Clinical trial NCT05160168
Conditions: Gastrointestinal Stromal Tumors (GIST) Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasm Digestive System Disease Gastrointestinal Diseases
Keywords: Gastrointestinal Stromal Tumor GIST KIT inhibitor THE-630 THE630 THE 630 GIST TKI GIST tyrosine kinase inhibitor GIST treatments GIST Imatinib relapse GIST Sunitinib relapse GIST Regorafenib relapse GIST Ripretinib relapse PDGFRA KIT-mutant GIST Advanced GIST
Sponsor: Theseus Pharmaceuticals
Start date: 2022-01-03; Completion date: 2024-02-02
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will assess the safety, efficacy, and pharmacokinetics of THE-630 in participants with advanced gastrointestinal stromal tumors (GIST).

Detailed description:
The drug being tested in this study is called THE-630, an orally administered KIT tyrosine kinase inhibitor. The study will be conducted in two parts: a dose escalation phase, followed by an expansion phase. The patient population of the initial dose escalation phase (Phase 1) of the trial will include patients with unresectable or metastatic GIST. Patients must have disease progression on or be intolerant to imatinib therapy and have also received at least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The primary objective of the dose escalation phase is to determine the safety profile of oral THE-630, including the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).

Once a recommended dose has been determined in the escalation phase, the expansion phase (Phase 2) will enroll 3 cohorts of patients with unresectable or metastatic GIST defined by prior therapy:

* Cohort 1: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib (≥5th Line).
* Cohort 2: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib and 0-1 additional lines of therapy in the advanced/metastatic setting (3rd-4th Line).
* Cohort 3: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib (including in the adjuvant setting) and who have not received additional systemic therapy for advanced GIST (2nd Line).

The safety and tolerability of orally administered THE-630 will continue to be assessed in the expansion cohorts. However, the primary objective of the expansion component of the trial is to evaluate the anti-tumor activity of THE-630 in these GIST patient populations.

Arms: arm 1: Participants with unresectable or metastatic GIST who will receive orally administered THE-630. arm 2: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase. arm 3: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib and 0-1 additional lines of therapy in the advanced/metastatic setting, who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase. arm 4: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib (including in the adjuvant setting) and who have not received additional systemic therapy for advanced GIST, who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.
Interventions: intervention 1: THE-630
Intervention descriptions: intervention 1: Oral THE-630 administered once daily in a continuous regimen

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Official Title: 
A Phase 1/2 Study of the Safety, Pharmacokinetics and 
Anti-Tumor Activity of the Oral KIT Inhibitor THE-630 
in Patients with Advanced Gastrointestinal Stromal 
Tumors (GIST) 
NCT Number: 
NCT05160168 
Document Date: 
07 Dec 2022 
 




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PROTOCOL REVISION HISTORY 
 
Protocol Version Number 
Date 
Version 1.0 (Original) 
02 Sep 2021 
Version 2.0 
07 Oct 2021 
Version 3.0 
25 Feb 2022 
Version 4.0 
07 Dec 2022 
Refer to Appendix 6 for a cumulative listing of Protocol Summary of Changes and Rationale. 
 
 




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INVESTIGATOR SIGNATURE PAGE 
 
TITLE 
A Phase 1/2 Study of the Safety, Pharmacokinetics and Anti-
Tumor Activity of the Oral KIT Inhibitor THE-630 in Patients 
with Advanced Gastrointestinal Stromal Tumors (GIST) 
PROTOCOL NUMBER 
THE630-21-101 
PROTOCOL VERSION 
Version 4.0, 07 Dec 2022 
 
AGREEMENT 
 
INVESTIGATOR STATEMENT: I understand that all documentation provided to me by 
Theseus Pharmaceuticals Inc. or its designated representative(s) concerning this study that has not 
been published previously will be kept in the strictest confidence. This documentation includes the 
study protocol, Investigator brochure, case report forms, and other scientific data. This study will 
not commence without the prior written approval of a properly constituted Institutional Review 
Board/Independent Ethics Committee. No changes will be made to the study protocol without the 
prior written approval of Theseus Pharmaceuticals Inc. and the Institutional Review Board, except 
where necessary to eliminate an immediate hazard to the patient. I have read, understood, and 
agree to abide by all the conditions and instructions contained in this protocol. 
 
Name of Institution 
 
Principal Investigator  
 
Principal Investigator’s Signature 
Date 


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EMERGENCY CONTACT INFORMATION 
 
In the event of a Serious Adverse Event (SAE) or Pregnancy, the Investigator must report the event 
within the electronic Case Report Form (eCRF) within 24 hours after becoming aware of the event. 
 
If the eCRF is unavailable, then the Investigator must fax or email the study Serious Adverse Event 
Form within 24 hours to the Worldwide Clinical Trials Pharmacovigilance Department: 
 
 
SAE Fax Number (US): 
 
SAE Fax Number (EU): 
  
SAE Email Address: 
 
 
 
For all protocol- or safety-related issues, the Investigator should contact the Worldwide 
Clinical Trials Medical Monitor(s) listed on the Study Contact List available within your 
Investigator Site File. 
Additional Sponsor contact for protocol- or safety-related issues:  
 
 
 
Telephone Number: 
 
Email: 
 
 
 
 
 
 


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STUDY SYNOPSIS 
Protocol number: THE630-21-101 
Study Treatment: THE-630 
Study Title:  A Phase 1/2 Study of the Safety, Pharmacokinetics and Anti-Tumor Activity of the Oral KIT Inhibitor 
THE-630 in Patients with Advanced Gastrointestinal Stromal Tumors (GIST) 
Site(s): Multi-site study. Approximately 7 sites in the United States will enroll for the Dose Escalation (Phase 1). 
An additional 18-20 sites will enroll for the Expansion (Phase 2) from within the United States and globally and 
may participate in backfill enrollment in the Phase 1 portion of the study. 
Study period (planned): 
Approximately 54 months 
Clinical phase: 
Phase 1/2 
Study Design: 
This is a first-in-human (FIH), multicenter, non-randomized, open-label Phase 1/2 study to evaluate the safety, 
pharmacokinetics (PK) and anti-tumor activity of oral THE-630 in patients with advanced GIST. The study will 
be conducted in two parts: a dose escalation phase, followed by an expansion phase. 
Dose Escalation (Phase 1) 
The patient population of the initial dose escalation phase (Phase 1) of the trial will include patients with 
unresectable or metastatic GIST. Patients must have disease progression on or be intolerant to imatinib therapy and 
have also received at least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The objectives of 
the dose escalation phase are to determine the safety, PK profile, and recommended Phase 2 dose (RP2D) of orally 
administered THE-630 in these patients. 
The dose escalation phase of this trial will employ sequential dose escalation of oral THE-630 using a standard 
3+3 design, starting at 3 mg once daily (QD) and increasing in increments until the maximum tolerated dose (MTD) 
is identified.  Initially, 3 patients will be enrolled at 3 mg administered orally QD and will be followed for 28 days. 
Increases of up to 100% over the previous dose level cohort will be employed until a ≥ grade 2 non-hematologic 
adverse event (AE) where relationship to THE-630 cannot be ruled out, a ≥ grade 3 hematologic AE where 
relationship to THE-630 cannot be ruled out is observed, a protocol defined dose limiting toxicity (DLT) is 
observed (either within the 28-day DLT period or an AE that otherwise would qualify as a DLT but occurs outside 
of that interval), or the dose level of 48 mg QD is reached. Further dose escalation will involve increments of no 
more than 50% of the previous dose, depending on safety findings, as long as there is no more than 1 of 6 patients 
in a cohort with a DLT. Alternative dosing regimens may be explored depending on initial PK findings and safety 
and tolerability data. Should a modification be required, the dose escalation scheme will be altered by interpolating 
non-once daily schedules into the initial escalation scheme. Prior to implementation of any alternative non-once 
daily dosing schedule, the protocol will be amended to describe the planned evaluation and justification for the 
specific alternative dosing schedule. 
Each dose escalation cohort will have a minimum of 3 patients enrolled and followed for 28 days. Increasing to 
the next dose level will depend on the safety findings of the previous cohorts. Expansion of a cohort from 3 to 6 
patients will occur if 1 of 3 patients experiences a DLT at a given dose. If 1 or more patients experience a DLT in 
the additional 3 patients in a dose cohort (i.e., for a total of ≥2 of 6 patients with a DLT), the dose level will be 
designated to have exceeded the MTD. If no patients experience a DLT in the additional 3 patients (i.e., for a total 
of ≤1 of 6 patients with a DLT), dose escalation will continue. In the case of non-safety-related dropouts during 
the first cycle of treatment, a cohort may be expanded to replace non-safety-related dropout patients.   
Additional patients may be enrolled in one or more dose levels that have been shown to have not exceeded the 
MTD (up to 20 patients per dose level; up to 40 additional patients total), defined as backfill enrollment.   
The specific dose for each subsequent cohort will be determined at a dose-escalation meeting that includes the 
Study Investigators and the Sponsor Clinical Study Team. Dose-escalation meetings will occur after all patients in 
the current cohort have completed at least 28 days of observation after their first dose of THE-630 or have 
experienced a DLT. Dose escalation will continue until the MTD or a RP2D below the MTD has been determined. 
Intra-patient dose escalation will be allowed according to the following scheme. All patients in the dose escalation 
phase will have the option to increase dose beyond that which was initially assigned while on the study if the 


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following conditions are met: 1) the patient tolerated their starting dose without a DLT or dose reductions or 
interruptions because of an AE for which relationship to THE-630 cannot be ruled out, 2) the Cycle 3 PK sample 
has been drawn per protocol, and 3) the proposed next dose level has been evaluated and it has been shown that it 
does not exceed the MTD. There must be Investigator and Sponsor medical monitor approval in place before an 
intra-patient dose escalation can begin.  
Expansion (Phase 2) 
Once a RP2D has been determined, the expansion phase (Phase 2) will enroll 3 cohorts of patients with unresectable 
or metastatic GIST defined by prior therapy: 
• 
Cohort 1: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to 
imatinib, sunitinib, regorafenib and ripretinib (≥5th Line). 
• 
Cohort 2: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to 
imatinib, sunitinib and 0-1 additional lines of therapy in the advanced/metastatic setting (3rd-4th Line). 
• 
Cohort 3: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to 
imatinib (including in the adjuvant setting) and who have not received additional systemic therapy for 
advanced GIST (2nd Line). 
The safety and tolerability of orally administered THE-630 will continue to be assessed in the expansion cohorts. 
However, the primary objective of the expansion component of the trial is to evaluate the anti-tumor activity of 
THE-630 in these GIST patient populations, as assessed by the Investigator, according to modified Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Demetri, 2013) (Appendix 1) for patients with GIST. 
Efficacy endpoints will include confirmed objective response rate (ORR), best overall response, best target lesion 
response, time to response, duration of response (DOR), disease control rate (DCR), Clinical Benefit Rate (CBR) 
at 16 weeks, progression-free survival (PFS) and overall survival (OS).  
Exploratory biomarker evaluation of the mutation status of KIT, platelet-derived growth factor receptor alpha 
(PDGFRA) and other genes implicated in tumor biology, and/or drug metabolism may be determined through 
analyses of tumor tissue and blood plasma samples to evaluate biomarkers of THE-630 efficacy and safety. An 
optional biopsy will be taken at the time of disease progression on THE-630 for patients who consent to the 
procedure. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue will be processed centrally and used for 
exploratory molecular genetic analysis. 
Study Objectives:  
Dose Escalation (Phase 1): 
Primary: To determine the safety profile of oral THE-630, including the DLTs, MTD, and RP2D 
Secondary:   
• 
To determine the PK profile of oral THE-630 and its active metabolite THE-973 
• 
To document preliminary evidence of antitumor activity of oral THE-630 in patients with advanced GIST 
Expansion (Phase 2): 
Primary: To determine the antitumor activity of oral THE-630 in patients with advanced GIST 
Secondary:  
• 
To evaluate the safety profile of oral THE-630 
• 
To further characterize the PK profile of oral THE-630 and its active metabolite THE-973 
Both Dose Escalation (Phase 1) and Expansion (Phase 2): 
Exploratory: To explore associations between tumor and plasma biomarkers and THE-630 efficacy and safety 


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Study Endpoints: 
Dose Escalation (Phase 1): 
Primary:  Safety profile of oral THE-630, including identification of DLTs and MTD, and determination of the 
RP2D  
Secondary:   
• 
Plasma PK parameters of THE-630 and its active metabolite THE-973 after single oral dose and at steady 
state after multiple oral doses 
• 
Efficacy assessments, according to modified RECIST 1.1 for patients with GIST including: confirmed 
ORR, best overall response, best target lesion response, time to response, DOR, DCR, CBR at 16 weeks, 
PFS, and OS 
Expansion (Phase 2): 
Primary:  Confirmed ORR, according to modified RECIST 1.1 for patients with GIST 
Secondary:   
• 
Efficacy assessments, according to modified RECIST 1.1 for patients with GIST, including: DOR, best 
overall response, best target lesion response, time to response, DCR, CBR at 16 weeks, PFS, and OS 
• 
Safety profile of oral THE-630 
• 
Plasma PK parameters of THE-630 and its active metabolite THE-973, after a single oral dose and at 
steady state after multiple oral doses 
Both Dose Escalation (Phase 1) and Expansion (Phase 2): 
Exploratory: Molecular analysis of patients’ tumor and plasma may include, but is not limited to: 
a. 
Presence of KIT mutations 
b. Presence of PDGFRA mutations 
Inclusion Criteria:  
Patients must meet the following criteria to be eligible for participation in the study: 
1. Male or female patient ≥ 18 years of age. 
2. For Dose Escalation Phase Cohorts (Phase 1): 
a. 
Have histologically- or cytologically-confirmed unresectable or metastatic GIST.  
b. Have progressed on or are intolerant to imatinib therapy and have also received at least 1 of the 
following: sunitinib, regorafenib, ripretinib, or avapritinib. 
3. For Expansion Phase Cohorts (Phase 2): 
a. 
Cohort 1: 
i. Have histologically- or cytologically confirmed unresectable or metastatic GIST. 
ii. Have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib. 
b. Cohort 2: 
i. Have histologically- or cytologically confirmed unresectable or metastatic GIST. 
ii. Have progressed on or are intolerant to imatinib and sunitinib. Patients in this cohort 
are allowed to have received up to 1 additional line of therapy in the 
advanced/metastatic setting. 
 


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c. 
Cohort 3: 
i. Have histologically- or cytologically confirmed unresectable or metastatic GIST. 
ii. Have progressed on or are intolerant to imatinib (including in the adjuvant setting). 
iii. Have not received additional systemic therapy for advanced GIST. 
4. Have at least 1 measurable lesion as defined by modified RECIST 1.1 (Appendix 1). 
5. Have archival or new tumor biopsy tissue available to submit for mutational testing. A tumor sample 
obtained after most recent prior systemic anticancer therapy is preferred. Patients without appropriate 
archival tissue available may be discussed with the study medical monitor and approved for enrollment 
on a case-by-case basis. 
6. Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 (Appendix 2). 
7. Adequate renal and hepatic function as defined by the following criteria: 
a. 
Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (<3.0 x ULN for patients with Gilbert 
syndrome), 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (or ≤5 × ULN 
if liver function abnormalities are due to underlying malignancy), and 
c. 
Estimated (using Cockcroft-Gault formula or using the method standard for the institution) or 
measured creatinine clearance ≥60 mL/min. 
8. Adequate bone marrow function as defined by the following criteria: 
a. 
Absolute neutrophil count (ANC) ≥1.5 × 109/L, 
b. Platelet count ≥75 × 109/L, and 
c. 
Hemoglobin ≥9.0 g/dL. 
9. For female patients of childbearing potential, have a negative serum or urine beta human chorionic 
gonadotropin (β-hCG) pregnancy test within 7 days prior to the first dose of study drug. 
a. 
Note: female patients of nonchildbearing potential (postmenopausal; hysterectomy; bilateral 
salpingectomy; or bilateral oophorectomy) do not require a pregnancy test. 
10. Female patients of childbearing potential must agree to abstain from heterosexual intercourse or use a 
highly effective form of contraception with their sexual partners during the dosing period and for a period 
of at least 30 days after the end of treatment. Male patients with partners of childbearing potential must 
agree that they will abstain from heterosexual intercourse or use condoms and their partners will use 
highly effective contraceptive methods during the dosing period until at least 90 days after the last dose 
of study drug. 
11. All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) (Appendix 3), or have resolved 
to baseline, at the time of first dose of study drug. Note: treatment-related grade >1 alopecia, treatment-
related grade 2 peripheral neuropathy, and treatment-related grade 2 hypothyroidism on a stable dose of 
thyroid hormone replacement therapy are allowed if deemed irreversible. 
12. Patient or legal guardian, if permitted by local regulatory authorities, signed and dated informed consent 
indicating that the patient has been informed of all pertinent aspects of the study. 
13. Willingness and ability to comply with scheduled visits and study procedures. 
Exclusion Criteria: 
Patients meeting any of the following criteria will not be eligible for participation in the study: 


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1. Received systemic anticancer therapy (including cytotoxic chemotherapy, investigational agent, 
antineoplastic monoclonal antibodies, or immunotherapy) less than 5 half-lives or 14 days (whichever is 
shorter) prior to the first dose of study drug. 
2. Patients known to be both KIT and PDGFRA wild-type. 
3. Received radiotherapy within 14 days prior to the first dose of study drug. 
4. Major surgical procedure within 28 days of the first dose of study drug. Minor surgical procedures such 
as central venous catheter placement or minimally invasive biopsy are allowed. 
5. Have known untreated or active central nervous system metastases. 
6. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected by Fridericia's formula (QTcF) > 
470 msec at screening, or history of long QTc syndrome. 
7. Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted to: 
a. 
Myocardial infarction (MI) within 6 months prior to the first dose of study drug 
b. Unstable angina within 6 months prior to first dose of study drug 
c. 
Symptomatic congestive heart failure (New York Heart Association classes II-IV) (Appendix 4) 
within 6 months prior to first dose of study drug 
d. Clinically significant, uncontrolled atrial arrhythmia (as determined by the Investigator) 
e. 
Any history of ventricular arrhythmia 
f. 
Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study 
drug 
g. Uncontrolled hypertension at study entry. Patients with hypertension should be under treatment 
on study entry to control blood pressure. 
8. Have an active uncontrolled infection, including, but not limited to, the requirement for intravenous 
antibiotics. 
9. Patients with a known allergy or hypersensitivity to any component of the study drug. Patients with a 
history of Stevens-Johnson syndrome on a prior tyrosine kinase inhibitor (TKI) are excluded. 
10. Any active bleeding excluding hemorrhoidal or gum bleeding. 
11. For patients with a known human immunodeficiency virus (HIV) infection, have CD4+ T-cell counts 
<350 cells/uL or history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic 
infection within the past 12 months. Patients with HIV infection should be on established antiretroviral 
therapy (ART) for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrollment. 
12. Has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, as evidenced by 
detectable viral load (HBV-DNA or HCV-RNA, respectively). Risk of HBV reactivation should be 
considered in all patients and the need for anti-HBV prophylaxis should be carefully assessed. Patients 
with chronic HBV infection with history of active disease who meet the criteria for anti HBV therapy 
should be on a suppressive antiviral therapy to be eligible for enrollment. Patients who are HCV Ab 
positive but HCV RNA negative due to prior treatment or natural resolution are eligible. Patients on 
concurrent HCV treatment at the time of enrollment are allowed if HCV RNA negative. 
13. Pregnant or breastfeeding. 
14. Malabsorption syndrome or other illness that could affect oral absorption. 
15. Patients with prior or concurrent malignancies other than GIST are allowed, except in the case where, in 
the opinion of the Investigator, the natural history or treatment of the other malignancy has the potential 
to interfere with the safety or efficacy assessment of the study drug. 
16. Have any condition or illness that, in the opinion of the Investigator, might compromise patient safety or 
interfere with the evaluation of the safety of the drug. 


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Number of patients (total and for each cohort): 
Approximately 90-160 patients will be enrolled in the study, assuming the following: 
• 
Dose Escalation (Phase 1): Approximately 30-100 patients, across an estimated 5 to 10 dose levels, which 
may include expanded cohorts to better inform selection of the RP2D (i.e., backfill enrollment) 
• 
Expansion Cohorts (Phase 2) 
• 
Cohort 1: approximately 20 patients 
• 
Cohort 2: approximately 20 patients 
• 
Cohort 3: approximately 20 patients 
Approximate minimum duration of patient participation: 
3 months across the following study periods: 
• 
Screening period: 2-3 weeks 
• 
Treatment period: at least 1 cycle (28 days) 
• 
Follow-up period after last dose of study drug: 30 days 
Thereafter, patients are to be followed for subsequent antineoplastic therapy and survival approximately every 3 
months until death, withdrawal of consent or closure of the study by the Sponsor. 
Study Drug Dosage: 
THE-630 drug product will be initially supplied as 1 mg, 3 mg,  12 mg, and 20 mg hard gelatin capsules containing 
a formulated blend of excipients and THE-630 HCl. Higher strengths of capsules and/or formulated tablets will be 
introduced depending on the safety, PK, and biological activity of THE-630. 
The dose escalation phase of the proposed phase 1/2 trial will employ sequential, dose escalation of oral THE-630 
using a standard 3+3 design, starting at a dose of 3 mg administered orally QD, and increasing in increments until 
the MTD is identified. Alternative dosing regimens may be explored depending on PK findings and safety and 
tolerability data. Should a modification be required, the dose escalation scheme will be altered by interpolating 
non-once daily schedules into the initial escalation scheme. Alternative dosing regimens will be in standalone 
cohorts and will follow the same Schedule of Events (Table 1) as outlined herein. Intermediate doses between the 
MTD and the next lower dose may be explored.  
Study Drug Administration:  
THE-630 will be administered orally QD with a glass of water (at least 8 ounces or 250 mL) in a fasted state, with 
no food intake from 2 hours before until 1 hour after study drug administration. 
Each dose should be administered at approximately the same time each day. Patients should be instructed to 
swallow capsules whole and to not chew the capsules. THE-630 capsules should not be opened or dissolved into 
liquid or food. If a patient vomits after taking a dose, the patient should not take an extra dose. Patients who forget 
to take or miss a dose (i.e., >6 hours after schedule time of administration) should not make up the missed dose. 
Patients will continue with the study treatment until progression of disease as determined by the Investigator, 
unacceptable toxicity, death or consent withdrawal.  
Concomitant Treatment and Additional Precautions:  
Palliative therapy and supportive care are permitted during the course of the trial for management of symptoms 
and underlying medical conditions that may develop during the study. The inclusion and exclusion criteria should 
be used to determine which medications a patient is allowed to be on at the time of screening and study entry. Once 
a patient has begun treatment, a condition may arise that requires the initiation of a new concomitant treatment.  
After a patient has begun study treatment, the addition of the following concurrent treatments are prohibited: 
1. Any other systemic anticancer therapy including, but not limited to, chemotherapeutic agents, 
immunotherapy, biological response modifiers (excluding growth factors), and/or systemic hormonal 


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therapy. Note: local radiotherapy used for palliative or symptomatic control of disease is allowed with 
appropriate treatment interruption at the discretion of the Investigator 
2. Medications that are potent inhibitors of 
, as THE-630 is observed 
to be a 
 substrate in vitro (refer to Appendix 5 for a list of these medications) 
3. Extensive surgery requiring in-patient care (patients may have an interruption in therapy for up to 4 weeks 
should emergency surgery be required) 
4. Use of any other investigational drug or device. 
In vitro, THE-630 is an inhibitor of 
. Therefore, THE-630 may have the potential to increase plasma 
concentrations of co-administered substrates of 
. Medications that are 
 substrates with a narrow 
therapeutic index should be used with caution (refer to Appendix 5 for a list of these medications). 
The effect of THE-630 in wound healing is not known; therefore, caution is advised on the grounds of potential 
antiangiogenic effect for any surgical procedures during the study. The appropriate interval of time between surgery 
and THE-630 required to minimize the risk of impaired wound healing and bleeding has not been determined. In 
the event unexpected major surgery is necessary during study participation, THE-630 dosing should be stopped 1 
week prior to surgery. After major surgery, THE-630 should not be administered for at least 2 weeks and until 
clinical assessment of satisfactory wound healing. 
The light absorption characteristics of THE-630 suggest the possibility that THE-630 treatment will be associated 
with phototoxicity. Patients should be advised to apply sunscreen and wear appropriate clothing to avoid direct sun 
exposure. Patients should also be advised to avoid high intensity ultraviolet B (UVB) sources such as tanning beds, 
tanning booths and sunlamps. 
Safety Evaluation: 
Safety assessments will include physical and laboratory examinations, vital signs, and ECGs. Adverse events (AEs) 
will be graded according to the National Cancer Institute (of the United States) Common Terminology Criteria for 
Adverse Events (NCI CTCAE v5.0) (Appendix 3). Periodic meetings with study investigators will be held to assess 
safety data during the dose escalation phase. All patients receiving at least 1 dose of THE-630 will be considered 
evaluable for safety. The AE incidence rates, as well as the frequency of overall toxicity, categorized by toxicity 
grades (severity), will be described. Listings of laboratory test results will also be generated, and descriptive 
statistics summarizing the changes in laboratory tests over time will be presented. 
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) 
The MTD is defined as the highest dose at which ≤1 of 6 DLT-assessment eligible patients experience a DLT 
within the first 28 days of treatment (end of Cycle 1). To be eligible for the DLT assessment, patients must complete 
at least 75% of their planned doses within Cycle 1, unless missed doses are due to AEs. The cohort may be 
expanded to better define the safety profile for confirmation of the MTD. The maximum administered dose in the 
trial will likely exceed the MTD. The RP2D is the MTD or less. An RP2D less than the MTD may be chosen if 
aspects of tolerability or efficacy not encompassed by the MTD determination suggest utilizing a lower dose.  
Dose-Limiting Toxicities (DLTs) 
A DLT is defined as any treatment-emergent AE meeting the criteria listed below occurring within the first 28 days 
of treatment (end of Cycle 1) for which relationship to THE-630 cannot be ruled out. For patients who are approved 
for intra-patient dose escalation to a dose shown to not exceed the MTD, any AEs observed at a dose above their 
starting dose will not be classified as DLTs. Toxicity grades will be defined by the NCI CTCAE v5.0 (Appendix 3).  
DLTs are defined by the following when occurring during Cycle 1 and relationship to THE-630 cannot be ruled 
out: 
• 
Non-hematologic toxicities 
o 
Any ≥ grade 3 non-hematologic toxicity, with the exception of: 
 
