Vemurafenib Plus Rituximab as a Chemotherapy-Free Alternative to Cladribine Followed by Mrd-Guided Rituximab in Front-Line Hairy Cell Leukemia (Hcl): a PHASE-2 Randomized Multicenter Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universita' Degli Studi Di Perugia

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Jan 2023 → ongoing

Decision date (initial)

2025-01-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Università degli Studi di Perugia, Dipartimento di Medicina e Chirurgia

External identifiers

EU CT number

2024-520119-41-00

EudraCT number

2021-001864-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

The primary objective of the trial is to show that the experimental therapy (VR) is no
less effective and less toxic than the standard therapy (monotherapy with CDA).

Secondary objectives 1

1. a) Time from starting treatment until resolution of cytopenias; b) Time from starting treatment until recovery of CD4+ T cells, CD8+ T cells, B cells and NK cells recovery to normal values; c) Proportion of patients in the control arm that reach a CR with sequential rituximab among patients not achieving CR after CDA monotherapy d) Proportion of patients clearing measurable/MRD e) Survival free from MRD f) Survival free from relapse g) Survival free from disease progression h) Survival free from a subsequent anti-leukemic treatment i) Survival free from death j) e k) Treatment-related toxicities l) Adverse events and toxicities of any grades m) Role of PET-CT in HCL staging and response to therapy n) Quality of life o) Pharmaco-economic analysis of global treatment costs p) In patients enrolled but not randomized (estimated to be <10%) due to concern(s), prospective evaluation of the efficacy and safety of any alternative treatment strategy

Conditions and MedDRA coding

Previously untreated patients with diagnosis of HCL

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Previously untreated patients with centrally reviewed diagnosis of HCL
2. 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.
3. 3. ECOG Performance Status of 0-2.
4. 4. Male or female HCL patients > =18 years of age.
5. 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).
6. 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.
7. 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.
8. 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:
9. 9. BRAF-V600E mutation centrally confirmed.
10. 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.
11. 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.
12. 12. Good renal function, as defined by creatinine clearance >50 ml/min.
13. 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).
14. 14. QTc interval < = 500 ms.

Exclusion criteria 4

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. 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.

Secondary endpoints 16

1. Time from starting treatment until resolution of cytopenias
2. 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).
3. Survival free from MRD (calculated in patients clearing MRD from the time of MRD clearing).
4. Time from starting treatment until recovery of CD4+ T cells, CD8+ T cells, B cells and NK cells recovery to normal values.
5. Survival free from relapse (calculated in patients obtaining a OR from the time of OR achievement).
6. Survival free from disease progression (calculated in all patients since starting treatment).
7. Survival free from a subsequent anti-leukemic treatment (calculated in patients undergoing a new treatment from the end of trial therapy).
8. Survival free from death (calculated in all patients since starting treatment)
9. Treatment-related toxicities (total counts and proportion of patients affected) separately grouped in grade 3, grade 4 or grade 5, by central assessment.
10. Treatment-related toxicities (total counts and proportion of patients affected) separately grouped in grade 3, grade 4 or grade 5, by local assessment.
11. Adverse events and toxicities of any grades (total counts and proportion of patients affected), by local assessment.
12. Role of PET-CT in HCL staging and response to therapy.
13. Quality of life, as quantified through ad hoc questionnaire.
14. Pharmaco-economic analysis of global treatment costs.
15. 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
16. Proportion of patients in the control arm that reach a CR with sequential rituximab among patients not achieving CR after CDA monotherapy.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita' Degli Studi Di Perugia

Sponsor organisation

Universita' Degli Studi Di Perugia

Address

Piazza Dell' Universita' 1

City

Perugia

Postcode

06123

Country

Italy

Scientific contact point

Organisation

Universita' Degli Studi Di Perugia

Contact name

Enrico Tiacci

Public contact point

Organisation

Universita' Degli Studi Di Perugia

Contact name

Enrico Tiacci

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications