A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients with Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)

This study is testing a drug called repotrectinib and is being studied as a
possible treatment for advanced or solid
tumours in patients that are known to have rearrangement (mutation) in the ALK,
ROS or NTRK 1-3 genes.

The proposed study comprises phase 1 and phase 2 portions as indicated in the
title of the protocol. Enrollment in Phase 1 is completed and the recommended
Phase 2 Dose (RP2D) of repotrectinib was established as 160 mg once daily for
the first 14 days and may be increased to 160 mg twice daily. Repotrectinib can
be taken with or without food. The EU (including the Netherlands) will take
part in only Phase 2 of the study.

The phase 2 portion of study is to determine whether repotrectinib is effective
cancer treatment, especially in groups of
participants whose tumours have the gene mutations mentioned above. The study
will also continue to look at the
side effects and response of tumours to different doses, as well as how
different foods affect how repotrectinib gets
into the body. The study will include approximately 630 participants between 6
treatment groups based on the
participant's tumour's gene mutation and previous cancer treatment:
Group 1. Participants that have the ROS1 gene mutation and have not undergone
any previous tyrosine kinase
inhibitor (TKI) therapy i.e. TKI-naïve, and a diagnosis of non small cell lung
cancer (NSCLC).
Group 2. Participants that have had one round of TKI therapy and 1
platinum-based chemotherapy, with the ROS1 gene mutation and a diagnosis of
NSCLC.
Group 3. Participants that have had two rounds of TKI therapy and NO
chemotherapy or immunotherapy, with the ROS1 gene mutation and a diagnosis of
NSCLC.
Group 4. Participants with the ROS1 gene mutation with a diagnosis of NSCLC
advanced solid tumours and have previously received 1 ROS1 TKI therapy and NO
chemotherapy or immunotherapy.
Group 5. Participants with the NTRK genes mutation with a diagnosis of advanced
solid tumours, that have not
previously received TRK treatment with TKI therapy.

Group 6. Participants with the NTRK genes mutation with a diagnosis of advanced
solid tumours, that have previously
received TKI therapy, chemotherapy and immunotherapy treatment.
All patients will take repotrectinib as a capsule taken by mouth at the RP2D
(160 mg once daily for the first 14 days and
which may increase to 160 mg twice daily depending on tolerability).
Phase 2 of this study consists of a Screening Phase and multiple Study Cycles
(each cycle is about 28 days).
Participants will need to visit the study site to complete study procedures as
follows:
• Screening Phase to determine if participants are eligible for the study
(within 28 days of the first dose of
repotrectinib).
- Several visits may be required to perform the screening assessments.
• Study Cycles
- Cycle 1: Day 1, Day 8, Day 15, and Day 22
- Cycle 2: Day 1 and Day 15
- Cycle 3 (and then every 4 weeks): Day 1
• End-of-Treatment visit (within 7 days after the last dose of repotrectinib
and after the decision to end treatment).
• Safety Follow-up visit (28 days after the last dose of repotrectinib)

This study has been transitioned to CTIS with ID 2024-512606-25-00 check the CTIS register for the current data.

Primary Objective phase 2 part of the study
- To determine the confirmed Objective Response Rate (ORR) as assessed by
Blinded Independent Central Review (BICR) of repotrectinib in each subject
population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1,
NTRK2, or NTRK3 gene rearrangement.


Secondary Objectives phase 2 part of the study
- To determine the Duration of Response (DOR), time to response (TTR), and
clinical benefit rate (CBR) of repotrectinib, as assessed by BICR, in each
subject population expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

- To estimate the progression-free survival (PFS) and overall survival (OS) of
subjects treated with repotrectinib with advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

- To evaluate the safety and tolerability of repotrectinib when administered at
the RP2D in subjects with advanced solid tumors that harbor a ROS1, NTRK1,
NTRK2, or NTRK3 gene rearrangement.

- To determine the intracranial objective response rate (IC-ORR) of
repotrectinib and Central Nervous System PFS (CNS-PFS) in subjects presenting
with measurable brain metastases at baseline, using modified RECIST v1.1
assessment.

-To confirm PK of repotrectinib at the RP2D.

- To assess treatment-related symptoms and general health status using
validated instruments of subject-reported outcomes (EORTC-QLQ-C30 and LC-13
when applicable) in subjects treated with repotrectinib.

The Phase 2 portion of the study will be with single-agent repotrectinib at the
identified RP2D and will enroll subjects with ROS1+, NTRK1+, NTRK2+, or NTRK3+
advanced solid malignancies.
The Phase 2 segment of this study will consist of 6 subject expansion cohorts
(EXP) (described in the Inclusion Criteria).

Subjects in Phase 2 will receive 160 mg repotrectinib orally once daily for the
first 14 days. This may be increased to 160 mg twice daily after the subject*s
treating physician has evaluated the subject*s tolerability for repotrectinib
on C1D15.

