A first-in-human (FIH) study of IDRX-42 in participants with metastatic and/or unresectable
gastrointestinal stromal tumors (GIST)

Similar results were seen in a xenograft model expressing secondary resistance
mutations in KIT exon 17.
.
There is a high unmet medical need for effective treatments for patients with
imatinib- and other tyrosine kinase inhibitor-resistant GIST driven by
mutational variants that are not controlled by available therapies. IDRX-42 is
highly active against KIT mutations in exons 11, 13, and 17, with high kinase
selectivity, and excellent metabolic stability, permeability, and solubility.
IDRX-42 (formerly M4205, substance code MSC2700000A) is a potent, highly
selective, orally administered, small molecule tyrosine kinase inhibitor,
targeting disease-specific oncogenic drivers and a range of clinically relevant
resistance mutations of KIT. IDRX-42 is being evaluated as a treatment for
patients with metastatic and/or surgically unresectable GIST. In preclinical
studies of IDRX-42 in GIST xenograft models expressing mutations in exon 11,
IDRX-42 demonstrated superior antitumor activity compared with imatinib. In
xenograft models expressing secondary resistance mutations in KIT exon 13,
IDRX-42 treatment resulted in strong and dose-dependent antitumor activity,
comparable to the second-line standard of care agent, sunitinib.
Similar results were seen in a xenograft model expressing secondary resistance
mutations in KIT exon 17.

This study has been transitioned to CTIS with ID 2024-514930-19-00 check the CTIS register for the current data.

This study aims to evaluate IDRX-42 administered to participants with
metastatic and/or surgically unresectable GIST.

This is a FIH, Phase 1/1b, open-label study in participants with metastatic
and/or surgically unresectable GIST. The study of IDRX-42 will occur in
participants after failure of at least prior imatinib in dose escalation and
confirmation (Phase 1) and cohorts 1, 2 and 4 (Phase 1b). Participants who are
treatment naïve (first line therapy) and refused or are ineligible for other
standard of care (SOC) therapies will be treated under Cohort 3 (Phase 1b).
Inter-dose level dose escalation per modified Fibonacci design will be
performed to assess DLTs and determine the MTD and/or RP1bD(s). Cohorts that
explore participants with various prior lines of therapy at the RP1bD(s) will
be added in Phase 1b to assess the preliminary antitumor effect of IDRX-42 and
further characterize the safety profile.

Phase 1 Dose Escalation
IDRX-42 dose level escalation will use a standard 3 + 3 design. The starting
dose (dose level [DL]1) will be 120 mg QD of IDRX-42 capsules. Up to 6
participants will be enrolled at DL1. More than 3 participants may be enrolled
to ensure that at least 3 DLT-evaluable participants are available for
analysis. If none of the first 3 evaluable participants experience a DLT during
the first cycle (28 days), up to 6 participants may be enrolled into the next
DL.
If 1 DLT is observed at any DL, up to 3 more participants (for a total of 6 per
DL) will be treated at the same DL. If no additional DLTs are observed,
participants may be enrolled into the next DL. If 2 or more DLTs are observed
at any DL, then the MTD will be defined as the previous DL examined. See
protocol Section 6.1.1 for proposed dose escalation DLs for IDRX-42. Additional
DLs and cohorts may be added depending on emerging safety data. During the dose
escalation portion of the study, selected DLs may be backfilled with additional
participants to acquire additional safety, pharmacodynamic, and response data
once the safety review committee (SRC) has determined the dose is safe. Any
backfill of selected cohorts requires approval from the Medical Monitor and no
more than a total of 12 participants will be enrolled in any cohort. Based on
the evaluation of the clinical data and PK profiles of IDRX-42, alternate
schedules may be explored, including twice daily (BID) dosing.
Further description of the DLT evaluation period including DLT definitions is
found in Section 6.1.1.2.
In the absence of an MTD, a maximum planned dose will be declared. This study
will utilize a SRC, tasked with reviewing all available safety information. The
SRC is responsible for dose escalation decisions including whether a waiting
period for any or all participants enrolled into a new cohort will be required,
if additional participants should be enrolled at a particular dose level
(resulting in > 6 participants), or if intermediate or additional dose levels
should be evaluated. The SRC will be composed of Principal Investigators,
Sponsor, and contract research organization medical representatives.

Phase 1 Dose Confirmation
Additional participants (up to approximately 30 total) may be added to selected
DLs to acquire additional safety, pharmacodynamic, and response data.
The selection of the DL(s) for further study will be guided by available
participants* safety, PK, pharmacodynamic, and antitumor activity data.
The RP1bD(s) will be chosen based on a holistic review of Phase 1 participants*
safety, antitumor activity, PK, and pharmacodynamic data by the SRC.

