Candidate Therapies in Combination or Sequentially with Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myelogenous Leukaemia (Cp-Cml) Patients in Complete Cytogenetic Response without Achieving a Deep Molecular Response: an Adaptive Trial Based on a Drop Loser Design - Actiw Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier De Versailles

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-516328-32-00

EudraCT number

2015-005208-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

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

Secondary objectives 9

1. To determine the safety of selected therapies
2. To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms
3. To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms
4. To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
5. To estimate treatment free remission (TFR) in patients eligible for discontinuation studies
6. To investigate the relationship between biological activity and the clinical efficacy of the selected therapies
7. To assess the effects of the treatments on the number and clonogenicity of CML stem cells and other biological markers of interest
8. To estimate duration of response, progression-free survival, event free survival and overall survival.
9. Men and Women of childbearing potential must be using an adequate method of contraception

Conditions and MedDRA coding

CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Patient aged 18y or more
2. Signed informed consent
3. Patient with chronic phase CML and M BCR-ABL1 transcript positivity
4. Treatment with imatinib, nilotinib, dasatinib, 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-ABLIS ≤ 1%
8. Detectable BCR-ABL1 with BCR-ABLIS > 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
13. Hematologic: a. Absolute neutrophil count (ANC) ≥ 1.5 × 109 /L, b. Platelet count ≥ 100 × 109 /L, c. Hemoglobin ≥ 9 g/dL. (may have been transfused). (avelumab arm only)
14. Hepatic: a. Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range. (Avelumab arm only)
15. Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) (avelumab arm only)
16. Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential. (avelumab arm only)
17. 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 (avelumab arm only)

Exclusion criteria 21

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 (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. Absence de phase chronique lors du diagnostic de la LMC
8. Individuals with an active malignancy
9. Known HIV-positivity
10. Known osteoporosis with curative therapy (prophylactic therapy is not an exclusion criteria) - (Pioglitazone arm only)
11. Patient requiring anti-diabetic medication (pioglitazone arm only)
12. IMMUNOSUPRESSANTS (Avelumab arm only): Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
13. AUTOIMMUNE DISEASE (Avelumab arm only): 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.
14. ORGAN TRANSPLANTATION (Avelumab arm only): Prior organ transplantation including allogenic stem-cell transplantation.
15. INFECTIONS (Avelumab arm only): Active infection requiring systemic therapy.
16. HIV/AIDS (Avelumab arm only): Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
17. HEPATITIS (Avelumab arm only): 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)
18. VACCINATION (avelumab arm only): Vaccination within 4 weeks of the first dose of Avelumab and while on trials is prohibited except for administration of inactivated vaccines
19. HYPERSENSITIIVTY TO STUDY DRUG (Avelumab arm only): Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
20. OTHER PERSISTING TOXICITIES (AVelumab arm only): 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
21. 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. (avelumab arm only)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary end-point is the cumulative incidence of patients achieving a deep molecular response defined by MR4.5 or deeper (BCR-ABLIS ≤ 0.0032 %) by 12 months.

Secondary endpoints 7

1. Adverse events
2. The cumulative rate of patients achieving MR4.5 by 24, 36, 48 months in experimental and control arms
3. The cumulative rate of patients achieving MR4 by 12, 24, 36, 48 months in experimental and control arms
4. The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
5. The rate of patients in treatment free remission during follow-up
6. Measurement of number and clonogenicity of CML stem cells using the leukemic stem cell markers followed by flow cytometry analysis and the LTC-IC assay and others markers (ancillary study)
7. Survival, progression free survival, event free survival, duration of response

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier De Versailles

Sponsor organisation

Centre Hospitalier De Versailles

Address

177 Rue De Versailles, Le Chesnay Le Chesnay

City

Le Chesnay Rocquencourt

Postcode

78150

Country

France

Scientific contact point

Organisation

Centre Hospitalier De Versailles

Contact name

Pr Philippe Rousselot

Public contact point

Organisation

Centre Hospitalier De Versailles

Contact name

Mélody FORT

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications