A Randomized, Open-Label, Phase 3 Study of Pralsetinib versus Standard of Care for First Line Treatment of RET fusion-positive, Metastatic Non-Small Cell Lung Cancer

Pralsetinib (also known as BLU-667) is a potent and selective inhibitor of
oncogenic rearranged during transfection (RET) alterations. RET receptor
tyrosine kinase is expressed in several neural, neuroendocrine and
genitourinary tissues types that normally requires ligand and co-receptor
binding for activation. Oncogenic RET rearrangements have been identified in
1-2% of non-small cell lung cancer (NSCLC) (Lin et al, 2015). These
rearrangements typically produce chimeric transcripts that encode a fusion
protein consisting of the RET kinase domain coupled to a protein with a
dimerization domain (eg, KIF5B, CCDC6, NCOA4), resulting in a constitutively
active kinase that promotes tumorigenesis.

This study has been transitioned to CTIS with ID 2023-505035-12-00 check the CTIS register for the current data

This is an international, randomized, open-label, Phase 3 study designed to
evaluate whether the potent and selective RET inhibitor, pralsetinib, improves
outcome when compared to a platinum chemotherapy-based regimen chosen by the
Investigator from a list of standard of care treatments, as measured primarily
by PFS, for patients with RET fusion-positive metastatic NSCLC who have not
previously received systemic anticancer therapy for metastatic disease.

All study visits are intended to be conducted on an outpatient basis, but may
be conducted on an inpatient basis, as needed. Informed consent may be obtained
up to 42 days (6 weeks) before study drug administration on C1D1. After
informed consent, patients will be evaluated for study eligibility during the
Screening Period, which is to be completed within 28 days or less before study
drug administration. For study eligibility, RET fusion status may be determined
locally or centrally. However, baseline tumor tissue samples for all patients
must also be submitted for confirmation of RET status by central testing.

After the Screening assessments are performed, patients will be randomly
assigned, in a 1:1 ratio, to 1 of 2 treatment arms: Arm A (pralsetinib) or Arm
B (a platinum-containing chemotherapy regimen from an Investigator's choice
list of standard of care regimens with or without pembrolizumab).

Main Treatment Period:
During the Main Treatment Period, patients randomized to Arm A will receive
pralsetinib by daily oral (PO) administration at a dose of 400 mg in continuous
21-day treatment cycles. Patients may continue to receive pralsetinib until
precluded by toxicity, centrally confirmed disease progression, noncompliance,
withdrawal of consent, death, or closure of the study by the Sponsor.
Patients randomized to Arm B will receive 1 of the following platinum-based
chemotherapy treatment regimens based on standard of care treatment cycles as
determined by the treating Investigator.
Nonsquamous histology
* Carboplatin or cisplatin / pemetrexed (with vitamin supplementation)
* Pembrolizumab / carboplatin or cisplatin / pemetrexed (with vitamin
supplementation)

Squamous histology:
Carboplatin or cisplatin / gemcitabine Investigator choice platinum-based
chemotherapy regimen may continue in accordance with standard of care (four
3-week treatment cycles). Patients with nonsquamous histology receiving
carboplatin- or cisplatin-containing regimens may optimally receive subsequent
maintenance pemetrexed (and pembrolizumab, if selected) for up to 2 years
unless stopped earlier for toxicity, confirmed disease progression,
noncompliance, withdrawal of consent, death, or closure of the study by the
Sponsor.

All patients will present to the study center on C1D1 for the first dose of
study drug; safety monitoring (including ECOG PS assessment, physical
examination, vital signs, electrocardiogram (ECG), safety laboratory tests, AE
and concomitant medication recording, etc.); QoL questionnaires; biomarker
sample collection; and PK assessments. Additional study visits for assessments
of safety and PK will be conducted periodically throughout study treatment in
accordance with the schedule of assessments (SoA). Disease assessments will be
performed at 6 weeks and 12 weeks, then every 9 weeks for the first 48 weeks,
and every 12 weeks thereafter, until confirmation of progressive disease by
central radiographic review. Tumor response and progression will be assessed in
accordance with RECIST 1.1. At any point in time between treatment cycles,
patients should attend or contact the study center for AE reporting,
evaluation, and medical intervention.

Patients who discontinue study treatment without documented progressive disease
will continue to undergo disease assessments until documentation of progressive
disease, initiation of another antineoplastic therapy, death, or closure of the
study by the Sponsor.

