A study of Iclusig (ponatinib), an oral kinase-inhibitor treatment administered, by standard dose or reduced doses, for patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) who no longer benefit from, or who have an abnormal gene (T315I positive) marker for resistance to other kinase-inhibitor treatments

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

1 Dec 2015 → 24 Apr 2025

Decision date (initial)

2024-10-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2024-514516-27-00

EudraCT number

2014-001617-12

ClinicalTrials.gov

NCT02467270

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Dose response, Therapy, Efficacy

To characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in patients with CP-CML who are resistant to prior TKI therapy or have T315I mutation, as measured by ≤ 1% BCR-ABL1IS at 12 months.

Secondary objectives 9

1. •To characterize the rate of major molecular response (MMR) at 12 and 24 months and rate of major cytogenetic response (MCyR) by 12 months
2. •To evaluate duration of MMR
3. •To characterize the rates of AOEs, VTEs, AEs, and serious AEs (SAEs)
4. •To evaluate safety differences among the 3 starting dose cohorts, particularly for AOEs and VTEs
5. •To collect sparse PK samples to contribute to population PK and exposure-response analyses of safety and efficacy
6. •To characterize the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating ≤ 1% BCR-ABL1IS and major molecular response (MMR) at and by 6, 12, 18, and 24 months
7. •To characterize the rate of discontinuation, dose reductions, and dose interruptions
8. •To characterize the rates of hematologic responses
9. •To evaluate time to response, duration of response, and survival outcomes

Conditions and MedDRA coding

Chronic Phase Chronic Myeloid Leukemia

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 01. Have CP-CML and have received at least two prior TKI therapies and have demonstrated resistance to treatment OR Have documented history of presence of T315I mutation after receiving any number of prior TKI. a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the following: i. < 15% blasts in bone marrow ii. < 30% blasts plus promyelocytes in bone marrow iii. < 20% basophils in peripheral blood iv. ≥ 100 × 109/L platelets (≥ 100,000/mm3) v. No evidence of extramedullary disease except hepatosplenomegaly vi. No prior diagnosis of AP- or BP-CML b. Cytogenetic assessment at screening must demonstrate the BCR-ABL1 fusion by presence of the t(9;22) Philadelphia chromosome i. Variant translocations are only allowed provided they meet inclusion criterion 1d c. Resistance to prior TKI therapy is defined as follows (patients must meet at least 1 criterion): i. Three months after the initiation of prior TKI therapy: No cytogenetic response (> 95% Ph+) or failure to achieve CHR or new mutation ii. Six months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >65% or new mutation iii. Twelve months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >35% or new mutation. iv. At any time after the initiation of prior TKI therapy, the development of a new BCR-ABL1 kinase domain mutation(s). v. At any time after the initiation of prior TKI therapy, the development of new clonal evolution vi. At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS transcript level of ≥1% or new mutation d. > 1% of BCR-ABL1IS as shown by real-time polymerase chain reaction
2. 02. Age ≥ 18 years old.
3. 03. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
4. 04. Have adequate renal function as defined by the following criterion: a. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution b. Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
5. 05. Have adequate hepatic function as defined by the following criteria: a. Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome b. Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present c. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present
6. 06. Have normal pancreatic status as defined by the following criterion: a. Serum lipase and amylase ≤ 1.5 × ULN
7. 07. Have normal QT interval corrected (Frederica) (QTcF) interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
8. 08. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
9. 09. Agree to use a highly effective form of contraception with sexual partners from randomization through at least 4 months after the end of treatment (for female and male patients who are fertile).
10. 10. Provide written informed consent.
11. 11. Be willing and able to comply with scheduled visits and study procedures.
12. 12. Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 grade ≤1.

Exclusion criteria 21

1. 01. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug
2. 02. Received interferon, cytarabine or immunotherapy within 14 days; or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], v4.0) from AEs (except alopecia) due to agents previously administered.
3. 03. Have undergone autologous or allogeneic stem cell transplant (SCT) < 60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
4. 04. Are being considered for hematopoietic SCT (HSCT) within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial)
5. 05. Are taking medications with a known risk of Torsades de Pointes.
6. 06. Have previously been treated with ponatinib.
7. 07. Have active central nervous system (CNS) disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
8. 08. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: a. Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (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 (CHF) (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment, or left ventricular ejection fraction (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
9. 09. Have uncontrolled hypertension (i.e., >150 and >90 for SBP and DBP, respectively). Patients with hypertension should be under treatment at study entry to ensure blood pressure control. Those requiring 3 or more antihypertensive medications should be discussed with the medical monitor.
10. 10. Have poorly controlled diabetes defined as HbA1c values of > 7.5%. Patients with preexisting, well-controlled, diabetes are not excluded.
11. 11. Have a significant bleeding disorder unrelated to CML.
12. 12. Have a history of alcohol abuse.
13. 13. Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic pancreatitis.
14. 14. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
15. 15. Have a history of another malignancy, other than cervical cancer in situ or 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.
16. 16. Are pregnant or lactating.
17. 17. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to the first dose of ponatinib.
18. 18. Have an active infection which requires intravenous antibiotics.
19. 19. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
20. 20. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug.
21. 21. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients listed in Section 14.7.1 of the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 01. ≤ 1% BCR-ABL1IS at 12 months for each starting dose cohort.

Secondary endpoints 14

1. 01. Molecular response rates: MMR at 12 and 24 months
2. 02. Cytogenetic response rates: MCyR by 12 months
3. 03. Duration of MMR
4. 04. Safety a.Rate of AOEs and VTEs in each dose cohort b.Rate of AEs in each dose cohort c.Rate of SAEs in each dose cohort
5. 05. Cytogenetic response rates: CCyR at 12 months
6. 06. Molecular response rates: MR4, and MR4.5 by and at 3-month intervals and MR1 (≤ 10% BCR-ABL1IS) at 3 months
7. 07. Hematologic response rate: Complete hematologic response (CHR) at 3 months
8. 08. Tolerability: a.Rate of discontinuation due to AEs in each dose cohort b.Dose reductions due to AE in each dose cohort c.Dose interruptions in each dose cohort
9. 09. Duration of response: a.Rate of ≤1% BCR-ABL1IS by 12 months and at and by 6, 18, and 24 months b.MMR at and by 6 and 18 months; and by 12 and 24 months
10. 10. Duration of response in responders
11. 11. Time to response
12. 12. Rate of progression to accelerated phase (AP-) or blast phase (BP-) CML
13. 13. PFS
14. 14. OS

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

95 Hayden Avenue

City

Lexington

Postcode

02421-7942

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Meliessa Hennessy

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 7

Locations

2 EU/EEA countries · 3 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 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