Self-limiting or medically controllable toxicities (e.g., nausea, fatigue, electrolyte 
disturbances) lasting ≤3 days 
 
Grade 3 vomiting or diarrhea lasting ≤ 3 days  


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 
Grade 3 elevations of creatine kinase (CK) that are asymptomatic, i.e., not accompanied by 
muscle pain or worsening renal function or other signs of rhabdomyolysis or cardiac muscle 
damage (such as abnormal CK-MB, Troponin) and recovered to ≤Grade 1 or baseline in <72 
hours 
 
Grade 3 hypertension that recovers to Grade 2 or below within 5 days  
 
Alopecia 
• 
Hematologic toxicities 
o 
Febrile neutropenia (fever, >101°F [>38.3°C]; ANC <0.5 × 109/L) 
o 
Prolonged grade 4 neutropenia (≥7 days) 
o 
Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection 
o 
Thrombocytopenia ≥ grade 3 with bleeding or grade 4 without bleeding lasting ≥7 days 
• 
Missed ≥25% of planned doses of THE-630 (in the aggregate, not necessarily consecutive) over 28 days due 
to AEs for which the relationship to THE-630 cannot be ruled out in the first cycle 
QT Interval Evaluation: 
The following ECG assessments will be required: triplicate ECGs at baseline on Cycle 1, Day 1 (C1D1) before the 
first administration of THE-630 and at 8 hours after dosing of THE-630; and triplicate ECGs on Cycle 1, Day 15 
prior to administration of the C1D15 dose; and at 1, 2, 4, and 8 hours after dosing of THE-630, corresponding to 
PK sampling timepoints. Adjustments to the timing of triplicate ECGs on C1D15 may be made based on the PK 
findings in the dose escalation phase. The ECG performed at screening and ECGs done after C1D15 may be a 
single ECG. ECGs will be recorded electronically and will be evaluated centrally. 
Pharmacokinetic Evaluation: 
Blood samples will be collected at pre-specified time points (see Pharmacokinetic and Electrocardiogram Schedule 
of Events (Table 2)) to assess the plasma concentrations of THE-630 and its active metabolite THE-973 following 
a single dose and multiple doses (steady state) of THE-630 in the dose escalation cohorts. PK parameters, such as 
time of maximum concentration, maximum concentration, area under the concentration-time curve, clearance, 
volume of distribution, terminal half-life, and accumulation ratio, will be estimated where possible. PK evaluation 
will also be performed for the expansion cohorts to obtain cohort-specific PK at the recommended dose established 
in the dose escalation phase of the trial. PK sampling time points are initially planned to be the same as the sampling 
time points in the dose escalation phase; however, adjustments may be made based on the PK findings in the dose 
escalation phase. 
Efficacy Evaluation: 
Efficacy will be assessed by the Investigator based on modified RECIST 1.1 for patients with GIST (Appendix 1). 
Disease assessment will be based on local magnetic resonance imaging (MRI) or computed tomography (CT) scans 
performed at the timepoints outlined in the Schedule of Events (Table 1). MRI and CT scans will be reviewed 
locally at the study center, ideally by the same individual for each patient at each time point. All radiographic 
images (e.g., CT scan, MRI) performed during the trial will be submitted to and stored by an imaging core lab for 
future independent evaluation as appropriate. 
Modifications to RECIST 1.1 For Patients with GIST (Demetri, 2013) 
1. No lymph nodes to be chosen as target lesions. Enlarged lymph nodes are to be followed up as non-target 
lesions 
2. No bone lesions to be chosen as target lesions 
3. 
18Fluorodeoxyglucose positron emission tomography (18FDG-PET) is not acceptable for radiological 
assessment 
4. A progressively growing new tumor nodule within a pre-existing tumor mass must meet the following 
criteria in order to be regarded as unequivocal evidence of progressive disease according to the 
aforementioned GIST-specific modifications to RECIST 1.1: 
a. 
The lesion must be ≥ 2 cm in size and definitely be a new active GIST lesion (e.g., enhanced 
with contrast or other criteria to rule out artifact); or  
b. The lesion must be expanding on at least 2 sequential imaging studies. 


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Exploratory Biomarker Evaluation: 
The mutation status of KIT, PDGFRA, and other genes implicated in tumor biology and/or drug metabolism may 
be determined through analyses of tumor tissue and blood plasma samples to evaluate biomarkers of THE-630 
efficacy and safety. 
Statistical analysis:   
Descriptive statistics and analyses will be provided for each dose level, and for patients combined across dose 
levels where applicable. All patients who receive at least 1 dose of THE-630 will be included in the safety analysis. 
For the expansion cohorts, estimates of clinical activity, including ORR, time to response and DOR, DCR, CBR, 
best target lesion response, PFS, and OS will be provided.  
Pharmacokinetic Analysis 
Where possible the following PK parameters (as appropriate) will be determined for THE-630 and its active 
metabolite THE-973. 
Following a single oral dose: 
Maximum plasma concentration (Cmax), time to Cmax (tmax), terminal phase half-life (t½λz), area under the plasma 
concentration-time curve from time zero to 24 hours (AUC0-24), from time zero to the time of the last measurable 
concentration (AUC0-t) and from time zero to infinity (AUC0-∞), apparent plasma clearance (CL/F), and apparent 
volume of distribution (V/F). Dose linearity for Cmax and AUC will be assessed. 
Following multiple oral doses (steady state): 
Maximum plasma concentration at steady state (Css,max), time to Css,max (tmax), area under the plasma concentration-
time curve from time zero to the end of the dosing interval (AUC0-τ), apparent plasma clearance at steady state 
(CLss/F), volume of distribution during terminal phase (Vz/F), and extent of accumulation on multiple dosing (RAC). 
Dose linearity for Cmax and AUC will be assessed. 
QTc Analysis 
Descriptive statistics of maximum QTcF and change from baseline will be calculated following the International 
Conference on Harmonisation (ICH) E14 guidelines: the proportion of treated patients with at least 1 on drug QTcF 
value >450 msec, 480 msec, and 500 msec; the proportion of treated patients with a maximum change in QTcF 
from baseline >30 msec and >60 msec. The Fridericia correction (QTcF) will be used throughout. The association 
between QTcF changes and plasma levels of THE-630 will be analyzed using mixed effects models (ICH E14, 
2017). 
Rationale for Number of Patients:   
The purpose of this phase 1/2 trial is to determine the RP2D and MTD, as well as evaluate the safety, tolerability, 
and anti-tumor activity of oral THE-630. The sample size for Phase 1 (dose escalation) is dependent upon the 
observed safety profile, which will determine the number of patients per dose cohort, as well as the number of dose 
escalations required to achieve the MTD or identify the RP2D. With this design, the estimate of the rate of DLT at 
the MTD is in the range of 0.17 to 0.26. The estimate of the rate of DLT at the highest dose, which is 1 step above 
the MTD, is 0.33 (Ting, 2006). 
The Phase 2 expansion cohorts will facilitate obtaining estimates of clinical activity in different GIST patient 
populations defined by prior therapy. 20 patients each in Expansion Cohorts 1, 2 and 3 will allow an estimate of 
ORR with the 95% confidence interval half width no larger than 23% for a given cohort. 


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Table 1 
Schedule of Events 
Assessment/Procedures 
Screening1  
Cycle 1 
Cycle 2 
Every 4 
weeks 
Every 8 
weeks 
End of 
Treatment21 
30 Days 
After Last 
Dose22 
Follow
-up23 
Cycle Day 
 
D1 
D2 
D8 
D15 
D16 
D1 
 
 
 
 
 
Window (Days) 
-14 
 
 
± 1 
± 2 
± 2 
± 3 
± 7 
± 717 
± 7 
± 7 
± 14 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics3 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history4 
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and cancer history5 
X 
 
 
 
 
 
 
 
 
 
 
 
Mutation status6 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior cancer therapy7 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination8 
X 
X1 
 
 
 
 
X 
X 
 
X 
 
 
Vital signs9 
X 
X1 
 
X 
X 
 
X 
X 
 
X 
 
 
ECOG Performance Status 
X 
X1 
 
 
 
 
X 
X 
 
X 
 
 
Hematology/chemistry/coagulation10 
X11 
X1, 11 
 
X 
X 
 
X11 
X 
 
X11 
 
 
Urinalysis (dipstick)10 
X 
X1 
 
X 
X 
 
X 
X 
 
X 
 
 
Pregnancy test12 
X 
X1 
 
 
 
 
 
X (every 
12 weeks) 
 
X 
 
 
12-lead Electrocardiogram (ECG)  
See Table 2 
 
 
Echocardiogram/MUGA Scan13 
X 
 
 
 
 
 
 
X (every 
12 weeks) 
 
X 
 
 
THE-630 Administration14 
 
DAILY  
 
 
THE-630 Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events/prior & concomitant 
medications15,16 
X 
THROUGHOUT THE STUDY 
 
PK sampling 
 
See Table 2 
 
 
 
 
Disease assessment17 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Tissue for exploratory biomarker studies18 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for exploratory biomarker 
studies19 
 
X 
 
 
 
 
X 
 
X 
(Starting 
C3D1) 
X (at disease 
progression) 
 
 
Tissue sample at disease progression20 
 
 
 
 
 
 
 
 
 
X (at disease 
progression) 
 
 
Subsequent anticancer therapy/survival  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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1. Screening assessments must be performed no more than 14 days prior to C1D1. The allowable window for the tumor imaging screening 
assessment is 28 days prior to C1D1. However, whenever feasible, baseline imaging should be performed as close as possible to C1D1. Vital 
signs should be repeated on C1D1 prior to first dose, regardless of the time from screening. Physical examination, ECOG Performance Status 
assessments, hematology, chemistry (including Troponin T), coagulation, urinalysis, and pregnancy test assessments do not need to be repeated 
on C1D1 if they were performed for screening within 7 days prior to C1D1 and, in the opinion of the Investigator, there is no reason to believe 
they have substantially changed. 
2. Informed consent, documented by a signed and dated consent form, must be obtained prior to any screening activities that are not otherwise 
considered part of normal patient care. Informed consent can be signed prior to the 14-day window. The screening period begins with informed 
consent signature. 
3. Demographic information will be obtained at screening, and consists of the patient’s age, sex, race, and ethnicity (as allowed by local law and 
regulations). 
4. A complete medical history will be taken at screening. Information to be documented includes relevant past illnesses, smoking history, ongoing 
medical conditions, and surgical procedures (not related to the primary diagnosis). 
5. The initial cancer diagnosis and the current cancer stage at the time of screening, along with tumor histology and all sites of disease, should be 
recorded. 
6. Known mutation status at screening (e.g., activating and resistance mutations in KIT and PDGFRA, as well as other previously identified 
abnormalities in other genes) should be recorded. Information on the specific point mutations, deletions, insertions, or gene rearrangements 
observed should be recorded, if available. 
7. Information regarding prior cancer therapy will be taken at screening, and includes cancer-related surgical procedures, radiation, and systemic 
therapies. Surgical procedures include curative and palliative, as well as diagnostic procedures (e.g., biopsy). Radiation will include both 
definitive and palliative treatment. Systemic therapy includes all regimens given, type of regimen (e.g., neo-adjuvant, adjuvant, for 
advanced/metastatic disease), each drug name in a regimen, the start and stop dates of each drug, the best response to the regimen, and the reason 
for discontinuation. Experimental or investigational therapy history must also be recorded. 
8. A complete physical examination, as defined in the protocol, must be performed at screening, the extent of which should be consistent with 
medical history and the patient’s underlying disease. Subsequent physical examinations may be directed to relevant findings. The End-of-
Treatment physical examination should be a complete physical examination.  
9. Vital signs include temperature, pulse, respiratory rate, and blood pressure (after patient is seated for 5 minutes). In addition, the screening 
assessment must include height and weight. Vital signs should be repeated on C1D1 prior to first dose, regardless of the time from screening.  
10. Hematology, serum chemistry, coagulation and urinalysis assessments will be performed locally according to the Schedule of Events throughout 
the study. Hematology assessments will include complete blood count (CBC) with 5-part differential, hemoglobin, and platelet count. Chemistry 
assessments will include the following: sodium, potassium, chloride, bicarbonate (or total carbon dioxide), blood urea nitrogen (BUN), creatinine, 
glucose, albumin, total protein, aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]), alanine transaminase 
(ALT/serum glutamic pyruvic transaminase [SGPT]), bilirubin (at least total and direct, or total and indirect), alkaline phosphatase, magnesium, 
phosphorous, calcium, creatine kinase (CK), amylase, and lipase. Coagulation studies include international normalized ratio (INR) and activated 
partial thromboplastin time (aPTT). If coagulation studies are within the normal range through C3D1 then they can be discontinued and obtained 
only as clinically indicated. Urinalysis (dipstick) will include pH, specific gravity, protein, ketone, glucose, urobilinogen, and occult blood.  
11. Troponin T will be obtained at screening, C1D1, C2D1, and at the End-of-Treatment visits, only. 


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12. The pregnancy test will be performed locally and must be a beta-human chorionic gonadotropin (β-HCG) test, and either urine or serum can be 
used. Women who are not of childbearing potential (status post-hysterectomy, status post-bilateral oophorectomy, or post-menopausal [defined 
as amenorrhea for at least 12 months]) and men do not need to have the test performed. Women of childbearing potential at study start must also 
complete the pregnancy test once every 12 weeks thereafter (i.e., C4D1, C7D1, etc.) and at the End-of-Treatment visit. If required by local 
standard medical practice, more frequent pregnancy testing is allowed. 
13. Echocardiogram or multiple gated acquisition (MUGA) scan will be performed at screening and once every 12 weeks after study start (i.e., C4D1, 
C7D1, etc.) and at the End-of-Treatment visit. Echocardiograms or MUGA scans will be performed locally in accordance with the institution’s 
standard practice. The same modality should be used throughout the study. 
14. THE-630 doses should be administered with a glass of water (at least 8 ounces or 250 mL) in a fasted state, with no food intake from 2 hours 
before until 1 hour after study drug administration.  Each dose should be administered at approximately the same time each day.  
15. AEs are to be recorded continuously from the time of informed consent throughout the entire study until at least 30 days after the last dose of 
study drug and graded per NCI CTCAE v5.0 (Appendix 3). Once a patient is deemed a screen failure, AE collection is no longer required. Beyond 
30 days after the last dose, ongoing AEs for which the relationship to THE-630 cannot be ruled out, and all ongoing serious adverse events 
(SAEs) should be followed at least every 4 weeks until they resolve to baseline (or to NCI CTCAE v5.0 grade ≤1), stabilize, or are considered 
to be chronic/irreversible. 
16. Prior medications include all treatment (including herbal treatments, vitamins, non-pharmacological treatment such as psychotherapy as 
appropriate) received within 30 days of and discontinued prior to the date of first dose of study drug. Concomitant treatments for all ongoing 
medical history conditions or AEs, as well as prophylactic treatments and supplements, must be reported from the date the informed consent is 
signed until at least 30 days after the last dose, and for all concomitant treatments related to serious toxicities or toxicities for which relationship 
to THE-630 cannot be ruled out until the medication is no longer taken or until patient contact discontinues. 
17. CT with intravenous (IV) contrast of the chest, and CT or MRI with IV contrast of the abdomen and pelvis will be performed at screening. At 
subsequent time points all body regions that contained sites of disease (target or non-target) at screening will be imaged. If a patient is not tolerant 
of IV contrast, non-contrast CT or MRI may be performed. For each patient, the same method of tumor imaging used at baseline should be used 
throughout the study. Disease assessment by CT and MRI scans will be performed at screening and at 8-week intervals thereafter (on Day 28 [±3 
days] of every even-numbered cycle), through Cycle 12 after the initial dose of study drug, and every 3 cycles thereafter until disease progression. 
More frequent imaging is recommended at any time if clinically indicated; confirmation of complete response (CR) or partial response (PR) 
should be performed at least 4 weeks after initial response. Imaging assessment will also be performed at End of Treatment if more than 4 weeks 
have passed since the last imaging assessment and progression had not previously been documented. All radiographic images (e.g., CT scan, 
MRI) performed during the trial will be submitted to and stored by an imaging core lab for future independent evaluation as appropriate.  
18. At screening, all patients must be confirmed to have availability of archival FFPE tumor tissue, or provide a new FFPE tumor tissue sample, for 
exploratory biomarker studies to be processed centrally, including molecular genetic analysis of KIT, PDGFRA, and other genes implicated in 
tumor biology. Refer to Laboratory Manual for tissue requirements. 
19. At the following timepoints: C1D1 (pre-dose), C2D1, C3D1 and on day 1 of every odd cycle post C3 through C11, and upon disease progression, 
a blood sample (approximately 20 mL) will be collected and processed centrally for exploratory biomarker studies to evaluate circulating 
biomarkers associated with THE-630 efficacy and toxicity. 
20. An optional biopsy will be taken at the time of disease progression on THE-630 for patients who consent to the procedure. FFPE tumor tissue 
will be processed centrally and used for exploratory biomarker studies, including molecular genetic analysis of KIT, PDGFRA, and other genes 
implicated in tumor biology. 


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21. End-of-Treatment assessments must be performed within 14 days (±7 days) of the patient’s last dose of study drug or the patient/Investigator 
decision to discontinue study treatment, whichever occurs later. Physical examinations, laboratory tests (hematology/chemistry/coagulation, 
urinalysis (dipstick), and pregnancy test), ECG and echocardiogram/MUGA can be omitted if they had been previously performed within 14 
days since the last assessments and if, in the Investigator’s judgment, significant change is unlikely. 
22. The 30 Days After Last Dose assessments, which include monitoring of AEs and concomitant medications, must be performed 30 days (±7 days) 
after the last dose of study drug. The 30 Days After Last Dose visit may be performed by phone. 
23. Follow-up assessments (i.e., contacting the patient for survival and subsequent anticancer therapy) must be performed every 12 weeks (±14 days) 
after the End-of-Treatment assessment through patient death, loss to follow-up, or withdrawal of consent, whichever occurs first. All new 
systemic anticancer therapies should be reported. 
 
 


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Table 2  
Pharmacokinetic and Electrocardiogram Schedule of Events 
Cycle Day 
Screening 
Cycle 1 
Cycle 2 
D1 
Cycle 3 
D1 
Every 4 
weeks 
End of 
Treatment 
D1 
D2 
D8 
D15 
D16 
Window (Days) 
-14 
 
 
± 1 
± 2 
± 2 
± 3 
± 7 
± 7 
± 7 
Assessment/ 
Timepoint 
Single 
ECG1 
PK2 
Triplicate 
ECG1 
PK2 
PK2 
PK2 
Triplicate 
ECG1 
PK2 
PK2 
Single 
ECG1 
PK2 
Single 
ECG1 
Single 
ECG1 
Single 
ECG1 
Any time 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pre-dose 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
0.5-hour post-dose  
+/- 5 min 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
1-hour post-dose 
+/- 5 min 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
2-hour post-dose 
+/- 10 min 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
4-hour post-dose 
+/- 10 min 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
6-hour post-dose 
+/- 10 min 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
8-hour post-dose 
+/- 10 min 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
1. ECGs should be conducted after at least 5 minutes of recumbency or semi-recumbency. An ECG is required at screening to determine eligibility; 
this may be a single ECG. Triplicate ECGs must be taken on C1D1 and C1D15. Triplicate ECGs should be taken 1 to 2 minutes apart over a 5-
minute timeframe. ECG measurements should coincide with the PK measurements that have the same time points. As such, triplicate ECGs 
should be taken directly before obtaining the PK sample at the allotted time points on C1D1 and C1D15. Adjustments to the timing of triplicate 
ECGs on C1D15 may be made based on the PK findings in the dose escalation phase. Subsequent ECGs (after C1D15) only need to be done 
once. Additional ECGs may be performed at the Investigator’s discretion to ensure patient safety. In particular, ECG monitoring should be 
performed during the study if a patient has, during the study, been prescribed medication that can prolong the QT interval or medication that can 
potentially alter the QT interval. ECGs will be recorded electronically and will be evaluated centrally. For consistency, the Fridericia correction 
– QTcF – method must be used for all calculations of QTc intervals. 
2. Blood samples will be collected at pre-specified time points (pre- and post-dosing) and processed centrally to assess the plasma concentrations 
of THE-630 and its active metabolite THE-973 and pharmacokinetic parameters following a single dose and multiple doses (steady state), in 
both the dose escalation and expansion cohorts. For patients in the dose escalation phase, blood samples will be collected according to the 
schedule in Table 2. Pre-dose samples on C1D2 and C1D16 should be collected 24 hours [±60 minutes] after the dose on the previous day. For 
the expansion cohorts, PK sampling time points are initially planned to be the same as the sampling time points described above for the dose 
escalation phase; however, adjustments may be made based on the PK findings in the dose escalation phase. 
 


