Informations générales (source: ClinicalTrials.gov)
Candidate Therapies in Combination or Sequentially With Tyrosine Kinase Inhibitors in Chronic Phase-chronic Myelogenous Leukemia Patients in CCR Without Achieving a Deep Molecular Response: an Adaptative Trial Based on a Drop Loser Design (ACTIW)
Interventional
Phase 1/Phase 2
Versailles Hospital (Voir sur ClinicalTrials)
juillet 2016
juin 2023
29 juin 2024
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:
A. 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:
A. To determine the safety of selected therapies
B. To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms
C. To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms
D. To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL
copies) by 12, 24, 36, 48 months in experimental and control arms
E. To estimate treatment free remission (TFR) in patients eligible for discontinuation
studies
F. To investigate the relationship between biological activity and the clinical efficacy
of the selected therapies
G. To assess the effects of the treatments on the number and clonogenicity of CML stem
cells and other biological markers of interest
H. To estimate duration of response, progression-free survival, event free survival and
overall survival.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| AP-HP - Hôpital Saint Antoine | Simona LAPUSAN | Contact (sur clinicalTrials) | |||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| CHU Côte de Nacre - Caen - France | Hyacynthe Johnson-Ansah | Contact (sur clinicalTrials) | |||
| CHU de LIMOGES - Limoges - France | Amélie PENOT | Contact (sur clinicalTrials) | |||
| CHU de Rennes - Pontchaillou - Rennes - France | ESCOFFRE-BARBE Martine | Contact (sur clinicalTrials) | |||
| CHU Estaing - Clermont-Ferrand - France | Marc BERGER | Contact (sur clinicalTrials) | |||
| CHU Lille - Lille - France | COITEUX Valérie | Contact (sur clinicalTrials) | |||
| CHU Tours - Tours - France | DARTIGEAS Caroline | Contact (sur clinicalTrials) | |||
| Delphine REA _St louis - Paris - France | Delphine REA | Contact (sur clinicalTrials) | |||
| Hôpital La Source - Orléans - France | BENBRAHIM Omar | Contact (sur clinicalTrials) | |||
| Hopital l'Archet - Nice - France | Laurence LEGROS | Contact (sur clinicalTrials) | |||
| Hôpital René Huguenin - Saint-Cloud - France | Sylvie GLAISNER | Contact (sur clinicalTrials) | |||
| Institut P Calmette - Marseille - France | CHARBONNIER Aude | Contact (sur clinicalTrials) | |||
| Martine GARDEMBAS - Angers - France | Martine GARDEMBAS | Contact (sur clinicalTrials) | |||
| Pascale CONY.MAKHOUL - Annecy - France | Pascale CONY.MAKHOUL | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Cayssials - Poitiers - France | Emilie Cayssials | Contact (sur clinicalTrials) | |||
| CH Henri Mondor - Créteil - France | ROY Lydia | Contact (sur clinicalTrials) | |||
| Eric JOURDAN - Nimes - France | Eric JOURDAN | Contact (sur clinicalTrials) | |||
| Etienne - Bordeaux - France | Gabriel Etienne | Contact (sur clinicalTrials) | |||
| Franck NICOLINI - Lyon - France | Franck NICOLINI | Contact (sur clinicalTrials) | |||
| Institut Universitaire contre le Cancer - Toulouse - France | Françoise HUGUET | Contact (sur clinicalTrials) | |||
| Rousselot - Le Chesnay - France | Philippe Rousselot | Contact (sur clinicalTrials) | |||
| Thorsten BRAUN - Bobigny - France | Thorsten BRAUN | Contact (sur clinicalTrials) | |||
| Viviane DUBRUILLE - Nantes - France | Viviane DUBRUILLE | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria:
1. Patient aged 18y or more
2. Signed informed consent
3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1
transcript positivity at diagnosis
4. Treatment with imatinib, nilotinib, dasatinib or bosutinib for more than 2 years
overall
5. No switch between tyrosine kinase inhibitors within the last 3 months
6. No dose modification within the last 3 months
7. Complete cytogenetic response or BCR-ABL1IS ≤ 1%
8. Detectable BCR-ABL1 with BCR-ABL1IS > 0.0032% (less than MR4.5)
9. ECOG grade 0 to 2
10. ASAT and ALAT ≤ 2.5 N
11. Bilirubin in serum ≤ 2.5 N
12. 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.
1. Hematologic:
1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
2. Platelet count ≥ 100 × 109/L,
3. Hemoglobin ≥ 9 g/dL. (may have been transfused).
2. Hepatic:
a. Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range.
3. Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault
formula (or local institutional standard method)
4. Pregnancy test: Negative serum or urine pregnancy test at screening for women of
childbearing potential.
5. 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.
Common
1. Patient aged 18y or more
2. Signed informed consent
3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1
transcript positivity at diagnosis
4. Treatment with imatinib, nilotinib, dasatinib or bosutinib for more than 2 years
overall
5. No switch between tyrosine kinase inhibitors within the last 3 months
6. No dose modification within the last 3 months
7. Complete cytogenetic response or BCR-ABL1IS ≤ 1%
8. Detectable BCR-ABL1 with BCR-ABL1IS > 0.0032% (less than MR4.5)
9. ECOG grade 0 to 2
10. ASAT and ALAT ≤ 2.5 N
11. Bilirubin in serum ≤ 2.5 N
12. 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.
1. Hematologic:
1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
2. Platelet count ≥ 100 × 109/L,
3. Hemoglobin ≥ 9 g/dL. (may have been transfused).
2. Hepatic:
a. Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range.
3. Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault
formula (or local institutional standard method)
4. Pregnancy test: Negative serum or urine pregnancy test at screening for women of
childbearing potential.
5. 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.
Common
1. Pregnant or lactating women,
2. Participation in another clinical trial with any investigative drug within 30 days
prior to study enrolment,
3. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)
4. 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
5. Grade III or IV fluid retention
6. Known BCR-ABL kinase domain mutation
7. CML patient not in chronic phase at diagnosis
8. Individuals with an active malignancy
9. Known HIV-positivity
These specific exclusion criteria will apply for the pioglitazone arm in addition to the
common criteria.
1. Known osteoporosis with curative therapy (prophylactic therapy is not an exclusion
criteria)
2. Patient requiring anti-diabetic medication
These specific exclusion criteria will apply for the Avelumab arm in addition to the
common criteria:
1. IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the
following:
1. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection);
2. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent;
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
2. AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when receiving
an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or
hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are
eligible.
3. ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell
transplantation.
4. INFECTIONS: Active infection requiring systemic therapy.
5. HIV/AIDS: Known history of testing positive for HIV or known acquired
immunodeficiency syndrome.
6. 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)
7. VACCINATION: Vaccination within 4 weeks of the first dose of Avelumab and while on
trials is prohibited except for administration of inactivated vaccines
8. 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)
9. 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.
10. OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI CTCAE
v. 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.
11. 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.