VEMURAFENIB for Hairy cell leukaemia

Inclusion criteria

• {"criterion_text":"- 1. Previously untreated patients with centrally reviewed diagnosis of HCL\n- 10. No nausea, vomiting, malabsorption, external biliary shunt, significant bowel resection, or neurological disorder that would preclude adequate absorption. Patients must be able to swallow tablets.\n- 11. No (suspected or documented) active uncontrolled serious infection, as defined by the presence of: i) febrile neutropenia (a single temperature of >38.3°C or a sustained temperature of =38°C for >1 hour) in a neutropenic patient (<1000 neutrophils x 109/L without G-CSF support), which has not resolved within =7 days from its onset despite anti-microbial therapy; and/or ii) a radiologically or clinically documented focus of infection (e.g., abscess, pneumonia, cellulitis, etc.) that has not been resolved by medical or surgical therapy.\n- 12. Good renal function, as defined by creatinine clearance >50 ml/min.\n- 13. Good hepatic function, as defined by a Child-Pugh score =6 (online calculator available for example at https://www.mdcalc.com/calc/340/child-pugh-score-cirrhosismortality), noting that abnormalities of each component of this score (e.g., bilirubin or INR) must be attributed to hepatic insufficiency and not to other causes (e.g., Gilbert syndrome or treatment with anti-coagulant drugs, respectively; in this case the abnormality unrelated to hepatic impairment is given the lowest score).\n- 14. QTc interval < = 500 ms.\n- 2. Need of treatment, i.e. at least one of the following: neuthrophils <1x109 per liter, hemoglobin <10 g per deciliter, platelets <100x109 per liter, bulky/symptomatic splenomegaly, clinically relevant infiltration of other organs (e.g., lymphadenopathy), disease-related opportunistic infections or autoimmune disorders.\n- 3. ECOG Performance Status of 0-2.\n- 4. Male or female HCL patients > =18 years of age.\n- 5. Negative serum pregnancy test within 14 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been post-menopausal (i.e., with an intact uterus, but with no mestrual bleeding for >=1 year in the absence of hormonal contraception).\n- 6. Women of childbearing potential and men must use highly effective contraception methods during treatment, as well as for at least 6 months after treatment with cladribine or vemurafenib and at least 12 months after treatment with rituximab, including: intra-uterine devices or systems, hormonal implants or tube ligation for women; and vasectomy or condom for men. Oral contraceptives are not highly effective, also in light of potential drug-drug interaction. At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception]. Patients undergoing cladribine treatment should be counseled for fertilty preservation before cladribine treatment because of possible infertility due to cladribine therapy.\n- 7. No medical, psychological, familial, sociological or geographical condition which may hamper compliance with the study protocol and follow-up schedule, or interfere with the interpretation of study results or would anyway make the patient inappropriate for enrollment in this study.\n- 8. Signed informed consent (prior to performing any study-related procedures). After enrollment in the study, patients must also fulfill the following additional specific inclusion criteria for randomization to CDA+sR or VR:\n- 9. BRAF-V600E mutation centrally confirmed."}

Exclusion criteria

• {"criterion_text":"- 1.Concurrent administration of other any anti-cancer therapies. Prior splenectomy for diagnosis and/or therapy of HCL is not allowed.\n- 2. Pregnancy or lactation.\n- 3. Other active advanced cancer with projected life expectancy <1 year.\n- 4. Cytopenias do not represent exclusion criteria as they are caused by HCL."}

Primary endpoints

• {"endpoint_text":"- The primary efficacy endpoint is the rate of complete remission (CR) at ~6 months after treatment initiation (VR or monotherapy with CDA) in randomized patients, adjudication of the primary endpoint will be centrally performed by an external independent committee unaware of treatment assignments.","definition_or_measurement_approach":"Rate of complete remission (CR) assessed at ~6 months after treatment initiation; adjudicated centrally by an external independent committee blinded to treatment assignments (includes bone marrow biopsy assessment)."}
• {"endpoint_text":"- The primary safety endpoint is the proportion of randomized patients experiencing =1 drug-related toxicity of maximum grade =3 according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 that occurs within 6 months from starting treatment (VR or monotherapy with CDA) as reported by the investigators and that is at least possibly related to the study drugs.","definition_or_measurement_approach":"Proportion of randomized patients with ≥1 drug-related toxicity of maximum grade ≥3 per CTCAE v5.0 occurring within 6 months from treatment start, as reported by investigators."}