Crossover Treatment Period:
Patients randomized to Arm B who experience disease progression, as confirmed
by central radiology review, on Investigator*s choice platinum-based
chemotherapy regimen may be offered the opportunity to cross over to the
pralsetinib treatment arm (Arm A) after a confirmation of their disease
progression by central radiology review. Patients must separately consent to
cross over to pralsetinib treatment after disease progression and meet minimal
criteria for crossover.

Upon entering the Crossover Treatment period on Crossover Cycle 1 Day 1
(CC1D1), patients will have the following assessments performed: ECOG PS
assessment, physical examination, vital signs, ECG, safety laboratory tests, AE
and concomitant medication recording, QoL questionnaires, PK and biomarker
sample collections. Patients will also present to the study center on Day 1 of
every subsequent cycle to repeat the applicable procedures as indicated in the
SoA. At any point in time between treatment cycles patients should attend or
contact the study center for AE reporting, evaluation, and medical
intervention. Disease assessments will be performed at 6 weeks and 12 weeks,
then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter until
new disease progression, initiation of new antineoplastic therapy, death,
patient withdrawal of consent, or closure of the study by the Sponsor.

End of Treatment Period:
All patients will attend an End of Treatment (EOT) Visit 14 days (±7 days)
after the permanent discontinuation of study drug (ie, last dose) or before a
patient starts another antineoplastic therapy. A follow-up telephone contact
for a safety assessment to confirm resolution of any AEs will be made 30 days
(±7 days) after the last dose of study drug or at the time the patient
initiates another antineoplastic therapy.

Follow-up Period:
After discontinuation of study drug, patients without confirmed progressive
disease will be followed for PFS until confirmation of progressive disease by
central radiology review, withdrawal of consent, initiation of another
antineoplastic therapy, or death. All patients will be followed for overall
survival by telephone contact approximately every 3 months from the EOT visit
until death, withdrawal of consent, or closure of the study by the Sponsor.

It is anticipated that patients will receive at least 1 cycle of study
treatment (pralsetinib if randomized to Arm A and a platinum-containing
chemotherapy regimen from an Investigator's choice list of standard of care
regimens if randomized to Arm B). After Cycle 1, patients randomized to Arm B
will receive study treatment in accordance with standard of care, patients
randomized to Arm A may continue to receive study treatment until precluded by
toxicity, noncompliance, pregnancy, progressive disease, withdrawal of consent,
death, or closure of the study by the Sponsor.

Drug side effects
Patients may experience side effects from the drugs used in this study. Side
effects can vary from mild to very serious and may vary from person to person.
Every patient taking part in the study will be watched carefully for any side
effects. However, not all of the side effects that could occur are known.
Patients will be given medications to help lessen some of the side effects.
Many side effects go away soon after the causative factor is removed. However,
in some cases, side effects can be serious and may be long lasting or may never
go away. There also is a rare risk of death. Patients will be encouraged to
talk to the study doctor about any side effects they experience while taking
part in the study. They will also be given a patient identification card to
carry with them at all times in case they cannot make it to the study site and
have to go for treatment elsewhere so the medical professional treating the
patient can contact the study doctor and obtain information about the study,
study drugs and their possible side effects. If patients develop serious side
effects their treatment with study medication will be stopped. They will be
treated or monitored until resolution or stabilisation of the side effect.
Patients who experience less serious side effects will have their treatment
interrupted until the side effect subsides after which they may resume their
treatment, however, the dose may be reduced.

Less effective experimental therapy
Although there is some data on the use of pralsetinib in NSCLC patients, the
drug may be less effective than the standard treatment. For some patients the
experimental treatment or the standard treatment they are assigned to receive
may not work and their health may not improve as a result of participation in
the study. Patients whose NSCLC worsens while they are receiving study
treatment will be taken off the study drugs. They will then be able to receive
standard of care treatment appropriate for their health condition at the time.
They will also be followed for survival as part of their participation in this
study.

Dietary and medication restrictions
Patients taking pralsetinib as part of the study will not be allowed to consume
grapefruit, grapefruit juice or take St. John*s Wort. This is to limit their
effect on the metabolism of pralsetinib. There is also a number of prescription
medications that patients will not be allowed to take. There are some drugs
that will have to be used with caution. All medications that patients are
taking will be reviewed by their study doctor and patients will be advised
which medications will have to be stopped, replaced or restricted.