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TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ............................................................................................. 2 
PROTOCOL SIGNATURE PAGE ................................................................................................ 3 
INVESTIGATOR SIGNATURE PAGE ........................................................................................ 4 
EMERGENCY CONTACT INFORMATION ............................................................................... 5 
STUDY SYNOPSIS ....................................................................................................................... 6 
TABLE OF CONTENTS .............................................................................................................. 20 
LIST OF TABLES ........................................................................................................................ 25 
LIST OF FIGURES ...................................................................................................................... 25 
ABBREVIATIONS ...................................................................................................................... 26 
1. 
BACKGROUND INFORMATION ...................................................................................... 30 
1.1 
Gastrointestinal Stromal Tumor (GIST) .................................................................... 30 
1.1.1 
Unmet Medical Need and Current Available Therapies ............................. 30 
1.2 
THE-630 Background ................................................................................................ 32 
1.2.1 
Preclinical Information ................................................................................ 32 
1.2.2 
Clinical Trial Experience ............................................................................ 35 
2. 
STUDY OBJECTIVES AND PURPOSE ............................................................................. 35 
2.1 
Rationale for the Study .............................................................................................. 35 
2.1.1 
Rationale for Clinical Development ............................................................ 35 
2.1.2 
Selection of Starting Dose ........................................................................... 36 
2.1.3 
Potential Risks and Benefits ........................................................................ 36 
2.2 
Study Objectives ........................................................................................................ 37 
2.2.1 
Dose Escalation (Phase 1) ........................................................................... 37 
Primary Objective ............................................................................................ 37 
Secondary Objectives ....................................................................................... 37 
2.2.2 
Expansion Cohorts (Phase 2) ...................................................................... 37 
Primary Objective ............................................................................................ 37 
Secondary Objectives ....................................................................................... 37 
2.2.3 
Exploratory Objective (both Phases) ........................................................... 37 
3. 
EXPERIMENTAL PLAN ..................................................................................................... 37 
3.1 
Study Design .............................................................................................................. 37 


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3.2 
Number and Type of Patients .................................................................................... 38 
3.3 
Study Duration ........................................................................................................... 39 
3.3.1 
Approximate Duration of Patient Participation ........................................... 39 
3.3.2 
Approximate Duration of Study .................................................................. 39 
3.4 
Sites and Regions ....................................................................................................... 40 
4. 
PATIENT ELIGIBILITY ...................................................................................................... 40 
4.1 
Inclusion Criteria ....................................................................................................... 40 
4.2 
Exclusion Criteria ...................................................................................................... 42 
4.3 
Reproductive Potential ............................................................................................... 43 
5. 
STUDY TREATMENT ......................................................................................................... 44 
5.1 
Study Drug ................................................................................................................. 44 
5.2 
Study Drug Administration........................................................................................ 44 
5.3 
Dose Escalation Scheme ............................................................................................ 44 
5.4 
Definition of Dose-Limiting Toxicity ....................................................................... 46 
5.5 
Definition of Maximum Tolerated Dose and Recommended Phase 2 Dose ............. 47 
5.6 
Dose Modifications .................................................................................................... 48 
5.6.1 
Intra-patient Dose Escalation ...................................................................... 48 
5.7 
Prior and Concomitant Therapy ................................................................................. 49 
5.7.1 
Prior Therapy and Procedures ..................................................................... 49 
5.7.2 
Concomitant Therapy and Procedures ........................................................ 50 
5.7.3 
Additional Precautions ................................................................................ 50 
5.7.4 
Treatment Compliance ................................................................................ 51 
5.8 
Withdrawal of Patients .............................................................................................. 51 
5.8.1 
Patient Discontinuation ............................................................................... 51 
5.8.2 
Patients ‘Lost to Follow-up’ Prior to Last Scheduled Visit ........................ 52 
5.9 
Treatment Supply ....................................................................................................... 52 
5.9.1 
Blinding ....................................................................................................... 52 
5.9.2 
Formulation, Packaging, and Labeling ....................................................... 52 
5.9.2.1 Storage ......................................................................................................... 53 
5.10 
Study Drug Quality Complaints ................................................................................ 53 
5.11 
Study Drug Accountability ........................................................................................ 53 
6. 
STUDY PROCEDURES ....................................................................................................... 54 
6.1 
Study Schedule .......................................................................................................... 54 


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6.2 
Screening Period ........................................................................................................ 54 
6.2.1 
Rescreening ................................................................................................. 55 
6.3 
Treatment Period ....................................................................................................... 55 
6.3.1 
Cycle 1 Day 1 .............................................................................................. 55 
6.3.2 
Cycle 1 Day 2 .............................................................................................. 56 
6.3.3 
Cycle 1 Day 8 .............................................................................................. 56 
6.3.4 
Cycle 1 Day 15 ............................................................................................ 57 
6.3.5 
Cycle 1 Day 16 ............................................................................................ 57 
6.3.6 
Cycle 2 Day 1 .............................................................................................. 57 
6.3.7 
Cycle 2 Day 28 and Day 28 of All Even Cycles Through Cycle 12 and 
every 3 Cycles Thereafter............................................................................ 58 
6.3.8 
Cycle 3 Day 1 .............................................................................................. 58 
6.3.9 
Cycle 4 Day 1 and Day 1 of all Subsequent Cycles .................................... 58 
6.3.10 
Additional Cycles ........................................................................................ 59 
6.3.11 
End of Treatment ......................................................................................... 59 
6.4 
Follow-up Period ....................................................................................................... 60 
6.4.1 
30 Days After Last Dose ............................................................................. 60 
6.4.2 
Survival Follow-up ...................................................................................... 60 
7. 
DESCRIPTION OF STUDY ASSESSMENTS .................................................................... 60 
7.1 
Pretreatment Assessments ......................................................................................... 60 
7.1.1 
Demography ................................................................................................ 60 
7.1.2 
Medical History ........................................................................................... 60 
7.1.3 
Diagnosis, Cancer History, and Prior Cancer Therapy ............................... 60 
7.1.4 
Mutation Status ........................................................................................... 61 
7.2 
Efficacy Assessments ................................................................................................ 61 
7.2.1 
Disease Assessment and Tumor Imaging .................................................... 61 
7.3 
Safety Assessments .................................................................................................... 61 
7.3.1 
Physical Examination .................................................................................. 61 
7.3.2 
Vital Signs ................................................................................................... 62 
7.3.3 
ECOG Performance Status .......................................................................... 62 
7.3.4 
Clinical Laboratory Evaluations .................................................................. 62 
7.3.5 
Pregnancy Test ............................................................................................ 64 
7.3.6 
Pharmacokinetics ........................................................................................ 64 


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7.3.7 
Electrocardiogram ....................................................................................... 65 
7.3.8 
Echocardiograms/MUGA ............................................................................ 65 
7.3.9 
Adverse Event Collection ............................................................................ 65 
7.4 
Exploratory Assessments ........................................................................................... 65 
7.4.1 
Biomarkers/ Molecular Genetic Analysis ................................................... 65 
7.5 
Sample Collection, Storage and Shipping ................................................................. 66 
7.6 
Considerations for Phase 2 Expansion ...................................................................... 66 
8. 
ADVERSE EVENT DATA COLLECTION AND REPORTING ....................................... 67 
8.1 
Reference Safety Information .................................................................................... 67 
8.2 
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
 ................................................................................................................................... 67 
8.2.1 
Severity Categorization ............................................................................... 67 
8.2.2 
Relationship Categorization ........................................................................ 68 
8.2.3 
Outcome Categorization .............................................................................. 68 
8.2.4 
Symptoms of the Disease Under Study ....................................................... 69 
8.2.5 
Clinical Laboratory Evaluations .................................................................. 69 
8.2.6 
Pregnancy .................................................................................................... 69 
8.2.7 
Abuse, Misuse, Overdose, and Medication Error ....................................... 70 
8.3 
Serious Adverse Events ............................................................................................. 71 
8.3.1 
Serious Adverse Event Definition ............................................................... 71 
8.3.2 
SAE Reporting Procedures .......................................................................... 72 
8.3.3 
Information to be Provided by the Investigator for a SAE ......................... 72 
8.3.4 
Follow-up Information on a SAE ................................................................ 72 
8.3.5 
Serious Adverse Event Collection Timeframe ............................................ 72 
8.3.6 
Serious Adverse Event Onset and Resolution Dates ................................... 73 
8.3.7 
Fatal Outcome ............................................................................................. 73 
8.3.8 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting ................................................................... 73 
9. 
STATISTICAL CONSIDERATIONS .................................................................................. 74 
9.1 
General Considerations .............................................................................................. 74 
9.2 
Analysis Populations ................................................................................................. 74 
9.3 
Study Endpoints ......................................................................................................... 75 
9.3.1 
Primary Endpoints ....................................................................................... 75 


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9.3.2 
Secondary Endpoints ................................................................................... 75 
9.3.3 
Other Endpoints ........................................................................................... 75 
9.3.4 
Definition of Efficacy Endpoints ................................................................ 76 
9.4 
Determination of Sample Size ................................................................................... 76 
9.5 
Efficacy Analysis ....................................................................................................... 77 
9.6 
Safety Analysis .......................................................................................................... 77 
9.6.1 
Pharmacokinetic Analysis ........................................................................... 78 
9.6.2 
QTcF Analysis ............................................................................................. 78 
9.7 
Protocol Deviations/Violations .................................................................................. 79 
10. ADMINISTRATIVE PROCEDURES .................................................................................. 79 
10.1 
Institutional Review Board or Independent Ethics Committee ................................. 79 
10.2 
Informed Consent ...................................................................................................... 79 
10.3 
Patient Privacy ........................................................................................................... 80 
10.4 
Study Monitoring ....................................................................................................... 81 
10.5 
Changes to the Protocol ............................................................................................. 81 
10.6 
Adherence to the Protocol ......................................................................................... 82 
10.7 
Recording, Access, and Retention of Source Data .................................................... 82 
10.7.1 
Case Report Forms ...................................................................................... 82 
10.8 
Study or Site Termination .......................................................................................... 83 
10.9 
Financial Disclosure .................................................................................................. 84 
10.10 Good Clinical Practice Compliance........................................................................... 85 
10.10.1 Quality Control and Quality Assurance ...................................................... 85 
10.10.2 Publications ................................................................................................. 85 
10.10.3 Audit/Inspection .......................................................................................... 86 
10.10.4 Indemnity/Liability and Insurance .............................................................. 86 
11. REFERENCES ...................................................................................................................... 87 
12. APPENDICES ....................................................................................................................... 90 
12.1 
Appendix 1: Modifications to Response Evaluation Criteria in Solid Tumors version 
1.1 (RECIST 1.1), for Patients with GIST................................................................. 91 
12.2 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale ........................................................................................................................... 95 
12.3 
Appendix 3: Common Terminology Criteria for Adverse Events (v5.0) .................. 96 
12.4 
Appendix 4: New York Heart Association (NYHA) Classification .......................... 97 


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12.5 
Appendix 5. Potent Inhibitors of 
 and Substrates of 
 with Narrow 
Therapeutic Index ...................................................................................................... 98 
12.6 
Appendix 6. Protocol Amendment Summary of Changes and Rationale ................. 99 
LIST OF TABLES 
Table 1 
Schedule of Events ..................................................................................................... 15 
Table 2  
Pharmacokinetic and Electrocardiogram Schedule of Events ................................... 19 
Table 3 
Dose Escalation Procedures ....................................................................................... 44 
Table 4 
Definition of Dose-Limiting Toxicities* ................................................................... 47 
Table 5 
Dose Modification Guidelines ................................................................................... 48 
Table 6 
Excluded Prior Therapy and Washout Periods .......................................................... 49 
Table 7 
Excluded Concomitant Treatment ............................................................................. 50 
Table 8 
Clinical Laboratory Tests ........................................................................................... 64 
 
LIST OF FIGURES 
Figure 1 
Relationship Between Levels of Exposure in Humans for Approved KIT TKIs and 
Potency in Cellular Assays Performed in the Presence of Human Serum Proteins ... 33 
Figure 2 
Study Design Flow Chart ........................................................................................... 39 
Figure 3 
Example Dose Escalation Schema ............................................................................. 45 
 


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ABBREVIATIONS 
AAG 
α1-acid glycoprotein 
ADL 
activities of daily living 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase (SGPT) 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ART 
antiretroviral therapy 
AST 
aspartate transaminase (SGOT) 
ATP 
adenosine triphosphate 
AUC 
area under the curve 
 
 
BUN 
blood urea nitrogen 
Cav 
average concentration 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CDER 
Center for Drug Evaluation and Research 
cDNA 
complementary deoxyribonucleic acid 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CL/F 
apparent total clearance of drug from plasma 
CLss/F 
apparent plasma clearance at steady state 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CR 
complete response 
CS 
clinically significant 
Css 
plasma concentration at steady state 
CT 
computed tomography 
CRO 
contract research organization 
CYP 
cytochrome 
DCR 
disease control rate 


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DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FIH 
first in human 
FMO 
flavin monooxygenases 
FOCP 
females of child-bearing potential 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HSA 
human serum albumin 
IB 
investigator’s brochure 
ICCs 
interstitial cells of Cajal 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
The International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
IV 
Intravenous 


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MAPK 
mitogen-activated protein kinase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/kg 
milligrams per kilogram 
MHRA 
Medicines and Healthcare Products Regulatory Agency (UK) 
MI 
myocardial infarction 
MPV 
mean platelet volume 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCS 
not clinically significant 
nM 
nanomolar 
NOAEL 
no-observed-adverse-effect level 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PDGFRA 
platelet-derived growth factor receptor alpha 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 
QD 
once daily (may be abbreviated as “od” in the UK) 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia's formula 
RAC 
accumulation index or ratio 
RBC 
red blood cell 
RDW 
red cell distribution width 
RE 
response evaluable 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
recurrence-free survival 
RP2D 
recommended Phase 2 dose 


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RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SDH 
succinate dehydrogenase 
SOP 
standard operating procedure 
STD10 
severely toxic to 10% of tested rodents 
SUSAR 
suspected, unexpected, and serious adverse reactions 
t½λz 
terminal-phase half-life 
tmax 
time to maximum plasma concentration 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
μM 
micron 
UVB 
ultraviolet B 
V/F 
apparent volume of distribution 
Vz/F 
volume of distribution during terminal phase 
WBC 
white blood cell 
 
 


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1. 
BACKGROUND INFORMATION 
1.1 
Gastrointestinal Stromal Tumor (GIST) 
Gastrointestinal stromal tumors (GIST) are the most common form of soft tissue sarcoma, a 
relatively rare subset of cancers of mesenchymal origin. The annual worldwide incidence of GIST 
is reported to be between 11 and 19.6 cases per million population (Corless, 2014), with 
approximately 4000-6000 new cases per year in the US (Corless, 2008). Improvements in the 
surgical and oncological management of GIST have led to an increase in prevalence, which is 
estimated to be over 10‐times that of the incidence, with the number of patients living with GIST 
estimated to be 135‐155 per million per year (Søreide, 2016). Median age at diagnosis is reported 
to be in the 6th decade in most studies. Approximately half of patients with GIST have metastatic 
or unresectable disease at diagnosis. GIST originate in the interstitial cells of Cajal (ICCs), located 
in the smooth muscle across the gastrointestinal tract. GIST most frequently arise in the stomach, 
followed by the small intestine, and less frequently in colon/rectum and esophagus (Søreide, 2016).  
GIST are primarily driven by activating mutations in the receptor tyrosine kinases (RTKs) KIT 
(CD117) or PDGFRA.  Activating mutations in KIT are observed in approximately 80-85% of 
GIST and are most frequently found in exon 11 (the juxtamembrane domain) followed by exon 9 
(the extracellular domain) (Corless, 2011; Gramza, 2009). An additional approximately 10% of 
GIST contain an activating mutation in PDGFRA that are most frequently found in exon 18 (the 
activation loop) followed by exon 12 (the juxtamembrane domain) (Emile, 2012; Corless, 2014). 
These mutations in KIT and PDGFRA activate downstream signalling, leading to tumor initiation, 
growth, progression and metastasis. The remaining 5-10% of GIST are classified as wild-type for 
both KIT and PDGFRA. This group contains tumors with a diverse set of molecular drivers, 
including gain-of-function mutations in RAS or BRAF and loss-of-function mutations in NF1 that 
activate the RAS/mitogen-activated protein kinase (MAPK) pathway, deficiency in succinate 
dehydrogenase (SDH) and accumulation of the oncometabolite succinate, and a subset without any 
of the foregoing changes identified (Corless, 2011; Serrano, 2020). 
1.1.1 
Unmet Medical Need and Current Available Therapies 
Surgical resection is a potentially curative treatment for patients with localized GIST, but up to 
50% of patients will experience recurrence (Kee, 2012). A 3-year course of adjuvant therapy with 
imatinib is standard treatment for resected patients with a high risk of relapse, based on a 
randomized trial yielding a recurrence-free survival (RFS) and OS advantage of 3 years vs. 1 year 
of adjuvant treatment (GLEEVEC USPI). Radiotherapy and traditional chemotherapy have proven 
ineffective in this disease, leading to a poor prognosis for patients with advanced GIST before the 
advent of target therapies (Corless, 2014). The approval of the first KIT-targeted therapy, the TKI 
imatinib, in 2002 greatly improved outcomes for patients with metastatic or unresectable 
GIST. Imatinib therapy in this setting is not curative, but 1st line treatment yields a substantial 
median PFS of 18.9 and 23.2 months for 400 mg QD and 800 mg QD, respectively (GLEEVEC 
USPI).  While most patients receive initial clinical benefit from imatinib therapy and 
approximately 50% have an objective response to therapy, resistance inevitably develops, with 
more than half of patients progressing within 2 years. In most patients, progression is associated 
with the acquisition of secondary resistance mutations in KIT, with nearly all occurring in either 


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exons 13 or 14 (in the adenosine triphosphate (ATP) binding pocket) or exons 17 or 18 (in the 
activating loop). Significant heterogeneity of resistance mutations across different lesions, and 
even within different areas of the same lesion, is observed in TKI resistant GIST (Corless, 2014). 
Outcomes are substantially worse for patients with KIT-driven tumors who progress following 1st 
line treatment with imatinib. Multiple KIT TKIs (sunitinib, regorafenib, and ripretinib) are 
approved in an unselected GIST population, but there are limitations to their benefit. Sunitinib was 
approved in 2006 as a 2nd line therapy for GIST patients who had disease progression on or 
intolerance to imatinib. KIT exon 9 mutations are more sensitive to sunitinib compared to imatinib 
(Kee, 2012). Sunitinib also shows strong pre-clinical activity against KIT exon 13 and 14 
mutations but not mutations in exon 17 and 18 (Corless, 2014). In the post-imatinib setting, only 
6.8% of patients achieve an objective response, and 50% of all patients will have progressed by 6 
months, with resistance predominantly associated with mutations in KIT exon 17 and 18 
(SUTENT USPI; Corless, 2011). Regorafenib was approved as 3rd line treatment (after imatinib 
and sunitinib) for patients with metastatic or unresectable GIST in 2013. In this setting, regorafenib 
yielded a low ORR of 5% (Demetri, 2013). More than half of patients will progress within six 
months, with a median PFS of 4.8 months (STIVARGA USPI). More recently, in 2020, ripretinib 
was approved for 4th line GIST, in patients who have received prior treatment with 3 or more 
kinase inhibitors, including imatinib. At the primary analysis, the ORR for ripretinib in this setting 
was 9% and median PFS was 6.3 months (QINLOCK USPI).  Ripretinib has also been studied in 
the 2nd line, post-imatinib setting, in a randomized phase 3 trial compared to sunitinib. Ripretinib 
was not superior to sunitinib in terms of PFS, the primary endpoint. In the ITT population, median 
PFS was 8.0 and 8.3 months, for ripretinib and sunitinib respectively (Bauer, 2022). Finally, 
avapritinib was approved in 2020 for the treatment of patients with unresectable or metastatic 
GIST with PDGFRA exon 18 mutations, including PDGFRA D842V mutations (AYVAKIT 
USPI).  
While currently approved therapies have demonstrated potent inhibition of certain subsets of 
clinically relevant mutations in KIT, no approved drug has potent and broad activity against both 
classes of KIT resistance mutations (ATP binding pocket [exon 13/14] and activation loop [exon 
17/18]), and thus none of the TKIs approved in patients previously treated with imatinib have 
yielded robust responses both in patients with exon 13/14 mutations and exon 17/18 mutations. As 
noted above, sunitinib has potent activity against mutations in the ATP binding pocket but not in 
the activation loop. Compared to sunitinib, regorafenib has somewhat more potent activity against 
activation loop mutations, but less potent activity against ATP binding pocket mutations (Garner, 
2014). Ripretinib, while potent against mutations in the activation loop, has been shown to have 
markedly reduced anti-tumor activity against mutations in the ATP binding pocket compared to 
sunitinib in preclinical models (Banks, 2020). Importantly, refractory disease is highly 
heterogeneous, with most patients’ tumors having multiple resistance mutations present. 
Consequently, GIST patients may present with a polyclonal mix of KIT mutations that are not 
effectively treated by sunitinib, regorafenib or ripretinib. THE-630 has been developed to address 
this unmet need and offer potent inhibition of all classes of KIT activating and resistance 
mutations. 


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1.2 
THE-630 Background 
To address the limitations of existing targeted therapies in GIST and based on a structure-guided 
drug design approach, Theseus Pharmaceuticals has discovered and is developing THE-630, a 
novel, synthetic, orally administered, next-generation KIT inhibitor that has broad and potent 
activity against all major classes of activating and resistance mutations observed in KIT-mutant 
GIST patients. 
1.2.1 
Preclinical Information 
The KIT inhibitory activity of THE-630 was examined in 3 cancer cell lines: GIST-T1, Kasumi, 
and P815, which are derived from a human GIST, human acute myeloid leukemia (AML), and 
murine mastocytoma, respectively. In GIST-T1 cells, which contain an activating deletion in KIT 
exon 11 (Del560_578), THE-630 potently inhibited cell viability, KIT phosphorylation, and 
phosphorylation of signaling proteins downstream of KIT, with IC50s <10 nanomolar (nM) and 
induced a marker of apoptosis. In two cell lines that contain activating mutations in KIT exon 17, 
Kasumi (N822K mutation) and P815 (murine D814Y mutation; equivalent to human D816Y), 
THE-630 inhibited cell viability with IC50s of 2 and 33 nM, respectively. 
To broadly assess the inhibitory activity of THE-630 against major classes of KIT activating and 
resistance mutations, 17 different mutant variants of KIT were introduced into BaF3 cells, making 
cell viability dependent on the activity of the KIT variant in the absence the growth factor IL-3. 
These variants include combinations of three different activating mutations and ten different 
resistance mutations known to arise in tumors of GIST patients after treatment with imatinib and 
other KIT inhibitors. These cellular assays were performed under standard cell culture conditions 
as well as in the presence of physiologic concentrations of 2 key human serum proteins – human 
serum albumin (HSA) and α1−acid glycoprotein (AAG) –to better mimic the functional effects 
that protein binding in humans might have on drug activity.  
THE-630 potently inhibited the activity of 17 KIT variants expressed in BaF3 cells with a high 
degree of selectivity over parental BaF3 cells. The overall potency against the major classes of 
KIT activating and resistance mutations compares favorably to that of all approved KIT inhibitors 
under standard cell culture conditions and in the presence of human serum proteins. Figure 1 below 
shows 1) all 17 IC50s, determined in the presence of human serum proteins, for THE-630 and all 4 
approved KIT inhibitors, and 2) for the approved KIT inhibitors, shows TKI concentrations 
achieved in patients treated at the clinically approved dose. TKI concentrations in patients are 
represented by the average concentration (Cav) which is calculated as the Area Under the (plasma 
concentration – time) Curve over a 24-hour period, or AUC0-24h divided by 24. For imatinib, 
sunitinib, regorafenib, and ripretinib, the Cav values are 3385, 136, 5059, and 2126 nM, 
respectively (for ripretinib, this value is the sum of the Cav for ripretinib and its similarly active 
metabolite DP-5439). Based on these analyses, achieving an approximately 100 nM (54 ng/mL) 
steady-state average concentration of THE-630 in patients (equivalent to an AUC0-24h of 
approximately 1300 ng*h/mL) is predicted to be associated with potent inhibitory activity against 
all classes of activating and resistance mutations observed in KIT-mutant GIST.   










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2.2 
Study Objectives 
2.2.1 
Dose Escalation (Phase 1) 
Primary Objective 
• To determine the safety profile of oral THE-630, including the dose-limiting toxicities 
(DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D)  
Secondary Objectives 
• To determine the pharmacokinetic (PK) profile of oral THE-630 and its active metabolite 
THE-973 
• To document preliminary evidence of antitumor activity of oral THE-630 in patients with 
advanced GIST 
2.2.2 
Expansion Cohorts (Phase 2) 
Primary Objective 
• To determine the antitumor activity of oral THE-630 in patients with advanced GIST 
Secondary Objectives 
• To evaluate the safety profile of oral THE-630 
• To further characterize the PK profile of oral THE-630 and its active metabolite THE-973 
2.2.3 
Exploratory Objective (both Phases) 
• To explore associations between tumor and plasma biomarkers and THE-630 efficacy and 
safety 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 1/2, open-label, multicenter trial to evaluate the safety, pharmacokinetics, and anti-
tumor activity of THE-630 in patients with advanced GIST. The study will be conducted in two 
parts: a dose escalation phase (Phase 1) and a subsequent expansion phase (Phase 2).  
Phase 1 will employ a sequential dose escalation of oral THE-630 following a standard 3+3 design. 
Each cohort will have a minimum of 3 patients enrolled and followed for 28 days. Dose-escalation 
meetings will occur after all patients in the current cohort have either completed at least 28 days 
of observation after their first dose of THE-630 or have experienced a DLT. If no patients 
experience a DLT in the additional 3 patients (i.e., for a total of ≤1 of 6 patients with a DLT), dose 
escalation will continue until the MTD is identified. The RP2D is the MTD or less. 


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Upon identification of the RP2D, the expansion phase (Phase 2) will enroll 3 cohorts of patients 
with unresectable or metastatic GIST, with eligibility defined by prior therapy, as outlined within 
Section 4.1. Patients will continue with the study treatment until progression of disease as 
determined by the Investigator, unacceptable toxicity, death, or consent withdrawal. 
3.2 
Number and Type of Patients 
The study will include male and female patients with histologically- or cytologically-confirmed 
unresectable or metastatic GIST. The study will enroll approximately 90-160 patients total, with 
approximately 30-100 patients, across an estimated 5 to 10 dose levels, which may include 
expanded cohorts to better inform selection of the RP2D (i.e., backfill enrollment), enrolling in the 
dose escalation (Phase 1) and approximately 60 patients enrolling in the expansion (Phase 2).  
The dose escalation phase (Phase 1) will include patients who have disease progression on, or who 
are intolerant to, imatinib therapy and have also received at least 1 of the following: sunitinib, 
regorafenib, ripretinib, or avapritinib. The total number of patients to be enrolled will depend on 
the observed safety profile, which will determine the number of patients per dose cohort, as well 
as the number of dose escalations required to achieve the MTD and/or RP2D of THE-630. 
Assuming 5-10 dose levels will be studied for the QD dose schedule and a maximum of 6 patients 
will be enrolled per dose level, approximately 30 to 60 patients may be accrued during dose 
escalation.  Additional patients may be enrolled in one or more dose levels that have been shown 
to have not exceeded the MTD (up to 20 patients per dose level; up to 40 additional patients total), 
defined as backfill enrollment. This backfill enrollment will be done to better estimate the RP2D 
and better characterize the safety, pharmacokinetics, and evidence of antitumor activity of THE-
630, and backfill enrollment may be concurrent with dose escalation to identify the MTD. 
The expansion phase (Phase 2) will include 3 cohorts of patients defined by history of prior therapy 
and relative progression and intolerance. During the expansion phase, approximately 20 patients 
per cohort will be enrolled. The expansion phase of the study is designed to better characterize the 
safety, tolerability and preliminary antitumor activity of the study drug when provided at the RP2D 
and schedule. 
In Phase 2, safety reviews will be conducted after 30 and 60 Phase 2 cohort patients have been 
enrolled and treated with THE-630 for at least 28 days (enrollment will not be held for completion 
of these safety reviews). At these timepoints, patient safety will be reviewed at safety review 
meetings that includes the Study Investigators and the Sponsor’s clinical team. Safety data 
collected to date will be assessed to characterize whether any unexpected, significant, or 
unacceptable risks have been observed. In addition, throughout the study, ongoing periodic safety 
review will be undertaken by a Sponsor internal safety review team to review individual and 
summary data collected in the safety and clinical databases, including surveillance for serious 
adverse events (SAEs) according to regulatory guidelines. 
 


