Exploring new frontiers in systemic mastocytosis

Introducing PIONEER – a clinical trial of avapritinib for people with indolent or smoldering systemic mastocytosis

About systemic mastocytosis

PIONEER is a phase 2 clinical trial that will compare the safety and effectiveness of an investigational medicine called avapritinib against a placebo in people with indolent or smoldering systemic mastocytosis (SM) whose symptoms aren’t adequately controlled with standard therapies.

Indolent and smoldering systemic mastocytosis are rare conditions caused by the accumulation of mast cells in the body’s organs, including the bone marrow and skin. Mast cells are an important type of immune cell that normally play a role in the body to help fight infection and trigger the allergic response. In systemic mastocytosis, mast cells are inappropriately released, causing many symptoms that can negatively impact daily life. People with indolent and smoldering systemic mastocytosis often experience severe symptoms which can include rashes, GI problems, fatigue, “brain fog,” severe allergies, risk of anaphylaxis, bone pain, osteoporosis and more.

Systemic mastocytosis is classified into five main subtypes – indolent SM, smoldering SM, aggressive SM, SM with associated hematologic neoplasm, and mast cell leukemia. Across all these subtypes, up to 95% of people have a specific mutation (genetic alteration) in a gene called KIT. The mutation, known as KIT D816V, plays a central role in the activation and accumulation of mast cells in people with systemic mastocytosis. Avapritinib is an investigational medicine that was specifically designed to block the KIT D816V mutation.

Who is eligible to participate in the Pioneer clinical trial?

You may be eligible to take part in the PIONEER clinical trial if you:

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Are confirmed to have either indolent or smoldering systemic mastocytosis*
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Are at least 18 years old
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Have moderate-to-severe symptoms (assessed via a questionnaire)
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Haven’t been able to control these symptoms using existing therapies (including H1 and H2 blockers, leukotriene inhibitors, and corticosteroids, among others)

*Smoldering SM patients can enroll in part 2 of the PIONEER study

You are not eligible to take part in the PIONEER clinical trial if you:

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Have one of several types of systemic mastocytosis, including aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm, mast cell sarcoma, mast cell leukemia, mast cell activation syndrome (MCAS) or cutaneous mastocytosis without documented systemic involvement.

If you have aggressive SM, SM with associated hematologic neoplasm, or mast cell leukemia, you may qualify for a different clinical trial called PATHFINDER.

Other eligibility criteria apply and these will be assessed during screening tests.

About the investigational medicine

If you take part in the PIONEER clinical trial, you may receive the investigational medicine avapritinib. Avapritinib is designed to selectively target KIT D816V, the underlying driver of systemic mastocytosis, and is hoped to help manage symptoms. Avapritinib comes in a tablet form and should be swallowed whole with water once a day.

What does taking part in the PIONEER clinical trial involve?

The PIONEER clinical trial for indolent and smoldering systemic mastocytosis takes place in three parts.

Part 1

This phase is designed to determine the most effective dose of avapritinib. Three dose levels of avapritinib along with best supportive care* (BSC) will be tested compared to placebo (a “sugar pill” containing no active medication) and BSC. Part 1 is expected to last from 6 to 12 months. Only indolent SM patients are eligible for Part 1.

Part 2

This phase will compare the dose determined to be most effective from Part 1 and BSC against a placebo (a “sugar pill” containing no active medication) and BSC. Part 2 lasts about 12 weeks for all patients. Indolent and smoldering SM patients are both eligible for enrollment in Part 2.

Part 3

After completing Part 2, participants (including those on placebo and BSC) will begin Part 3, which looks into the long-term safety and effectiveness of avapritinib combined with best supportive care for up to 5 years. During this phase, all participants will receive the active study treatment.

*”Best supportive care” means other treatments to help manage symptoms and make patients more comfortable.

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Screening Period

The first step in the screening process is to ensure best supportive care treatments are stable. Patients will be asked to complete a questionnaire to describe their symptoms to verify if they meet the severity criteria. If determined eligible based on symptoms, additional testing will be done to confirm their overall suitability. The screening period varies and could take up to 14 weeks in some cases (from start of screening to your first dose of avapritinib).

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Dosing period

Total duration on study can be up to 5 years (through Part 3) and dosing will be daily in 28-day cycles.

You will take the study treatment as a tablet. It should be swallowed whole with water once a day.

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Follow up period

All participants must have a follow-up visit 14 days after their last dose of study treatment. Follow-up calls and site visits may be required periodically thereafter

You will continue with the study treatment until:
*Your disease worsens * You can’t tolerate any side effects you may have *You decide to leave the trial * The trial doctor decides you should leave the trial * The trial sponsor decides to discontinue the trial

PIONEER Trial Clinic Visits

During the trial, a variety of health assessments will be conducted to check on your systemic mastocytosis and see how you are responding to the study treatment. In most cases, these assessments will be done at a clinical site.

Health assessments will vary between visits, but may include:

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MRI or CT scan and X-ray

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Bone marrow biopsy

(temperature, blood pressure, heart rate and weight)

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(painless heart scan)

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Skin biopsy

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Quality of life Questionnaires

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Blood tests

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Pregnancy test

(If applicable)

How often will these visits take place?*

Part 1

About once a week for one month, then about once a month for six to twelve months

Part 2

About once a week for one month, then about once a month for two months

Part 3

About once a week for one month, then about once a month for five months, then every three months for a total of two years. After two years, participants will have visits once every six months for a total duration of five years.

More information about health assessments and visit length will be found in the informed consent form, which you will need to read and sign if you want to take part in the PIONEER clinical trial.

*Please note that these numbers are approximate. One treatment cycle is 28 days.

    How can I learn more about the PIONEER trial?

    If you think you meet the criteria specified above and are interested in taking part in the PIONEER trial, or you would simply like more information, please call: +1 617-714-6707 or email: SM@blueprintmedicines.com. A member of our team will talk you through the next steps and will connect you to a suitable trial doctor.

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