Multicenter, Open-Label, Single Arm, Phase II Exploratory Study to Evaluate the Reinduction and second stop of TKI with Ponatinib in CML in Molecular Response (ResToP)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Cris De Investigacion Para Vencer El Cancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2020 → 12 Jan 2026

Decision date (initial)

2023-12-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Incyte Biosciencies International Sarl

External identifiers

EU CT number

2023-508993-27-00

EudraCT number

2018-003281-14

ClinicalTrials.gov

NCT04160546

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

Evaluate the proportion of patients still in MMR

Secondary objectives 6

1. - Evaluate the toxicity and safety profile of 15 mg/24h dose treatment of ponatinib combined with ASA.
2. - Evaluate thromboembolic, hemorrhagic, hemolytic and gastrointestinal events for study period
3. - Evaluate the proportion of patients still in MR4
4. - Evaluate the proportion of patients still in MMR
5. - Progression-free survival (PFS).
6. - Treatment-free survival (TFS).

Conditions and MedDRA coding

Chronic myelogenous leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Male or female patients ≥ 18 years of age.
2. 2. ECOG Performance Status of 0, 1, or 2.
3. 3. Patient with diagnosis of BCR-ABL positive and Ph+ CML-Chronic Phase.
4. 4. 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.
5. 5. Patients who are able to take oral therapy
6. 6. 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.
7. 7. 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)
8. 8. 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.
9. 9. Patients with preexisting, well-controlled diabetes can be included.
10. 10. Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
11. 11. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential). diately.
12. 12. Be willing and able to comply with scheduled visits and study procedures.
13. 13. Patients with the ability to comprehend and sign the informed consent
14. 14. Written informed consent obtained prior to any screening procedures.

Exclusion criteria 25

1. 1. Prior accelerate phase, blast crisis or autologous or allogenic transplant
2. 2. 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.
3. 3. 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).
4. 4. Are taking medications with a known risk of torsades de pointes (Annex 5).
5. 5. Patient ever attempted to permanently discontinue TKI treatment.
6. 6. 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).
7. 7. 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.
8. 8. 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.
9. 9. Have a history of alcohol abuse.
10. 10. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
11. 11. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
12. 12. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
13. 13. 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.
14. 14. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement) within 14 days prior to first dose of ponatinib.
15. 15. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1.
16. 16. 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.
17. 17. 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.
18. 18. 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.
19. 19. Have an ongoing or active infection; this includes, but is not limited to, the requirement for intravenous antibiotics.
20. 20. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
21. 21. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients
22. 22. 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.
23. 23. Patients must not have a contraindication or a known hypersensitivity to ASA.
24. 24. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
25. 25. Patients with previous or current hepatitis B virus infection

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients with a maintained MMR within 52 weeks following ponatinib TFR.

Secondary endpoints 6

1. - Incidence of treatment-emergent adverse events (new or worsening from baseline).
2. - Incidence of thromboembolic and hemorrhagic events, hematologic events and gastrointestinal events.
3. - Proportion of patients still in MR4 within 52 weeks following ponatinib TFR.
4. - Proportion of patients who still have a MMR within 24 weeks following ponatinib TFR.
5. - Progression free survival (PFS)
6. - Treatment-free survival (TFS)

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Cris De Investigacion Para Vencer El Cancer

Sponsor organisation

Fundacion Cris De Investigacion Para Vencer El Cancer

Address

Calle De La Princesa De Eboli 9

City

Madrid

Postcode

28050

Country

Spain

Scientific contact point

Organisation

Fundacion Cris De Investigacion Para Vencer El Cancer

Contact name

APICES SOLUCIONES S.L, Clinical Operations Department

Public contact point

Organisation

Fundacion Cris De Investigacion Para Vencer El Cancer

Contact name

APICES SOLUCIONES S.L, Clinical Operations Department

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 2 files

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

Application history

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