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Figure 2 
Study Design Flow Chart 
 
3.3 
Study Duration 
3.3.1 
Approximate Duration of Patient Participation  
The expected minimum duration of patient participation is approximately 3 months across the 
following study periods: 
• 
Screening period: 2-3 weeks 
• 
Treatment period: at least 1 cycle (28 days) 
• 
Follow-up period after last dose of study drug: 30 days 
Patients who respond to treatment will have a longer duration of participation. After treatment 
discontinuation, patients are to be followed for subsequent antineoplastic therapy and survival 
approximately every 3 months until death, withdrawal of consent or closure of the study by the 
Sponsor. 
3.3.2 
Approximate Duration of Study  
The total estimated duration of the study is approximately 4.5 years, including 2.5 years to accrue 
patients and approximately 2 years for treatment and follow-up of the last patient. The study will 
end when either all patients die or 2 years have passed since the last patient enrolled on the study 
started study treatment, whichever comes first. 


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3.4 
Sites and Regions 
This is a multi-site study with approximately 7 sites in the United States participating in the Dose 
Escalation (Phase 1). An additional approximate 18-20 sites from within the United States and 
globally will participate in the Expansion (Phase 2), and may participate in backfill enrollment in 
the Phase 1 portion of the study. 
4. 
PATIENT ELIGIBILITY 
4.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for participation in the study: 
1. Male or female patient ≥ 18 years of age. 
2. For Dose Escalation Phase Cohorts (Phase 1): 
a. Have histologically- or cytologically-confirmed unresectable or metastatic GIST.  
b. Have progressed on or are intolerant to imatinib therapy and have also received at 
least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib. 
3. For Expansion Phase Cohorts (Phase 2): 
a. Cohort 1: 
i. Have histologically- or cytologically confirmed unresectable or metastatic 
GIST. 
ii. Have progressed on or are intolerant to imatinib, sunitinib, regorafenib and 
ripretinib. 
b. Cohort 2: 
i. Have histologically- or cytologically confirmed unresectable or metastatic 
GIST. 
ii. Have progressed on or are intolerant to imatinib and sunitinib. Patients in 
this cohort are allowed to have received up to 1 additional line of therapy in 
the advanced/metastatic setting. 
c. Cohort 3: 
i. Have histologically- or cytologically confirmed unresectable or metastatic 
GIST. 
ii. Have progressed on or are intolerant to imatinib (including in the adjuvant 
setting). 
iii. Have not received additional systemic therapy for advanced GIST. 
4. Have at least 1 measurable lesion as defined by modified Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 (Appendix 1). 


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5. Have archival or new tumor biopsy tissue available to submit for mutational testing. A 
tumor sample obtained after most recent prior systemic anticancer therapy is preferred. 
Patients without appropriate archival tissue available may be discussed with the study 
medical monitor and approved for enrollment on a case-by-case basis. 
6. Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 
(Appendix 2). 
7. Adequate renal and hepatic function as defined by the following criteria: 
a. Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (<3.0 x ULN for patients 
with Gilbert syndrome), 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN 
(or ≤5 × ULN if liver function abnormalities are due to underlying malignancy), 
and 
c. Estimated (using Cockcroft-Gault formula or using the method standard for the 
institution) or measured creatinine clearance ≥60 mL/min. 
8. Adequate bone marrow function as defined by the following criteria: 
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L, 
b. Platelet count ≥75 × 109/L, and 
c. Hemoglobin ≥9.0 g/dL. 
9. For female patients of childbearing potential, have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test within 7 days prior to the first dose of study 
drug. 
a. Note: female patients of nonchildbearing potential (postmenopausal; hysterectomy; 
bilateral salpingectomy; or bilateral oophorectomy) do not require a pregnancy test. 
10. Female patients of childbearing potential must agree to abstain from heterosexual 
intercourse or use a highly effective form of contraception with their sexual partners during 
the dosing period and for a period of at least 30 days after the end of treatment. Male 
patients with partners of childbearing potential must agree that they will abstain from 
heterosexual intercourse or use condoms and their partners will use highly effective 
contraceptive methods during the dosing period until at least 90 days after the last dose of 
study drug. 
11. All toxicities from prior therapy have resolved to ≤ grade 1 according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) 
(Appendix 3), or have resolved to baseline, at the time of first dose of study drug. Note: 
treatment-related grade >1 alopecia, treatment-related grade 2 peripheral neuropathy, and 
treatment-related grade 2 hypothyroidism on a stable dose of thyroid hormone replacement 
therapy are allowed if deemed irreversible. 
12. Patient or legal guardian, if permitted by local regulatory authorities, signed and dated 
informed consent indicating that the patient has been informed of all pertinent aspects of 
the study. 
13. Willingness and ability to comply with scheduled visits and study procedures. 


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4.2 
Exclusion Criteria 
Patients meeting any of the following criteria will not be eligible for participation in the study: 
1. Received systemic anticancer therapy (including cytotoxic chemotherapy, investigational 
agent, antineoplastic monoclonal antibodies, or immunotherapy) less than 5 half-lives or 
14 days (whichever is shorter) prior to the first dose of study drug. 
2. Patients known to be both KIT and PDGFRA wild-type. 
3. Received radiotherapy within 14 days prior to the first dose of study drug. 
4. Major surgical procedure within 28 days of the first dose of study drug. Minor surgical 
procedures such as central venous catheter placement or minimally invasive biopsy are 
allowed. 
5. Have known untreated or active central nervous system metastases. 
6. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected (QTc) by 
Fridericia's formula > 470 msec at screening, or history of long QTc syndrome. 
7. Have significant, uncontrolled, or active cardiovascular disease, including, but not 
restricted to: 
a. Myocardial infarction (MI) within 6 months prior to the first dose of study drug 
b. Unstable angina within 6 months prior to first dose of study drug 
c. Symptomatic congestive heart failure (New York Heart Association classes II-IV) 
(Appendix 4) within 6 months prior to first dose of study drug  
d. Clinically significant, uncontrolled atrial arrhythmia (as determined by the 
Investigator) 
e. Any history of ventricular arrhythmia 
f. Cerebrovascular accident or transient ischemic attack within 6 months prior to first 
dose of study drug 
g. Uncontrolled hypertension at study entry. Patients with hypertension should be 
under treatment on study entry to control blood pressure. 
8. Have an active uncontrolled infection, including, but not limited to, the requirement for 
intravenous antibiotics. 
9. Patients with a known allergy or hypersensitivity to any component of study drug. Patients 
with a history of Stevens-Johnson syndrome on a prior TKI are excluded. 
10. Any active bleeding excluding hemorrhoidal or gum bleeding. 
11. For patients with a known human immunodeficiency virus (HIV) infection, have CD4+ T-
cell counts <350 cells/uL or history of acquired immunodeficiency syndrome (AIDS)-
defining opportunistic infection within the past 12 months. Patients with HIV infection 
should be on established antiretroviral therapy (ART) for at least 4 weeks and have an HIV 
viral load less than 400 copies/mL prior to enrollment. 


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12. Has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, as 
evidenced by detectable viral load (HBV-DNA or HCV-RNA, respectively). Risk of HBV 
reactivation should be considered in all patients and the need for anti-HBV prophylaxis 
should be carefully assessed. Patients with chronic HBV infection with history of active 
disease who meet the criteria for anti HBV therapy should be on a suppressive antiviral 
therapy to be eligible for enrollment. Patients who are HCV Ab positive but HCV RNA 
negative due to prior treatment or natural resolution are eligible. Patients on concurrent 
HCV treatment at the time of enrollment are allowed if HCV RNA negative. 
13. Pregnant or breastfeeding. 
14. Malabsorption syndrome or other illness that could affect oral absorption. 
15. Patients with prior or concurrent malignancies other than GIST are allowed, except in the 
case where, in the opinion of the Investigator, the natural history or treatment of the other 
malignancy has the potential to interfere with the safety or efficacy assessment of the study 
drug. 
16. Have any condition or illness that, in the opinion of the Investigator, might compromise 
patient safety or interfere with the evaluation of the safety of the drug. 
4.3 
Reproductive Potential 
Female patients should be either: 
• 
Of nonchildbearing potential, defined as status post-hysterectomy, status post-bilateral 
oophorectomy, or post-menopausal (defined as amenorrhea for at least 12 months), or, 
• 
Agreeable to abstain from heterosexual intercourse or use a highly effective form of 
contraception with their sexual partners during the dosing period, and for a period of at 
least 30 days after the end of treatment. 
Females of childbearing potential (FOCP) must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test within 7 days prior to the first dose of study drug. 
Females of nonchildbearing potential do not require a pregnancy test. 
Acceptable forms of contraception for FOCP include: 
• 
Intrauterine devices (IUDs) and intrauterine hormone-releasing system (IUS),  
• 
Progestogen-only hormonal contraception that inhibit ovulation (oral, injectable, 
implants), 
• 
Combined (estrogen and progestogen containing) hormonal contraceptives that inhibit 
ovulation (oral, depot, patch, injectable, or intravaginal),  
• 
Bilateral tubal occlusion, 
• 
Vasectomized partner with testing showing there is no sperm in the semen, or 
• 
Male or female condoms with spermicide (i.e. double barrier methods). For countries 
where a spermicide is not available or condom plus spermicide is not accepted as highly 
effective contraception, this option is not appropriate. 


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Females who are using hormonal contraceptives must continue to use the same contraceptive 
during the study and for 30 days after study drug discontinuation. 
Male patients with partners of childbearing potential must agree that they will abstain from 
heterosexual intercourse or use condoms and their partners will use highly effective contraceptive 
methods during the dosing period until at least 90 days after the last dose of study drug. 
It is not known whether THE-630 passes into the breast milk. Mothers should not breastfeed during 
study drug administration. 
5. 
STUDY TREATMENT 
5.1 
Study Drug 
THE-630 is an investigational drug that will be administered only to eligible enrolled patients at 
qualified centers. 
5.2 
Study Drug Administration 
THE-630 doses should be administered with a glass of water (at least 8 ounces or 250 mL) in a 
fasted state, with no food intake from 2 hours before until 1 hour after study drug administration. 
Each dose should be administered at approximately the same time each day. Patients should be 
instructed to swallow capsules whole and to not chew the capsules. THE-630 capsules should not 
be opened or dissolved into liquid or food. If a patient vomits after taking a dose, the patient should 
not take an extra dose. Patients who forget to take or miss their dose (i.e., >6 hours after scheduled 
time of administration) should not make up the missed dose. 
5.3 
Dose Escalation Scheme 
The dose escalation phase of this trial will employ sequential dose escalation of oral THE-630 
using a standard 3+3 design. Initially, 3 patients will be enrolled at the starting dose of 3 mg once 
daily (QD) and will be followed for 28 days (end of Cycle 1). After 3 patients complete Cycle 1 
and have safety evaluations performed through Cycle 2 Day 1, dose escalation will proceed as 
summarized in Table 3. 
Table 3 
Dose Escalation Procedures 
Outcomes 
Action 
Dose Escalation Cohorts (n=3-6 each) 
No DLT  
• Escalate to the next planned dose level.  
DLT in 1 of 3 patients  
• Expand cohort up to 6 patients.  
No additional DLT in 6 patients  
• Escalate to the next planned dose level.  
DLT in ≥2 patients  
• MTD exceeded; stop dose escalation.  
Note: DLT is defined in Section 5.4. 
DLT = dose-limiting toxicity, MTD = maximum tolerated dose, RP2D = recommended phase 2 dose 


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The specific dose of each subsequent cohort will be determined through the review of safety data 
during dose-escalation meetings that include the investigators and the Sponsor’s clinical team. 
Dose-escalation meetings will occur after all patients in the current cohort have completed at least 
28 days (1 cycle) of observation after their first dose of THE-630 or have experienced a DLT 
(Section 5.4). The dose-escalation meeting may be convened earlier at the discretion of the 
Sponsor if important safety issues arise requiring the attention of the committee.  
Incremental dose escalation will occur in the following manner until the MTD or an RP2D below 
the MTD has been determined (see also Figure 3): 
• 
Increases of up to 100% over the previous dose level cohort will be employed until one or 
more of the following is observed: 
o 
≥ Grade 2 non-hematologic adverse event (AE) where relationship to THE-630 
cannot be ruled out, 
o 
≥ Grade 3 hematologic AE where relationship to THE-630 cannot be ruled out,  
o 
A protocol-defined DLT (Section 5.4) or an AE occurring outside of the 28-day 
DLT window that would otherwise qualify as a DLT, or 
o 
The dose level of 48 mg QD is reached. 
• 
Further dose escalation will involve increments of no more than 50% of the previous dose, 
depending on safety findings 
 
Figure 3 
Example Dose Escalation Schema 
 


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Alternative dosing regimens of THE-630 (to continuous once daily dosing) may be explored 
depending on initial PK findings and safety and tolerability data. Should a modification be 
required, the dose escalation scheme will be altered by interpolating non-once daily schedules into 
the initial escalation scheme. Alternative dosing regimens will be in standalone cohorts and will 
follow the study Schedule of Events (Table 1). Intermediate doses between the MTD and the next 
lower dose may be explored. Prior to implementation of any alternative, non-once daily dosing 
schedule, the protocol will be amended to describe the planned evaluation and justification for the 
specific alternative dosing schedule. 
Each cohort will have a minimum of 3 patients enrolled and be followed for 28 days (end of Cycle 
1). Patients who do not receive/fail to take study drug for at least 21 of 28 days (at least 75% of 
planned doses; not necessarily consecutively) during the first cycle for reasons not considered to 
be a DLT will be replaced. The patients who are replaced will not be considered eligible for DLT 
assessments. 
Additional patients may be enrolled in one or more dose levels that have been shown not to have 
exceeded MTD (up to 20 patients per dose level; up to 40 additional patients total), defined as 
backfill enrollment. This backfill enrollment will be done to better estimate the RP2D and better 
characterize the safety, pharmacokinetics, and evidence of antitumor activity of THE-630, and 
backfill enrollment may be concurrent with dose escalation to identify the MTD. Backfill 
enrollment patients will not be included in the primary DLT analysis for the purposes of dose 
escalation.   
In the case of non-safety-related dropouts during the first cycle of treatment, a cohort may be 
expanded to replace non-safety-related dropout patients.   
Although decisions regarding dose escalation will be made based on review of data from Cycle 1, 
safety data will also be collected from all patients continuing treatment and this will be reviewed 
periodically during dose-escalation meetings. 
5.4 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any treatment-emergent AE meeting the criteria defined within Table 4 and 
occurring within the first 28 days of treatment (end of Cycle 1) for which relationship to THE-630 
cannot be ruled out. Toxicity grades will be defined by the NCI CTCAE v5.0 (Appendix 3). 
For patients who are approved for intra-patient dose escalation to a dose shown not to exceed the 
MTD, any AEs observed at a dose above their starting dose will not be classified as DLTs. 
 


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Table 4 
Definition of Dose-Limiting Toxicities* 
Toxicity 
DLT Definition 
Non-hematologic 
• 
Any ≥ grade 3 non-hematologic toxicity, with the exception of: 
o 
Self-limiting or medically controllable toxicities (e.g., nausea, 
fatigue, electrolyte disturbances) lasting ≤3 days 
o 
Grade 3 vomiting or diarrhea lasting ≤ 3 days 
o 
Grade 3 elevations of creatine kinase (CK) that are 
asymptomatic, i.e., not accompanied by muscle pain or 
worsening renal function or other signs of rhabdomyolysis or 
cardiac muscle damage (such as abnormal CK-MB, Troponin) 
and recovered to ≤Grade 1 or baseline in <72 hours 
o 
Grade 3 hypertension that recovers to Grade 2 or below within 5 
days 
o 
Alopecia 
Hematologic 
• 
Febrile neutropenia (fever, >101°F [>38.3°C]; absolute neutrophil 
count [ANC] <0.5 × 109/L) 
• 
Prolonged Grade 4 neutropenia (≥7 days) 
• 
Neutropenic infection: ≥ Grade 3 neutropenia with ≥ Grade 3 
infection 
• 
Thrombocytopenia ≥ Grade 3 with bleeding, or Grade 4 without 
bleeding lasting ≥7 days 
Other 
The occurrence of a patient missing ≥25% of planned THE-630 doses 
within the first 28 days (Cycle 1) due to AEs for which relationship to 
THE-630 cannot be ruled out  
*AEs occurring within the first 28 days of treatment (Cycle 1) and relationship to THE-630 cannot be ruled out 
 
5.5 
Definition of Maximum Tolerated Dose and Recommended Phase 2 Dose 
The MTD is defined as the highest dose at which no more than 1 of 6 DLT-assessment eligible 
patients experiences a DLT within the first 28 days of treatment (end of Cycle 1). To be eligible 
for the DLT assessment, patients must complete at least 75% of their planned doses within Cycle 1, 
unless missed doses are due to AEs. The cohort may be expanded to better define the safety profile 
for confirmation of the MTD. The maximum administered dose in the trial will likely exceed the 
MTD. 
The RP2D is the MTD or less. The RP2D will be selected based on an integrated evaluation of 
available safety, tolerability, efficacy, and PK data for all dose levels on the defined schedule. An 
RP2D less than the MTD may be chosen if aspects of tolerability or efficacy not encompassed by 
the MTD determination suggest utilizing a lower dose. 
Clinically significant toxicities or AEs that meet the definition of dose limiting but occur after 
Cycle 1 may be considered when determining the RP2D. Once the RP2D is established, additional 
patients will be dosed in the Expansion phase of the study (Phase 2), which is designed to better 
characterize the safety, tolerability, antitumor activity, and PK profile of oral THE-630. 


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5.6 
Dose Modifications 
Comprehensive assessments of any AEs experienced by the patient will be performed throughout 
the course of the study. Anticipated adverse drug reactions that may be experienced are described 
in the IB. The severity of the event, as well as clinical judgment, will be utilized to determine 
appropriate management of the patient for any AE experienced while participating in this study. 
Dose interruptions or reductions will be implemented for patients who experience AEs for which 
relationship to THE-630 cannot be ruled out as indicated in the following section and in Table 5. 
After dose reduction, patients should continue therapy at the reduced dose. Dose reductions may 
be implemented a second time if additional toxicity ensues. If study drug is held for more than 2 
weeks, resumption of therapy must be discussed with the medical monitor. Re-escalation of doses 
will occur only after consultation with the medical monitor, the escalation dose must not exceed 
the patient’s dose before reduction, and the patient must have recovered from the adverse event. If 
toxicity requiring dose reduction occurs in the first dose cohort, then the patient must discontinue 
therapy. 
Table 5 
Dose Modification Guidelines 
Toxicity Grade 
Action 
Non-hematologic Toxicity 
Grade 1 
Continue therapy at same dose level. 
Grade 2 
Continue therapy at same dose level. If symptoms are intolerable, 
recurrent, or not controlled by supportive care, withhold therapy until 
toxicity is ≤ grade 1 and reduce to next lower dose level. 
Grade 3 
Withhold therapy until toxicity is ≤ grade 1 or has returned to baseline, 
then resume therapy. Therapy may be resumed at the same dose or at the 
next lower dose level, based on the Investigator’s judgment. 
Grade 4 
Withhold therapy until toxicity is ≤ grade 1 or has returned to baseline, 
then resume therapy at the next lower dose level. Therapy may also be 
discontinued based on the Investigator’s judgment. 
Hematologic Toxicity 
Grade 1 
Continue therapy at same dose level. 
Grade 2 
Continue therapy at same dose level. 
Grade 3 
Withhold therapy until toxicity is ≤ grade 2 or has returned to baseline, 
then resume therapy. Therapy may be resumed at the same dose or at the 
next lower dose level, based on the Investigator’s judgment. 
Grade 4 
Withhold therapy until toxicity is ≤ grade 2 or has returned to baseline, 
then resume therapy at the next lower dose level. Therapy may also be 
discontinued based on the Investigator’s judgment. 
5.6.1 
Intra-patient Dose Escalation 
All patients in the dose escalation phase will have the option to increase dose beyond that which 
was initially assigned while on the study if the following conditions are met: 
• 
The patient has tolerated their starting dose without a DLT or dose reductions or 




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5.7.2 
Concomitant Therapy and Procedures 
Palliative therapy and supportive care are permitted during the study for management of symptoms 
and underlying medical conditions that may develop during the study. Once a patient has begun 
treatment, a condition may arise that requires the initiation of a new concomitant treatment. 
Concomitant medications for all ongoing medical history conditions or AEs must be reported from 
the date the informed consent is signed until at least the 30 Days After Last Dose assessments, and 
for all concomitant medications related to serious toxicities or toxicities for which relationship to 
THE-630 cannot be ruled out until the medication is no longer taken or until patient contact 
discontinues. 
Table 7 details prior therapies that are prohibited during the treatment period of the study.  
Table 7 
Excluded Concomitant Treatment 
Systemic anticancer therapy (i.e., chemotherapeutic agents, immunotherapy, biological response modifiers 
(excluding growth factors), and/or systemic hormonal therapy.  
Note: local radiotherapy used for palliative or symptomatic control of disease is allowed with appropriate treatment 
interruption at the discretion of the investigator 
Medications that are potent inhibitors of 
 (refer to Appendix 5 for a list of these medications). 
Extensive surgery requiring in-patient care  
Any other investigational drug or device 
Therapy and procedures not listed in Table 7 are considered allowable, including palliative therapy 
and supportive care for management of symptoms and underlying medical conditions that may 
develop during the study.  
Should emergency surgery requiring in-patient care be required, patients may have an interruption 
in THE-630 dosing for up to four (4) weeks. Before a patient may resume treatment, the 
Investigator must assess the patient for continued stability and to ensure the patient does not meet 
any discontinuation criteria. 
5.7.3 
Additional Precautions 
In vitro, THE-630 is an inhibitor and substrate of 
, 
Therefore, THE-630 may have the potential to increase plasma concentrations of co-administered 
substrates of 
. Medications that are 
 substrates with a narrow therapeutic index should 
be used with caution (refer to Appendix 5 for a list of these medications). 
The effect of THE-630 in wound healing is not known; therefore, caution is advised on the grounds 
of potential antiangiogenic effect for any surgical procedures during the study. The appropriate 
interval of time between surgery and THE-630 required to minimize the risk of impaired wound 
healing and bleeding has not been determined. In the event unexpected major surgery is necessary 
during study participation, THE-630 dosing should be stopped one (1) week prior to surgery. After 
major surgery, THE-630 should not be administered for at least two (2) weeks and until clinical 
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The light absorption characteristics of THE-630 suggest the possibility that THE-630 treatment 
will be associated with phototoxicity. Patients should be advised to apply sunscreen and wear 
appropriate clothing to avoid direct sun exposure. Patients should also be advised to avoid high 
intensity ultraviolet B (UVB) sources such as tanning beds, tanning booths and sunlamps. 
5.7.4 
Treatment Compliance 
A diary will be provided to patients on Day 1 of each cycle to document the date and time of each 
study drug dose for all treatment cycles (Section 5.2). Patients must be instructed to bring their 
unused study drug, empty/used study drug packaging, and completed patient diary to every visit.  
The Investigator (or designee) will reconcile the patient diary entries with the returned study drug 
and document treatment compliance for each patient at each visit. Study drug accountability must 
be assessed at the container/packaging level for unused study drug that is contained within the 
original tamper evident sealed container (e.g., bottles) and at the individual count level for opened 
containers/packaging. The pharmacist/designee will record details on the study drug accountability 
form. Study monitors will review patient treatment compliance during site visits and at the 
completion of the study.  
5.8 
Withdrawal of Patients 
A patient may withdraw from the study treatment at any time for any reason without prejudice to 
their future medical care by the physician or at the institution. The Investigator or Sponsor may 
withdraw the patient at any time in the interest of patient safety. The withdrawal of a patient from 
study drug by the Investigator should be discussed where possible with the medical monitor before 
the patient stops study drug. 
If study drug is discontinued, regardless of the reason, the final evaluations are to be performed as 
completely as possible. Whenever possible, all patients who discontinue study drug should also 
undergo the protocol-specified End of Treatment and follow-up visits. Comments (spontaneous or 
elicited) or complaints made by the patient must be recorded in the source documents. The reason 
for termination and date of stopping study drug must be recorded on the electronic Case Report 
Form (eCRF) and source documents. 
5.8.1 
Patient Discontinuation 
Patients will be discontinued from further study drug administration in the event of any of the 
following: 
• 
Intolerable toxicity as determined by the Investigator 
• 
Progression of disease requiring an alternate therapy, in the opinion of Investigator 
• 
Entry into another therapeutic clinical study or start of new anticancer therapy 
• 
Significant deviation from the protocol or eligibility criteria, in the opinion of the medical 
monitor or Investigator 
• 
Noncompliance with study or follow-up procedures 


