criteri di inclusione: 

1. Be ≥18 years of age (or the higher legal age of consent in most jurisdictions in which the study is taking place) at the time of informed consent
2. Diagnosis of CLL/SLL that meets iwCLL diagnostic criteria (Hallek et al, 2018).
3. For I+V cohorts: ECOG performance status of 0-1.
For ibrutinib monotherapy cohorts: ECOG performance status of 0-2 (Section 10.7).
4. Active disease meeting at least 1 of the following iwCLL criteria (Hallek et al, 2018) for requiring treatment:
    a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
    b. Massive (ie, ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
    c. Massive nodes (ie, ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
    d. Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or LDT <6 months.
    e. Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids.
    f. Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine).
    g. Disease-related symptoms as defined by any of the following:
        i. Unintentional weight loss ≥10% within the previous 6 months.
        ii. Significant fatigue (ie, ECOG performance scale 2 or worse; cannot work or unable to perform usual activities).
        iii. Fevers ≥100.5°F or 38.0°C for ≥2 weeks without evidence of infection.
        iv. Night sweats for ≥1 month without evidence of infection.
5. Measurable nodal disease by CT, defined as at least 1 lymph node ≥1.5 cm in longest diameter.
Sex and Contraceptive/Barrier Requirements
6. All POCBP must have a negative highly sensitive serum -hCG pregnancy test upon study entry.
7. A participant using oral contraceptives must use an additional contraceptive method (above that required in Inclusion Criterion 12).
8. Criterion modified by Amendment 1
8.1. A participant must agree not to be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or until 1 month after last dose or per local label if more conservative (eg, 3 months in EU/Canada and 1 month in US).
9. Criterion modified by Amendment 1
9.1. A participant must be (as defined in Section 10.5)
    a. Not of childbearing potential, or
    b. Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study treatment and until 1 month after last dose or per local label if more conservative (eg. 3 months in EU/Canada and 1 month in US). The investigator must evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study treatment. Examples of highly effective methods of contraception are located in Section 10.5.
10. A participant must agree not to donate gametes (eg, ova, oocytes, or sperm) or freeze for future use for the purposes of assisted reproduction during the study and for 3 months after the last dose of study treatment.
11. A participant must agree not to plan to conceive a child while enrolled in this study or within 3 months after the last dose of study treatment.
12. A participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for at least 3 months after receiving the last dose of study treatment. If the participant’s partner is a POCBP, the
participant must use condoms (with or without spermicide) and the sexual partner of the participant must also be practicing a highly effective method of contraception where conception is possible (see Section 10.5). A participant who is vasectomized
must still use a condom (with or without spermicide) and the partner is also required to use a highly effective method of contraception where conception is possible.
Informed Consent
13. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
14. Willing and able to adhere to the lifestyle restrictions specified in this protocol (Section 5.3).
Clinical Laboratory Values
15. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days (except for pegylated G-CSF [pegfilgrastim] and darbepoetin, which require at least 14 days) prior to screening laboratory assessment defined as:
    a. ANC >750/μL independent of growth factor support;
    b. Platelet count >50,000/μL independent of transfusion support for at least 7 days prior to enrollment;
    c. Hemoglobin >8.0 g/dL independent of transfusion support for >7 days prior to enrollment.
16. Adequate hepatic function, defined as:
    a. Serum AST or ALT ≤3.0×ULN;
    b. Bilirubin ≤1.5×ULN (unless bilirubin rise is due to congenital nonhemolytic hyperbilirubinemias or of non-hepatic origin);
    c. Prothrombin time/international normal ratio <1.5×ULN and activated partial thromboplastin time <1.5×ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder).
17. Adequate renal function, defined as follows (using the Cockcroft-Gault equation [Cockcroft 1976]):
    a. For I+V cohorts:
        i. In participants aged <75 years at enrollment, CrCl ≥45 mL/min;
        ii. In participants aged ≥75 years at enrollment, CrCl ≥60 mL/min.
    b. For ibrutinib monotherapy cohorts, CrCl ≥45 mL/min.

Criteri di esclusione: 

Medical history of:
    a. Other malignancies, except:
        i. Any malignancy that was not progressing nor requiring treatment change in the last 12 months.
        ii. Malignancies treated within the last 12 months and considered at very low risk for recurrence:
1. Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS).
2. Skin cancer (non-melanoma or melanoma).
3. Non-invasive cervical cancer.
4. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving
antihormonal agents.
5. Localized prostate cancer (M0, N0) with a Gleason Score ≤7 a, treated locally only (RP/RT/focal treatment).
        iii. Other malignancy that is considered at minimal risk of recurrence.
    b. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as those participants with a declining hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first
dose of study treatment, or the need for prednisone >20 mg daily (or corticosteroid equivalent) to treat or control the autoimmune disease.
    c. Recent infection requiring systemic treatment that is ongoing or was completed ≤14 days before the first dose of study treatment, or any uncontrolled active systemic infection.
    d. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
    e. Stroke or intracranial hemorrhage within 6 months prior to enrollment.
    f. Difficult to control hypertension (defined as requiring ≥3 hypertensive medications) or screening systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg. For participants whose screening blood pressure exceeds a systolic blood pressure of 160 mmHg or a diastolic blood pressure of 100 mmHg, the investigator should review and manage the participant
appropriately according to individual practice. The participant may be rescreened if it can be demonstrated that the blood pressure reading was a single isolated elevation or is subsequently controlled and stable.
    g. History of myocardial infarction, ventricular arrhythmia, unstable angina, or acute coronary syndrome within 12 months prior to enrollment (if >1 year, cardiology consultation is recommended prior to study enrollment).
2. Known or suspected Richter’s transformation or CNS involvement.
3. Known allergies, hypersensitivity, or intolerance to excipients of ibrutinib or venetoclax.
4. Allergy to xanthine oxidase inhibitors and cannot receive rasburicase.
5. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class II, III, or IV congestive heart failure as defined by the New York Heart Association Functional Classification (see Section 10.8). For participants who
in the investigator’s opinion are considered to have a significant cardiac risk at baseline, the investigator should consider pursuing a cardiology evaluation before screening. It is the investigator’s responsibility to assess the risks and benefits of
subsequent study enrolment.
6. Major surgery within 4 weeks prior to first dose of study treatment.
7. Unable to swallow capsules/tablets or malabsorption syndrome, disease significantly
affecting gastrointestinal function, or resection of the stomach or small bowel,
symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete
bowel obstruction.
8. Currently active, clinically significant hepatic impairment (Child-Pugh Class A, B, or C [see Section 10.9 for a description of Child-Pugh classification]).
9. Lactating or pregnant.
Disease Characteristics
10. Participant received prior systemic anticancer therapy (including but not limited to chemotherapy, targeted therapy, immunomodulating therapy, radiotherapy, and/or monoclonal antibody) for treatment of CLL or SLL.
11. Participant has active brain metastases.
12. Participant has leptomeningeal disease, or spinal cord compression.
Prior/Concomitant Therapy or Clinical Study Experience
13. Contraindications to the use of ibrutinib or venetoclax per local prescribing information.
14. Taken any disallowed therapies as noted in Section 6.7 before the planned first dose of study treatment.
15. Received or plans to receive any immunotherapy, live attenuated vaccine, or investigational drug within 4 weeks before the planned first dose of study treatment or is currently enrolled in an investigational study.
16. Received an investigational treatment within 3 months before the planned first dose of study treatment, or is currently enrolled in an investigational study.
Diagnostic Assessments
17. Active hepatitis B or C virus infection according to local laboratory range, on all available tests for the past 6 months or other clinically active liver disease.
Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants who are HBsAg negative with antibodies to total anti-HBc with or without the presence of anti-HBs) must be screened using RT-PCR
measurement of HBV DNA levels. Those who are RT-PCR positive will be excluded.
Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR.
Known hepatitis C infection or positive serologic testing for hepatitis C virus (anti-HCV antibody.
Positive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained.
Positive hepatitis C RNA test result at screening or within 3 months prior to first dose
of study treatment. NOTE: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
18. Known history of HIV.
19. Other clinically active liver disease of infectious origin.
Other Exclusions
20. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise their wellbeing) or that could prevent, limit, or confound the protocol-specified assessments.
Note: Investigators must ensure that all study enrollment criteria have been met at screening. If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant must be
excluded from participation in the study. Section 5.4 describes options for screening. The required source documentation to support meeting the enrollment criteria are listed in Section 10.3.10.

Trattamento sperimentale: 

Ibrutinib (IMBRUVICA®, JNJ-54179060) è un inibitore di BTK a legame covalente somministrato per via orale, per il trattamento di tumori maligni a cellule B, co-sviluppato da Pharmacyclics LLC, un’azienda di AbbVie, e Janssen Research & Development LLC.
Venetoclax è un inibitore orale di BCL-2, una proteina anti-apoptotica. La overespressione di BCL-2 è stata riscontrata nelle cellule con leucemia linfocitica cronica (LLC) dove media la sopravvivenza delle cellule tumorali ed è stata associata a resistenza alla chemioterapia.

Trattamento di controllo: 

NA

Obiettivi primari dello studio: 

L’obiettivo primario di questo studio è valutare se l’efficacia dei regimi di I+V e ibrutinib in monoterapia, valutata dallo sperimentatore mediante ORR (Overall Response Rate [tasso di risposta complessiva]), sarà accettabile quando si utilizza un approccio di trattamento personalizzato in cui il dosaggio di ibrutinib viene proattivamente ridotto o quando la dose viene reattivamente modificata (secondo l’etichetta aggiornata di ibrutinib) in risposta agli EA. In base ai controlli storicamente utilizzati, l’ORR sarà considerato inaccettabilmente basso quando sarà ≤75%, per I+V e ibrutinib in monoterapia, rispettivamente.

Obiettivi secondari dello studio: 

Gli obiettivi secondari principali sono valutare ulteriormente i parametri di efficacia (ad es., tasso di risposta completa [Complete Response, CR], durata della risposta [Duration of Response, DoR], sopravvivenza libera da progressione [Progression Free Survival, PFS], sopravvivenza complessiva [Overall Survival, OS]) e il profilo di sicurezza.

Data di inizio dell'arruolamento: 22.05.2024

Centri partecipanti

Nord Italia

Centro Italia

Sud Italia e isole

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2023-504044-34

Data di inserimento: 16.01.2025

Promotore

Janssen Research & Development, LLC

Principal Investigator ITALIA

Riferimento: Dr. Info non applicabile

Telefono: 00000

Email: na@na.it

Localita: na