Clinical trial NCT03193281: KISS Study: Kinase Inhibition With Sprycel Start up
Official title: KISS Study: A Phase II Study of Dasatinib Followed by Imatinib in Newly Diagnosed, Previously Untreated Patients With Chronic Phase CML
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Keywords: Dasatinib
Imatinib
Lead sponsor: University of Auckland, New Zealand
Sponsor class: OTHER
Collaborators: name: Leukaemia & Blood Cancer New Zealand
First posted: 2017-06-20
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A Phase II, multicentre, open-label, prospective non-randomised study of treatment modification in response to maintenance of MR3.0 at 12 months.

Molecular response will be measured 3 monthly. Patients who achieve MR3.0 by 12 months, with a confirmed response at 13 months on treatment, will switch treatment to imatinib. Those patients who do not achieve this confirmed response will remain on dasatinib.

For patients who achieve confirmed MR3.0 by 13 months we define two study stages. Stage 1 is the first 12 months after recruitment (i.e. before the possible switch to imatinib) and Stage 2 includes the months 13 - 37.
Primary purpose: TREATMENT

Brief summary: Chronic myeloid leukaemia (CML) is due to a chromosomal abnormality in white blood cells which results in abnormal multiplication. CML in its earlier, slower growing chronic phase (CP) is well controlled by the tyrosine kinase inhibitor (TKI) drug imatinib, which targets the consequences of the chromosomal abnormality, inducing a response and subsequent remission (as measured using molecular techniques on patient blood or bone marrow samples in the lab). Dasatinib, a newer TKI drug, similar in design to imatinib, gives a more rapid molecular response, however the long term side-effects are less known than imatinib.

This study will investigate the efficacy and safety of a treatment plan for patients with newly diagnosed CML-CP, where dasatinib will be used to more rapidly induce a molecular response (MR3.0) within 12 months, after which imatinib will be used to maintain the CML in that remission. It is hypothesised that imatinib is safe and effective in maintaining MR3.0 in patients with CML who achieve MR3.0 at 12 months following initial induction therapy with dasatinib.

Detailed description: The KISS Study is a Phase II, multicentre, open-label, prospective non-randomised study of treatment modification in response to maintenance of MR3.0 at 12 months. Patients must be newly diagnosed with chronic phase CML (CML-CP) (\<3 months) and previously untreated with the exception of hydroxyurea.

Patients will be recruited from hospital haematology clinics. The majority of patients will have been referred to a haematologist due to suspected CML. Written informed consent will be ensured before any study-specific procedures are undertaken or study data collected, however the majority of assessments carried out for this study are based on standard of care.

Patients' eligibility will be determined by the usual procedures carried out for CML diagnosis. Results from both diagnostic procedures and confirmatory screening procedures will constitute baseline data. Once a patient has had their eligibility confirmed and has signed informed consent, they will be enrolled into the trial.

The trial consists of two stages:

Stage 1: The first 12 months after recruitment (before the possible switch to imatinib).

Stage 2: Months 13 - 37.

The following measurements/data will be recorded throughout the trial at protocol specified time points:

* Haematology and biochemistry.
* PB Q-PCR for BCR-ABL1.
* Chest x-ray, ECG, ECHO.
* Medical assessment including physical exam, ECOG performance, weight, vital signs, assessment of extra medullary disease (liver, lymph nodes and spleen), spleen measurement below left costal margin, adverse events and concomitant medications.
* Haematological and molecular response assessments.
* Treatment adherence assessment.
* Patient questionnaire (MDASI-CML).

All patients will commence dasatinib (Sprycel®) 100 mg daily. Molecular monitoring of blood BCR-ABL1 transcripts to measure molecular response will occur 3 monthly by Q-PCR as per standard of care procedures. Patients who achieve a BCR-ABL1 level of ≤ 0.1% (MR3.0) by 12 months on treatment will switch treatment to imatinib 400 mg daily if MR3.0 is confirmed at 13 months (and they give their consent to switch). Those patients who do not achieve MR3.0 at 12 months or MR3.0 is not confirmed at 13 months, will remain on dasatinib. Patients with confirmed MR3.0 who choose not to switch to imatinib will continue on dasatinib. Patients that are intolerant of dasatinib in the first 12 months, those that switch to imatinib at 12 months and then lose MR3.0 or those intolerant of imatinib will be treated off study.

Eligibility criteria: INCLUSION CRITERIA:

1. Male or female patients ≥ 18 years of age.
2. ECOG performance status score of 0-2.
3. Patients must have all of the following:

   1. Be enrolled within 3 months of initial diagnosis of CML-CP (date of initial diagnosis is the date of first cytogenetic analysis).
   2. Cytogenetic or molecular confirmation of Ph+ or variants of (9;22) translocations.

      patients may have secondary chromosomal abnormalities in addition to the Ph+.
   3. Documented chronic phase CML as defined by:

      * \< 15% blasts in peripheral blood and bone marrow.
      * \< 30% blasts plus promyelocytes in peripheral blood and bone marrow.
      * \< 20% basophils in peripheral blood.
      * ≥ 100 x 109/L platelets (unless considered related to hydroxyurea).
      * no evidence of extramedullary leukaemic involvement, with the exception of hepatosplenomegaly.
   4. BCR-ABL1 transcript that can be monitored by Q-PCR.
   5. Baseline full blood count (within 14 days of enrolment) remains consistent with chronic phase CML criteria.
4. Voluntary written informed consent.

EXCLUSION CRITERIA:

1. Any prior treatment for CML with other than hydroxyurea.
2. Patients with the following laboratory values:

   1. serum bilirubin \> 2.0 x the institutional upper limit of the normal range (ULN).
   2. ALT \> 2.0 x the institutional upper limit of the normal range (ULN).
   3. creatinine \> 2.0 x the institutional upper limit of the normal range (ULN).
   4. International normalised ratio (INR) or partial thromboplastin time (PTT) \> 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants.
3. Patients with uncontrolled medical disease such as diabetes mellitus, thyroid dysfunction, neuropsychiatric disorders or infection.
4. Patients with:

   1. Grade 3/4 cardiac problems as defined by the New York Heart Association Criteria.
   2. Uncontrolled hypertension.
   3. Grade 3/4 respiratory dysfunction.
   4. Past or current history of pleural effusions or pulmonary arterial hypertension.
5. Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required.
6. Patients who have undergone major surgery within 4 weeks of study Day 0, or who have not recovered from prior major surgery.
7. Patients who are:

   1. pregnant.
   2. breast feeding.
   3. of childbearing potential without a negative pregnancy test on/prior to Day 0.
   4. male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential).
8. Patients with another uncontrolled malignancy with the exception of basal cell skin carcinoma or cervical carcinoma in situ.
9. Patients with positivity for hepatitis B antigen and / or hepatitis B core antibody (unless receiving prophylactic therapy with lamivudine or more potent agent)
10. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable.

Primary outcomes:
measure: To estimate the proportion of patients who remain in MR3.0 for the duration of 2 years following a change of therapy from dasatinib to imatinib at 13 months.
timeFrame: 2 years
Secondary outcomes:
measure: To estimate progression free survival (PFS), failure free survival (FFS) and overall survival (OS) for patients that switch to imatinib at 13 months.
timeFrame: 3 years
measure: To estimate the proportion of patients who regain MR3.0 on dasatinib or another TKI therapy after having a confirmed loss of MR3.0 on imatinib, for patients that switch to imatinib at 13 months.
timeFrame: 3 years
measure: To estimate time to MR3.0, MR4.5 and MR5.0 for patients that switch to imatinib at 13 months.
timeFrame: 3 years
measure: To describe adverse event profiles on Stage 1 and Stage 2 of the study and overall for patients that switch to imatinib at 13 months.
timeFrame: 3 years
measure: To describe the quality of life on Stage 1 and Stage 2 of the study and overall for those that switch to imatinib at 13 months.
timeFrame: 3 years
Other outcomes:
measure: To estimate PFS, FFS and OS for the following groups: 1) the entire cohort 2) patients not eligible to switch to imatinib at 13 months 3) patients that are eligible but do not switch.
timeFrame: 3 years
measure: To estimate time to MR3.0, MR4.5 and MR5.0 for the following groups: 1) the entire cohort 2) patients not eligible to switch to imatinib at 13 months 3) patients that are eligible but do not switch.
timeFrame: 3 years
measure: To describe adverse event profiles on each stage of study therapy for the following groups: 1) the entire cohort 2) patients not eligible to switch to imatinib at 13 months 3) patients that are eligible but do not switch.
timeFrame: 3 years
measure: To describe the quality of life on each stage of study therapy for the following groups: 1) the entire cohort 2) patients not eligible to switch to imatinib at 13 months 3) patients that are eligible but do not switch.
timeFrame: 3 years
Locations:
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: New Plymouth
country: New Zealand
facility: Taranaki Base Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Takapuna
country: New Zealand
facility: North Shore Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
Study officials:
affiliation: University of Auckland, New Zealand
name: Peter Browett, MBChB
role: PRINCIPAL_INVESTIGATOR
References: