A phase 3, randomized, placebo-controlled, double-blind study of vimseltinib to assess the efficacy and safety in patients with tenosynovial giant cell tumor (MOTION)

TGCT is a rare tumor arising from the synovium of joints, bursae, and tendon
sheaths. Translocation of the CSF1 gene has been identified in TGCT patients,
resulting in overproduction of CSF1 and recruitment of CSF1R-positive
inflammatory cells in the affected joint.

Vimseltinib (DCC-3014) is an oral, small molecule, selective inhibitor of
colony-stimulating factor 1 receptor (CSF1R) developed by the Sponsor using its
proprietary switch control kinase inhibitor technology platform. CSF1R is a
tyrosine kinase receptor expressed predominantly on monocytes and macrophages.
Vimseltinib binds to the pocket controlling the conformation of the CSF1R
kinase domain and locks the kinase domain in the inactive form. In vitro
studies have demonstrated vimseltinib to be a potent and selective inhibitor of
CSF1R kinase. Vimseltinib is currently being evaluated for the treatment of
advanced solid tumors and tenosynovial giant cell tumor (TGCT) in an ongoing
Phase 1/2 clinical development study (Study DCC-3014-01-001; NCT03069469;
NL70948.058.19).

This study has been transitioned to CTIS with ID 2024-513624-42-00 check the CTIS register for the current data.

Primary Objective:
• To evaluate anti-tumor activity of vimseltinib using Response Evaluation
Criteria in Solid Tumors (RECIST) v1.1 by blinded independent radiological
review (IRR)
Secondary Objectives:
• To assess anti-tumor activity of vimseltinib using tumor volume score (TVS)
and modified RECIST (mRECIST) by blinded IRR
• To assess the effects of vimseltinib on range of motion (ROM)
• To assess the effects of vimseltinib on physical function, worst stiffness,
worst pain, and quality of life (QoL) using patient-reported outcome (PRO)
measures
• To assess safety and tolerability of vimseltinib

This is a multicenter, randomized, placebo-controlled study of vimseltinib in
patients with tenosynovial giant cell tumor (TGCT), consisting of 2 parts: Part
1 is double blinded and Part 2 is open label. Symptomatic patients with
histologically confirmed TGCT for whom surgical resection will potentially
cause worsening functional limitation or severe morbidity will be eligible.
Patients who received anti-colony-stimulating factor 1/colony-stimulating
factor 1 receptor (CSF1/CSF1R) therapy previously (except for imatinib or
nilotinib) will be excluded. The study will evaluate efficacy, safety, clinical
outcome assessments, pharmacokinetics (PK), and pharmacodynamics of vimseltinib
in this population.

The study will consist of a 42-day screening period prior to the first dose of
study drug, a Part 1 double-blinded treatment period of 24 weeks (referred to
in 28-day cycles) and a Part 2 open-label period until Week 49. Participants
will continue treatment after Week 49 during the extension period. There will
also be an End-of-Treatment (EOT) Visit within 7 days after the decision to
stop study drug, a Safety Follow-up visit 30 days (±5 days) after the last dose
of study drug, and a Disease Follow-up period of up to 2 years or until
initiation of new TGCT treatment or surgery, whichever occurs first.
Participants will be allowed to undergo surgical resection only after
completion of Part 1.

Approximately 120 participants will be randomized in a 2:1 ratio to receive
either vimseltinib at the dose of 30 mg twice weekly (biw) (n=80) or placebo
(n=40) for 24 weeks. Randomization will be stratified for tumor location (lower
limb/all other) and region (U.S./non-U.S.).

At Week 25, the primary and secondary endpoints will be assessed, and
participants randomized to placebo in Part 1 will have the option to crossover
and receive open-label vimseltinib in Part 2 upon completion of Part 1.
Participants randomized to placebo in Part 1 with confirmed disease progression
by blinded IRR before Week 25 are eligible for early entry into Part 2.
Participants randomized to vimseltinib in Part 1 with confirmed disease
progression by IRR before Week 25 will discontinue from study, while those
without confirmed disease progression by IRR before Week 25 will continue to
receive vimseltinib in Part 2 upon completion of Part 1.

