CML study comparing 2 different doses of ponatinib versus nilotinib

• Research type

  Research Study

• Full title

  A Randomized, Open-Label Study of Ponatinib Versus Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib

• IRAS ID

  186859

• Contact name

  Heather Oakervee

• Contact email

  heather.oakervee@bartshealth.nhs.uk

• Sponsor organisation

  Ariad Pharmaceuticals Inc

• Eudract number

  2015-001318-92

• Duration of Study in the UK

  7 years, 0 months, 1 days

• Research summary

  Summary of Research

  Ponatinib is being studied as a possible cancer treatment for the treatment of patients with chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia who are no longer benefitting from their current treatment. The purpose of the trial is to evaluate the effectiveness and safety of 2 starting doses of ponatinib (30mg or 15mg) compared to 400mg of nilotinib, another drug that is currently used for treatment of CML. Participants will be randomly assigned to one of these three groups taking different doses of the study medication. Participants and the Study Doctor will know which dose and which medication they will receive. The length of time participants will take the study medication will depend on their cancer status (if there is benefit from treatment) and how well the drugs are tolerated, up to a maximum of 5 years.

  Summary of Results

  Summary of Clinical Study Results
  Thank you to the participants who took part in the study called “A Randomized, Open-label Study of Ponatinib Versus Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib”.

  This study helped researchers find out if a medicine called ponatinib could help treat participants with chronic myeloid leukemia whose standard treatment no longer works.

  Phases of Chronic Myeloid Leukemia (CML)
  Chronic phase: The cancer spreads slowly and patients have few or no symptoms. Most patients are diagnosed during this phase.
  Accelerated phase: Symptoms become more serious as abnormal cells build up.
  Blast phase: The cancer spreads beyond the bone marrow. Patient survival time is generally less than a year.

  Why was this study done?
  Cancer is a disease where cells in the body grow out of control. It can start in any part of the body. Leukemia is a cancer that affects cells in the bone marrow. Bone marrow is a soft, spongy tissue found in the center of most bones where new blood cells are made. Myeloid leukemia affects young myeloid cells, which go on to become either red blood cells, certain kinds of white blood cells, or cells that make platelets.

  Myeloid leukemia can be either acute or chronic. Acute leukemia develops and spreads quickly. Blood cells do not fully mature, and abnormal cells build up rapidly. Chronic leukemia develops more slowly and is less severe. Most blood cells can still function but not as well as healthy cells. CML can go undetected for a long time since symptoms do not appear immediately.

  Symptoms arise because there are not enough healthy blood cells.

  • Low red blood cell counts lead to tiredness and shortness of breath.
  • Low platelet counts lead to easy bruising and more frequent bleeding.
  • Low white blood cell counts lead to the immune system not being able to fight germs and infections well. Abnormal white blood cells, also called blasts, build up in the spleen and the lymph nodes. This causes swelling and pain.

  Patients are usually diagnosed during the first phase of CML, the chronic phase. One of the causes of CML is an abnormal genetic structure called the Philadelphia chromosome. It leads to the production of defective proteins that cause the uncontrolled growth of cancer cells. The main protein involved is tyrosine kinase. Patients with CML are treated with tyrosine kinase inhibitors (TKIs), which are medicines that block the defective protein.

  Imatinib is the first-line medicine used to treat CML. However, it may stop working over time or patients may become intolerant to it. If that happens, another TKI called nilotinib is one of the next choices for treatment. Some patients can develop another genetic defect called a T315I mutation. This defect prevents most TKIs from working.
  In this study, researchers wanted to see how well a TKI called ponatinib worked to treat participants with chronic phase CML who had become resistant to imatinib. They wanted to compare its effects to nilotinib treatment. Ponatinib is still effective even if a patient has the T315I mutation. Both medicines can be taken as tablets by mouth.

  Researchers also wanted to know about any side effects that might be caused by the study treatments.

  When was this study done?
  This study started in December 2015 and ended in January 2021.
  Who took part in this study?

  Who was allowed to take part in this study?
  Participants could take part in this study if they:
  • Were 18 years of age or older
  • Had CML that was in the chronic phase
  • Were resistant to treatment with imatinib

  Participants could not take part in this study if they:
  • Were previously treated with other anti-CML therapies other than imatinib
  • Received a stem cell transplant

  For more information on who could take part in this study, please refer to the websites listed on the last page of this summary.

  How many people took part in this study?
  A total of 44 participants took part in the study. One participant left before being treated. There were 23 (53%) men and 20 (47%) women. Participants were between 22 and 83 years old.

  The study took place in 90 clinics around the world. The list of countries where the study took place is shown below.

  Countries where the study took place
  Austria Hungary
  Canada Italy
  Czech Republic North Korea
  France Russia

  What happened during the study?

  What did researchers want to know?

  The study was conducted on participants living with chronic phase CML who had developed resistance to imatinib treatment. Researchers wanted to find out if ponatinib could help stop cancer growth. They wanted to see how well ponatinib worked as compared to another treatment, nilotinib.

  The main question researchers wanted to answer was:

  How many participants achieved a major molecular response within 12 months of treatment?

  Patients with CML have a gene called BCR-ABL1 that is located on the Philadelphia chromosome. Continued growth of cancer relies on this gene to be copied into new cells. Researchers took blood samples from participants and measured the number of BCR-ABL1 gene present. They also measured the amount of normal ABL1 gene. If participants had 1/1000th or less of the BCR-ABL1 gene in their blood compared to the ABL1 gene, that meant they achieved a major molecular response. In other words, it was a sign that the treatment was working.