Risks associated with study procedures
Risks with biopsies
Patients who do not have their tumour tissue stored at the hospital will have
to undergo biopsy at screening to confirm RET fusion status. The exact
procedure depends on the location of the tumour.
General risks of biopsies include minor local bleeding, pain at the needle
insertion site* swelling under the skin that contains blood* sleepiness, if
patients receive a pain killer and/or a medicine to make them relax. Rarely,
infection and shortness of breath can occur. If patients receive a pain killer
and/or medicine to make them relax, in some cases they may experience slow
heart rate and low blood pressure.

Risks with Infusions
All standard of care drugs will be given by infusion into a vein over up to an
hour. Administration of cisplatin will have to include pre-and
post-administration hydration procedures which may take many hours and involve
IV infusions. In order to do the infusion, the study staff may insert a
catheter (a small hollow tube) into a vein in patient*s arm by a needle. The
needle is removed, but the tube temporarily remains in patient*s vein. The
catheter will be flushed or cleaned out with a small amount of salt water
before and after it is used.

There could be discomfort or pain when the catheter and needle are inserted.
There is a risk of feeling faint or passing out. There is also a risk of
infection, bleeding, soreness, blood clots, tenderness, or bruising at the
puncture site. A swelling at the infusion site can develop if fluid
accidentally enters the tissue rather than the vein.

Blood sampling
During this study, small amounts of blood will be drawn from a vein and used
for tests. Drawing blood may cause pain where the needle is inserted, and there
is a small risk of bleeding, bruising or infection. Rarely, some people
experience dizziness, upset stomach, or fainting when their blood is drawn.

Electrocardiogram (ECG)
Patients will have small, soft pads, placed temporarily on different parts of
their body. There is no pain or discomfort during an ECG* however, the area of
skin in which the ECG pads will be stuck may need to be shaved, and the pads
may cause a skin reaction such as redness or itching. Taking the pads off may
cause localised irritation to the skin and/or hair loss, similar to having a
bandage taken off.

Risks with imaging procedures
Patients* response to treatment will be assessed with the use of imaging
procedures which include CT and MRI scans. Each CT scan that patients will
receive on the study provides the dose of radiation equivalent to 5-8 years*
natural background radiation. A contrast dye may be injected into the vein or
administered orally before the CT scan. This may cause a slight discomfort,
bruising, swelling and sometimes an allergic reaction. Severe allergic
reactions (for example, a drop in blood pressure, difficulty in breathing, or
kidney problems) are very rare. Patients will have a kidney function test to
determine if the contrast can be given safely. Some patients may find the CT
scanner mildly claustrophobic.
Patients who are unable to undergo CT scans may be asked to have an MRI scan
instead. Unlike CT, an MRI scan does not provide a dose of harmful X-ray
radiation. For most patients, the risks or side effects associated with
undergoing MRI are minimal. However, patients cannot have any metal implants to
have an MRI scan. Patients will be asked questions to make sure they can safely
have an MRI scan. There may be some anxiety and claustrophobia associated with
the MRI scanner. Patients will be asked to lie still for around 30 minutes
during each scan. As part of the MRI scan, a contrast agent may be injected
into the vein. The risks associated with the contrast agent include mild
nausea, headache, hives and temporary low blood pressure, although such
reactions are very rare. Patients will have kidney function tests to ensure the
contrast agent can be given safely. As images are taken, a loud banging noise
will be produced. Earplugs or headphones will be available if needed.

It may also be necessary to perform any biopsy procedures using CT guidance to
help the doctors accurately locate the tumour. The dose from the procedure will
vary depending on its complexity, but may be equivalent to up to eight years*
natural background radiation.

The ionising radiation from CT, and CT-guided biopsy procedures can cause cell
damage that may, after many years or decades, turn cancerous. The theoretical
chance of this happening to a patient who stays on the study for 2 years is
around 1.7 %. Each additional year of participation would further increase the
theoretical risk by around 0.5%.

However, the real risk is considered to be much smaller due to the short life
expectancy of the participants in the study.

Reproductive risks
To avoid exposing a developing baby or breastfed infant to harmful effects of
the study drugs and exposing the foetus to ionising radiation from some imaging
procedures, pregnant or breastfeeding women will not be allowed to participate
in the study.

Women who can have children and men with female partners who can have children
will also be required to use effective contraception during treatm