Anti-tumor activity will be assessed by RECIST v1.1. Tumor volume score and
mRECIST will be used as additional assessments of anti-tumor activity. Range of
motion assessments will be performed and PRO measures will be collected. Safety
will be assessed using Common Terminology Criteria for Adverse Events (CTCAE)
v5.0. Correlation between efficacy or safety with PK and pharmacodynamics will
be explored.

Study Drug, Dosage, and Route of Administration: Vimseltinib 30 mg or matching
placebo twice weekly will be administered as oral capsules on an empty stomach,
at least 1 hour before and no sooner than 2 hours after ingestion of food.

Side effects associated with the vimseltinib
Very common
• Periorbital oedema (Swelling around the eyes due to accumulation of fluid)
(28%)
• Increased levels of an enzyme produced by the liver in blood, which in rare
cases, may indicate liver injury (23%)
• Fatigue (23%)
• Increased levels of an enzyme produced by the heart or muscle in blood, which
may indicate muscle injury/inflammation, rarely heart injury (22%)
• An increase in enzymes produced by the pancreas in the blood which may
indicate pancreatic injury or inflammation (17%)
• Diarrhea (12%)
• Nausea (12%)
• Face edema (Swelling of the face due to accumulation of fluid) (12%)
• Itching (12%)
Side effects reported in more than 3 patients (5%) but less than 6 patients
(10%):
• Peripheral Edema (swelling of the arms and/or legs due to accumulation of
fluid) (8%)
• Rash (8%)
• Muscle pain or muscle aches (7%)
• Abdominal pain (5%)
• Headache (5%)
• Vomiting (5%)

Of all the patients who have received vimseltinib, approximately 5% stopped the
study treatment because
of side effects related to the study drug.

Possible Drug Interactions
Vimseltinib may interfere with other drugs that you are taking. Likewise,
other drugs may interfere with vimseltinib. Allergic reactions may occur.

Blood draws
Blood draws may cause injection site swelling and/or pain, dizziness,
lightheadedness, bleeding, and/or bruising. You may faint and/or develop an
infection with redness and irritation of the vein at the site where blood is
drawn. Frequent blood collection may cause anemia (low red blood cell count).
Fasting may cause your blood sugar to drop. You may feel tired, hungry, and/or
nauseous. If you have diabetes, it is important to talk to your doctor about
managing your blood sugar while fasting.

MRI Risks
MRI scans use radio frequency waves (like those in an AM/FM radio) and a
powerful magnet to take pictures of inside the body. An MRI scanner is a large
tube, open at both ends. During the scan, the subject will lie inside the
tube. The dye used for MRIs may cause headache, nausea, stomach pain, and
convulsions. There is the possibility of a severe allergic reaction that may be
life threatening in which may lead to difficulty breathing and a decreased
blood pressure.

ECG Risks
The tape used to adhere the electrodes to the skin may cause some redness
and/or swelling.

Pregnancy risks
Vimseltinib can cause harm to an unborn baby when administered to pregnant
women. The effects of vimseltinib on the reproductive system (sperm, eggs),
conception, and lactation are not known.

Phototoxicity risks
Strong sunlight, sunlamps, and other sources of ultraviolet radiation (a type
of light) for the duration of the study to prevention of phototoxicity.

Tumor biopsy
The risks associated with a tumor biopsy may include bleeding, pain, and
infection. Once anesthesia wears off, you may feel pain that can last for
several days. Risks associated with local anesthesia include pain during
administration, prolonged numbness, infection, or a reaction to the anesthesia.

Unknown Risks
There may be risks to subjects that are currently not known or cannot be
predicted. Their condition may worsen, remain the same, or improve as a result
of participating in this research study. Subjects should tell the study doctor
or staff about all problems, illnesses, or injuries that happen to them during
the study, even if they think they are not related to their taking part in this
study. Subjects might have side effects or discomforts that are not listed in
this form. Some side effects may not be known yet. New ones could happen to
them. They should tell the study doctor or study staff right away if they have
any problems.


Benefit:
Treatment with the study drug may lead to a partial or complete shrinkage of
the tumor. Anti-tumor activity data as of 07 Jun 2021 demonstrated an objective
response rate (ORR) of 50% in 32 patients across 3 dose escalation cohorts, and
an ORR of 42% (all Partial response) in 19 patients in expansion Cohort A at
the recommended Phase 2 dose, which is also the selected Phase 3 dose.
Objective responses were generally achieved after at least 2 cycles of
treatment and responses were durable.