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• 
Pregnancy 
• 
Patient withdrawal of consent or decision to discontinue participation 
• 
Termination of the study by the Sponsor 
• 
Any other reason that, in the opinion of the Investigator, would justify removal of the 
patient from the study 
In the event that a patient is withdrawn from the study, every effort must be made by the 
Investigator to document and report the reasons for withdrawal as thoroughly as possible. The 
reason(s) for withdrawal must be clearly reported on the appropriate page of the patient’s eCRF. 
An eCRF must be completed for any patient enrolled, and an End-of-Treatment reason must be 
recorded for any patient who is enrolled, regardless of whether they receive study drug. 
If a patient is discontinued from the trial for any reason, every effort must be made to perform all 
End-of-Treatment and 30 Days After Last Dose assessments per the schedule of events. In the 
event that the patient fails to return for the necessary visit(s), an effort must be made to contact the 
patient to determine the reason, and this information should be recorded in the appropriate source 
record and reported as a deviation. 
All patients who permanently discontinue the study drug will be followed for survival. For patients 
who discontinue the study treatment due to a reason other than documented progressive disease 
(PD), additional tumor assessments should be documented, if available, until disease progression 
or start of another systemic anti-cancer therapy. 
5.8.2 
Patients ‘Lost to Follow-up’ Prior to Last Scheduled Visit 
At least 3 documented attempts must be made to contact any patient lost to follow-up at any time 
point prior to the last scheduled contact (office visit or telephone contact). One of these 
documented attempts must include a written communication sent to the patient’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they return 
any unused study drug and return to the site for final safety evaluations. 
5.9 
Treatment Supply 
5.9.1 
Blinding 
The study will not be blinded. 
5.9.2 
Formulation, Packaging, and Labeling 
THE-630 drug product will be supplied as 1 mg, 3 mg, 12 mg and 20 mg hard gelatin capsules 
containing a formulated blend of excipients and THE-630 HCl. Higher strengths of capsules and/or 
formulated tablets will be introduced depending on the safety, PK, and biological activity of THE-
630. The drug product is manufactured in accordance with cGMP. THE-630 drug product will be 
supplied in white high-density polyethylene (HDPE) bottles with child-resistant caps with liner. 
Bottle labels will bear the appropriate label text as required by governing regulatory agencies. At 


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a minimum, such text will include product name, product strength, number of capsules or tablets, 
and lot number. 
5.9.2.1 Storage 
The Investigator has overall responsibility for ensuring that study drug is stored in a secure, 
limited-access location.  Limited responsibility may be delegated to the pharmacy or member of 
the study team, but this delegation must be documented. Study drug is distributed by the pharmacy 
or nominated member of the study team.    
Study drug will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within an 
established temperature range. The Investigator is responsible for ensuring that the temperature is 
monitored throughout the duration of the study and that records are maintained; the temperature 
should be monitored continuously by using either an in-house system, a mechanical recording 
device, such as a calibrated chart recorder, or by manual means, such that both minimum and 
maximum thermometric values over a specific time period can be recorded and retrieved as 
required. Such a device (i.e., certified Min/Max Thermometer) would require manual resetting 
upon each recording. The Sponsor must be notified upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The Sponsor will determine the ultimate impact of excursions on the study drug and 
will provide supportive documentation as necessary. Under no circumstances should product be 
dispensed to patients until the impact is determined and product is deemed appropriate for use by 
Sponsor. 
5.10 
Study Drug Quality Complaints 
For information on defining and reporting study drug quality complaints, please refer to the 
Pharmacy Manual. 
5.11 
Study Drug Accountability 
The Investigator or designee will acknowledge receipt of the study drug, documenting shipment 
content and condition. Accurate records of all study drug dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.  
The Investigator has overall responsibility for administering/dispensing study drug. Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the Investigator. This 
delegation must be documented in the applicable study delegation of authority form. 
The Investigator or his/her designee will dispense the study drug only to patients included in this 
study following the procedures set out in the study protocol. Each patient will be given only the 
study drug carrying his/her treatment assignment. All dispensing will be documented on the study 
drug source document records. The Investigator is responsible for assuring the retrieval of all study 
supplies from patients. 


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Direct shipment of study drug to patient’s home or local pharmacy may be allowed with prior 
authorization from the Sponsor provided that chain of custody is maintained and documented and 
local policies and regulations are followed. 
The Sponsor or its representatives must be permitted access to review the study drug supplies 
storage, distribution procedures, and records. Based on entries in the study drug accountability 
forms, it must be possible to reconcile study drug delivered with those used and returned. All study 
drug must be accounted for and all discrepancies investigated and documented to the Sponsor’s 
satisfaction. 
No study drug stock or returned inventory from a Theseus-sponsored study may be removed from 
the site where originally shipped without prior knowledge and consent by the Sponsor or designee. 
If such transfer is authorized by the Sponsor or designee, all applicable local, state, and national 
laws must be adhered to for the transfer.  
At the end of the study, or as instructed by the Sponsor or designee, all unused stock, patient-
returned study drug, and empty/used study drug packaging may be destroyed at the site or a local 
facility, or returned to the Sponsor depot. All study drug must be counted and verified by clinical 
site personnel prior to destruction or return. Records identifying what was destroyed or returned, 
when, how, and by whom must be maintained with copies provided to the Sponsor. Destruction of 
study drug at the site or a local facility must be in accordance with local, state, and national laws, 
as well as investigational site pharmacy’s Standard Operating Procedures (SOPs). 
For unused supplies where the original supplied tamper-evident feature is verified as intact, the 
tamper evident feature must not be broken, and the labeled amount is to be documented in lieu of 
counting. Returned study drug must be packed in a tamper-evident manner to ensure product 
integrity. Contact the Sponsor for authorization to return any study drug prior to shipment. 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
See Table 1 (Schedule of Events) for the schedule of study procedures. This Schedule of Events 
applies to patients in both the Phase 1 and Phase 2 portions of the study. 
6.2 
Screening Period 
Screening assessments must be performed no more than 14 days prior to Cycle 1, Day 1. The 
allowable window for the tumor imaging screening assessment is 28 days prior to Cycle 1, Day 1. 
However, whenever feasible, baseline imaging should be performed as close as possible to Cycle 
1, Day 1. Informed consent form signature must be obtained before any screening assessments are 
performed. The screening period begins with informed consent signature. 
Patient numbers are assigned to all patients as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), this number is assigned to patients according to the 
sequence of presentation for study participation. 


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The following clinical assessments will be performed during screening: 
• 
Signing the informed consent form 
• 
Review of inclusion and exclusion criteria 
• 
Patient demographics, medical and surgical history, diagnosis and cancer history, and 
known mutation status 
• 
Physical examination and vital signs 
• 
ECOG performance status test 
• 
12-lead ECG (single) 
• 
Laboratory assessments: hematology, chemistry (including Troponin T), coagulation, 
urinalysis 
• 
Pregnancy test for FOCP 
• 
Echocardiogram/multiple gated acquisition (MUGA) scan 
• 
Disease assessment by computed tomography (CT) scan with intravenous (IV) contrast of 
the chest and CT scan or magnetic resonance imaging (MRI) with IV contrast of the 
abdomen and pelvis 
• 
Confirmation of availability of archival or collection of new formalin-fixed, paraffin-
embedded (FFPE) tumor tissue for exploratory biomarker studies 
• 
Recording of prior and concomitant therapy and treatments, including prior anti-cancer 
therapy 
A screen failure is a patient who has given informed consent and failed to meet the inclusion and/or 
meet at least 1 of the exclusion criteria and has not been administered study drug.  
6.2.1 
Rescreening 
Patients may be rescreened with the approval of the Sponsor. All screening procedures that remain 
within the timeframe for eligibility do not need to be repeated, i.e., 28 days prior to C1D1 for 
tumor imaging and 14 days prior to C1D1 for all other screening assessments.  
6.3 
Treatment Period 
6.3.1 
Cycle 1 Day 1 
The following evaluations and procedures will be performed during this visit: 
• 
Confirmation that inclusion and exclusion criteria are still met 
• 
Vital signs 
• 
The following procedures must be performed if they were conducted more than 7 days 
before Cycle 1 Day 1 or if, in the opinion of the Investigator, there is reason to believe the 
results have substantially changed:  


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o Physical examination 
o ECOG performance status test 
o Laboratory assessments: hematology, chemistry (including Troponin T), 
coagulation, and urinalysis 
o Pregnancy test for FOCP 
• 
Triplicate 12-lead ECGs at time 0 (pre-dose), and at 8 hours (±10 minutes) after dosing of 
THE-630. When the time point for triplicate ECG collection coincides with PK sample 
collection, the triplicate ECGs should be taken directly before obtaining the PK sample at 
the allotted time points (i.e., times 0 and 8 hour).  
• 
Blood samples for PK at times 0 (pre-dose), 0.5 (±5 minutes), 1 hour (±5 minutes), 2, 4, 
6, 8 hours (±10 minutes) after the first dose on Cycle 1 Day 1 
• 
Blood samples for exploratory biomarkers at time 0 (pre-dose) 
• 
THE-630 administration  
• 
Adverse events assessment 
• 
Recording of concomitant medications 
6.3.2 
Cycle 1 Day 2 
The following evaluations and procedures will be performed during this visit: 
• 
Blood sample for PK at time 24 hours (±60 minutes) after the first dose on Cycle 1 Day 1 
and prior to THE-630 administration on Cycle 1 Day 2 
• 
THE-630 administration 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
6.3.3 
Cycle 1 Day 8 
The following evaluations and procedures will be performed during this visit (±1 day): 
• 
Vital signs 
• 
Laboratory assessments: hematology, chemistry, coagulation, and urinalysis 
• 
Pre-dose blood sample for PK 
• 
THE-630 administration 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 


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6.3.4 
Cycle 1 Day 15 
The following evaluations and procedures will be performed during this visit (±2 days): 
• 
Vital signs 
• 
Laboratory assessments: hematology, chemistry, coagulation, and urinalysis 
• 
Blood samples for PK at times 0 (pre-dose), 0.5 (±5 minutes), 1 hour (±5 minutes), 2, 4, 
6, 8 hours (±10 minutes) after the dose on Cycle 1 Day 15 
• 
Triplicate 12-lead ECGs at times 0 (pre-dose), 1 hour (±5 minutes), 2, 4, and 8 hours (±10 
minutes) after dose on Cycle 1 Day 15. When the time points for triplicate ECG collection 
coincide with PK sample collection, the triplicate ECGs should be taken directly before 
obtaining the PK sample at the allotted time points (i.e., times 0, 1, 2, 4, and 8 hour). 
• 
THE-630 administration  
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
6.3.5 
Cycle 1 Day 16 
The following evaluations and procedures will be performed during this visit (±2 days): 
• 
Blood sample for PK at time 24 hours (±60 minutes) after the dose on Cycle 1 Day 15 and 
prior to THE-630 administration on Cycle 1 Day 16  
• 
THE-630 administration 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Record concomitant medications 
6.3.6 
Cycle 2 Day 1 
The following evaluations and procedures will be performed during this visit (±3 days): 
• 
Vital signs 
• 
Physical examination 
• 
ECOG performance status test 
• 
Laboratory assessments: hematology, chemistry (including Troponin T), coagulation, and 
urinalysis 
• 
12-lead ECG (single) 
• 
Pre-dose blood sample for PK  
• 
Blood sample for exploratory biomarkers 


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• 
THE-630 administration 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
6.3.7 
Cycle 2 Day 28 and Day 28 of All Even Cycles Through Cycle 12 and every 3 
Cycles Thereafter 
The following evaluations and procedures will be performed during this visit (±3 days): 
• 
Disease assessment by CT scan and MRI (every even cycle through C12 and every 3 
cycles thereafter until disease progression, i.e., C2, C4, C6, C8, C10, C12, C15, C18, etc.) 
6.3.8 
Cycle 3 Day 1 
The following evaluations and procedures will be performed during this visit (±7 days): 
• 
Vital signs 
• 
Physical examination 
• 
ECOG performance status test 
• 
Laboratory assessments: hematology, chemistry, coagulation, and urinalysis 
• 
12-lead ECG (single) 
• 
Pre-dose blood sample for PK  
• 
Blood sample for exploratory biomarkers 
• 
THE-630 administration 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
6.3.9 
Cycle 4 Day 1 and Day 1 of all Subsequent Cycles 
The following evaluations and procedures will be performed during this visit (±7 days): 
• 
Vital signs 
• 
Physical examination 
• 
ECOG performance status test 
• 
Laboratory assessments: hematology, chemistry, coagulation, and urinalysis. Note: If 
coagulation studies are within the normal range through C3D1 then they can be 
discontinued thereafter and obtained only as clinically indicated. 
• 
12-lead ECG (single) 


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• 
Pregnancy test for FOCP (every 3 cycles, i.e., C4, C7, C10, etc.). If required by local 
standard medical practice, more frequent pregnancy testing is allowed. 
• 
Echocardiogram/MUGA scan (every 3 cycles, i.e., C4, C7, C10, etc.) 
• 
Blood sample for exploratory biomarkers (every odd cycle post C3 through C11, i.e., C5, 
C7, C9, C11) 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
6.3.10 
Additional Cycles 
Patients will continue with the study treatment until one or more of the discontinuation criteria are 
met (Section 5.8.1).  
6.3.11 
End of Treatment 
The End of Treatment visit must be performed within 14 days (± 7 days) of the patient’s last dose 
of study drug or the patient/Investigator decision to discontinue study treatment, whichever occurs 
later. 
The following evaluations and procedures will be performed during this visit: 
• 
Vital signs 
• 
ECOG performance status test 
• 
The following procedures must be performed if they were conducted more than 14 days 
prior to the End of Treatment visit or, if in the opinion of the Investigator, there is reason 
to believe the results have substantially changed: 
o Physical examination 
o Laboratory assessments: hematology, chemistry (including Troponin T), 
coagulation, and urinalysis 
o Pregnancy test for FOCP 
o 12-lead ECG (single) 
o Echocardiogram/MUGA scan 
• 
Disease assessment by CT scan and MRI (if more than 4 weeks have passed since the last 
imaging assessment and progression had not previously been documented) 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
• 
Blood sample for exploratory biomarkers (at disease progression, only) 


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• 
Tissue sample for exploratory biomarker analysis (optional; at disease progression, only) 
6.4 
Follow-up Period 
6.4.1 
30 Days After Last Dose 
The 30 Days After Last Dose visit must be performed within 30 days (± 7 days) of the patient’s 
last dose of study drug. This visit may be performed by telephone and includes reviewing adverse 
events and concomitant medications. 
6.4.2 
Survival Follow-up 
Follow-up assessments (i.e., contacting the patient for survival and subsequent anticancer therapy) 
must be performed every 12 weeks (±14 days) after the End-of-Treatment assessment through 
patient death, loss to follow-up, or withdrawal of consent, whichever occurs first. All new systemic 
anticancer therapies should be reported. 
7. 
DESCRIPTION OF STUDY ASSESSMENTS 
7.1 
Pretreatment Assessments 
7.1.1 
Demography 
The patients’ demographic information will be obtained during screening. Demographic 
information will consist of patients’ date of birth (or age), sex, race, and ethnicity, as permitted by 
local law and regulations. 
7.1.2 
Medical History 
A complete medical history will be recorded at screening and updated, as needed, prior to 
administration of the first THE-630 dose. The medical history will include relevant past illnesses, 
smoking history, ongoing medical conditions, and surgical procedures (not related to the primary 
diagnosis). 
7.1.3 
Diagnosis, Cancer History, and Prior Cancer Therapy 
The initial cancer diagnosis and the current cancer stage at the time of screening, along with tumor 
histology and all sites of disease, will be recorded. 
Information regarding prior cancer therapy will be recorded at screening, to include: 
• 
Cancer-related surgical procedures, radiation, and systemic therapies 
• 
Surgical procedures include curative and palliative, as well as diagnostic procedures (e.g., 
biopsy) 
• 
Radiation will include both definitive and palliative treatment 


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• 
Systemic therapy includes all regimens given, type of regimen (e.g., neo-adjuvant, 
adjuvant, for advanced/metastatic disease), each drug name in a regimen, the start and 
stop dates of each drug, the best response to the regimen, and the reason for 
discontinuation 
• 
Experimental or investigational therapy 
7.1.4 
Mutation Status 
Known mutation status will be recorded at screening. Mutation status will include activating and 
resistance mutations in KIT and PDGFRA, as well as other previously-identified abnormalities in 
other genes. Information on the specific point mutations, deletions, insertions, or gene 
rearrangements observed are to be recorded, if available. 
7.2 
Efficacy Assessments 
7.2.1 
Disease Assessment and Tumor Imaging 
Efficacy will be assessed by the Investigator based on modified RECIST 1.1 for patients with 
GIST (Demetri, 2013) (Appendix 1). Disease assessment will be based on local MRI or CT scans 
performed at screening and throughout the study. CT scans with IV contrast of the chest, and CT 
or MRI with IV contrast of the abdomen and pelvis will be performed at screening. At subsequent 
time points as outlined in the Schedule of Events (Table 1), all body regions that contained sites 
of disease (target or non-target) at screening will be imaged. If a patient is not tolerant of IV 
contrast, non-contrast CT or MRI may be performed. For each patient, the same method of tumor 
imaging used at baseline should be used throughout the study.  
MRI and CT scans will be reviewed locally at the study center, ideally by the same individual for 
each patient at each time point. All radiographic images (e.g., CT scan, MRI) performed during 
the trial will be submitted to and stored by a central imaging laboratory for potential future 
independent evaluation as appropriate. 
Patients must have at least 1 measurable lesion per modified RECIST 1.1. Target and non-target 
lesions must be selected at study start and assessed throughout the course of treatment according 
to the modified RECIST 1.1 guidelines. Disease assessment by CT and MRI scans will be 
performed at screening and at 8-week intervals thereafter (on Day 28 [±3 days] of every even-
numbered cycle), through Cycle 12 after the initial dose of study drug, and every 3 cycles thereafter 
until disease progression. More frequent imaging is recommended at any time if clinically 
indicated; confirmation of complete response (CR) or partial response (PR) should be performed 
at least 4 weeks after initial response. Imaging assessment will also be performed at End of 
Treatment if more than 4 weeks have passed since the last imaging assessment. 
7.3 
Safety Assessments 
7.3.1 
Physical Examination 
A complete physical examination must be performed at screening to include evaluations of: 


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• 
Head, eyes, ears, nose, throat 
• 
Neck, chest (including heart and lungs) 
• 
Abdomen 
• 
Limbs 
• 
Skin 
• 
A complete neurological examination  
The extent of the physical examination at screening should be consistent with a patient’s medical 
history and underlying disease and should therefore be expanded to include additional body 
systems, as determined by the Investigator. Physical examinations at subsequent treatment period 
visits specified within the Schedule of Events (Table 1) may be directed to relevant clinical 
findings. The physical examination performed at the End of Treatment visit (or Early Termination 
visit) must be a complete physical examination. 
Abnormalities identified at screening are to be documented as medical history in the patient’s 
source documents and on the medical history eCRF. Changes after screening are to be captured as 
AEs on the AE eCRF page, as deemed by the Investigator. 
7.3.2 
Vital Signs 
Vital sign measurements include body temperature, heart rate, respiratory rate, and blood pressure 
and will be collected at the time points specified in the Schedule of Events (Table 1). All vital sign 
measurements will be measured after the patient has been seated for 5 minutes. All blood pressure 
measurements should be performed using the same method, the same arm, and in the same position 
throughout the study.  
Height and weight need only be measured at screening. 
As a patient progresses in the study, any deviations from screening vital signs which are deemed 
clinically significant in the opinion of the Investigator will be recorded as an AE. 
7.3.3 
ECOG Performance Status 
The ECOG performance status must be assessed using the ECOG Performance Status Scale 
(Appendix 2) at the time points specified in the Schedule of Events (Table 1). 
7.3.4 
Clinical Laboratory Evaluations 
Clinical laboratory tests to be performed, including hematology, chemistry, coagulation 
parameters, and urinalysis, are summarized in Table 8. The Schedule of Events (Table 1) outlines 
the timepoints at which blood and urine samples will be collected throughout the study. Clinical 
laboratory tests will be analyzed by the local laboratory. The name, address, local accreditations, 
and reference ranges of each local laboratory used in this study will be maintained in the 


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Investigator’s files at each site. All clinical laboratory assays will be processed and analyzed 
according to the local laboratory’s normal procedures.  
Reference ranges are supplied by the laboratory and used to assess the clinical laboratory data for 
clinical significance and out-of-range pathological changes. The Investigator must assess out-of-
range clinical laboratory values for clinical significance, indicating if the value(s) is/are not 
clinically significant (NCS) or clinically significant (CS). Abnormal clinical laboratory values, 
which are unexpected or not explained by the patient’s clinical condition may be, at the discretion 
of the Investigator or Sponsor, repeated until confirmed, explained, or resolved as soon as possible.  


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Table 8 
Clinical Laboratory Tests 
Category 
Assays 
Hematology 
Complete blood count (CBC) with 5-part differential: hemoglobin, 
hematocrit, RBC count, WBC count, MCV, MCH, MCHC, RDW, 
platelet count, MPV, and absolute and relative numbers of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils 
Chemistry 
 
Electrolytes 
Sodium, potassium, chloride, bicarbonate (or total carbon dioxide), 
magnesium, phosphorous, calcium 
Liver function tests 
AST, ALT, bilirubin (at least total and direct, or total and indirect), 
albumin, total protein 
Renal function tests 
BUN, creatinine 
Pancreatic function tests 
Amylase, lipase 
Other 
CK, ALP, glucose, Troponin T 
Coagulation 
INR, aPTT 
Urinalysis (dipstick) 
pH, specific gravity, protein, ketone, glucose, urobilinogen, and occult 
blood 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 8.2.5). In these instances, the AE corresponding to the laboratory abnormality will be 
recorded on the AE eCRF. 
7.3.5 
Pregnancy Test 
For all FOCP, pregnancy testing will be performed at screening and once every 12 weeks after 
study start, as specified in the Schedule of Events (Table 1). If required by local standard medical 
practice, more frequent pregnancy testing is allowed. The pregnancy test will be performed locally 
using a beta-human chorionic gonadotropin (β-HCG) test and either a urine, or serum sample may 
be used. 
7.3.6 
Pharmacokinetics 
Blood samples for PK assessments will be processed centrally to assess the plasma concentrations 
of THE-630, its active metabolite THE-973, and pharmacokinetic parameters following a single 
dose and multiple doses (steady state), in both the dose escalation and expansion cohorts. Blood 
samples will be collected at pre-specified time points (pre- and post-dosing) as outlined in the 
Pharmacokinetic and Electrocardiogram Schedule of Events (Table 2).  
For each visit with a PK blood draw, a record of study drug administration timing must be collected 
as described in Section 5.2. The collection date and time that each PK blood sample is drawn must 
also be recorded. For C1D1 and C1D15, the timing of a patient’s last meal prior to coming into 
the clinic and the timing of the first meal after dosing will be recorded. 
Instructions for PK sample handling, processing, and shipment are available within the study-
specific Laboratory Manual. 