Phase 1b Exploratory Cohorts
Upon determination of RP1bD(s) in the Phase 1 portion of the study, Phase 1b
may commence to evaluate the RP1bD(s) of IDRX-42 in participants with GIST.
Phase 1b of the study is planned to further evaluate preliminary antitumor
activity, safety, and tolerability of IDRX-42, and characterize the PK and
pharmacodynamic profile of IDRX-42 in participants with metastatic and/or
unresectable GIST. Enrollment into 4 exploratory cohorts can occur
simultaneously for each of the following participant populations. If two doses
are explored in Phase 1b, a 1:1 randomization may be utilized for assignment of
dose within each cohort:
Cohort 1: Metastatic and/or surgically unresectable GIST participants who have
progressed on imatinib only (second line therapy) and refused or are ineligible
for other standard of care (SOC) therapies
Cohort 2: Metastatic and/or surgically unresectable GIST participants who have
progressed on both imatinib and sunitinib (third line therapy) or progressed on
imatinib, sunitinib, and an additional agent (i.e., regorafenib or ripretinib)
(fourth line therapy), or progressed on imatinib, sunitinib, regorafenib, and
ripretinib (fifth line or greater therapy)
Cohort 3 Applicable in US, UK, China, and South Korea Only: Metastatic and/or
surgically unresectable GIST participants who are treatment naïve (first line
therapy) and refused or are ineligible for other standard of care (SOC)
therapies
Cohort 4: Participants who meet the same criteria as Cohort 2 (third line or
greater) and have also had prior treatment with investigational agents NB003 or
THE-630 or a line of therapy of bezuclastinib plus sunitinib combination
IDRX-42 will be administered until disease progression, unacceptable toxicity,
death, withdrawal of consent by participant, Investigator decision to
discontinue treatment, Sponsor's decision to terminate the study, or other
protocol specified reason for discontinuation of study treatment.

Recommended Dose Modification Guidelines
Dose modification guidelines for IDRX-42-related toxicity are summarized in
Table 6 in the protocol. Deviation from these guidelines must be discussed with
the study Medical Monitor.

Response Assessments
The primary efficacy assessment endpoint in Phase 1 is ORR as determined by
Investigator response assessments per mRECIST v1.1 response criteria (Demetri
2013) based upon imaging scans performed at the time points outlined in the
Schedule of Assessments (Table 1). Additional Phase 1 efficacy assessment
endpoints include PFS, TTR, and DOR. The primary efficacy endpoint in Phase 1b
is ORR as determined by Independent Review response assessments per mRECIST
v1.1 criteria (Demetri 2013) based upon imaging scans performed at the time
points outlined in the Schedule of Assessments (Table 1). Additional Phase 1b
efficacy assessment endpoints include PFS, CBR, TTR, and DOR.
Response assessments will be conducted at C2D1, C3D1, C5D1, and every 2 cycles
thereafter.

Safety Assessments
Safety will be assessed by adverse events (AEs), physical examinations, vital
signs, hematology and chemistry laboratories, and electrocardiograms (ECGs).
AEs will be coded using the latest Medical Dictionary for Regulatory Activities
(MedDRA) version available at the time of database creation and will be graded
according to the National Cancer Institute Common Terminology Criteria for
Adverse Event (NCI CTCAE) version 5.0 or higher. The MedDRA dictionary may be
up-versioned once per year.

Pharmacokinetic/Pharmacodynamic Assessments
Blood samples will be taken pre-dose and at various time points throughout the
study in order to characterize the PK of IDRX-42 in participants with
metastatic and/or surgically unresectable GIST (Table 2). In order to determine
the effects of IDRX-42 on mutational burden as a measure of pharmacodynamic
activity in participants with metastatic and/or surgically unresectable GIST,
blood will be obtained at various time points throughout the study (Table 2).

IDRX-42 will be administered orally daily in continuous 28-day cycles in both
Phase 1 and Phase 1b of this study.

The primary therapy for patients with resectable or potentially resectable GIST
is surgery. However, recurrence occurs in more than half of patients with
resectable disease. For most patients with metastatic and/or surgically
unresectable GIST, first-line treatment with imatinib demonstrates limited
effectiveness. Frequently secondary mutations lead to drug resistance,
necessitating treatment with second-, third-, and fourth line therapies such as
sunitinib, regorafenib, and ripretinib, respectively. Heterogeneous activating
mutations that are resistant to existing kinase inhibitors limit the clinical
benefit of these therapies. Thus, there remains a high unmet need for an
effective treatment for metastatic or unresectable GIST.
Based on the results of the toxicology studies, IDRX-42 comprises a nonclinical
safety profile that is adequate for the treatment of patients suffering from
life-threatening malignancies. Repeat-dose toxicity studies showed that the
main target organs of toxicity are the hematopoietic system, male reproductive
organs, and the liver. These are known effects for the drug class of KIT
inhibitors and have been observed with currently available KIT inhibitors. No
indications for phototoxicity of IDRX-42 were observed, and the genotoxic risk
of IDRX-42 is considered to be low. Metabolism is the predominant elimination
pathway prior to excretion and importantly, no human-specific metabolites were
identified following cross-species in vitro metabolism assessments in
hepatocytes.
Recommendations during clinical use include the monitoring of main target
organs of toxicity determined in general toxicity testing including standard
hematological monitoring with complete blood counts and monitoring of hepatic
enzymes. As no formal data are available on reproductive and developmental
toxicity, a strict use of contraceptives for male participants under treatment
and for women of childbearing potential is considered mandatory.
Overall, the nonclinical profile supports the evaluation of IDRX-42 in
participants with metastatic and/or surgically unresectable GIST, a
life-threatening condition with a high unmet need with the MRSD for the FIH
study of 120 mg/day (Section 4.3.2).