| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myeloid Leukaemia (CML) in Blast Phase |
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| E.1.1.1 | Medical condition in easily understood language |
| CML is a cancer of the white blood cells which build up, disrupting the normal balance of cells in the blood and bone marrow. In Blast phase, the cancer invades the bone marrow and other organs. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009013 |
| E.1.2 | Term | Chronic myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The aim of this trial is to find a safe and effective dose of a drug called Ponatinib when used in combination with chemotherapy in patients with Chronic Myeloid Leukaemia (CML) whose disease has moved in to blast phase. |
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| E.2.2 | Secondary objectives of the trial |
To find out how safe it is to treat patients in Blast Phase Chronic Myeloid Leukaemia with ponatinib and chemotherapy. To find out how effective this combination (ponatinib and chemotherapy) is by the end of the trial, to find out how good ponatinib is at maintaining a response to treatment once the combination (ponatinib and chemotherapy) treatment has ended (and after Stem Cell Transplant - if applicable to the patient), and how long that response can be maintained (i.e. until the patients leukaemia relapses or progresses).
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Blood Sample Collection for Biobank
Objective: To study biology of blast crisis CML (genetic, epigenetic, proteomic, metabolomic etc.) and assess drug sensitivity/insensitivity.
Chronic myeloid leukaemia provides several tractable clinical and laboratory characteristics that allow us to study response to therapy at a clonal level – particularly the ability to grow colonies which contain sufficient numbers of cells for simultaneous genotyping and phenotypic analyses. Blood samples collected in this study will also be used to undertake genome-wide characterisation of patient-specific features that determine response and resistance to therapy. It is proposed to use respectively high-throughput sequencing, transcriptional profiling (at clonal level), epigenetic approaches and signalling studies to characterise patient-specific factors that determine response to therapy. By focusing on samples from patients in a prospective clinical trial and integrating results, genome-wide insights into the patient-specific genetic and epigenetic factors that determine response to treatment can be achieved.
All projects requesting cells from the Biobank will require approval from the NCRI CML Working Party before samples can be released to the researcher.
2. Buccal Cell Sample collection for Biobank
Objective: To study biology of blast crisis CML (genetic, epigenetic, proteomic, metabolomic etc)
A sample of buccal cells will be requested at baseline. If this sample proves insufficient to analyse, a further sample of constitutional DNA (hair follicle) will be requested at a later date if the patient consents.
This sample should be shipped to the Biobank with the baseline blood.
All projects requesting cells from the Biobank will require approval from the NCRI CML Working Party before samples can be released to the researcher.
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| E.3 | Principal inclusion criteria |
All of the following:
• Ph-positive or BCR-ABL positive CML in blastic transformation. Defined as one or more of the following being present:
o Blasts ≥30% in peripheral blood or bone marrow
o Extramedullary blast proliferation or large foci or clusters of blasts in the bone marrow biopsy
• Age: ≥16
• Suitable for intensive chemotherapy (FLAG-IDA)
• Adequate renal function defined as serum creatinine ≤1.5 X upper limit of normal (ULN)
• Adequate liver function defined as:
o Total bilirubin < 1.5 X ULN, unless due to Gilbert’s syndrome
o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 X ULN (< 5 X ULN if liver involvement with leukaemia. Patients with disordered liver function >5 X ULN due to leukaemia may enter with a dose reduction of FLAG-IDA as per local guidelines and will be considered on a per patient basis following discussion with the Chief Investigator and Trial Office.)
• Normal pancreatic status defined as:
o Serum Amylase ≤ 1.5 X ULN
• Normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤470 ms in females.
• Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study until 4 months after the last dose of ponatinib.
• Ability to comply with study procedures, in the Investigator’s opinion.
• Valid Informed Consent
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| E.4 | Principal exclusion criteria |
• Any of the following will exclude:
• Received chemotherapy other than hydroxycarbamide, anagrelide, low dose arabinosylcytarabine (LDAC), steroids, or interferon within 4 weeks of registration
• Changed TKI therapy more than once since confirmation of blast phase CML or had prior treatment with ponatinib at any time.
• Previous treatment with intensive acute leukaemia-style chemotherapy (FLAG-IDA). (Unless treatment was during an initial blast phase which returned to chronic phase for a prolonged period of time and the patient is now in a second blast phase.)
• Prior allogeneic or autologous Stem Cell Transplant
• Significant or active cardiovascular disease, specifically including but not restricted to:
o Myocardial infarction, stroke or revascularization within 12 months prior to registration
o History of clinically significant atrial arrhythmia
o Any history of or ventricular arryhthmia
o Unstable angina or transient ischemic attack within 6 months prior to registration
o Congestive heart failure within 6 months prior to registration
o Left ventricular ejection fraction (LVEF) less than lower limit of normal within 6 months prior to registration
o Any history of unprovoked venous thromboembolism including deep venous thrombosis or pulmonary embolism
o Uncontrolled hypertension (sustained diastolic blood pressure >90 mm Hg; systolic >140 mm Hg).
• History of acute pancreatitis within 1 year prior to registration
• History of chronic pancreatitis.
• Uncontrolled hypertriglyceridaemia (>450 mg/dL)
• Are pregnant or lactating
• Are known galactose intolerant
• Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or Bone Marrow biopsy) within 14 days prior to registration
• Suffer from any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the safety of the study treatment
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Tolerability; Identification of the dose of ponatinib that can be safely delivered in combination with chemotherapy (FLAG-IDA) is defined in terms of dose limiting toxicities.
Dose Limiting Toxicity will be defined as:
• Before the start of the second cycle of combination therapy or up to 8 weeks from the start of the first cycle of combination therapy, whichever is sooner:
o Grade 3 or 4 clinically significant non-haematological toxicity that cannot be managed with optimal medical care and that in the opinion of the investigator is related to the ponatinib and is likely to endanger the life of the patient or result in long term effects
o Pancreatitis grade 2 or above
o Increased serum amylase grade 3 or 4*
o Prolongation of the QT interval grade 3 or 4
o Myocardial infarction
o Stroke
o Development or progression of a thromboembotic event requiring revascularisation
o Unprovoked venous thromboembolism
• Toxicities will be measured and graded according to Version 4 CTCAE criteria.
*In cases where the patient displays an increased serum amylase level but no clinical signs of pancreatitis, please test the pancreatic isoenzyme level to differentiate between pancreatic and salivary amylase levels. If the pancreatic amylase level is within the ULN but the salivary amylase level is not, this would not be classified as a DLT and treatment may continue. Similarly, some ethnic populations, particularly African individuals may display a high normal level of amylase due to salivary amylase as opposed to pancreatic amylase. It is recommended to test isoenzyme levels to confirm if this is the case.
Efficacy: Haematological response (HR) or cytogenetic response (CyR)
HR is defined as achieving all the following criteria:
Platelets >50x10^9/L (unsupported)
Neutrophils >1.0 x10^9/L (unsupported)
Blasts < 5% peripheral blood and bone marrow (where assessable)
CyR is defined as achieving at least a minor cytogenetic response (i.e. <65 % Ph+ cells)
An assessment for the primary outcome measure must be conducted prior to commencing the 2nd cycle of therapy. This can be at any time from 4-8 weeks after commencing combination therapy following haematological recovery to at least neutrophils ≥1.0x10^9/L and Platelets ≥ 50 x10^9/L. An assessment should be carried out at 8 weeks after commencing combination therapy if haematological recovery is not achieved.
Given the heterogeneity of blast crisis CML and the advanced stage of disease, there may be instances of DLTs or reports of efficacy (as defined above) that occur outside of the 8 week period. If such events occur outside of the 8 week period but prior to the TSC meeting being conducted, the events will be formally reported to the TSC to take into consideration during their review of each patient.
Cumulative reports of safety and efficacy from previously enrolled patients will also be reported to the TSC for consideration.
Patients who are unable to be formally evaluated for tolerability and efficacy due to withdrawal, treatment discontinuation or death, that is unrelated to treatment, before commencing the second cycle of therapy, may be replaced depending on the nature of the withdrawal/discontinuation. The trials office will notify centres of any patient replacement.
If a patient is evaluable for the tolerability outcome but not the efficacy outcome, the efficacy outcome may be inferred, as described in Section 12.1.1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
2 cycles (8-16 weeks) of ponatinib in combination with chemotherapy (FLAG-IDA) for the tolerability/efficacy
1 cycle (4-8 weeks)for the dose limiting toxicities
1 cycle (4-8 weeks)for the efficacy |
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| E.5.2 | Secondary end point(s) |
• Toxicity profile of ponatinib + chemotherapy (FLAG-IDA) within 6 months or up to transplant (whichever time point arrives first). Toxicities will be measured and graded according to the CTCAE criteria version 4.
• Complete Cytogenetic Response (CCyR) within 2 cycles of treatment
• Major Molecular Response (MMR) within 2 cycles of treatment
• Haematological response within 2 cycles of treatment
• 3 year disease free survival (DFS)
• 3 year overall survival (OS)
• 1 and 3 year relapse rate post allogeneic transplant or maintenance therapy
• 1 and 3 year treatment related mortality
• Incidence of Cytomegalovirus (CMV) reactivation rate and Graft Versus Host Disease (GVHD) post-transplant
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
6 months for toxicity profile of ponatinib and chemotherapy
8-16 weeks for complete cytogenetic response
8-16 weeks for haematological response
8-16 weeks for major molecular response
3 years for disease free survival and overall survival
1 year and 3 years for the relapse rates and mortality
Any GVHD that happens within the first 100 days after SCT is considered acute GVHD (aGVHD). GVHD occurring after 100 days post-SCT is termed chronic GVHD (cGVHD). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1 study to determine the optimal dose of ponatinib in combination with intensive chemotherapy. |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Efftox design version 4.0.12 for dose escalation and de-escalation decisions |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of trial will be the last patient's last visit. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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