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7.3.7 
Electrocardiogram  
12-lead ECGs will be obtained throughout the study as specified in the Pharmacokinetic and 
Electrocardiogram Schedule of Events (Table 2). The screening ECG to determine eligibility may 
be a single ECG. Triplicate ECGs are required throughout Cycle 1 and should be taken 1 to 2 
minutes apart over a 5-minute timeframe. Subsequent ECGs (after C1D15) may be single ECGs. 
Additional ECGs may be performed at the Investigator’s discretion to ensure patient safety. In 
particular, ECG monitoring should be performed during the study if a patient has, during the study, 
been prescribed medication that can prolong the QT interval or medication that can potentially 
alter the QT interval. For consistency, the Fridericia correction – QTcF – method must be used for 
all calculations of QTc intervals. 
During C1D1 and C1D15, triplicate ECG measurement timepoints will coincide with PK 
measurement time points. As such, triplicate ECGs should be taken directly before obtaining the 
PK sample at the allotted time points on C1D1 and C1D15. Adjustments to the timing of triplicate 
ECGs on C1D15 may be made based on the PK findings in the dose escalation phase. 
ECGs should be conducted after at least 5 minutes of recumbency or semi-recumbency. 
ECGs will be recorded locally at each site and electronically submitted for central aggregate 
analysis. The eligibility of the patient is based on the assessment of the ECG by the Investigator. 
7.3.8 
Echocardiograms/MUGA 
Echocardiograms or MUGA scans will be performed at screening and once every 12 weeks after 
study start, as specified in the Schedule of Events (Table 1). Echocardiograms or MUGA scans 
will be performed locally in accordance with the institution’s standard practice. The same modality 
should be used throughout the study. 
7.3.9 
Adverse Event Collection 
At each study visit, patients will be questioned in a general way to ascertain if AEs have occurred 
since the previous visit (e.g., “Have you had any health problems since your last visit?”). All AEs 
will be assessed, documented, and reported in accordance with ICH Good Clinical Practice (GCP) 
guidelines. Section 8 outlines the definitions, collection periods, criteria and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE eCRF completion 
guidelines for the Investigator, as well as training, will be provided. 
7.4 
Exploratory Assessments 
7.4.1 
Biomarkers/ Molecular Genetic Analysis 
Tumor tissue and blood samples will be collected for exploratory biomarker/molecular genetic 
analyses.  
The availability of a tumor tissue sample will be confirmed at screening, either as an archival 
sample, or a new FFPE tumor tissue sample. A tumor sample obtained after the patient’s most 


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recent prior systemic anticancer therapy is preferred. For patients who consent, an additional, 
optional tumor tissue sample will be collected at the time of disease progression on THE-630. 
Patients have the right to withdraw consent from this additional component, with no impact on 
participation in the main study. The tissue sample(s) will be processed centrally for molecular 
genetic analysis of KIT, PDGFRA, and other genes implicated in tumor biology. 
Blood samples will be collected throughout the study at timepoints specified in the Schedule of 
Events (Table 1). Each blood sample will be collected and processed centrally to evaluate 
circulating biomarkers associated with THE-630 efficacy and toxicity. 
Instructions for tumor tissue and blood sample collection, handling, processing, and shipment are 
available within the study-specific Laboratory Manual. 
To ensure patient confidentiality, samples will be stored and analyzed in a de-identified format.  
Any results of this exploratory research may be reported separately from the main Clinical Study 
Report. Results may be used internally to help support the design of additional clinical studies, 
form part of scientific publications, or be made known to the regulatory authorities as part of a 
new drug application. 
7.5 
Sample Collection, Storage and Shipping 
All samples must be collected by appropriately trained individuals. Use of Universal Precautions 
is recommended when collecting any biological specimen. Plasma and blood samples must be 
stored as outlined in the study-specific Laboratory Manual until shipment. Specific instructions 
regarding the handling and shipment of these specimens will also be provided in the Laboratory 
Manual. Retention time and possible future use of biological samples will be included in the Patient 
Informed Consent Form. 
7.6 
Considerations for Phase 2 Expansion 
During Phase 2 expansion, if circumstances prevent a patient from completing on-site visits (e.g., 
precautions needed to mitigate risk to the patient during  a pandemic, natural disaster, or social or 
political unrest), then the following procedures may be conducted off-site, with Sponsor approval 
in place before implementation of any off-site study procedures. This option applies only to 
patients who have completed at least 2 cycles of dosing and have completed study procedures on-
site through Cycle 2 Day 28. 
• 
Informed consent, as permitted by site IRB/EC, SOPs, and local regulatory authorities 
• 
ECOG performance status test 
• 
Laboratory assessments: hematology, chemistry, coagulation, urinalysis, and pregnancy 
testing (for FOCP) 
• 
12-lead ECG (single) 
• 
Echocardiogram/MUGA scan 
• 
Disease assessment by CT scan and MRI  


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• 
THE-630 administration 
• 
THE-630 compliance 
• 
Adverse events assessment 
• 
Recording of concomitant medications 
Off-site methods include but are not limited to the procedure(s) occurring at a facility closer to the 
patient’s home and/or procedures conducted through remote methods (e.g., telemedicine). Sites 
must clearly document the details of all procedures and/or visits that are performed off-site. 
8. 
ADVERSE EVENT DATA COLLECTION AND REPORTING  
8.1 
Reference Safety Information 
The reference for safety information for this study is the IB which the Sponsor has provided under 
separate cover to all Investigators. 
8.2 
Definition of Adverse Events, Period of Observation, Recording of Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E2A, 1995). All AEs should be captured on the AE eCRF.  
All AEs are collected from the time of informed consent through at least 30 days after the last dose 
of study drug. Beyond 30 days after the last dose, ongoing AEs for which relationship to THE-630 
cannot be ruled out, and all ongoing serious adverse events (SAEs) should be followed at least 
every 4 weeks until they resolve to baseline (or to NCI CTCAE v5.0 grade ≤1), stabilize, or are 
considered to be chronic/irreversible. In addition, SAEs observed by the investigator or reported 
by the patient that occur after 30 days after the last dose of study drug through the end of the 
survival follow-up period should be reported if there is a reasonable possibility that the event may 
have been caused by THE-630, even if the investigator becomes aware of such events after the end 
of the survival follow-up period. 
Once a patient is deemed a screen failure, AE collection is no longer required. 
All AEs are to be recorded on the appropriate AE pages in the eCRF and in source documents. 
Where possible, a diagnosis, rather than a list of symptoms, should be recorded. If a diagnosis has 
not been made, then each symptom should be listed individually.  In addition to untoward AEs, 
unexpected benefits outside the study drug indication should also be captured on the AE eCRF. 
8.2.1 
Severity Categorization 
AE severity should be graded per the NCI CTCAE v5.0 definitions listed in Appendix 3. 


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The severity of AEs must be recorded over the course of the event, including the start and stop 
dates. An event that changes with worsening severity should be captured as a new event. 
Worsening of pre-treatment events, after initiation of study drug, must be recorded as new AEs 
(for example, if a patient experiences mild intermittent dyspepsia prior to dosing of study drug, 
but the dyspepsia becomes severe and more frequent after first dose of study drug has been 
administered, a new AE of severe dyspepsia [with the appropriate date of onset] is recorded on the 
appropriate eCRF). 
If the AE is not defined in the CTCAE, the Investigator will determine the severity of the AE based 
on the following definitions: 
• 
Mild (grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity 
• 
Moderate (grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest 
• 
Severe (grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy 
• 
Life-Threatening (grade 4): The patient is at immediate risk of death 
• 
Death (grade 5): The patient dies as a direct result of the complication or condition 
induced by the AE 
8.2.2 
Relationship Categorization 
An Investigator must make the assessment of causal relationship to study drug for each AE. The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility 
that the event may have been caused by the study drug.  If relationship to THE-630 can be clearly 
and incontrovertibly ruled out (e.g. due to the underlying disease or an extraneous cause), then the 
AE should be classified as “not related.” Otherwise, without clear relationship to another cause, a 
possible cause-and-effect relationship between the study drug and the occurrence of the AE should 
be suspected and the AE should be considered “related.” The causality assessment must be 
documented in the source document. 
In addition, if the Investigator determines that an SAE is associated with study procedures, the 
Investigator must record this causal relationship in the source documents and on the SAE form and 
report such an assessment in accordance with the SAE reporting requirements. 
The Investigator may change opinion of causality in light of follow-up information. 
8.2.3 
Outcome Categorization 
The outcome of AEs must be recorded during the study on the eCRF. Outcomes are as follows: 
• 
Fatal 
• 
Not Recovered/Not Resolved 
• 
Recovered/Resolved 


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• 
Recovered/Resolved with Sequelae  
• 
Recovering/Resolving 
• 
Unknown 
8.2.4 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease. However, unexpected and 
significant worsening of the symptoms should be recorded as an AE. 
Death due to disease progression in the absence of signs and symptoms should be reported as the 
primary tumor type (e.g., metastatic GIST). 
Note: The term “disease progression” should not be used to describe the adverse event. 
8.2.5 
Clinical Laboratory Evaluations 
A change in a clinical laboratory value can represent an AE if the change is clinically relevant or 
if, during treatment with the study drug, a shift of a parameter is observed from a normal value to 
an abnormal value, or a further worsening of an already abnormal value. When evaluating such 
changes, the extent of deviation from the reference range, the duration until return to the reference 
range, either while continuing treatment or after the end of treatment with the study drug, and the 
range of variation of the respective parameter within its reference range, must be taken into 
consideration. 
If, at the end of the treatment phase, there are abnormal clinical laboratory values which were not 
present at baseline, further clinical or laboratory investigations should be performed until the 
values return to within the reference range or until a plausible explanation (e.g., concomitant 
disease) is found for the abnormal clinical laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a patient, 
whether a change in a clinical laboratory parameter is clinically significant and therefore represents 
an AE. 
8.2.6 
Pregnancy  
All pregnancies are to be reported from the time informed consent is signed until 90 days after the 
last dose of study drug. 
Any female patients who become pregnant while participating in the study must be permanently 
discontinued from study drug. If the female partner of a male patient becomes pregnant while 
participating in the study, the male patient must notify the Investigator, immediately. Consent to 
report information regarding pregnancy outcomes should be obtained from the female partner. Any 
report of pregnancy for any female study participant or the partner of a male study participant must 
be reported within 24 hours after becoming aware of the event using the study Pregnancy 
Notification Form and the study’s medical monitor must be notified, immediately. The Investigator 


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or Investigator’s designee must submit the report via fax or email to the CRO’s Pharmacovigilance 
Department. 
Every effort should be made to gather information regarding the pregnancy outcome and condition 
of the infant. It is the responsibility of the Investigator to obtain this information within 30 days 
after the initial notification and approximately 30 days post-partum. The Investigator or 
Investigator’s designee must submit the report using the study Pregnancy Outcome Form via fax 
or email to the CRO’s Pharmacovigilance Department within 24 hours after becoming aware. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality are 
considered SAEs and must be reported in the clinical trial database (eCRFs) within 24 hours after 
becoming aware of the event and the study’s medical monitor must be notified, immediately. If 
the eCRF is unavailable, then the Investigator must submit the report via fax or email to the CRO’s 
Pharmacovigilance Department using the study the Serious Adverse Event Form, and also enter it 
into the clinical trial database when it becomes available. An elective abortion is not considered 
an SAE. 
In addition to the above, if the Investigator determines that the pregnancy meets serious criteria, it 
must be reported as an SAE using the study Serious Adverse Event Form as well as the study 
Pregnancy Report Form. The test date of the first positive serum/urine HCG test or ultrasound 
result will determine the pregnancy onset date. 
8.2.7 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the to the 
CRO’s Pharmacovigilance Department using the study Special Situations Report Form, whether 
or not the events result in an AE/SAE as described in Section 8.2 and Section 8.3.  The 24 hour 
reporting requirement does not apply to reports of abuse, misuse, overdose, or medication errors 
unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than one category. 
• 
Abuse – Persistent or sporadic intentional intake of study drug when used for a non-
medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society.  
• 
Misuse – Intentional use of study drug other than as directed or indicated at any dose 
(Note: this includes a situation where the study drug is not used as directed at the dose 
prescribed by the protocol).  
• 
Overdose – Intentional or unintentional intake of a dose of a study drug exceeding the 
protocol-defined dose. 
• 
Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of a study drug.  For studies, medication errors are reportable to the Sponsor only as 
defined below. 
Cases of patients missing doses of product are not considered reportable as medication errors. 
Medication errors should be collected/reported for all products under investigation. The 


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administration and/or use of an expired product should be considered as a reportable medication 
error.  
8.3 
Serious Adverse Events 
8.3.1 
Serious Adverse Event Definition 
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to study drug or not) that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital abnormality/birth defect 
• 
Is an important medical event  
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.   
The following hospitalizations are not considered to be SAEs because there is no “AE” (i.e., there 
is no untoward medical occurrence) associated with the hospitalization:  
• 
Hospitalizations for palliative therapy  
• 
Hospitalization planned before informed consent for pre-existing conditions which have 
not worsened after initiation of study drug  
• 
Hospitalization for routine maintenance of a device (e.g., pacemaker) that was in place 
before study entry  
• 
Social admission (e.g., patient has no place to sleep) 
However, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meets serious criteria must be reported as SAE(s). 
Adverse events that require emergency room care that do not result in hospital admission are not 
SAEs unless assessed by the Investigator to be an important medical event. 


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8.3.2 
SAE Reporting Procedures 
All SAEs are to be reported whether or not considered causally related to THE-630.  The 
Investigator or Investigator’s designee must record all initial and follow-up SAE information in 
the clinical trial database (eCRFs) within 24 hours after becoming aware of the event. In the event 
that the clinical trial database is not available, the SAE report must be sent to the CRO’s 
Pharmacovigilance Department within 24 hours using the study Serious Adverse Event Form, and 
also entered into the clinical trial database when it becomes available. The 24-hour timeframe also 
applies to additional new information (follow-up) on previously reported SAEs. 
8.3.3 
Information to be Provided by the Investigator for a SAE 
The Sponsor or designee will require all of the following information about the patient and the 
event: 
• 
Investigator identification 
• 
Patient identification code (e.g., sex, age, or date of birth) 
• 
Information on study drug (e.g., start/stop date, dose, and frequency of study drug 
administered) 
• 
Description of event 
In addition to the above information, the Sponsor will require the Investigator’s assessment of the 
following: 
• 
Severity of the SAE 
• 
Relationship of the SAE to the study drug 
• 
Outcome of the SAE 
8.3.4 
Follow-up Information on a SAE 
The Investigator may be asked to provide additional information for any event submitted, which 
may include a discharge summary or extracts from the medical record. Information provided about 
the event must be consistent with information recorded on the electronic study case report forms 
(eCRF) where safety data may also be recorded (e.g., AE CRF) within 24 hours of awareness. The 
Investigator is responsible for management of the patients through the course of the event. There 
should be routine follow-up through and including a minimum of 30 days after the last 
administration of study drug or the Investigator/patient decision to discontinue treatment, 
whichever occurs later, in all patients in order to monitor for the occurrence of SAEs. If an SAE 
continues after the 30- day evaluation period, the patient must be followed until the event resolves, 
stabilizes without further involvement expected, is lost to follow-up, or dies.  
8.3.5 
Serious Adverse Event Collection Timeframe 
All SAEs (regardless of relationship to study drug) are collected from the time the patient provides 
informed consent through at least 30 days after the last dose of study drug. Beyond 30 days after 


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the last dose, all ongoing SAEs should be followed at least every 4 weeks until they resolve to 
baseline (or to NCI CTCAE v5.0 grade ≤1), stabilize, are considered by the Investigator to be 
chronic/irreversible, the patient is lost to follow up, or the patient dies. 
8.3.6 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the patient prior to study entry or leading up to 
the onset date of the SAE or following the resolution date of the SAE must be recorded as an AE, 
if appropriate. 
8.3.7 
Fatal Outcome 
Any SAE that results in the patient’s death (i.e., the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at time of death that did not contribute to the patient’s death, the outcome 
should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the patient’s death or any ongoing events at the time of death, the 
action taken with the study drug should be recorded as “dose not changed” or “not applicable” (if 
the patient never received study drug). 
8.3.8 
Regulatory Agency, Institutional Review Board, Independent Ethics Committee, 
and Site Reporting 
The Sponsor, or its authorized designee (i.e., the CRO), is responsible for reporting suspected, 
unexpected, and serious adverse reactions (SUSARs) involving the study drug to all relevant 
regulatory authorities and participating investigators in accordance with ICH Guidelines and/or 
local regulatory requirements, as applicable. In addition, the Sponsor, or its authorized designee 
(i.e., the CRO), will be responsible for the submission of safety letters to applicable central 
Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). The Sponsor, or 
authorized designee, will notify investigators of SUSARs according to local regulatory 
requirements. This notification will be in the form of an expedited safety report. Upon receiving 
such notices, the Investigator must review and retain the notice with other study-related 
documentation. 
The Investigator and IRB/IEC will determine whether the informed consent requires revision. The 
Investigator should also comply with the IRB/IEC procedures for reporting any other safety 
information. 
SUSARs and other significant safety issues reported from the investigational product development 
program will be reported by the Sponsor or its designated representative, either as expedited safety 


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reports and/or in aggregate reports, to the relevant competent health authorities in all concerned 
countries. 
The Investigator is responsible for notifying the local IRB, local IEC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site, as required. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
General Considerations 
The dose escalation phase of this phase 1/2 trial will employ sequential dose escalation of oral 
THE-630 using a standard 3+3 design, starting at 3 mg administered orally once daily, and 
increasing in increments until the MTD is identified.  
Descriptive statistics and analyses will be provided for each dose level and for patients combined 
across dose levels, where applicable. Data from patients in the expansion phase will be primarily 
summarized by individual expansion cohort. Data from patients in the expansion phase cohorts 
may also be summarized together with data from patients in the dose escalation cohorts, as 
appropriate, in sensitivity analyses. Descriptive statistics (such as means, medians, standard 
deviations, and ranges for continuous data, and percentages for categorical data) will be used to 
summarize patient characteristics, treatment administration/compliance, efficacy, safety, and 
pharmacokinetic parameters. Data will also be displayed graphically, where appropriate. 
A Statistical Analysis Plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
9.2 
Analysis Populations 
The primary analyses of all efficacy and safety endpoints, unless noted otherwise, will be 
conducted on the Full Analysis Set defined as all patients that are enrolled and receive at least 1 
dose of THE-630. 
The PK Analysis Set will contain all patients who have received at least 1 dose of THE-630 and 
have at least 1 PK sample collected. These patients will be evaluated for PK analysis unless the 
number of data points required for analysis is not enough, or significant protocol deviations have 
affected the data, or if key dosing or sampling information is missing. 
Response-Evaluable (RE) Set: The RE Set includes all patients in the Full Analysis Set who have 
at least 1 target lesion per modified RECIST version 1.1, at Baseline and have at least 1 
postbaseline disease assessment. Selected efficacy analyses may be performed using the RE Set. 


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9.3 
Study Endpoints 
9.3.1 
Primary Endpoints 
Phase 1 
The primary endpoint of the dose escalation phase of the study is the safety profile of THE-630, 
including identification of DLTs and MTD, and determination of the RP2D. 
Phase 2 
The primary endpoint of each expansion phase cohort is confirmed Objective Response Rate 
(ORR), according to modified RECIST 1.1 for patients with GIST. 
9.3.2 
Secondary Endpoints 
Phase 1 
Secondary endpoints of the dose escalation phase include: 
1. Plasma PK parameters of THE-630 and its active metabolite THE-973 after single oral 
dose and at steady state after multiple oral doses 
2. Efficacy assessments, according to modified RECIST 1.1 for patients with GIST including: 
confirmed objective response rate (ORR), best overall response, best target lesion response, 
time to response, duration of response (DOR), disease control rate (DCR), Clinical Benefit 
Rate (CBR) at 16 weeks, PFS and OS 
Phase 2 
Secondary endpoints of the expansion phase cohorts include: 
1. Efficacy assessments, according to modified RECIST 1.1 for patients with GIST, 
including: DOR, best overall response, best target lesion response, time to response, DCR, 
CBR at 16 weeks, PFS and OS 
2. Safety profile of oral THE-630 
3. Plasma PK parameters of THE-630 and its active metabolite THE-973, after single oral 
dose and at steady state after multiple oral doses 
9.3.3 
Other Endpoints 
Exploratory endpoints applicable to both the dose escalation and expansion phases include: 
1. Molecular analysis of patients’ tumor and plasma including but not limited to: 
a. Presence of KIT mutations 
b. Presence of PDGFRA mutations 


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9.3.4 
Definition of Efficacy Endpoints 
• 
Confirmed ORR is defined as the proportion of the patients who are confirmed to have 
achieved complete response (CR) or partial response (PR), per modified RECIST version 
1.1 for patients with GIST (confirmed ≥4 weeks after initial response) after initiation of 
study treatment.  
• 
DOR is defined as the time interval from the time that the measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that the PD is objectively 
documented, or death. 
• 
CBR at 16 weeks is defined as the proportion of patients remaining on study who have 
not met criteria for progressive disease (PD) on or prior to the 16-week assessment (i.e., 
patients with an objective response or stable disease (SD) lasting 4 cycles from the start 
of treatment).  
• 
Best overall response will be defined as the best response achieved at any time point on 
study according to the following hierarchy: CR, PR, SD), or PD. The proportion of 
patients achieving a best response of CR or PR (objective response) at any time point on 
study will also be summarized. 
• 
Disease control rate is defined as the proportion of patients who have achieved CR, PR, 
or SD (in the case of SD, measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6 weeks) after the initiation of study treatment. 
• 
Time to response is defined as the time interval from the date of the first dose of the study 
treatment until the initial observation of CR or PR. 
• 
PFS is defined as the time interval from the date of the first dose of the study treatment 
until the first date at which disease progression is objectively documented, or death due 
to any cause, whichever occurs first. PFS will be censored for patients without 
documented disease progression or death. 
• 
OS is defined as the time interval from the date of the first dose of the study treatment 
until death due to any cause. It will be censored on the date of last contact for those patients 
who are alive. 
9.4 
Determination of Sample Size 
The purpose of this phase 1/2 trial is to determine the RP2D and MTD, as well as evaluate the 
safety, tolerability, and anti-tumor activity of oral THE-630. The sample size for Phase 1 (dose 
escalation) is dependent upon the observed safety profile, which will determine the number of 
patients per dose cohort, as well as the number of dose escalations required to achieve the MTD 
or identify the RP2D. With this design, the estimate of the rate of DLT at the MTD is in the range 
of 0.17 to 0.26. The estimate of the rate of DLT at the highest dose, which is 1 step above the 
MTD, is 0.33 (Ting, 2006). 
The Phase 2 expansion cohorts will facilitate obtaining estimates of clinical activity in different 
GIST patient populations defined by prior therapy. 20 patients each in Expansion Cohorts 1, 2 and 
3 will allow an estimate of ORR with the 95% confidence interval half width no larger than 23% 
for a given cohort. 


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9.5 
Efficacy Analysis 
Estimates of clinical activity, including ORR, CBR, best overall response, time to and duration of 
response, best target lesion response, DCR, and PFS, will be determined using modified RECIST 
1.1 for patients with GIST (as assessed by the Investigator). Overall survival (OS) will be 
measured. Data from patients in the expansion phase will be primarily summarized by individual 
expansion cohort.  Efficacy analyses for an expansion cohort will occur after all patients to be 
enrolled to that cohort have had the opportunity for at least 12 weeks of study treatment or have 
discontinued study treatment before 12 weeks. When appropriate, data from patients in the 
expansion cohorts will be summarized together with data from patients in the dose escalation 
phase, in sensitivity analyses. 
For analyses of ORR, CBR, and DCR, exact binomial 2-sided 95% CIs will be calculated. Patients 
with no measurable disease at baseline or no adequate postbaseline response assessment will be 
included as non-responders in full analysis set (FAS) analysis. 
Best target lesion response will be displayed using a “waterfall” plot.  
Duration of response (in responders), PFS, and OS will be analyzed using the Kaplan-Meier 
method. Patients without progression or death will be censored at their last tumor assessment (for 
duration of response or PFS) or at last study visit for OS. The proportion of patients with PFS  at 
6 months and 12 months will be computed along with 2-sided 95% CIs. The proportion of patients 
with OS at 12 and 24 months and associated 2-sided 95% CIs will also be computed. 
Patients’ molecular genetic status will be characterized by both mutation history and central testing 
results obtained from the tumor tissue sample provided at study entry in order to explore molecular 
genetic features that are associated with the anti-tumor activity of THE-630.  
9.6 
Safety Analysis 
Safety assessments will include physical and laboratory examinations, vital signs, 
Echocardiogram/MUGA scans and ECGs. Adverse events will be graded according to the NCI 
CTCAE v5.0.  All patients receiving at least 1 dose of THE-630 will be considered evaluable for 
safety. The AE incidence rates, as well as the frequency of occurrence of overall toxicity, 
categorized by the maximum toxicity grades (severity), will be described. The proportion of 
patients with at least 1 treatment-emergent AE, treatment-related AE (i.e. an AE where relationship 
to THE-630 cannot be ruled out), and treatment-emergent SAE will be described, as identified 
with preferred terms and MedDRA system organ class. Listings of laboratory test results and 
CTCAE grades will be generated, and descriptive statistics summarizing the changes in laboratory 
tests over time will be presented. 
Exposure to study treatment over time will be summarized with time on treatment, total amount 
of administrated treatment, dose intensity and relative dose intensity. 


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9.6.1 
Pharmacokinetic Analysis 
Where possible, the following PK parameters (as appropriate) will be determined for THE-630 
and its active metabolite, THE-973. 
Following a single oral dose: 
• 
Maximum plasma concentration (Cmax) 
• 
Time to Cmax (tmax) 
• 
Terminal phase half-life (t½λz) 
• 
Area under the plasma concentration-time curve (AUC)  
o from time zero to 24 hours (AUC0-24) 
o from time zero to the time of the last measurable concentration (AUC0-t) 
o from time zero to infinity (AUC0-∞) 
• 
Apparent plasma clearance (CL/F) 
• 
Apparent volume of distribution (V/F) 
• 
Dose linearity for Cmax and AUC 
Following multiple oral doses (steady state): 
• 
Maximum plasma concentration at steady state (Css,max) 
• 
Time to Css,max (tmax) 
• 
Area under the plasma concentration-time curve from time zero to the end of the dosing 
interval (AUC0-τ) 
• 
Apparent plasma clearance at steady state (CLss/F) 
• 
Volume of distribution during terminal phase (Vz/F) 
• 
Extent of accumulation on multiple dosing (RAC) 
• 
Dose linearity for Cmax and AUC 
9.6.2 
QTcF Analysis 
Descriptive statistics of maximum QTcF and change from baseline will be calculated following 
the ICH-E14 guidelines: the proportion of treated patients with at least 1 on-drug QTcF value >450 
ms, 480 ms, and 500 ms; and the proportion of treated patients with a maximum change in QTcF 
from baseline >30 ms and >60 ms. The Fridericia correction (QTcF) will be used throughout. The 
association between QTcF changes and plasma levels of THE-630 will be analyzed using mixed 
effects models. 


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9.7 
Protocol Deviations/Violations 
Protocol deviations will be identified prior to database lock and will be listed by dose level and 
phase/cohort in the clinical study report. 
10. 
ADMINISTRATIVE PROCEDURES 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
GCP as described in the ICH Harmonized Tripartite Guideline E6(R2): GCP: Integrated 
Addendum to ICH E6(R1) (ICH E6(R2), 2018), and 21 CFR Parts 50, 54, 56, and 312. Compliance 
with these regulations also constitutes compliance with the ethical principles described in the 
current revision of the Declaration of Helsinki. The study will also be carried out in keeping with 
local legal and regulatory requirements, including EU Regulation No 536/2014. 
10.1 
Institutional Review Board or Independent Ethics Committee 
It is the responsibility of the Investigator to submit this protocol, the informed consent document 
(approved by the Sponsor or its designate), relevant supporting information, and all types of patient 
recruitment information to the IRB/IEC for review, and all must be approved before the site may 
begin screening and enrolling patients. Prior to implementing changes in the study, the Sponsor 
and the IRB/IEC must also approve any revised informed consent documents and amendments to 
the protocol. 
On the approval letter, the study reference, the date of review and actions taken should be clearly 
stated. Study drug will not be released and the patient recruitment will not begin until this initial 
written approval has been received by the Sponsor or its designee. 
The Investigator is responsible for keeping the IRB/IEC apprised of the progress of the study and 
of any changes made to the protocol. The Investigator must also keep the IRB informed of any 
serious and significant AEs. 
10.2 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from all study patients 
prior to any study-related procedures, including screening assessments, and in accordance with 
applicable regulations and GCP. Documentation of informed consent must include the written 
informed consent for all study patients, as well as documentation within the medical record that 
describes the informed consent discussion and process. Each patient or the patient’s legally-
authorized representative is requested to sign the Patient Informed Consent Form (ICF) after the 
patient has received and read (or been read) the written patient information and received an 
explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the patient’s rights and responsibilities. A copy of the 
informed consent documentation (i.e., a complete set of patient information sheets and fully-
executed signature pages) must be given to the patient or the patient’s legally-authorized 
representative. If applicable, it is provided in a certified translation of the local language. Signed 


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consent forms must remain in each patient’s study file and must be available for verification at any 
time. The authorized person obtaining the informed consent must also sign the informed consent.   
The Investigator provides the Sponsor with a copy of the consent form which was reviewed by the 
IRB/IEC and which received their favorable opinion/approval. A copy of the IRB/IEC’s written 
favorable opinion/approval of these documents must be provided to the Sponsor, prior to the start 
of the study. Additionally, any modification of the sample patient information and consent 
document must be provided to the Sponsor. 
The Sponsor reserves the right to delay initiation of the study at a site where the informed consent 
forms do not meet the standards of applicable regulations and ICH E6(R2) Guidelines. 
If the patient has a primary physician the Investigator should, with the patient’s consent, inform 
them of the patient’s participation in the study. 
10.3 
Patient Privacy 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). A site that is not a Covered Entity as defined by HIPAA must provide documentation 
of this fact to the Sponsor. 
The confidentiality of records that may be able to identify patients will be protected in accordance 
with applicable laws, regulations, and guidelines. All patient and investigator personal data will 
be treated in compliance with applicable laws and regulations. 
After patients have consented to take part in the study, the Sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the Sponsor; third parties with whom the Sponsor may develop, register, or 
market THE-630; national or local regulatory authorities; and the IRB(s)/IEC(s) which gave 
approval for the study to proceed. The Sponsor and/or its representatives accessing the records and 
data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of patients' identities. The patient must be informed that 
their personal study-related data will be used by the sponsor in accordance with local data 
protection law. The patient must also be informed that their medical records may be examined by 
the sponsor’s or its representatives’ auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/EC members, and by inspectors from regulatory authorities. 
Patients will be assigned a unique identifying number. However, patients’ year of birth may also 
be collected and used to assist the Sponsor to verify the accuracy of the data. The results of studies 
– containing patients’ unique identifying number, relevant medical records, and possibly initials 
and dates of birth – will be recorded. They may be transferred to, and used in, other countries 
which may not afford the same level of protection that applies within the countries where this study 
is conducted. The purpose of any such transfer would include: to support regulatory submissions, 
to conduct data analyses in accordance with the objectives of this protocol and further analysis on 
the study drug and the condition concerned, to publish or present the study results, and to answer 
questions asked by regulatory or health authorities. In the event of data inclusion in a public 


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registry, all identifiable information from individual patients will be redacted according to 
applicable laws and regulations. 
10.4 
Study Monitoring 
Monitoring of the study will be performed by the designated CRO. At the monitoring visits, the 
progress of the study will be discussed with the Investigator, or his/her representative. The ICFs 
will be reviewed for signatures and the eCRFs checked for completeness and accuracy. Patient 
source data must be available for review. The Investigator and his/her staff are expected to 
cooperate with the study monitor and be available during at least a portion of the monitoring visit 
to review the eCRFs and any queries/resolutions, answer questions, and provide any missing 
information. 
The study monitor will record the date of each visit together with a summary of the status and 
progress of the study. Proposed actions will be confirmed with the Investigator in writing. 
Telephone contact will be made with the Investigator as necessary during the data collection period 
and during the data and report writing periods. 
10.5 
Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor. The protocol 
will be followed as written. 
Any change to the protocol must be documented in writing as an amendment or administrative 
change and must be approved by the Sponsor before implementation. Amendments specifically 
affecting the safety of patients, the scope of the investigation, or the scientific quality of the study 
require submission to health or regulatory authorities as well as additional approval by the applicable 
IRBs/IECs. These requirements should in no way prevent any immediate action from being taken by 
the Investigator, or by the Sponsor, in the interest of preserving the safety of all patients included in 
the study.  
If the Investigator determines that an immediate change to or deviation from the protocol is 
necessary for safety reasons to eliminate an immediate hazard to the patients, the medical monitor 
(or appropriate study team member) and the IRB/IEC for the site must be notified immediately. 
The Sponsor must notify the health or regulatory authority as required per local regulations.  
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory authority 
and IRB/IEC should be kept informed of such changes as required by local regulations. In these 
cases, the Sponsor may be required to send a letter to the IRB/IEC and the regulatory authorities 
detailing such changes. 
If the protocol amendment substantially alters the study design or potential risk to the patient, new 
written informed consent for continued participation in the study must be obtained from each 
patient. 


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10.6 
Adherence to the Protocol 
The Investigator and designees must adhere to the protocol as detailed in this document. The 
Investigator is responsible for enrolling only those patients who have met protocol eligibility 
criteria. Investigators are required to sign an Investigator Agreement to confirm acceptance and 
willingness to comply with the study protocol. 
10.7 
Recording, Access, and Retention of Source Data 
The Investigator must permit authorized representatives of the Sponsor, the regulatory authorities, 
the IRB/IEC, auditors, and interested commercial parties to inspect facilities and records relevant 
to this study. Source data to be reviewed during this study will include, but are not limited to, the 
patient’s medical file, original laboratory reports, scans, pathology reports, ECGs, etc. All key data 
must be recorded in the patient’s source documents. 
The study monitor, auditors, IRB/IEC, and/or regulatory inspectors may check the eCRF entries 
against the source documents. The consent form will include a statement by which the patients 
allow the monitor/auditor/inspector from the Sponsor or its representatives, regulatory authorities 
or the IRB/IEC access to source data which substantiate information recorded in the eCRFs. These 
personnel, bound by professional secrecy, will not disclose any personal information or personal 
medication information. 
As described in the ICH E6(R2) Guidelines, “essential documents,” including eCRFs, source 
documents, consent forms, laboratory test results, and the study drug inventory records, should be 
retained by the Investigator until at least two years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least two years have elapsed since the formal discontinuation of clinical development 
of the study drug. These documents should be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the responsibility of 
the Sponsor to inform the Investigator/institution as to when these documents no longer need to be 
retained. The Investigator must obtain written permission from the Sponsor prior to the destruction 
of any study document. 
All records must be made available at reasonable times for inspection and duplication, if required, 
by a properly authorized representative of the U.S. Food and Drug Administration (FDA) in 
accordance with the U.S. Code of Federal Regulations 21 CFR 312.68 or other regulatory 
authorities in accordance with regulatory requirements. 
10.7.1 
Case Report Forms 
Electronic case report forms (eCRF) will be used for data collection for this study. 
The Sponsor or designee will provide the study sites with secure access to and training on the 
electronic data capture application sufficient to permit site personnel to enter or correct information 
in the eCRFs on the patients for which they are responsible. 


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The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered on the eCRFs and any other data 
collection forms. Source documentation supporting the eCRF data must indicate the patients’ 
participation in the study and must document the dates and details of study procedures, AEs, other 
observations, and patient status.  
The Investigator, or designated representative, must complete the eCRF per the specifications and 
timeframe outlined within the study eCRF completion guidelines. The eCRFs must be signed 
electronically by the Investigator to attest that the data contained on the eCRFs, including any 
changes made to the eCRFs, is correct and endorse the final submitted data for the patients for 
whom the Investigator is responsible. 
A study monitor will review the eCRF data against the source data for completeness and accuracy, 
in accordance with the monitoring plan. Discrepancies between source data and data entered on 
the eCRF will be addressed by qualified site personnel. When a data discrepancy warrants 
correction, the correction will be made by authorized site personnel. 
The completed eCRFs are the sole property of the Sponsor and must not be made available in any 
form to third parties, except for authorized representatives of the Sponsor or appropriate regulatory 
authorities, without written permission from the Sponsor. 
The Sponsor will retain the eCRF data and corresponding audit trails. A copy of the final archival 
eCRF will be provided to the site for placement in the Investigator’s study file. 
The Investigator is responsible for maintaining adequate and accurate source documents from 
which accurate information will be transcribed into eCRFs which have been designed to capture 
all observations and other data pertinent to the clinical investigation. eCRFs should be completed 
by the Investigator or designee. Overwriting of information or use of liquid correcting fluid is not 
allowed in the source document. 
The eCRFs must be reviewed and electronically signed and dated by the Investigator once all data 
has been entered and all queries resolved. Once the study monitor has verified the contents of the 
completed eCRF against the source data, queries may be raised if the data are unclear or 
contradictory. The Investigator must address all queries. 
10.8 
Study or Site Termination 
The Sponsor reserves the right to suspend or terminate the study or part of the study at any time 
for any reason. If the Sponsor, Investigator, medical monitor, or regulatory agencies discover 
conditions during the study that indicate that the study or site should be terminated, this action 
may be taken after appropriate consultation between the Sponsor and the Investigator (in the case 
of site termination).  
The Sponsor may terminate the study at a study site or in its totality at any time for any of the 
following reasons: 
• 
Failure to enroll patients 
• 
Protocol violations 


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• 
Inaccurate or incomplete data 
• 
Unsafe or unethical practices 
• 
Questionable safety of the study drug 
• 
Suspected lack of efficacy of the study drug 
• 
Administrative decision 
In the event of the termination of the study by either the Sponsor or an investigator: 
• 
The Investigator will return all related study materials to the Sponsor. 
• 
A written statement describing why the study was terminated prematurely will be 
provided by either the Sponsor or the Investigator. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the guidelines for Good Clinical Practice (GCP), International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). If the study is 
suspended or terminated, the Sponsor will promptly inform the participating Investigators and 
regulatory authorities of the reason(s) for the termination or suspension. The IRBs/IECs will also 
be notified. Additionally, the discontinuation of a registered clinical study which has been posted 
to a designated public website will be updated accordingly. The Sponsor will make an end of study 
declaration to the relevant regulatory authorities. 
If the Investigator suspends or terminates the study at his or her site, then the Investigator must 
promptly inform the Sponsor and the IRB/IEC and provide them with a detailed written 
explanation. The Investigator must also return all study drug, containers, and other study materials 
to the Sponsor. Upon study completion, the Investigator will provide the Sponsor, IRB/IEC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
10.9 
Financial Disclosure 
Upon submission of a marketing application to the FDA for any drug, the Sponsor must provide 
the FDA with a list of clinical investigators who conducted a Theseus-sponsored clinical study and 
certify or disclose financial arrangements. 
The Investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the value of the compensation for conducting the study could be influenced by the 
outcome of the study. The following information is collected: any significant payments from the 
Sponsor or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in study drug; 
any significant equity interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
In consideration of participation in the study, the Sponsor pays the Investigator or nominated payee 
the sums set out in the payment schedule attached to the Investigator agreement. 


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10.10 
Good Clinical Practice Compliance 
The Investigator must undertake to perform the study in accordance with ICH E6(R2) Guidelines, 
local regulations, and local IRB/IEC requirements. 
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the study site prior to commitment to participate in this study. The Investigator should 
also be able to estimate or demonstrate a potential for recruiting the required number of suitable 
patients within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the 
Investigator and sub-Investigator(s) will be provided to the Sponsor (or designee) before starting 
the study. 
10.10.1 Quality Control and Quality Assurance 
A monitoring plan will be developed to ensure the human patient protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality and 
meet Theseus, ICH GCP Guideline, and local regulatory guidelines. 
The Investigator will permit authorized representatives of the Sponsor and the respective 
regulatory authorities to inspect facilities and records relevant to this study if needed. 
Initial site training will be provided by the Sponsor or designated CRO. Training for new staff will 
be provided by current study nurses and study coordinators under the supervision of the 
Investigator. Additional training will be provided by the Sponsor, as needed. 
The Data Management Team will implement quality control procedures beginning with the data 
entry system and generate data quality control checks that will be run on the database. Any missing 
data or data anomalies will be communicated to the site(s) for clarification/resolution. 
10.10.2 Publications 
The Investigator must notify the IRB/IEC of the conclusion of the clinical study. This report should 
be made within 3 months of the completion or termination of the study. The final report sent to the 
IRB/IEC should also be sent to the Sponsor and, along with the completed eCRFs, constitutes the 
final summary to the Sponsor, thereby fulfilling the Investigator’s regulatory responsibility. 
The Declaration of Helsinki states that every research study involving human subjects must be 
registered in a publicly accessible database before recruitment of the first subject 
(http://www.wma.net). Section 801 of the FDA Amendments Act mandates the registration with 
ClinicalTrials.gov of certain clinical studies of drugs (including biological products) and medical 
devices subject to FDA regulations for any disease or condition. The International Committee of 
Medical Journal Editors (ICMJE) requires study registration as a condition for publication of 
research results generated by a clinical study (http://www.icmje.org). In addition, the EMA 


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requires that clinical studies conducted in the European Union and other countries under their 
regulatory authority be registered (https://www.clinicaltrialsregister.eu/). 
The institution and Principal Investigator acknowledge that the study is a multicenter study and, 
as such, agree that they will not publish a publication, abstract, poster, or other disclosures 
(“Publication”) before a combined paper that identifies all the sites that participated in the study 
(“Multi-Center Publication”) is published. If the Multicenter Publication has not been completed 
within 18 months from the date of the completion, termination, or abandonment of the multicenter 
study, the institution may publish or present its individual results in accordance with the provisions 
stated below. In order to balance the institution’s right to publish with Theseus Pharmaceuticals’ 
proprietary interests, the institution will submit to Theseus material intended for publication, 
abstracts, posters, and other disclosures (“Proposed Disclosures”) at least 60 days prior to 
submitting for publication or other disclosure to allow for expeditious review by Theseus. If 
Theseus believes that any Proposed Disclosure contains any information relating to any patentable 
invention, the disclosure of such Proposed Disclosure shall be delayed for up to 60 days from the 
date Theseus receives the Proposed Disclosure to permit Theseus to file patent applications. If 
Theseus believes that any Proposed Disclosure contains Confidential Information, Theseus shall 
have the right to require that the institution delete any reference to Confidential Information, 
excluding the results of the study. If the institution and Principal Investigator choose not to publish, 
Theseus reserves the right to publish the results of the study, and, if appropriate, to include its 
medical staff in the author list of such publication in accordance with academic publication 
standards. Subject to applicable copyright law, if an institution and/or Principal Investigator 
publishes results of the study, institution and/or Principal Investigator hereby grants Theseus an 
irrevocable, royalty-free license to make and distribute copies of such publication under any 
copyright privileges that the institution and/or Principal Investigator may have. 
10.10.3 Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available for 
inspection upon request by representatives of, for example, the U.S. FDA (as well as other U.S. 
national and local regulatory authorities), the European Medicines Agency (EMA), the Medicines 
and Healthcare Products Regulatory Agency (MHRA), other regulatory authorities, the Sponsor 
or its representatives, and the IRB/IEC for each site. 
10.10.4 Indemnity/Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
 
 








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12. 
APPENDICES 
 
 


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12.1 
Appendix 1: Modifications to Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1), for Patients with GIST 
This study will utilize response criteria adapted from RECIST 1.1 (Eisenhauer, 2009) with 
modification for patients with GIST, as described by Demetri and colleagues (Demetri, 2013).  
The modifications to RECIST version 1.1 criteria for patients with GIST include: 
1. No lymph nodes to be chosen as target lesions. Enlarged lymph nodes are to be followed 
up as non-target lesions 
2. No bone lesions to be chosen as target lesions 
3. 18Fluorodeoxyglucose positron emission tomography (18FDG-PET) is not acceptable for 
radiological assessment 
4. A progressively growing new tumor nodule within a pre-existing tumor mass must meet 
the following criteria in order to be regarded as unequivocal evidence of progressive 
disease according to the aforementioned GIST-specific modifications to RECIST 1.1: 
a. The lesion must be ≥ 2 cm in size and definitely be a new active GIST lesion (e.g., 
enhanced with contrast or other criteria to rule out artifact); or  
b. The lesion must be expanding on at least 2 sequential imaging studies. 
Source: Demetri, 2013. 
 
The following summarizes RECIST 1.1 with integration of the modifications for patients 
with GIST noted above: 
Choosing Target Lesions 
• 
Select up to 5 lesions (up to 2 per organ). 
o Note: per the modification of RECIST 1.1 for patients with GIST, no lymph nodes are 
to be chosen as target lesions. Enlarged lymph nodes are to be followed up as non-
target lesions. No bone lesions are to be chosen as target lesions. 
• 
Select largest reproducibly measurable lesions. 
• 
If the largest lesion cannot be measured reproducibly, select the next largest lesion which 
can be. 
• 
Add up longest diameters (LD) of non-nodal lesions (axial plane). 
• 
Add short axis diameters of nodes. 


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• 
This is the sum of the longest diameters (SLD). 
Nontarget Lesions 
• 
All other sites of disease present at baseline and not classified as target lesions will be 
classified as nontarget lesions, including any measurable lesions that were not chosen as 
target lesions. 
• 
It is possible to record multiple nontarget lesions involving the same organ as a single 
item on the eCRF. 
Note: per the modification of RECIST 1.1 for patients with GIST, 18Fluorodeoxyglucose positron 
emission tomography (18FDG-PET) is not acceptable for radiological assessment 
Determining Response 
• 
Assess at baseline and on study with consistent imaging modalities  
o Measure target lesions and calculate SLD. 
o Visually assess nontarget lesions. 
o Search for new lesions. 
o Combine these assessments into the overall response. 
Target Lesion Response 
Complete Response 
(CR) 
• Disappearance of all target lesions. 
Partial Response (PR) 
• At least a 30% decrease in the SLD of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease 
(PD) 
• SLD increased by at least 20% from the smallest value on study 
(including baseline, if that is the smallest). 
• SLD must also demonstrate an absolute increase of at least 5 
mm. (2 lesions increasing from, for example, 2 mm to 3 mm, 
does not qualify). 
Stable Disease (SD) 
• Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
Nonevaluable (NE) 
• One or more lesions cannot be evaluated because of missing 
data or poor image quality unless a convincing argument can be 
made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response (e.g., PD 
based on other findings). 
Abbreviations: SLD, sum of the longest diameters. 
 
 


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Nontarget Lesion Response 
Complete Response 
(CR) 
• Disappearance of all extranodal nontarget lesions. 
• All lymph nodes must be nonpathological in size (<10 mm short 
axis). 
Non-CR/non-PD 
• Persistence of 1 or more nontarget lesions(s)  
Progressive Disease 
(PD) 
• Unequivocal progression of existing nontarget lesions 
(subjective judgment by experienced reader) 
Nonevaluable (NE) 
• One or more lesions cannot be evaluated because of missing 
data or poor image quality unless a convincing argument can be 
made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response (e.g., PD 
based on other findings). 
 
Note: per the aforementioned modifications to RECIST 1.1 for patients with GIST, a progressively 
growing new tumor nodule within a pre-existing tumor mass must meet the following criteria in 
order to be regarded as unequivocal evidence of progressive disease: 
a. The lesion must be ≥ 2 cm in size and definitely be a new active GIST lesions (e.g., 
enhanced with contrast or other criteria to rule out artifact); or 
b. The lesion must be expanding on at least 2 sequential imaging studies. 
 
New Lesions 
• 
Should be unequivocal and not attributable to differences in scanning technique or 
findings that may not be a tumor (does not have to meet criteria to be “measurable”) 
• 
If a new lesion is equivocal, continue to next time point. If confirmed at that time, PD is 
assessed at the date when the lesion was first seen. 
• 
Lesions identified in anatomic locations not scanned at baseline are considered new 
• 
New lesions on ultrasound should be confirmed on CT or MRI 
 
 


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Evaluation of Overall Time Point Response for Patients with Measurable Disease at Baseline 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 


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12.2 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physical strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about > 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
Source: Oken, 1982. 
 
 


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12.3 
Appendix 3: Common Terminology Criteria for Adverse Events (v5.0) 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 5.0 (published 27 Nov 2017) provides descriptive terminology to be used for 
adverse event reporting in clinical trials. A brief definition is provided to clarify the meaning of 
each adverse event (AE) term. To increase the accuracy of AE reporting, all adverse event terms 
in CTCAE, Version 5.0 have been correlated with single-concept, Medical Dictionary for 
Regulatory 
Activities 
(MedDRA) 
terms. 
The 
online 
version 
is 
available 
here: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf. 
CTCAE, Version 5.0 grading refers to the severity of the AE. CTCAE Grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline: 
Grade 
CTCAE Status 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate: minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADLa. 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADLb. 
4 
Life-threatening consequences: urgent intervention indicated.  
5 
Death related to adverse event.  
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events, NCI = National Cancer 
Institute.  
a: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.  
b: Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  
 
Source: Adapted from the Cancer Therapy Evaluation Program, 2017.  
 
 
 


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12.4 
Appendix 4: New York Heart Association (NYHA) Classification 
Class 
Patient Symptoms 
1 
No symptoms and no limitation in ordinary physical activity, e.g., 
shortness of breath when walking, climbing stairs etc. 
2 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
3 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g., walking short distances (20—100 m). 
Comfortable only at rest. 
4 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
Source: The Criteria Committee of the New York Heart Association 1994. 
 
 


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12.5 
Appendix 5. Potent Inhibitors of 
 and Substrates of 
 with Narrow 
Therapeutic Index 
 
This list is not intended to be exhaustive. A similar restriction will apply to other drugs that are 
potent inhibitors or substrates with narrow therapeutic indices; appropriate medical judgement is 
required. Please contact medical monitor with any queries relating to this issue. 
 
 


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12.6 
Appendix 6. Protocol Amendment Summary of Changes and Rationale 
Protocol Version 4.0 (07 Dec 2022) 
This amendment (Version 4.0) updates and supersedes Protocol THE630-21-101 Version 3.0 dated 
025 February 2022, as follows: 
• 
Section 1.1.1: GIST treatment landscape background was updated to include a summary 
of the recent outcome of the 2nd line Phase 3 study of ripretinib. 
• 
Section 2.1.3 was added to include a statement on potential risks and benefits of THE-
630.  
• 
Sections 3.2, 5.3, Figure 2: the maximum number of backfill patients has been updated to 
up to 40 (up to 20 per dose level), in order to better estimate the RP2D and better 
characterize the safety, pharmacokinetics and evidence of antitumor activity of THE-630. 
• 
Section 3.2: A description of the safety data review process for the Phase 2 portion of the 
study has been added. 
• 
Section 3.4 was amended to clarify that additional study sites that are included to 
participate in the Expansion portion of the study may also participate in backfill 
enrollment. 
• 
Section 4.1: inclusion criteria 5 was amended to clarify that patients without appropriate 
archival tissue available may be discussed with the study medical monitor and approved 
for enrollment on a case-by-case basis. 
• 
Section 4.1: inclusion criteria 7c was amended to allow creatinine clearance to be 
estimated using Cockroft-Gault formula or the method standard for the institution, to 
allow for flexibility when institutions standardly use a different estimation method from 
Cockroft-Gault. 
• 
Section 4.3: the description of acceptable forms of contraception was amended to 
harmonize with the Clinical Trials Facilitation and Coordination Group (CTFG) 
Recommendations related to contraception and pregnancy testing in clinical trials 
(Version 1.1).  
• 
Section 5.6.1 was amended to clarify that patients would not be eligible for intra-patient 
dose escalation if they have been enrolled at a dose level selected for backfill enrollment, 
in order to better characterize a given starting dose level and support estimation of RP2D. 
• 
Section 5.9.2 was amended to include 20 mg capsules in the list of supplied capsule 
strengths of THE-630 drug product. 
• 
Section 5.11 was amended to clarify that direct shipment of study drug to patient’s home 
or local pharmacy may be allowed with prior authorization from the Sponsor provided 
that chain of custody is maintained and documented and local policies and regulations are 
followed. 
• 
Section 7.5 was amended to clarify that descriptions of biological sample retention time 
and possible future use of samples will be included in the patient informed consent form. 
• 
Sections 10 was amended to reference EU Regulation No 536/2014. 