  Researchers also wanted to learn about any side effects the participants experienced due to the study treatments.

  What treatments were studied?
  Researchers studied two treatments. They were:
  • Ponatinib: 30 milligrams (mg) or 15 mg, taken as a tablet by mouth, once a day
  • Nilotinib: 400 mg, taken as a tablet by mouth, twice a day

  How was the study done?
  There are many types of clinical studies. This study was:
  • Phase 3: In a Phase 3 study, a treatment is tested in a large number of participants. Researchers wanted to enroll up to 600 participants but enrollment was stopped early.
  • Randomized: Who got which study treatment was decided randomly, like tossing a coin.
  • Open-label: Both the researchers and participants knew which study treatment the participants received.

  Before treatment, all participants were screened to be sure they were a good fit for the study. The screening included a physical exam and laboratory tests, including blood tests. They also took samples of bone marrow to look for signs of cancer.

  After screening, participants were randomized to one of the following treatment groups:
  • Ponatinib 30 mg
  • Ponatinib 15 mg
  • Nilotinib 400 mg
  Participants received their treatment in 28-day cycles. They continued to be treated as long as their cancer did not get worse and they could still tolerate the treatment. If they did not achieve a major molecular response within 12 months, they stopped treatment.

  If the participants taking ponatinib achieved a major molecular response, they were switched to a lower dose. If they lost response after that, they either switched back to the higher dose or stopped treatment.

  Participants visited the study clinic at least once per cycle. During these visits, researchers took blood samples, checked for side effects, and asked participants how they felt. Participants also had an end-of-treatment visit 30 days after the last dose of study medicine. Researchers stayed in contact with participants to see how long they survived.

  The table below shows how many participants were in each group and the doses they received.

  Treatment Groups
  Group Participants taking at How often? Dose after
  least 1 dose achieving a
  major molecular
  response
  Ponatinib 30 mg 10 Once a day 15 mg
  Ponatinib 15 mg 21 Once a day 10 mg
  Nilotinib 400 mg 12 Twice a day No change

  Researchers planned to enroll more participants but after 18 months stopped enrollment. The decision was not due to any safety concerns. Some participants were treated for up to 4 years.

  What were the results?
  How many participants achieved a major molecular response within 12 months of treatment?

  Researchers wanted to know if ponatinib was effective in treating chronic phase CML. They took blood samples throughout the study and checked to see if the amount of the abnormal BCR-ABL1 gene had gone down.

  Researchers found that a similar number of participants achieved a major molecular response in each group. The table below shows the total number of participants who got better in each group.

  Major molecular response within 12 months

  Ponatinib 30 mg Ponatinib 15 mg Nilotinib 400 mg
  (10 participants) (21 participants) (12 participants)

  Number of
  participants 4 (40%) 7 (33%) 5 (46%)
  with a major
  molecular
  response

  Since there were fewer participants than originally planned, researchers could not make a conclusion about how effective the different treatments were.

  For more information on study results, please refer to the websites listed on the last page of this summary.

  Were there any drug-related side effects?
  Side effects are unwanted medical problems thought to be caused by a medicine or medical treatment. A side effect is called ‘serious’ when it is life-threatening, causes lasting problems, or needs hospital care. Not all of the participants in this study had side effects.

  The table below shows how many participants in each group had side effects.
  Drug-related side effects
  Ponatinib 30 mg Ponatinib 15 mg Nilotinib 400 mg
  (10 participants) (21 participants) (12 participants)
  Number of participants (%)
  Participants with 9 (90%) 14 (67%) 12 (100%)
  any side effects
  Participants with 2 (20%) 2 (10%) 1 (8%)
  serious side effects
  Participants who 1 (10%) 4 (19%) 3 (25%)
  left the study due
  to side effects
  Deaths 0 1 (5%) 0

  There was only 1 serious side effect that happened in more than 1 participant. In the ponatinib 30 mg group, 2 participants had a decreased platelet count.

  The table below shows how many participants in each group had the most common side effects. Only side effects experienced by at least 3 participants taking ponatinib are included.

  Most common drug-related side effects
  Ponatinib 30 mg Ponatinib 15 mg Nilotinib 400 mg
  (10 participants) (21 participants) (12 participants)
  Number of participants (%)
  Low platelet 4 (40%) 5 (24%) 2 (17%)
  count
  Low neutrophil 1 (10%) 3 (14%) 2 (17%)
  count (a type of
  white blood cell)
  Muscle aches 1 (10%) 4 (19%) 1 (8%)
  Platelet count 2 (20%) 2 (10%) 0
  decreased
  High blood 2 (20%) 2 (10%) 0
  pressure
  Abnormal liver 2 (20%) 1 (5%) 1 (8%)
  protein increased
  (alanine
  aminotransferase)
  Pain in extremity 1 (10%) 2 (10%) 1 (8%)

  How has this study helped patients and researchers?
  Researchers look at the results of many studies to decide which medicines work best and are safest for patients. This summary gives the results for 43 participants in a single study. Other studies may have more participants and may give different results.

  Findings from this study may be used in other studies to further test ponatinib or to look for newer treatments to treat CML.

  Are there plans for further studies?
  Clinical studies with ponatinib are ongoing and further studies are planned.

• REC name

  London - City & East Research Ethics Committee

• REC reference

  15/LO/1879

• Date of REC Opinion

  26 Jan 2016

• REC opinion

  Further Information Favourable Opinion