Clinical trial NCT02836925: Ledipasvir+Sofosbuvir and Sofosbuvir+Velpatasvir for Pts With Indolent Bcell Lymphoma Associated With HCV Infection
Official title: A Multicenter Study to Evaluate the Anti-viral Activity of an Interferon-free Treatment With Ledipasvir/Sofosbuvir (G1 and G4) and Sofosbuvir/Velpatasvir (G2 and G3) for Patients With Hepatitis C Virus-associated Indolent B-cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Indolent B-cell Lymphoma
Hepatitis C
Keywords: hepatitis C
NHL
Indolent B-cell lymphoma
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2016-07-19
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a non-randomized, a single arm, phase II multicentre study of sofosbuvir plus ledipasvir (genotype 1 and 4) or sofosbuvir plus velpatasvir (genotype 2 and 3) for patients with hepatitis C virus-associated indolent B-cell lymphomas (HCV-RNA positive).

Detailed description: The study includes an antiviral treatment with interferon-free regimen followed by lymphoma restaging; following the end of antiviral treatment patients will be evaluated for sustained virological response and safety parameters every 3 months for 1 year and then every 6 months for 2 years. ORR and vital status will be also evaluated.

Eligibility criteria: Inclusion Criteria:

1. Age \>18 years
2. Indolent B cell lymphoma including: marginal zone lymphoma (nodal, extranodal, splenic and disseminated), lymphoplasmacytic lymphoma, small lymphocytic lymphoma, follicular lymphoma grade 1 and 2, CD5-negative B-cell lymphoma NOS
3. HCV-RNA positivity
4. Assessable HCV genotype
5. No previous therapy for the lymphoma
6. Measurable disease after diagnostic biopsy (longest axis ≥1.5 cm for nodal and ≥1 cm for extranodal lesions) and/or evaluable disease (quantifiable BM infiltrate and ≥5 x 109/l clonal B-cell in peripheral blood in case of exclusive BM/leukemic disease in CD5-negative Bcell lymphoma NOS)
7. No need of immediate lymphoma treatment defined as absence of all the following criteria: systemic symptoms, bulky nodal or extranodal mass (\>7 cm), symptomatic splenomegaly, progressive leukemic phase, serous effusions
8. Performance status \<2 according to ECOG scale
9. Adequate hematological counts: ANC \>1 x 109/L, hemoglobin \>9 g/dl (transfusion independent), platelet count \> 50 x 109/L (transfusion independent)
10. No central nervous system (CNS) disease (meningeal and/or brain involvement by lymphoma)
11. Adequate kidney function (creatinine clearance ≥ 45 ml/min)
12. Cardiac ejection fraction ≥45% (echocardiography or MUGA scan)
13. Normal lung function
14. Non peripheral neuropathy or active neurological non neoplastic disease of CNS
15. Non major surgical intervention prior 3 months to enrolment if not due to lymphoma and/or no other disease life-threatening that can compromise chemotherapy treatment
16. Disease free of prior malignancies other than lymphoma for \>3 years with exception of currently treated squamous cell and basal cell carcinoma of the skin or carcinoma in situ of the cervix or breast
17. Life expectancy \> 6 months
18. No psychiatric illness that precludes understanding concepts of the trial or signing informed consent
19. Written informed consent
20. Women must be:

    * postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months)
    * surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
    * completely abstinent (at the discretion of the investigator/per local regulations) (periodic abstinence from intercourse is not permitted) or
    * if sexually active, be practicing a highly effective method of birth control (eg, prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. They must also be prepared to continue birth control measures for at least 6 months after terminating treatment.
21. Women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at screening
22. Men must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study. Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 1 month after receiving the last dose of study drug if not taking ribavirin of for 6 months after receiving the last dose of study drug if taking ribavirin.

Exclusion Criteria:

1. Diagnosis of lymphoblastic lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma grade 3, primary mediastinal B-cell lymphoma
2. Previous anti-HCV treatment with sustained virological response
3. Diagnosis of cirrhosis (histological or Stiffness \>12 KpA)
4. CNS disease (meningeal and/or brain involvement by lymphoma)
5. History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
6. Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before first dose of study drug)
7. Concomitant therapy with amiodarone
8. Uncontrolled or severe cardiovascular disease including myocardial infarction within six months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina,
9. Cardiac ejection fraction \<45% (MUGA scan or echocardiography).
10. Creatinine clearance \<45 ml/min
11. Presence of major neurological disorders
12. HIV positivity, HBV positivity (HbsAg+ or HBV-DNA+) with the exception of HBcAb+, HbsAg-, HBsAb+/- patients with HBV-DNA negativity
13. Ongoing systemic bacterial, fungal or viral infections at the time of initiation of study treatment (defined as requiring therapeutic dosing of an antimicrobial, antifungal or antiviral agent)
14. Major surgical intervention prior 3 months to enrollment if not due to lymphoma and/or other
15. Prior malignancies other than lymphoma in the last 3 years with exception of currently treated squamous cell and basal cell carcinoma of the skin or carcinoma in situ of the cervix or breast
16. Life expectancy \<6 months
17. Any other coexisting medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent.
18. If female, the patient is pregnant or breast-feeding.

Primary outcomes:
measure: SVR12
timeFrame: 12 weeks from the end of the treatment
Secondary outcomes:
measure: ORR
timeFrame: 12 weeks from the end of treatment
measure: PFS
timeFrame: 36 months
measure: EFS
timeFrame: 36 months
measure: OS
timeFrame: 36 months
measure: ORR for lymphoma
timeFrame: 12 weeks from the end of treatment
measure: Rapid virological response
timeFrame: 4 weeks
measure: Extended rapid virological response
timeFrame: 4 weeks
measure: Early virological response
timeFrame: 4 weeks
measure: Toxicity - Incidence of Adverse Events
timeFrame: 12 months
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: A.O. Spedali Civili
state: BS
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (Cro)
state: Pordenone
city: Vicenza
country: Italy
facility: Ospedale San Bortolo
state: VI
city: Milano
country: Italy
facility: Ematologia e Trapianto IRCCS, Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: Ospedale San Raffaele Ematologia
city: Padova
country: Italy
facility: U.O. Ematologia AO di Padova
city: Parma
country: Italy
facility: A.O. Universitaria Di Parma
city: Pavia
country: Italy
facility: Ematologia Policlinico San Matteo
city: Piacenza
country: Italy
facility: Ospedale Civile Piacenza
city: Roma
country: Italy
facility: Ematologia - Policlinico Umberto I Università Sapienza
city: Rozzano
country: Italy
facility: Dipartimento di Oncologia Medica ed Ematologia, Istituto Humanitas
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi
Study officials:
affiliation: Fondazione IRCCS Policlinico San Matteo di Pavia
name: Luca Arcaini
role: PRINCIPAL_INVESTIGATOR
References: