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

Primary Purpose

Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Ibrutinib
Sponsored by
Jeanette Lundin
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • St Olavs HospitalRecruiting
  • Falu lasarettRecruiting
  • Gävle HospitalRecruiting
  • Skåne University Hospital
  • Sahlgrenska University Hospital
  • Karolinska University HospitalRecruiting
  • Norrland's University Hospital
  • Akademiska hospitalRecruiting
  • Örebro University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intermittent ibrutinib

Arm Description

Intermittent treatment with ibrutinib.

Outcomes

Primary Outcome Measures

Safety measured as type, frequency and severity of adverse events.
Type, frequency and severity of adverse events and relationship to intermittent ibrutinib dosing.

Secondary Outcome Measures

Overall response at each treatment cycle.
Response when re-starting ibrutinib, at each cycle.
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.
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.
Number of ibrutinib treatment cycles and OFF therapy periods.
The number of cycles each patient stop and re-start ibrutinib.
Cumulative dose of ibrutinib.
The cumulative dose of ibrutinib for each patient.
Overall survival.
Overall survival.
Risk of early rebound phenomenon.
Observation of early rebound phenomemon at each re-start of ibrutinib.
Time to need of alternative treatment.
Time to need of alternative treatment.

Full Information

First Posted
February 19, 2021
Last Updated
February 24, 2021
Sponsor
Jeanette Lundin
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1. Study Identification

Unique Protocol Identification Number
NCT04771507
Brief Title
A Pilot Study on Intermittent Ibrutinib in Patients With Advanced-phase Chronic Lymphocytic Leukemia (CLL)
Acronym
IbruOnOff
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

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Recruiting
Study Start Date
February 23, 2018 (Actual)
Primary Completion Date
April 1, 2023 (Anticipated)
Study Completion Date
December 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jeanette Lundin

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
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.
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intermittent ibrutinib
Arm Type
Experimental
Arm Description
Intermittent treatment with ibrutinib.
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Other Intervention Name(s)
Imbruvica
Intervention Description
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.
Primary Outcome Measure Information:
Title
Safety measured as type, frequency and severity of adverse events.
Description
Type, frequency and severity of adverse events and relationship to intermittent ibrutinib dosing.
Time Frame
Through study completion, 1-24 months.
Secondary Outcome Measure Information:
Title
Overall response at each treatment cycle.
Description
Response when re-starting ibrutinib, at each cycle.
Time Frame
Through study completion, 1-24 months.
Title
Time to PR and PR-L at each cycle.
Description
Time to partial response (PR) and partial response with persistent lymphocytosis (PR-L) when re-starting ibrutinib, at each cycle.
Time Frame
Through study completion, 1-24 months.
Title
Time to stop until restart of ibrutinib due to progress
Description
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.
Time Frame
Through study completion, 1-24 months.
Title
Number of ibrutinib treatment cycles and OFF therapy periods.
Description
The number of cycles each patient stop and re-start ibrutinib.
Time Frame
Through study completion, 1-24 months.
Title
Cumulative dose of ibrutinib.
Description
The cumulative dose of ibrutinib for each patient.
Time Frame
Through study completion, 1-24 months.
Title
Overall survival.
Description
Overall survival.
Time Frame
Through study completion, 1-24 months.
Title
Risk of early rebound phenomenon.
Description
Observation of early rebound phenomemon at each re-start of ibrutinib.
Time Frame
Through study completion, 1-24 months.
Title
Time to need of alternative treatment.
Description
Time to need of alternative treatment.
Time Frame
Through study completion, 1-24 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ability to understand and voluntarily provide written informed consent and comply with the requirements of the study. Age 18 years and older. There is no upper age limit in this trial. Able to adhere to the study visit schedule and other protocol requirements. 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. Having received at least 6 months of ibrutinib therapy and having achieved at least clinical PR according to IWCLL criteria. ECOG performance status of </= 2 at screening. 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 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. Agree to use reliable forms of contraception. Post-menopausal females and surgically sterilized females are exempt from this criterion. Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or breast feeding females. 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. Use of any other experimental therapy within the last 14 days. Concurrent use of other anti-cancer agents or treatments than ibrutinib (except a low dose of corticosteroids, max 10 mg of prednisone/day). Positivity for HIV or infectious hepatitis, type A, B or C. Opportunistic infections within the last 3 months. Patient planned for or being a potential candidate for allo-SCT. Uncontrolled hemolytic anemia or autoimmune thrombocytopenia. CNS involvement or history of Richter's transformation. Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) within 28 days of the first dose of ibrutinib. Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jeanette Lundin, MD PhD
Phone
0700 85 67 86
Ext
46
Email
jeanette.lundin@sll.se
First Name & Middle Initial & Last Name or Official Title & Degree
Sanna Nyström, PhD
Phone
08 517 759 27
Ext
46
Email
sanna.nystrom@sll.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeanette Lundin, MD PhD
Organizational Affiliation
Karolinska University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St Olavs Hospital
City
Trondheim
ZIP/Postal Code
7030
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emadoldin Feyzi, MD PhD
Email
emadoldin.feyzi@stolav.no
First Name & Middle Initial & Last Name & Degree
Emadoldin Feyzi, MD PhD
Facility Name
Falu lasarett
City
Falun
State/Province
Dalarna
ZIP/Postal Code
791 82
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Max Flogegård
Email
max.flogegard@ltdalarna.se
First Name & Middle Initial & Last Name & Degree
Max Flogegård, MD
Facility Name
Gävle Hospital
City
Gävle
State/Province
Gävleborg
ZIP/Postal Code
801 87
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anders Uddevik, MD
Email
anders.uddevik@regiongavleborg.se
First Name & Middle Initial & Last Name & Degree
Anders Uddevik, MD
Facility Name
Skåne University Hospital
City
Lund
State/Province
Skåne
ZIP/Postal Code
222 42
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jenny Klintman, MD
Email
jenny.klintman@skane.se
First Name & Middle Initial & Last Name & Degree
Jenny Klintman, MD
Facility Name
Sahlgrenska University Hospital
City
Gothenburg
ZIP/Postal Code
413 45
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Catharina Lewerin, MD PhD
Email
catharina.lewerin@vgregion.se
First Name & Middle Initial & Last Name & Degree
Catharina Lewerin, MD PhD
Facility Name
Karolinska University Hospital
City
Stockholm
ZIP/Postal Code
17176
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeanette Lundin, MD PhD
Email
jeanette.lundin@sll.se
First Name & Middle Initial & Last Name & Degree
Sanna Nyström, PhD
Email
sanna.nystrom@sll.se
First Name & Middle Initial & Last Name & Degree
Jeanette Lundin, MD PhD
Facility Name
Norrland's University Hospital
City
Umeå
ZIP/Postal Code
901 85
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florentin Späth, MD PhD
Email
florentin.spaeth@umu.se
First Name & Middle Initial & Last Name & Degree
Floretin Späth, MD PhD
Facility Name
Akademiska hospital
City
Uppsala
ZIP/Postal Code
751 85
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mattias Mattsson, MD
Email
mattias.mattsson@akademiska.se
First Name & Middle Initial & Last Name & Degree
Mattias Mattsson, MD
Facility Name
Örebro University Hospital
City
Örebro
ZIP/Postal Code
701 85
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Magdalena Kättström, MD
Email
magdalena.kattstrom@regionorebrolan.se
First Name & Middle Initial & Last Name & Degree
Magdalena Kättström, MD

12. IPD Sharing Statement

Learn more about this trial

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

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