Clinical trial NCT04771507: A Pilot Study on Intermittent Ibrutinib in Patients With Advanced-phase Chronic Lymphocytic Leukemia (CLL)
Official title: A Pilot Study on Intermittent and Repeated Dosing of Ibrutinib in the Treatment of Patients With Advanced-phase Chronic Lymphocytic Leukemia (CLL)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2021-02-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients treated with ibrutinib for at least 6 months and have achieved at least partial response will after inclusion stop the ibrutinib treatment and be followed-up for the study. If progress, they will re-initiate ibrutinib treatment. When they achieve at least partial response they stop the treatment again, and so on.
Primary purpose: TREATMENT

Brief summary: Ibrutinib, an inhibitor of Bruton´s tyrosine kinase (BTK) is approved in CLL as continuous, daily administration of 420 mg orally until progression. Ibrutinib drug costs in health care are rapidly increasing and are difficult to predict, as long-term follow up analyses have shown that many patients remain on therapy for several years, in some cases even many years. It has been observed that patients who stop ibrutinib due to side effects may often remain with continued CLL disease control i.e. in stable partial remission even when off ibrutinib therapy. There are also emerging data on mutations within BTK, with loss of efficacy of ibrutinib, during long-term continuous administration. These observations raise the question whether alternative dosing strategies may be feasible. This pilot study will explore intermittent and repeated dosing of ibrutinib, until alternative therapy is required due to resistance or intolerance to ibrutinib. An "ON-OFF" dosing strategy will be applied, where advanced-phase CLL patients who have received at least 6 months of ibrutinib and who have achieved a stable PR will stop ibrutinib and be followed off therapy until clinical progression, at which ibrutinib will be re-instituted. Such "ON-OFF" ibrutinib cycles may be repeated until non-tolerability or resistance, or need of continuous dosing of ibrutinib (i.e. early progression when off the drug). If successful, the study will indicate a way forward towards reducing ibrutinib drug costs in health care without affecting long-term disease control, possibly also with fewer ibrutinib-related side effects due to a lower cumulative dose of ibrutinib. Long-term effects on potential mutations within BTK and its downstream signaling molecules will also be analysed.


Eligibility criteria: Inclusion Criteria:

1. Ability to understand and voluntarily provide written informed consent and comply with the requirements of the study.
2. Age 18 years and older. There is no upper age limit in this trial.
3. Able to adhere to the study visit schedule and other protocol requirements.
4. Before start ibrutinib for the first time: diagnosed with CLL/SLL and active disease in need of treatment after having failed chemoimmunotherapy for CLL defined as a) refractory according to iwCLL criteria; or b) relapsed and deemed not suitable for additional chemo- or chemoimmunotherapy or c) del 17p and/or TP53 mutation irrespective of prior therapy.
5. Having received at least 6 months of ibrutinib therapy and having achieved at least clinical PR according to IWCLL criteria.
6. ECOG performance status of \</= 2 at screening.
7. Laboratory test results:

   * Absolute neutrophil count \>/= 0.5 x 109/L
   * Platelet count \>/= 30 x 109/L
   * Serum creatinine \< 177 µmol/L
   * ASAT (SGOT) and ALAT (SGPT) \>/= 2 x ULN or \>/= 5 x ULN unless attributable to CLL/SLL
8. Disease free of prior malignancies for \>/= 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
9. Agree to use reliable forms of contraception. Post-menopausal females and surgically sterilized females are exempt from this criterion.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2. Pregnant or breast feeding females.
3. Any condition, including the presence of laboratory abnormalities, which according to the responsible physician places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
4. Use of any other experimental therapy within the last 14 days.
5. Concurrent use of other anti-cancer agents or treatments than ibrutinib (except a low dose of corticosteroids, max 10 mg of prednisone/day).
6. Positivity for HIV or infectious hepatitis, type A, B or C.
7. Opportunistic infections within the last 3 months.
8. Patient planned for or being a potential candidate for allo-SCT.
9. Uncontrolled hemolytic anemia or autoimmune thrombocytopenia.
10. CNS involvement or history of Richter's transformation.
11. Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) within 28 days of the first dose of ibrutinib.
12. Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor.

Primary outcomes:
measure: Safety measured as type, frequency and severity of adverse events.
timeFrame: Through study completion, 1-24 months.
Secondary outcomes:
measure: Overall response at each treatment cycle.
timeFrame: Through study completion, 1-24 months.
measure: Time to PR and PR-L at each cycle.
timeFrame: Through study completion, 1-24 months.
measure: Time to stop until restart of ibrutinib due to progress
timeFrame: Through study completion, 1-24 months.
measure: Number of ibrutinib treatment cycles and OFF therapy periods.
timeFrame: Through study completion, 1-24 months.
measure: Cumulative dose of ibrutinib.
timeFrame: Through study completion, 1-24 months.
measure: Overall survival.
timeFrame: Through study completion, 1-24 months.
measure: Risk of early rebound phenomenon.
timeFrame: Through study completion, 1-24 months.
measure: Time to need of alternative treatment.
timeFrame: Through study completion, 1-24 months.
Other outcomes:
Locations:
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Falun
country: Sweden
facility: Falu lasarett
state: Dalarna
city: Gävle
country: Sweden
facility: Gävle Hospital
state: Gävleborg
city: Lund
country: Sweden
facility: Skåne University Hospital
state: Skåne
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Umeå
country: Sweden
facility: Norrland's University Hospital
city: Uppsala
country: Sweden
facility: Akademiska hospital
city: Örebro
country: Sweden
facility: Örebro University Hospital
Study officials:
affiliation: Karolinska University Hospital
name: Jeanette Lundin, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: