To demonstrate the efficacy of ponatinib administered at 2 starting doses (30 and 15 mg QD) compared to nilotinib administered at 400 mg BID in patients with CP-CML who are resistant to imatinib, as measured by MMR by 12 months
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Major molecular response (MMR) by 12 months for each cohort
Secondary outcome
Cytogenetic response rates:
- Major cytogenetic response (MCyR) by 12 months
- Complete cytogenetic response (CCyR) by 12 months
- Molecular response rates: MR2, MR3/MMR, MR4, MR4.5 at 3-month intervals and
MR1 (*10% BCR-ABLIS ) at 3 months
Safety
- Vascular occlusive events in each cohort
- AEs in each cohort
- SAEs in each cohort
- Time to response
- Duration of response:
- MR2 and MMR at 3, 6, 9, and 12 months, and then at 3-month intervals until
completion of treatment
- MCyR at 12 months, by cytogenetic analysis
- Duration of response in responders
- Duration of therapy
- Progression-free survival
- Overall survival
Other Secondary Endpoints
- Hematologic response: complete hematologic response (CHR)
- Tolerability:
- Discontinuations due to AEs in each cohort
- Dose reductions due to toxicity (prior to response) in each cohort
Background summary
Most patients with newly diagnosed CML are initially treated with an imatinib
regimen with good results. However, 30% to 50% of all newly diagnosed CP-CML
patients who are treated in the first-line setting with imatinib are in need of
another treatment, either because they become resistant to imatinib (20%-25%)
or because they become intolerant of imatinib (15%-20%). A review of efficacy
in the second-line setting demonstrates that there is potential for
improvement. Among the available second-line therapies (nilotinib, dasatinib,
or [in the US] bosutinib), major cytogenetic response (MCyR) rates in
second-line CP-CML range from 51% with nilotinib therapy (n=321) to 62% in
dasatinib treated patients (n=387) indicating that second-line therapy
initially fails to achieve a response in a substantial fraction of patients.
Additionally, none of the available second-line agents have activity against
all of the known mutants and the T315I mutation is refractory to all TKIs with
the exception of ponatinib. Thus, both with regard to response rates and
activity against resistant mutants, an unmet need remains in many patients who
fail first-line TKI therapy. Ponatinib is a novel, synthetic, orally active TKI
specifically designed to optimally inhibit native BCR-ABL. It is also active
against mutated forms of the protein that can arise during treatment with other
TKIs and cause resistance, including the T315I gatekeeper mutant.
Pharmacokinetic analysis of samples from the ongoing phase 1 clinical study
(AP24534-07-101) showed that the threshold for pan-BCR-ABL activity is
surpassed with =15 mg once daily dosing (Cmax) and with =30 mg once daily
(steady-state trough).
Clinical study data, particularly from the phase 1 dose escalation study and
the pivotal phase 2 PACE study, support the preclinical findings and have
established the favorable benefit-risk profile of ponatinib. In the phase 1
study, the activity of ponatinib was observed in heavily pretreated patients
with Ph+ leukemias with resistance to TKIs . Data from the pivotal phase 2
study demonstrated the efficacy of ponatinib 45 mg daily in patients with CML
and Ph+ ALL whose disease is resistant or who exhibit intolerance to prior
therapy. These data have formed the basis of regulatory approvals in the US,
EU, Australia, Israel, and Canada.
The impact of ponatinib dose on achievement of MCyR in patients with CP-CML has
been evaluated using a multivariate analysis of data from the phase 2 study
adjusting for covariates and an analysis of response by dose tertile. Both
analyses show that increasing dose intensity is associated with higher response
rates in this predominantly fourth-line population of CP-CML patients.
Nevertheless, response rates are still high in the lowest tertile, with the
understanding that this is not a second-line patient population. Increasing
dose intensity also correlated with an increased probability of experiencing
AEs. Taken together, these data underpin the rationale for investigating lower
doses of ponatinib in conjunction with dose reduction following response. This
study will employ starting doses of 30 mg and 15 mg to achieve response and
then reduce dosing to lower the risk of AEs while maintaining response.
Nilotinib is the second drug that was approved for the treatment of CML and
Ph+ALL
that is resistant to imatinib therapy. It is approved in the US for chronic
phase CML in adult patients who are resistant to or intolerant of prior therapy
that included imatinib, and in the European Union for chronic phase CML with
resistance or intolerance to prior therapy including imatinib. The approved
dose in both the US and the EU is
400 mg twice daily for this indication. Both the National Comprehensive Cancer
Network (NCCN) and the European Leukemia Net (ELN) recommend consideration of
the use of nilotinib in patients initially treated with imatinib whose disease
develops resistance to therapy. Like ponatinib, nilotinib-treated patients have
experienced
peripheral vascular events. In both the ponatinib and nilotinib development
programs, most of these patients had additional risk factors for cardiovascular
disease. The use of nilotinib as a comparator thus offers the opportunity to
compare these agents directly in a single patient population.
This protocol describes a phase 3, open-label, randomized study of ponatinib
for the treatment of patients with refractory chronic myeloid leukemia (CML) in
chronic phase (CP) whose imatinib therapy has failed. The goal of this study is
to test the hypothesis that ponatinib will be efficacious and safe in treating
second-line CP-CML
patients, that it will be superior to nilotinib, that each of the starting
doses will demonstrate the continued efficacy of ponatinib, and that the dose
reduction strategy will lessen arterial occlusive complications.
Study objective
To demonstrate the efficacy of ponatinib administered at 2 starting doses (30
and 15 mg QD) compared to nilotinib administered at 400 mg BID in patients with
CP-CML who are resistant to imatinib, as measured by MMR by 12 months
Study design
This is a multi-center, randomized study to demonstrate the efficacy and safety
of 2 starting doses of ponatinib as compared to nilotinib. Eligible patients
must have CP-CML, be resistant to first-line imatinib treatment and have
received no other TKIs.
Intervention
Patients will be randomized to receive once daily oral administration of either
30 mg ponatinib QD (once daily) (Cohort A), 15 mg ponatinib QD (Cohort B), or
400 mg nilotinib BID (twice daily) (Cohort C). They will be randomized in a
ratio of 1:2:1, respectively. Upon achievement of major molecular response
(MMR) as defined in the protocol, patients in Cohort A will have their daily
dose of ponatinib reduced to 15 mg and patients in cohort B will have their
daily dose of ponatinib reduced to 10 mg. The dose of nilotinib for patients in
Cohort C will not be adjusted based on response. The primary endpoint of MMR
by12 months is defined according to standard criteria as *0.1% BCR-ABL/ABL.
Study burden and risks
Patients are asked to undergo procedures described in the flowchart on pages 45
- 46 of the study protocol. These procedures include physical examination, ECOG
performance score, eye examination, vital signs, urine pregnancy tests (female;
chidbearing patients), ECG, ECHO, bone marrow aspiration, blood draw,
completing questionnaire, diaries and administration of study drug (oral).
Additionally, fertile patients who are sexually active must agree to use an
effective form of contraception with their sexual partners throughout
participation in the study. Patients are also asked to inform their study
doctor on their medication use and change in health status.
The following are the most serious/frequent risks of ponatinib; blood vessel
blockage, heart failure, liver problems, high blood pressure, inflammation of
the pancreas, bleeding, low blood cell counts, Low blood counts including white
blood cells (which may increase the risk of infection), platelets (which may
increase the risk of bleeding), or red blood cells (which can cause you to feel
tired or short of breath); Increased lipase; Nausea, Fever, Increased enzymes
from the liver in the blood, Skin rash, Pain in the belly, Fatigue, Headache,
Dry skin, Constipation, High blood pressure, Vomiting, Diarrhea, Decreased
appetite, Weakness, Shortness of breath, Dizziness, Cough, Abnormal buildup of
fluid (which may cause swelling in the hands, feet, ankles, face or all over
the body), An upper respiratory infection like the common cold, Pain that may
occur in the joints, muscles, bone, back or limbs, Trouble getting adequate
amount or quality of sleep, Muscle cramps and pain. Patients may have pain,
swelling, or bruising or possible infection during blood draws and/or bone
marrow aspiration. Additionally, the adhesive used for the electrodes from ECG
the may irritate patient's skin
Landsdowne Street 26
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Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Have CP-CML and are resistant to first-line imatinib treatment.
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 must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome.
i Conventional chromosome banding must be performed
ii A minimum of 20 metaphases must be assessable at entry
iii Variant translocations are not allowed
c. BCR-ABL transcript levels must be assessable using the International Scale.
i b2a2 or b3a2 transcript type
d. Resistance is defined as follows. Patients must meet at least 1 criterion.
i Three months after the initiation of therapy: No cytogenetic response (>95% Ph+) or failure to achieve CHR.
ii Six months after the initiation of therapy: BCR-ABLIS >10% and/or >35% Ph+.
iii Twelve months after the initiation of therapy: BCR-ABLIS >1% and/or Ph+ >0.
iv At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of MCyR.
v At any time after the initiation of therapy, the development of new clonal evolution in the absence of MCyR.
vi At any time after the initiation of therapy, the loss of CHR, the loss of CCyR, or the confirmed loss of MMR (in 2 consecutive tests, one of which has a BCR-ABLIS transcript level of <=1%.