On Study Assessments (Phase 1 and Phase 2)
Tumor assessments will be performed at Screening, at the end of Cycle 2 (within
the Phase 1a study this was approximately 7 weeks from the initial
repotrectinib treatment ± 2 days; and in Phase 1c given the duration of Cycle 1
is 4 weeks, it will correspond to 8 weeks from the initial repotrectinib
treatment ± 7 days), every 2 cycles (± 7 days) up to the end of Cycle 18 and
then every 3 cycles (± 7 days) up to the end of Cycle 36 and then every 4
cycles (± 7 days) thereafter until documented progression of disease regardless
of treatment delays resulting from toxicity, and at the End of Treatment (EOT)
if more than 4 weeks have passed since the last imaging assessment). At EOT
visit, the subject must undergo an EOT tumor assessment evaluation (CT or MRI;
MRI of the Brain and Bone Scan, if applicable) PRIOR to treatment
discontinuation to evaluate for radiologic disease progression if treatment is
being discontinued for a reason other than BICR-confirmed radiographic disease
progression. After treatment discontinuation, tumor assessments should continue
at the current scan interval at the time of treatment discontinuation until a
subject begins a new course of cancer therapy or withdraws consent if there is
no BICR -confirmed radiologic progression at the time of treatment
discontinuation.
An EOT Visit will be conducted within 28 days of last dose of repotrectinib.
Additionally, each subject will be contacted by telephone approximately every 3
months following study discontinuation until death, loss to follow-up, or
withdrawal of consent in order to assess disease progression and survival
status.
For Phase 2, all efforts should be made to obtain the EOT radiographic scan
before treatment discontinuation, and where possible inform and discuss with
the Sponsor*s Medical Monitor when considering treatment discontinuation.
Disease progression must be determined by BICR. For subjects in Phase 2 with
CNS disease who have been on study for at least 2 cycles of treatment with a
best response of Stable Disease (SD) per RECIST v1.1 AND without
treatment-related grade >= 2 AEs, dose escalation to 160 mg BID will be allowed
as per Investigator*s discretion and after discussion with the Sponsor*s
Medical Monitor.
Subjects may continue repotrectinib treatment after clinical or radiographic
progression if he or she is continuing to experience clinical benefit, in the
opinion of the Investigator, and after discussion with the Sponsor Medical
Monitor.
Safety will be monitored via laboratory assessments, physical examinations,
electrocardiograms (ECG), vital signs, and AEs. Study assessments for the Phase
1 and Phase 2 portion will be performed as per the Study Calendars. In Phase
2, a Data Monitoring Committee (DMC) will be established to monitor safety and
conduct benefit-risk assessment on a routine basis that will be outlined in a
separate DMC charter.

The Phase 2 portion of the study will be with single agent repotrectinib at the
identified RP2D and will enroll subjects with ROS1+, NTRK1+, NTRK2+, or NTRK3+
advanced solid malignancies. Based on safety, PK and preliminary efficacy data
obtained in Phase 1, the RP2D of repotrectinib 160 mg QD for the first 14 days,
which may be increased to 160 mg BID after subject evaluation at C1D15.

Interviews Every visit
Physical examination Every visit
Vitals signs Every visit
Tumor biopsy Screening (if required) and about 1 week after starting treatment
(optional)
Blood draws Every visit
Urine collection Every visit (except Cycle 2 Day 15)
Heart tests Screening, Cycle 1 Days 1 and 15, then once every month (less
frequent after 4 months), and end of treatment
Tumor imaging tests Screening, and then every 2 months (less frequent after 18
months)
Cerebrospinal fluid sampling (optional) Only if your doctor does this as part
of your regular treatment
Pregnancy tests Screening, and then every month


Very common treatment-related effects reported in 10% or more patients include
the following:
• Dizziness, which can cause the feeling of being lightheaded, woozy, or
unbalanced,
at times when standing up quickly. Less commonly, this may be associated with a
drop in blood pressure or vertigo. Most of the symptoms were mild or moderate
and did not affect activities of daily living such as preparing meals, bathing,
shopping for groceries or clothes, or using the telephone. A few patients, have
experienced serious or severe symptoms, described as unsteadiness while
standing or walking and being unable to move. Dizziness was managed by dose
interruptions or a dose reduction. Avoid driving or using heavy machinery if
you are having symptoms of dizziness
• Dysgeusia, which is a distortion of the sense of taste, or a condition in
which a foul, salty, rancid, or metallic taste sensation persists in the mouth.
Less commonly, dry mouth or difficulty swallowing may occur.
• Paresthesia is a burning or prickling sensation that is usually felt in the
hands, arms, legs, or feet, but can also occur in other parts of the body.
Less commonly, paresthesia may occur in the mouth, in addition to numbness in
the mouth, or a feeling of burning on top of your mouth and/or tongue.
• Gastrointestinal effects, that may include constipation, nausea, and less
commonly, vomiting, diarrhea, reflux (liquid content of the stomach moves up
into the throat), inflammation of the mouth or digestive tract lining,
abdominal pain, an upset stomach or decreased appetite.
• Anemia caused by a decrease in red blood cells that carry oxygen, which can
cause tiredness (fatigue) or may make you more susceptible to infections. A few
patients have experienced severe anemia that required a blood transfusion.
• Ataxia is a sign of poor muscle control that may cause clumsy, voluntary
movements. Less commonly, it may be associated with tremors, walking difficulty
and balance, which may lead to a fall.
• Liver function laboratory tests showing liver enzyme increases (ALT, AST),
and other less common liver test results such as GGT increase may occur. Your
doctor will do blood tests to check your liver function during treatment.
• Creatine kinase, a laboratory test, may show an increase in the blood, which
may be severe when certain tissues like muscles are damaged. Less commonly,
blood lactate dehydrogenase may also be increased. Tell your doctor if you are
feeling any new or worsening signs and symptoms of muscle problems such as
unexplained muscle pain, tenderness, muscular weakness that may be severe or
serious, or muscle spasms.


A complete list of all possible risks and side effects can be found in Appendix
D of the applicable consent forms.