Evaluation of Pioglitazone and Avelumab in Combination with Tyrosine Kinase Inhibitors for Chronic Phase Chronic Myelogenous Leukemia in Cytogenetic Response

Trial ID: 2024-516328-32-00
Protocol: P13/12
Sponsor: Centre Hospitalier De Versailles

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Diseases & Conditions

Chronic myeloid leukaemia

Objectives

The primary objective of this study is to select **molecules** in combination or sequentially with imatinib, nilotinib, dasatinib, and bosutinib that have the potential to produce a 25% increase in the cumulative incidence of MR4.5 compared to the control. This is clinically relevant as achieving a deeper molecular response in patients with **Chronic Phase Chronic Myelogenous Leukaemia (CP-CML)** can significantly impact long-term disease management and patient outcomes.

Secondary objectives include:

To determine the safety of selected therapies.
To determine the rate of MR4 by 12, 24, 36, and 48 months in experimental and control arms.
To determine the rates of MR4.5 by 24, 36, and 48 months in experimental and control arms.
To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, and 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 the duration of response, progression-free survival, event-free survival, and overall survival.
Men and women of childbearing potential must be using an adequate method of contraception.

Participants

The clinical trial involves participants diagnosed with **chronic phase chronic myelogenous leukemia (CP-CML)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a general health status that meets specific hematologic, hepatic, and renal criteria, such as an absolute neutrophil count of at least 1.5 × 10⁹/L and a platelet count of at least 100 × 10⁹/L. The trial does not include a vulnerable population. Participants must have been treated with imatinib, nilotinib, dasatinib, or bosutinib for more than two years without any switch or dose modification in the last three months. They must also have a complete cytogenetic response or a BCR-ABLIS of 1% or less, with detectable BCR-ABL1 levels greater than 0.0032% but less than MR4.5. The trial requires participants to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of candidate therapies in combination or sequentially with tyrosine kinase inhibitors in patients with **chronic phase chronic myelogenous leukaemia (CP-CML)** who have achieved a complete cytogenetic response but not a deep molecular response. This is a Phase II, randomized, double-blind, controlled trial with an adaptive design based on a drop loser methodology. The trial aims to identify molecules that can potentially increase the cumulative incidence of MR4.5 by 25% compared to the control. The trial is expected to run until December 31, 2028, with recruitment having started on February 22, 2016.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, hematologic and hepatic function, and prior treatment history. Following successful screening, participants will be randomized to receive either the experimental treatment or control. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment protocol. The primary endpoint is the cumulative incidence of patients achieving a deep molecular response (MR4.5 or deeper) by 12 months. Secondary endpoints include adverse events, cumulative rates of achieving MR4.5 and MR4 at various time points, and survival metrics.

The expected length of participant involvement is up to 48 months, with conditions for early termination including significant adverse events, withdrawal of consent, or failure to adhere to the study protocol. Participants will have a final end-of-study visit to assess long-term outcomes and any residual effects of the treatment. The trial will utilize **pioglitazone** in tablet form and **avelumab** as a solution for infusion, with specific dosing regimens and administration routes outlined in the protocol. The study is not classified as low intervention and is conducted under rigorous scientific and ethical standards to ensure the validity and reliability of the results.

Treatment

The clinical trial involves the administration of **Actos 15 mg tablets**, which contain the active substance **pioglitazone**. Pioglitazone is a chemical compound classified under the ATC code A10BG03. The pharmaceutical form of this medication is a tablet, and it is administered orally. The maximum daily dose of Actos is 45 mg, with a total maximum dose of 16,425 mg over a treatment period of up to 12 months. The medication is manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH and is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to Actos, the trial also includes the administration of **Avelumab**, a solution for infusion containing the active substance avelumab, which is a protein-based compound. Avelumab is administered via intravenous infusion. The maximum daily dose is 10 mg/kg, with a total maximum dose of 8,000 mg over a treatment period of up to 4 months. Avelumab is designated as an orphan drug under the designation number EU/3/15/1590. The administration of Avelumab will be closely monitored to ensure adherence to the dosing schedule and to assess participant compliance.

Both Actos and Avelumab are used in this trial to evaluate their efficacy in combination or sequentially with tyrosine kinase inhibitors in patients with chronic phase chronic myelogenous leukaemia (CP-CML) who have achieved a complete cytogenetic response but not a deep molecular response. The trial aims to identify treatments that can increase the cumulative incidence of MR4.5 by 25% compared to the control group. No placebo or standard-of-care therapy is specified as a comparator treatment in this study.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **cumulative incidence** of patients achieving a deep molecular response, defined as MR4.5 or deeper (BCR-ABLIS ≤ 0.0032%), within 12 months. Secondary endpoints include the cumulative rate of patients achieving MR4.5 at 24, 36, and 48 months, as well as MR4 at 12, 24, 36, and 48 months, in both experimental and control arms. Additionally, the trial will evaluate the cumulative rate of patients with undetectable BCR-ABL1 transcript, with a sensitivity of 40,000 ABL copies, at the same time intervals. The rate of patients in treatment-free remission during follow-up will also be measured.

Further assessments will include the measurement of the number and clonogenicity of chronic myelogenous leukemia (CML) stem cells using leukemic stem cell markers, followed by flow cytometry analysis and the LTC-IC assay, as part of an ancillary study. Survival metrics such as overall survival, progression-free survival, event-free survival, and duration of response will also be analyzed. These efficacy parameters will be collected and analyzed at specified time points throughout the trial duration, which is estimated to conclude by December 31, 2028.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient aged 18y or more
Signed informed consent
Patient with chronic phase CML and M BCR-ABL1 transcript positivity
Treatment with imatinib, nilotinib, dasatinib, 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-ABLIS ≤ 1%
Detectable BCR-ABL1 with BCR-ABLIS > 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
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)
Hepatic: a. Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range. (Avelumab arm only)
Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) (avelumab arm only)
Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential. (avelumab arm only)
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)

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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 (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
Absence de phase chronique lors du diagnostic de la LMC
Individuals with an active malignancy
Known HIV-positivity
Known osteoporosis with curative therapy (prophylactic therapy is not an exclusion criteria) - (Pioglitazone arm only)
Patient requiring anti-diabetic medication (pioglitazone arm only)
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).
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.
ORGAN TRANSPLANTATION (Avelumab arm only): Prior organ transplantation including allogenic stem-cell transplantation.
INFECTIONS (Avelumab arm only): Active infection requiring systemic therapy.
HIV/AIDS (Avelumab arm only): Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
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)
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
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)
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
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)