Therapies in Combination or Sequentially With Tyrosine Kinase Inhibitors (TKIs) in Chronic Phase Chronic Myelogenous Leukemia Patients in CCR (ACTIW) (ACTIW)

STATUS

Recruiting
End date

Jun 24, 2023
participants needed

100
sponsor

Versailles Hospital

Updated on 23 February 2022

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Summary

Patients will be randomized in phase II trials to continue on the same TKI versus one of the alternative treatment approaches. If a patient is not eligible for one of the treatments, he (she) will be randomized between the options for which he (she) is eligible.

The trial will start with current available treatment options (experimental arms). New available treatment options may be open at any times later on. Authorized TKIs are imatinib, nilotinib, dasatinib, bosutinib and ponatinib.

For all options the treatment duration is for a minimum of 12 months and will be continued in the absence of adverse events following investigator decision. Each therapeutic option will be detailed in term of combination modalities, dose, dose adaptation, specific warnings, specific exclusion and inclusion criteria. The decision to introduce a new option will depend on the general pace of recruitment and on the assessment of the potential efficacy and safety of the new treatment, and will be implemented after scientific review by a protocol amendment.

Primary objective:

To select molecules in combination or sequentially with imatinib, nilotinib, dasatinib, bosutinib or ponatinib potentially able to produce a 25% increase in the Cumulative Incidence of MR4.5 as compare to control.

Secondary objectives:

To determine the safety of selected therapies
To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms
To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms
To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
To estimate treatment free remission (TFR) in patients eligible for discontinuation studies
To investigate the relationship between biological activity and the clinical efficacy of the selected therapies
To assess the effects of the treatments on the number and clonogenicity of CML stem cells and other biological markers of interest
To estimate duration of response, progression-free survival, event free survival and overall survival.

Description

Patients will be randomised to continue on TKI (same daily dose) versus one of the alternative novel treatment approaches. If a patient is not eligible for one of the treatments, he can be randomised for the options for which he is eligible. All treatment options may be open at all times. Investigators must specify before randomization for which treatment option they want their patient be included and randomized.

Perspectives New treatment options will be introduced over time. The decision to introduce a new option will depend on the general pace of recruitment and the assessment of the potential efficacy and safety of the new treatment in this patient population, and will be implemented after scientific review by a protocol amendment.

The available treatment arms are:

TKI alone same daily dose (control arm)
TKI in combination with pioglitazone
TKI in combination with Avelumab (anti-PD-L1 antibody)

Planned treatment arms for the future may be :

TKI in combination with pegylated interferon
TKI in combination with arsenic trioxide
TKI in combination with Homoharringtonine

Protocol plan:

Control arm (Imatinib, nilotinib, dasatinib, bosutinib or ponatinib):

Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months

2. Pioglitazone arm

TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
PIOGLITAZONE (Actos):

30 mg per day for 12 months. The dose will be increased to 45 mg per day after 2 months in the absence of grade >1 related AE.

After 12 Months :

Continue TKI at the same daily dose and STOP pioglitazone.

3. AVELUMAB arm

TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
AVELUMAB: 10mg/kg every 2 weeks, for a maximum of 8 IV infusions over a 4 months' period. (If MR4.5 is acheived by the first 3 months the 7th and 8th infusions will be omitted)
After 12 Months :Continue TKI at the same daily dose. 4. Other experimental arm TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
Arsenic trioxide : to be determined after amendment
Pegylated Interferon : to be determined after amendment
Homoharringtonine : to be determined after amendment
Drug X
Drug Y

Details

Condition	Leukemia, Myeloid, Chronic-Phase
Treatment	Avelumab, pioglitazone
Clinical Study Identifier	NCT02767063
Sponsor	Versailles Hospital
Last Modified on	23 February 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Patient aged 18y or more
	Signed informed consent
	Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1 transcript positivity at diagnosis
	Treatment with imatinib, nilotinib, dasatinib or bosutinib for more than 2 years overall
	No switch between tyrosine kinase inhibitors within the last 3 months
	No dose modification within the last 3 months
	Complete cytogenetic response or BCR-ABL1IS 1%
	Detectable BCR-ABL1 with BCR-ABL1IS > 0.0032% (less than MR4.5)
	ECOG grade 0 to 2
	ASAT and ALAT 2.5 N
	Bilirubin in serum 2.5 N
	Men and Women of childbearing potential must be using an adequate method of contraception
	These specific inclusion criteria will apply for the Avelumab arm in addition
	to the common criteria
	Hematologic
	Absolute neutrophil count (ANC) 1.5 109/L
	Platelet count 100 109/L
	Hemoglobin 9 g/dL. (may have been transfused)
	Hepatic
	Total bilirubin level 1.5 the upper limit of normal (ULN) range
	Renal: Estimated creatinine clearance 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
	Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential
	Contraception: Highly effective contraception for both male and female subjects throughout the study and for at least 30 days after last Avelumab treatment administration if the risk of conception exists
Exclusion Criteria
	Pregnant or lactating women
	Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment
	Prior history of hematopoietic stem cell transplantation (autologous or allogenic)
	Cardiovascular disease
	Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure
	Myocardial infarction within the previous 6 months
	Symptomatic cardiac arrhythmia requiring treatment
	Grade III or IV fluid retention
	Known BCR-ABL kinase domain mutation
	CML patient not in chronic phase at diagnosis
	Individuals with an active malignancy
	Known HIV-positivity
	These specific exclusion criteria will apply for the pioglitazone arm in
	addition to the common criteria
	Known osteoporosis with curative therapy (prophylactic therapy is not an exclusion criteria)
	Patient requiring anti-diabetic medication
	These specific exclusion criteria will apply for the Avelumab arm in addition
	to the common
	criteria
	IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the
	following
	intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
	Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent
	Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
	AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid diseases not requiring immunosuppressive treatment are eligible
	ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell transplantation
	INFECTIONS: Active infection requiring systemic therapy
	HIV/AIDS: Known history of testing positive for HIV or known acquired immunodeficiency syndrome
	HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
	VACCINATION: Vaccination within 4 weeks of the first dose of Avelumab and while on trials is prohibited except for administration of inactivated vaccines
	HYPERSENSITIIVTY TO STUDY DRUG: Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions tomonoclonal antibodies (NCI CTCAE v4.03 Grade 3)
	CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure ( New York Heart Association Classification Class II), or serious cardiac arrhythmia equiring medication
	OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI CTCAE
	4.03 Grade > 1); however, alopecia, sensory neuropathy Grade 2, or other Grade 2 not constituting a safety risk based on investigator's judgment are acceptable
	Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study

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Therapies in Combination or Sequentially With Tyrosine Kinase Inhibitors (TKIs) in Chronic Phase Chronic Myelogenous Leukemia Patients in CCR (ACTIW) (ACTIW)