2. Be male or female <=18 years old.
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Have adequate renal function as defined by the following criterion:
a. Serum creatinine <=1.5 × upper limit of normal (ULN) for institution.
5. Have adequate hepatic function as defined by all of 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. Have normal pancreatic status as defined by the following criterion:
a. Serum lipase and amylase <=1.5 × ULN.
7. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
8. Agree to use a highly effective form of contraception with sexual partners from the time of randomization through at least four (4) months after end of study treatment (for female and male patients who are fertile).
9. Provide written informed consent.
10. Be willing and able to comply with scheduled visits and study procedures.
11. Have fully recovered (<= grade 1 or returned to baseline or deemed irreversible) from the acute effects of prior cancer therapy (ie, hydroxyurea or imatinib) before initiation of study drug.
Exclusion criteria
1. Have previously been treated with any approved or investigational TKIs other than imatinib or treated with imatinib within 14 days prior to receiving study drug.
2. Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy.
3. Underwent autologous or allogeneic stem cell transplant.
4. Are in CCyR or MMR.
5. 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 history of a revascularization procedure, including vascular surgery or the placement of a stent
d. History of venous thromboembolism, including deep venous thrombosis, superficial venous thrombosis, or pulmonary embolism, within 6 months prior to enrollment
e. Congestive heart failure (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than 45% or less than the institutional lower limit of normal (whichever is higher) within 6 months prior to enrollment
6. Have cardiac conduction abnormalities as follows:
a. QTcF >450 msec on the average of 3 serial baseline ECGs (using the QTcF formula); congenital long QT syndrome, or a known family history of long QT syndrome; or inability to determine the QTcF
b. Presence of a complete left bundle branch block
c. Use of a ventricular pacemaker
d. History of clinically significant (as determined by the treating physician) atrial arrhythmia
e. Resting bradycardia <50 beats per minute
f. Any history of ventricular arrhythmia
7. Are taking medications with a known risk of Torsades de Pointes or that have the potential to prolong the QT interval (Appendix A), unless the medication can be discontinued or be substituted by another without the risk.
8. Are taking medicines that are strong CYP3A4 inhibitors, unless the medication can be discontinued or be substituted by another that is not an inhibitor (Appendix B)
9. Are taking medicines that are strong CYP3A4 inducers, unless the medication can be discontinued or be substituted by another that is not an inducer (Appendix B)
10. Have uncontrolled hypertension (diastolic blood pressure >90 mmHg and/or systolic >150 mmHg). Patients with hypertension should be under treatment at study entry to effect blood pressure control.
11. Have poorly controlled diabetes, defined as HbA1c values over the previous year of >7.5% (59 mmol/mL) on more than 3 occasions. Patients with preexisting, well-controlled, diabetes are not excluded.
12. Have uncorrected hypokalemia or hypomagnesemia.
13. 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. A history of CNS involvement itself is not an exclusion if the CNS has been cleared of disease with a documented negative lumbar puncture.
14. Have a significant bleeding disorder unrelated to CML.
15. Have a history of thrombophilia (eg, Protein C deficiency)
16. Have a history of alcohol abuse.
17. Have a history of acute pancreatitis within 1 year of study entry or history of chronic pancreatitis.
18. Have history of malabsorption syndrome or other gastrointestinal condition that could affect oral absorption of study drug.
19. Have a history of a different malignancy, other than cervical cancer in situ or basal cell or squamous cell carcinoma of the skin, except if patient has been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
20. Are pregnant or lactating.
21. Have undergone major surgery within 14 days prior to first dose of study treatment. Minor surgical procedures, such as catheter placement or bone marrow biopsy are allowed.
22. Have an ongoing or active infection. This includes but is not limited to the requirement for intravenous antibiotics.
23. Have any surgical or medical condition / illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the study drug
24. Have hypersensitivity to the active substance in ponatinib and nilotinib or to any of the inactive ingredients listed in Section 14.9.1.1 for ponatinib and in Section 14.9.1.2 for nilotinib
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-001318-92-NL |
| ClinicalTrials.gov | NCT02627677 |
| CCMO | NL55013.078.15 |