A Pilot Study on Intermittent Ibrutinib in Patients With Advanced-phase Chronic Lymphocytic Leukemia (CLL) (IbruOnOff)

A Pilot Study on Intermittent and Repeated Dosing of Ibrutinib in the Treatment of Patients With Advanced-phase Chronic Lymphocytic Leukemia (CLL)

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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Ibrutinib

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jeanette Lundin, MD PhD; Phone Number: 46 0700 85 67 86; Email: jeanette.lundin@sll.se
• Study Contact Backup: Name: Sanna Nyström, PhD; Phone Number: 46 08 517 759 27; Email: sanna.nystrom@sll.se

Study Locations

• Norway
  • Trondheim, Norway, 7030
    • Recruiting
    • St Olavs hospital
    • Contact: Emadoldin Feyzi, MD PhD; Email: emadoldin.feyzi@stolav.no
    • Principal Investigator: Emadoldin Feyzi, MD PhD
• Sweden
  • Gothenburg, Sweden, 413 45
    • Not yet recruiting
    • Sahlgrenska University Hospital
    • Contact: Catharina Lewerin, MD PhD; Email: catharina.lewerin@vgregion.se
    • Principal Investigator: Catharina Lewerin, MD PhD
  • Stockholm, Sweden, 17176
    • Recruiting
    • Karolinska University Hospital
    • Contact: Jeanette Lundin, MD PhD; Email: jeanette.lundin@sll.se
    • Contact: Sanna Nyström, PhD; Email: sanna.nystrom@sll.se
    • Principal Investigator: Jeanette Lundin, MD PhD
  • Umeå, Sweden, 901 85
    • Not yet recruiting
    • Norrland's University Hospital
    • Contact: Florentin Späth, MD PhD; Email: florentin.spaeth@umu.se
    • Principal Investigator: Floretin Späth, MD PhD
  • Uppsala, Sweden, 751 85
    • Recruiting
    • Akademiska hospital
    • Contact: Mattias Mattsson, MD; Email: mattias.mattsson@akademiska.se
    • Principal Investigator: Mattias Mattsson, MD
  • Örebro, Sweden, 701 85
    • Recruiting
    • Orebro University Hospital
    • Contact: Magdalena Kättström, MD; Email: magdalena.kattstrom@regionorebrolan.se
    • Principal Investigator: Magdalena Kättström, MD
  • Dalarna
    • Falun, Dalarna, Sweden, 791 82
      • Recruiting
      • Falu Lasarett
      • Contact: Max Flogegård; Email: max.flogegard@ltdalarna.se
      • Principal Investigator: Max Flogegård, MD
  • Gävleborg
    • Gävle, Gävleborg, Sweden, 801 87
      • Recruiting
      • Gävle Hospital
      • Contact: Anders Uddevik, MD; Email: anders.uddevik@regiongavleborg.se
      • Principal Investigator: Anders Uddevik, MD
  • Skåne
    • Lund, Skåne, Sweden, 222 42
      • Not yet recruiting
      • Skåne University Hospital
      • Contact: Jenny Klintman, MD; Email: jenny.klintman@skane.se
      • Principal Investigator: Jenny Klintman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intermittent ibrutinib; Intermittent treatment with ibrutinib.	Drug: Ibrutinib; Ibrutinib will be stopped at inclusion in the and the patient will be followed OFF therapy. At clinical progress, ibrutinib will be restarted (ON period) at the same standard dose as used at inclusion. When the patient achieve at least partial response again, a new OFF period is started, and so on.; Other Names: Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety measured as type, frequency and severity of adverse events.	Type, frequency and severity of adverse events and relationship to intermittent ibrutinib dosing.	Through study completion, 1-24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response at each treatment cycle.	Response when re-starting ibrutinib, at each cycle.	Through study completion, 1-24 months.
Time to PR and PR-L at each cycle.	Time to partial response (PR) and partial response with persistent lymphocytosis (PR-L) when re-starting ibrutinib, at each cycle.	Through study completion, 1-24 months.
Time to stop until restart of ibrutinib due to progress	Time from the patient going off ibrutinib until it has to be re-started due to progressive, for each cycle.disease (PD), at each cycle.	Through study completion, 1-24 months.
Number of ibrutinib treatment cycles and OFF therapy periods.	The number of cycles each patient stop and re-start ibrutinib.	Through study completion, 1-24 months.
Cumulative dose of ibrutinib.	The cumulative dose of ibrutinib for each patient.	Through study completion, 1-24 months.
Overall survival.	Overall survival.	Through study completion, 1-24 months.
Risk of early rebound phenomenon.	Observation of early rebound phenomemon at each re-start of ibrutinib.	Through study completion, 1-24 months.
Time to need of alternative treatment.	Time to need of alternative treatment.	Through study completion, 1-24 months.

Collaborators and Investigators

• Sponsor: Jeanette Lundin
• Investigators: Principal Investigator: Jeanette Lundin, MD PhD, Karolinska University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2018
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): December 1, 2027

Study Registration Dates

• First Submitted: February 19, 2021
• First Submitted That Met QC Criteria: February 24, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid
• Other Study ID Numbers: HCK-LT-CLL02/2017

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No