Phase II Study on Reinduction and Cessation of Ponatinib in Chronic Myelogenous Leukemia Patients in Molecular Response

Trial ID: 2023-508993-27-00
Protocol: FCR173011/ResToP
Sponsor: Fundacion Cris De Investigacion Para Vencer El Cancer

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Diseases & Conditions

Chronic myeloid leukaemia

Objectives

The primary objective of this study is to **evaluate the proportion of patients still in MMR** (major molecular response) following treatment with ponatinib in patients with **chronic myelogenous leukemia** (CML). This is clinically relevant as maintaining MMR is a critical indicator of successful long-term disease management and can potentially lead to improved patient outcomes.

Secondary objectives include:

Evaluate the toxicity and safety profile of a 15 mg/24h dose treatment of ponatinib combined with ASA.
Evaluate thromboembolic, hemorrhagic, hemolytic, and gastrointestinal events during the study period.
Evaluate the proportion of patients still in MR4 (molecular response 4).
Assess progression-free survival (PFS).
Assess treatment-free survival (TFS).

Participants

The clinical trial involves participants diagnosed with **chronic myelogenous leukemia** (CML) in the chronic phase, specifically those who are BCR-ABL positive and Ph+ and have previously failed the first attempt of tyrosine kinase inhibitor (TKI) discontinuation. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2, indicating they are ambulatory and capable of self-care. Participants are required to have adequate end organ function and normal marrow function, as well as normal electrolyte levels or levels corrected to within normal limits. Individuals with preexisting, well-controlled diabetes are eligible for inclusion. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must be able to take oral therapy and have a normal QTcF interval on screening ECG evaluation. The selection process for the trial population is not specified, and no specific lifestyle considerations such as diet or physical activity are mentioned.

Plans and Procedures

The clinical trial is designed as a **multicenter, open-label, single-arm, Phase II exploratory study** to evaluate the reinduction and second stop of tyrosine kinase inhibitor (TKI) therapy with **ponatinib** in patients with **chronic myelogenous leukemia** (CML) who are in molecular response. The primary objective is to assess the proportion of patients maintaining a major molecular response (MMR) within 52 weeks following ponatinib treatment-free remission (TFR). Secondary endpoints include the incidence of treatment-emergent adverse events, thromboembolic and hemorrhagic events, and the proportion of patients maintaining MMR and MR4 within specified timeframes, as well as progression-free survival and treatment-free survival.

The trial is expected to run until December 31, 2025, with an estimated recruitment start date of January 17, 2020. Participants will be involved in the study for a maximum treatment period of 104 weeks. The study involves several key visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. Participants must have a diagnosis of BCR-ABL positive and Ph+ CML in the chronic phase and have previously failed a TKI discontinuation attempt but achieved and maintained MR4 for more than one year after TKI reintroduction.

Following the screening, participants will undergo regular follow-up visits to monitor their response to the treatment and any adverse events. The end-of-study visit will evaluate the long-term outcomes and the maintenance of molecular response. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The study drug, Iclusig 15 mg film-coated tablets, is administered orally, with a maximum daily dose of 15 mg. The trial is not classified as a low-intervention study and does not involve a pediatric formulation.

Treatment

The clinical trial involves the administration of **Iclusig** 15 mg film-coated tablets, which contain the active substance **ponatinib**. Ponatinib is a chemical compound, also known by its synonyms AP-24534 and Benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-. The pharmaceutical form of the medication is a film-coated tablet, designed for **oral use**. The maximum daily dose is 15 mg, with a total treatment period extending up to 104 weeks. The medication is manufactured by Incyte Biosciences Distribution B.V. and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is a multicenter, open-label, single-arm, Phase II exploratory study aimed at evaluating the reinduction and second stop of tyrosine kinase inhibitor (TKI) therapy with ponatinib in patients with chronic myeloid leukemia (CML) who are in molecular response. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the proportion of patients who maintain a **Major Molecular Response (MMR)** within 52 weeks following treatment-free remission (TFR) with ponatinib. This primary endpoint will provide insight into the effectiveness of the treatment in sustaining molecular response in patients with Chronic Myeloid Leukemia (CML) in the chronic phase. Secondary endpoints include the incidence of treatment-emergent adverse events, thromboembolic and hemorrhagic events, hematologic and gastrointestinal events, the proportion of patients maintaining MMR within 24 weeks following ponatinib TFR, and the proportion of patients still in MR4 within 52 weeks. Additionally, progression-free survival (PFS) and treatment-free survival (TFS) will be evaluated. These parameters will be measured and collected at specified intervals throughout the study duration to ensure comprehensive analysis of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients ≥ 18 years of age.
ECOG Performance Status of 0, 1, or 2.
Patient with diagnosis of BCR-ABL positive and Ph+ CML-Chronic Phase.
Patients who failed the first attempt of TKI discontinuation and after TKI reintroduction they achieve again MR4 and it is maintained and confirmed for more than one year.
Patients who are able to take oral therapy
Adequate end organ function as defined by: a. Direct bilirubin ≤ 1.5 x ULN b. SGOT(AST) and SGPT(ALT) ≤ 2.5 x ULN, c. Serum lipase and amylase ≤ 1.5 x ULN, d. Alkaline phosphatase ≤ 2.5 x ULN, e. Serum creatinine ≤ 1.5 x ULN.
Patients must have the following electrolyte values ≥ LLN limits or corrected to within normal limits with supplements prior to the first dose of study medication: a. Potassium, b. Magnesium, c. Total calcium (corrected for serum albumin)
Patients must have normal marrow function as defined below: a. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, b. Platelets ≥ 100 x 109/L. c. Hemoglobin > 9 g/dL.
Patients with preexisting, well-controlled diabetes can be included.
Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential). diately.
Be willing and able to comply with scheduled visits and study procedures.
Patients with the ability to comprehend and sign the informed consent
Written informed consent obtained prior to any screening procedures.

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Exclusion Criteria

Prior accelerate phase, blast crisis or autologous or allogenic transplant
Patients with known atypical transcript. An atypical transcript is defined by the presence of any transcript in the absence of the major transcripts b3a2 (e14a2) and b2a2 (e13a2) or p210 protein.
CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past).
Are taking medications with a known risk of torsades de pointes (Annex 5).
Patient ever attempted to permanently discontinue TKI treatment.
Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g., uncontrolled diabetes (defined as HbA1c > 9%), uncontrolled infection).
Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: a. Any history of MI, unstable angina, cerebrovascular accident, or TIA. b. Any history of peripheral vascular infarction, including visceral infarction. c. Any revascularization procedure, including the placement of a stent. d. Congestive heart failure (NYHA class III or IV) within 6 months prior to enrollment, or LVEF less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment. e. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia. f. Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment.
Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
Have a history of alcohol abuse.
History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
Have a history of another malignancy, other than cervical cancer in situ or no metastatic basal cell or squamous cell carcinoma of the skin; the exception is if patients have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement) within 14 days prior to first dose of ponatinib.
Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1.
Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. See Annex 6 for a list of these medications. This list may not be comprehensive.
Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echinacea (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, Hyperico, and Ginkgo.
Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to study entry.
Have an ongoing or active infection; this includes, but is not limited to, the requirement for intravenous antibiotics.
Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
Patients must not have a contraindication or a known hypersensitivity to ASA.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Patients with previous or current hepatitis B virus infection