Secondary endpoints

• {"endpoint_text":"- Time from starting treatment until resolution of cytopenias","definition_or_measurement_approach":"Time-to-event from treatment start until documented resolution of cytopenias."}
• {"endpoint_text":"- Proportion of patients clearing measurable/minimal residual disease (MRD) by PCR and/or flow cytometry and/or immunohistochemistry in bone marrow and blood cell samples, as well as by PCR in the plasma (liquid biopsy).","definition_or_measurement_approach":"Proportion clearing MRD assessed by PCR and/or flow cytometry and/or immunohistochemistry in bone marrow and blood, and by PCR in plasma (liquid biopsy)."}
• {"endpoint_text":"- Survival free from MRD (calculated in patients clearing MRD from the time of MRD clearing).","definition_or_measurement_approach":"Time from MRD clearance to recurrence of MRD or other event; calculated in patients who clear MRD."}
• {"endpoint_text":"- Time from starting treatment until recovery of CD4+ T cells, CD8+ T cells, B cells and NK cells recovery to normal values.","definition_or_measurement_approach":"Time-to-event to normalization of CD4+, CD8+, B and NK cell counts to normal values from treatment start."}
• {"endpoint_text":"- Survival free from relapse (calculated in patients obtaining a OR from the time of OR achievement).","definition_or_measurement_approach":"Time from achievement of overall response (OR) to relapse; calculated in patients achieving OR."}
• {"endpoint_text":"- Survival free from disease progression (calculated in all patients since starting treatment).","definition_or_measurement_approach":"Progression-free survival measured from treatment start in all patients."}
• {"endpoint_text":"- Survival free from a subsequent anti-leukemic treatment (calculated in patients undergoing a new treatment from the end of trial therapy).","definition_or_measurement_approach":"Time from end of trial therapy to initiation of subsequent anti-leukemic treatment; calculated in patients who undergo new treatment."}
• {"endpoint_text":"- Survival free from death (calculated in all patients since starting treatment)","definition_or_measurement_approach":"Overall survival measured from treatment start in all patients."}
• {"endpoint_text":"- Treatment-related toxicities (total counts and proportion of patients affected) separately grouped in grade 3, grade 4 or grade 5, by central assessment.","definition_or_measurement_approach":"Counts and proportions of treatment-related toxicities by grade (3,4,5) assessed centrally."}
• {"endpoint_text":"- Treatment-related toxicities (total counts and proportion of patients affected) separately grouped in grade 3, grade 4 or grade 5, by local assessment.","definition_or_measurement_approach":"Counts and proportions of treatment-related toxicities by grade (3,4,5) assessed locally."}
• {"endpoint_text":"- Adverse events and toxicities of any grades (total counts and proportion of patients affected), by local assessment.","definition_or_measurement_approach":"Counts and proportions of adverse events/toxicities of any grade as assessed locally."}
• {"endpoint_text":"- Role of PET-CT in HCL staging and response to therapy.","definition_or_measurement_approach":"Assessment of PET-CT utility in staging and response evaluation for HCL."}
• {"endpoint_text":"- Quality of life, as quantified through ad hoc questionnaire.","definition_or_measurement_approach":"Quality-of-life measured using ad hoc questionnaire(s) (e.g., QLQ-C30, EQ-5D-5L referenced in documents)."}
• {"endpoint_text":"- Pharmaco-economic analysis of global treatment costs.","definition_or_measurement_approach":"Health economic analysis of overall treatment costs."}
• {"endpoint_text":"- In patients enrolled but not randomized due to concern(s) against the standard and/or experimental treatment (including, but not limited to, active severe infection or risk thereof, including risk of severe Covid19 in unvaccinated patients; renal or hepatic impairment; severe QTc prolongation; history of an aggressive cancer type frequently associated with RAS mutations that was unlikely eradicated, lack of the BRAF-V600E mutation; etc.), prospective evaluation of the efficacy and safety of any","definition_or_measurement_approach":"Prospective evaluation of efficacy and safety of alternative treatment strategies in patients enrolled but not randomized due to contraindications; detailed measurement approach as per protocol."}
• {"endpoint_text":"- Proportion of patients in the control arm that reach a CR with sequential rituximab among patients not achieving CR after CDA monotherapy.","definition_or_measurement_approach":"Proportion in control arm achieving CR after sequential rituximab among those not achieving CR after CDA monotherapy."}

Italy

Earliest CTIS Part Ii Submission Date

09-12-2024

Latest Decision Or Authorization Date

24-02-2026

Processing Time Days

442

Number Of Sites

20

Number Of Participants

120

Primary sponsor

Full Name

Universita' Degli Studi Di Perugia

Organisation Type

Educational Institution

Country Of Registered Address

Italy