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• 
Section 10.3 was amended to provide additional detail pertaining to patient privacy. and 
to clarify that only patients’ year of birth will be collected (as the study database does not 
collect patients’ initials or date of birth) 
• 
Synopsis was updated to reflect all applicable changes. 
 
Protocol Version 3.0 (25 Feb 2022) 
This amendment (Version 3.0) updates and supersedes Protocol THE630-21-101 Version 2.0 dated 
07 October 2021, as follows: 
• 
Sections 2.1.1, 3.1, 3.2, 4.1, 9.4, Figure 2: Due to the evolving GIST investigational 
landscape, the phase 2 study design has been amended to remove original expansion 
Cohort 3, which was to enroll patients with unresectable or metastatic GIST who had 
progressed on or were intolerable to imatinib and ripretinib. 
• 
Section 4.1, Figure 2: The entry criteria for expansion Cohort 2 has been amended to 
remove the exclusion of prior ripretinib, in line with the parallel amendment to remove 
original expansion Cohort 3. 
• 
Section 6.3.1, Table 1 footnote 1: To clarify a discrepancy with Table 1 footnote 13 and 
Section 7.3.8, language indicating ECHO/MUGA scan should be performed on C1D1 if 
not performed with 7 days prior was removed.  
• 
Section 5.9.2 was amended to include 12 mg capsules in the list of supplied capsule 
strengths of THE-630 drug product. 
• 
Section 8.2 was amended to explicitly clarify that SAEs observed by the investigator or 
reported by the patient that occur after 30 days after the last dose of study drug through 
the end of the survival follow-up period should be reported if there is a reasonable 
possibility that the event may have been caused by THE-630.   
• 
Section 8.2.2 was amended to clarify that the Investigator may change opinion of causality 
in light of follow-up information. 
• 
Section 8.2.6 was amended to clarify that reports of pregnancy with be submitted on the 
study Pregnancy Notification Form rather than in the clinical trial database (eCRF) and 
that pregnancy outcomes should be reported on the Pregnancy Outcome Form. 
• 
Section 8.2.7 was amended to clarify that situations of abuse, misuse, overdose and 
medication error will be submitted using the study Special Situations Report Form. 
• 
Section 8.3 was amended with minor clarifications on instructions for SAE reporting. 
• 
Section 11: References were updated to correct identified inconsistencies with citations in 
the body of the protocol. 
• 
Correction was made to fix minor typos throughout. 
• 
Synopsis was updated to reflect all applicable changes. 
 


Theseus Pharmaceuticals, Inc. 
 
07 Dec 2022 
Protocol THE630-21-101 
< Version 4.0, FINAL > 
Page 101 of 101 
Protocol Version 2.0 (07 Oct 2021) 
This amendment (Version 2.0) updates and supersedes Protocol THE630-21-101 Version 1.0 dated 
02 Sep 2021, as follows: 
• 
Exclusion criterion #12 was modified to align more closely with FDA guidance (Cancer 
Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C 
Virus Infections, Guidance for Industry 2020). The following text was added: “Risk of 
HBV reactivation should be considered in all patients and the need for anti-HBV 
prophylaxis should be carefully assessed. Patients with chronic HBV infection with 
history of active disease who meet the criteria for anti HBV therapy should be on a 
suppressive antiviral therapy to be eligible for enrollment. Patients who are HCV Ab 
positive but HCV RNA negative due to prior treatment or natural resolution are eligible. 
Patients on concurrent HCV treatment at the time of enrollment are allowed if HCV RNA 
negative.” 
• 
Sections 5.6, 5.6.1, 5.7.2, 8.2, 8.2.2, Table 1 footnotes 15, 16; Table 4: To conform 
language, “drug-related” was removed as a descriptor of AEs and replaced with “AEs for 
which relationship to THE-630 cannot be ruled out.” 
• 
Section 8.2.2: Text was amended to make the AE causality definition of “related” more 
explicitly consistent with the definition of a DLT. The text was updated to clarify that a 
causality of “related” should be assigned for all AEs for which a relationship to THE-630 
cannot be clearly and incontrovertibly ruled out. 
• 
Sections 5.8.1, 6.3.10: Removed text related to the option of continued treatment despite 
objective progression if the patient is continuing to experience clinical benefit in the 
opinion of the Investigator. 
• 
Synopsis was updated to reflect all applicable changes. 
 

SAP_001.pdf: 
 
 
 
 
 
Official Title: 
A Phase 1/2 Study of the Safety, Pharmacokinetics and 
Anti-Tumor Activity of the Oral KIT Inhibitor THE-630 
in Patients with Advanced Gastrointestinal Stromal 
Tumors (GIST) 
NCT Number: 
NCT05160168 
Document Date: 
09 Jan 2024 
 


REF: 
Page 1 of 45 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
Statistical Analysis Plan 
Title: A Phase 1/2 Study of the Safety, Pharmacokinetics and Anti- Tumor Activity 
of the Oral KIT Inhibitor THE-630 in Patients with Advanced Gastrointestinal 
Stromal Tumors (GIST) 
Protocol Number: THE630-21-101 
Protocol Version: Version 3.0/25FEB2022 
SAP Version 3.0 
SAP Issue Date: 09-JAN-2024 
SAP Author: 
, MS. 
Previous SAP Versions 
1.0, 05-AUG-2022 
2.0, 26-OCT-2023 
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Confidentiality Statement 
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Page 2 of 45 
 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Table of Contents 
1 
INTRODUCTION ............................................................................................... 7 
2 
STUDY OBJECTIVES ....................................................................................... 7 
2.1 
Primary Objectives .......................................................................................................... 7 
2.2 
Secondary Objectives ...................................................................................................... 7 
2.3 
Exploratory Objectives ................................................................................................... 8 
3 
ENDPOINTS ....................................................................................................... 8 
3.1 
Primary Endpoint ............................................................................................................ 8 
3.1.1 
Phase 1 ...................................................................................................................... 8 
3.2 
Secondary Endpoints ...................................................................................................... 8 
3.2.1 
Phase 1 ...................................................................................................................... 8 
4 
PLANNED ANALYSES ..................................................................................... 8 
4.1 
Analysis Sets ................................................................................................................... 8 
4.1.1 
Screened Set .............................................................................................................. 9 
4.1.2 
Enrolled Set ............................................................................................................... 9 
4.1.3 
Full Analysis Set ....................................................................................................... 9 
4.1.4 
DLT-evaluable Analysis Set (phase 1 only) ............................................................. 9 
4.2 
Derived Data ................................................................................................................... 9 
4.2.1 
Age ............................................................................................................................ 9 
4.2.2 
Baseline ................................................................................................................... 10 
4.2.3 
Duration / Study Day / Time ................................................................................... 10 
4.2.4 
Prior Systemic Anticancer Therapy (SACT) .......................................................... 10 
4.2.5 
Conventions for Missing and Partial Dates ............................................................ 10 
4.2.6 
Missing / Partial Start / Stop Date of Adverse Events (AE) and Concomitant 
Medications ........................................................................................................................... 10 
4.2.7 
Missing Last Dates of Study Drug Dosing ............................................................. 11 
4.2.8 
Missing Diagnosis Dates ......................................................................................... 12 
4.2.9 
Inexact Values ......................................................................................................... 12 
4.2.10 
Exposure to Study Drug .......................................................................................... 12 
4.2.11 
Compliance ............................................................................................................. 13 
4.2.12 
Body Mass Index (BMI) ......................................................................................... 13 
4.2.13 
Safety Endpoints ..................................................................................................... 13 
4.2.13.1 
Electrocardiogram (ECG) Data ..................................................................... 13 
 
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Sponsor: 
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Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.2.13.2 
Dose Limiting Toxicities (DLT) ................................................................... 13 
4.2.13.3 
Unscheduled Visits ....................................................................................... 14 
4.2.14 
Efficacy endpoints .................................................................................................. 14 
4.2.14.1 
Best Overall Response (BOR), Confirmed ................................................... 15 
4.2.14.2 
Confirmed Objective Response Rate (ORR) ................................................ 15 
4.2.14.3 
Clinical Benefit Rate (CBR) at 16 Weeks .................................................... 15 
4.2.14.4 
Disease Control Rate (DCR) ......................................................................... 16 
4.2.14.5 
Best Percent change from baseline in sum of the longest diameter of target 
lesions 
16 
4.2.14.6 
Duration of Follow-up .................................................................................. 16 
4.3 
Conventions .................................................................................................................. 16 
4.3.1 
Decimal Places ........................................................................................................ 17 
4.4 
Patient Disposition ........................................................................................................ 17 
4.5 
Protocol Deviations ....................................................................................................... 18 
4.6 
Baseline Comparability ................................................................................................. 18 
4.7 
Medical History ............................................................................................................ 18 
4.8 
Baseline Characteristics ................................................................................................ 18 
4.9 
Prior and Concomitant Medications ............................................................................. 19 
4.10 
Non-Pharmacological Procedures ................................................................................. 19 
4.11 
Exposure to Study Drug ................................................................................................ 19 
4.12 
Treatment Compliance .................................................................................................. 19 
4.13 
Efficacy Analyses ......................................................................................................... 19 
4.13.1 
Efficacy Analysis .................................................................................................... 19 
4.14 
Pharmacokinetic Analyses ............................................................................................ 20 
4.15 
Safety Analyses ............................................................................................................. 20 
4.15.1 
Adverse Events ....................................................................................................... 20 
4.15.2 
Laboratory Data ...................................................................................................... 21 
4.15.3 
Vital Signs ............................................................................................................... 22 
4.15.4 
Echocardiogram/MUGA ......................................................................................... 23 
4.15.5 
ECOG Performance Status ..................................................................................... 23 
4.15.6 
Electrocardiogram Data .......................................................................................... 23 
4.15.7 
Physical Examination .............................................................................................. 24 
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Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.15.8 
Tissue/Blood Samples for Biomarkers ................................................................... 24 
5 
INTERIM ANALYSIS ...................................................................................... 24 
6 
DATA SAFETY MONITORING BOARD ANALYSIS ................................. 24 
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ................................... 24 
8 
REFERENCES .................................................................................................. 25 
9 
LIST OF TABLES, FIGURES AND LISTINGS ............................................. 26 
10 APPENDIX 1: RECIST ..................................................................................... 33 
10.1 
Target Lesion Response ................................................................................................ 33 
10.2 
Overall Visit Response ................................................................................................. 35 
10.3 
BOR-confirmation of CR and PR required ................................................................... 36 
11 APPENDIX 3: SAS CODE ............................................................................... 37 
11.1 
ORR .............................................................................................................................. 37 
12 APPENDIX 4: LABORATORY TESTS .......................................................... 38 
12.1 
Select Laboratory Parameters-CTCAE Grades ............................................................ 38 
13 APPENDIX 5: CRITERIA BASED ON HY’S LAW ...................................... 45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sponsor: 
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Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
REVIEW / APPROVAL SIGNATURES 
 
3ODQ$XWKRUௗௗ 
, Senior Principal Statistician 
6LJQDWXUHௗ 
ௗ 
Electronically signed by:
 
Reason: I am the author of this document 
Date: Jan 9, 2024 17:34 EST 
Plan Reviewer, 
, Principal Statistician 
6LJQDWXUHௗ 
 
Electronically signed by: 
 
Reason: I am the reviewer of this 
document 
Date: Jan 9, 2024 16:52 CST 
3ODQ$SSURYHU6SRQVRUௗ&OLQLFLDQ
 MD, Consultant for Theseus 
Pharmaceuticals, Inc. 
6LJQDWXUHௗ 
ௗ 
Electronically signed by: 
 
Reason: I approve this document 
Date: Jan 10, 2024 09:17 EST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Confidentiality Statement 
 
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Page 6 of 45 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
SAP Amendments prior to database lock 
 
Version Issue Date 
Section 
Revision / Addition 
2.0 
26-OCT-2023 
1 
Removed unnecessary text given in original 
version. Added details regarding why there is an 
amendment 
2.0 
26-OCT-2023 
3,4,5 
(Original) 
Removed Phase 2 endpoints, sample size and 
randomization section (Captured in SAP V1.0) 
2.0 
26-OCT-2023 
Multiple 
Removed sections referring to phase 2, Dose 
Expansion (EXP). 
Removed displays and other details that 
reference phase 2 or EXP. 
2.0 
26-OCT-2023 
Multiple 
The follow populations, subgroups, endpoints 
and/or displays were dropped due to the 
reduction in scope for the terminated study (eg, 
removal of Prior SACT subgroup analyses, 
reduction in number of analysis sets, and 
descriptions of response): 
-Response-Evaluable Analysis Set 
- Prior SACT Subgroup 
- Best Overall Response (BOR) and ORR, 
Confirmed and unconfirmed 
- Duration of Response (DOR), Confirmed 
responders-displays 
- Displays: 
- Table and/or figures referencing above were 
dropped or amended not to reflect said data. 
- OS: Table display 
- Labs: Table display (e.g., descriptive 
summaries, CTCAE grade increases) 
- Tissue/Blood Samples: All displays 
- Figures: labs, vital signs, and Spider Plots 
3.0 
 
 
Reduction in the number of TFLs required (the 
following displays/endpoints are dropped): 
-All listings except for listings referenced as a 
table. 
-PFS, OS and time to response 
-Vital Signs/ECG/ Prior/Concomitant 
medications (e.g., Descriptive summaries) 
-several AE displays by preferred term 
 
 
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Page 7 of 45 
 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
1 INTRODUCTION 
This is a Phase 1/2, open-label, multicenter trial to evaluate the safety, pharmacokinetics, and 
antitumor activity of THE-630 in patients with advanced GIST. The plan was to conduct the study 
in two parts: a dose escalation phase (Phase 1) and a subsequent expansion phase (Phase 2). 
Enrollment was stopped after 32 patients were enrolled in Phase 1. Phase 2 will not be initiated. 
Due to the termination of this study, the scope of reporting has changed. This amendment 
documents the updates to planned analyses due to the reduction in scope of the study. All details 
regarding the original study objectives, planned statistical displays and analysis components are 
detailed in SAP version 1.0. In general, the analyses planned have remained consistent with those 
defined in SAP version 1.0, but the scope has been reduced due to the lack of an expansion phase, 
and shorter follow-up of the study. 
 
 
2 STUDY OBJECTIVES 
Below objectives are as defined in the protocol. However, due to the termination of the study, 
certain objectives (e.g., Phase 2) are no longer applicable. 
2.1 Primary Objectives 
The primary objectives for the study are as follows: 
x Dose Escalation (Phase 1): To determine the safety profile of oral THE-630, including 
the DLTs, MTD, and RP2D 
x Expansion Cohorts (Phase 2): To determine the antitumor activity of oral THE-630 in 
patients with advanced GIST 
 
2.2 Secondary Objectives 
The secondary objectives for the study are as follows: 
x Dose Escalation (Phase 1): 
o To determine the PK profile of oral THE-630 and its active metabolite THE-973 
o To document preliminary evidence of antitumor activity of oral THE-630 in 
patients with advanced GIST 
x Expansion Cohorts (Phase 2): 
 
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Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
o To evaluate the safety profile of oral THE-630 
o To further characterize the PK profile of oral THE-630 and its active metabolite 
THE-973 
2.3 Exploratory Objectives 
The exploratory objective for both phase 1 and phase 2 of the study is as follows: 
x To explore associations between tumor and plasma biomarkers and THE-630 efficacy 
and safety 
 
 
3 ENDPOINTS 
3.1 Primary Endpoint 
3.1.1 Phase 1 
The primary endpoint of the dose escalation phase of the study is the safety profile of THE-630, 
including identification of DLTs and MTD, and determination of the RP2D. 
 
 
3.2 Secondary Endpoints 
3.2.1 Phase 1 
Secondary endpoints of the dose escalation phase include: 
x Plasma PK parameters of THE-630 and its active metabolite THE-973 after single oral 
dose and at steady state after multiple oral doses 
x Efficacy assessments, according to modified RECIST 1.1 for patients with GIST 
including: confirmed objective response rate (ORR), best overall response, best target 
lesion response, time to response, disease control rate (DCR), Clinical Benefit Rate 
(CBR) at 16 weeks, PFS and OS 
 
 
4 PLANNED ANALYSES 
4.1 Analysis Sets 
 
 
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Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.1.1 Screened Set 
The Screened Set includes all patients who signed informed consent and were allocated a patient 
number. 
4.1.2 Enrolled Set 
The Enrolled Set includes all screened set patients who meet eligibility criteria. 
4.1.3 Full Analysis Set 
The Full Analysis Set (FAS) includes all enrolled patients who receive at least one dose of THE- 
630. Unless otherwise stated, all primary efficacy and safety analyses will be conducted on the 
Full Analysis Set. 
4.1.4 DLT-evaluable Analysis Set (phase 1 only) 
The DLT-evaluable Analysis Set (Phase 1 only) will include patients enrolled in the Phase 1 dose 
escalation portion who completed at least 75% of the planned total dose during Cycle 1 (DLT 
evaluation period, i.e. 21 of 28 days) and patients who have experienced a protocol-defined DLT, 
regardless of dosing adherence in Cycle 1. Patients who do not receive study drug for at least 21 
of 28 days (at least 75% of planned doses; not necessarily consecutively) during the first cycle for 
reasons not considered to be a DLT will be excluded from the DLT-evaluable Analysis Set. 
Additionally, patients who were enrolled as backfill enrollment will be excluded from the DLT- 
evaluable Analysis Set. 
4.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
4.2.1 Age 
Age is defined as the age in years at time of informed consent as collected in the CRF. 
The follow age groups (categorical) will be created for summary purposes: 
Age group 1 (years): 18- 
Age Group 2 (years): 18-49, 50-64, 65- 
 
 
 
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Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.2.2 Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) 
collected prior to first dose date and time of study drug for a given patient. 
4.2.3 Duration / Study Day / Time 
Study day will be calculated as the number of days from first dose of study drug. 
x date of event – date of first dose of study drug + 1, for events on or after first dose 
x date of event – date of first dose of study drug, for events before first dose 
4.2.4 Prior Systemic Anticancer Therapy (SACT) 
Prior TKIs (tyrosine kinase inhibitor) will be identified programmatically and through manual 
review of the data by the sponsor on an on-going basis. Final identification will be approved by 
the Sponsor before database lock. Additionally, for reporting purposes, prior SACTs that have 
different versions (e.g., salt vs no salt) and hence coded to different codes but will be considered 
the same SACT. These will be identified programmatically and through a manual review by the 
sponsor. Final identification will be approved by the Sponsor before database lock. 
4.2.5 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual patient listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
4.2.6 Missing / Partial Start / Stop Date of Adverse Events (AE) and 
Concomitant Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows. 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the patient has stopped taking 
the concomitant medication, the stop date will be imputed as the date of the patient’s last clinic 
visit in the study. 
x If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the patient’s last clinic visit in the study if in the same year. 
 
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Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
x If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the patient’s last clinic visit in which 
case the date of patient’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
x If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug. 
x If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the patient’s screening date or the stop date of the event / 
concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
x If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
x If the stop date occurs before the start of study drug, 
o the start date of the concomitant medication will be imputed as the “01-Jan” of the 
same year. 
o the start date of the event will be imputed as the “01-Jan” of the same year or 
patient’s screening date, whichever is latest. 
Partial start date (month and year present, but day missing) 
x If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 
year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used. 
x If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date unless this partial start date is same 
month as patient’s screening visit in which case the date of screening will be used. 
4.2.7 Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study drug 
will be taken for analysis purposes as the date of patient’s last clinic visit in the study or has been 
 
 
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Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
indicated to have discontinued treatment or has died whichever is earlier but no earlier than the 
date of first dose. 
If only the month and year of the last dose was recorded, then the date of last dosing will be taken 
for analysis purposes as, the last day of the month of the recorded last dose or the date of patient’s 
last clinic visit in the study or has been indicated to have discontinued treatment or has died 
whichever is earlier but no earlier than date of first dose. 
4.2.8 Missing Diagnosis Dates 
If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year. 
4.2.9 Inexact Values 
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for analysis purposes. 
4.2.10 Exposure to Study Drug 
Duration of exposure to study drug will be calculated as follows from the date of last dosing minus 
the first day of dosing + 1. The duration of exposure calculation will not take into account 
interruptions in therapy/missed doses. Duration of exposure to study drug will be reported in 
months. Patients will also be assigned to a duration of exposurHFDWHJRU\PRQWKWR
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actual number of days dosed will be calculated taking into account interruptions and missed doses. 
Cumulative dose taken (mg) will be the sum of all doses taken by a patient taking into account any 
interruptions/missed doses, dose reductions or dose increases as recorded in the eCRF 
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Dose intensity (mg/day) is calculated as cumulative dose taken (mg)/duration of exposure (days). 
 
 
 
 
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Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Relative dose intensity is calculated as 100* (dose intensity/expected dose intensity). Expected 
dose is based on assigned dose level and duration of exposure not adjusted for prescribed 
interruptions, dose reduction or increases. 
4.2.11 Compliance 
Treatment compliance for Cycle 1 will be calculated as follows: ([cumulative] amount of treatment 
actually taken [mg] during Cycle 1)/Total [cumulative] amount of treatment that should have been 
taken [mg]) during Cycle 1 x 100. Total (cumulative) amount taken for cycle 1, similar to 
calculation in Section 6.2.10 limiting to Cycle 1. Total (cumulative) amount of treatment that 
should have been taken (mg) during Cycle 1 will be calculated for each dose level prescribed 
within Cycle 1*(end date of that dose level -start date of dose level+1) and summed across dosing 
records within Cycle 1 for a given patient. Patients will also be categorized by Cycle 1compliance 
based on the following compliancHOHYHOVWRWR 90%). 
4.2.12 Body Mass Index (BMI) 
BMI at screening will be derived based on screening height and weight. 
BMI = weight (kg) divided by height (m) squared (unit=kg/m2). 
4.2.13 Safety Endpoints 
4.2.13.1 Electrocardiogram (ECG) Data 
Triplicate ECGs should be taken on Cycle 1, Day 1 (pre-dose and 8 hrs post-dose) and Day 15 
(pre-dose and following hrs post-dose: 1, 2, 4, 8); otherwise, single ECGs are required at specific 
time points per protocol schedule of events. 
For triplicate ECG data recorded on continuous scales, the mean value rounded to the integer will 
be presented. For overall interpretation if more than one value is recorded, the most severe (worst 
case) of the respective readings will be taken. 
4.2.13.2 Dose Limiting Toxicities (DLT) 
DLTs during Phase 1 (dose escalation phase) are defined as any treatment-emergent adverse 
event (AE) that meets the following criteria within the first 28 days of treatment (e.g, occurring 
during Cycle 1) and for which the relationship to THE-630 cannot be ruled out: 
x Non-hematologic toxicities 
o $Q\*UDGHQRQ-hematologic toxicity, with the exception of: 
 
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Page 14 of 45 
 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
x Self-limiting or medically controllable toxicities (e.g., nausea, fatigue, 
HOHFWURO\WHGLVWXUEDQFHVODVWLQJ days 
x *UDGHYRPLWLQJRUGLDUUKHDODVWLQJ days 
x Grade 3 elevations of creatine kinase (CK) that are asymptomatic, i.e., not 
accompanied by muscle pain or worsening renal function or other signs of 
rhabdomyolysis or cardiac muscle damage (such as abnormal CK-MB, 
7URSRQLQDQGUHFRYHUHGWR*UDGHRUEDVHOLQHLQ hours 
x Grade 3 hypertension that recovers to Grade 2 or below within 5 days 
x Alopecia 
 
x Hematologic toxicities 
o )HEULOHQHXWURSHQLDIHYHU!)>!&@$1&î 109/L) 
o 3URORQJHG*UDGHQHXWURSHQLD days) 
o 1HXWURSHQLFLQIHFWLRQ*UDGHQHXWURSHQLDZLWK*UDGH infection 
o 7KURPERF\WRSHQLD*UDGHZLWKEOHHGLQJRU*UDGHZLWKRXWEOHHGLQJ lasting 
GD\V 
 
x 
 0LVVHGRISODQQHGGRVHVRI7+(-630 (in the aggregate, not necessarily 
consecutive) over 28 days due to AEs for which the relationship to THE-630 cannot be 
ruled out in the first cycle[note the treatment-related AE(s) included should not have met 
other DLT criteria] 
DLTs will be reported as AEs and identified as a DLT in the database. 
 
4.2.13.3 Unscheduled Visits 
Only scheduled post-baseline laboratory, vital signs, ECHO/MUGA and ECG values will be 
tabulated by visit. Certain summaries may have any time, post-baseline/worst post- 
baseline/minimum post-baseline/maximum post-baseline which would include post-baseline 
scheduled/repeat/ unscheduled assessments. All post-baseline assessments will be listed in the 
relevant appendices to the CSR. 
4.2.14 Efficacy endpoints 
 
 
 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.2.14.1 Best Overall Response (BOR), Confirmed 
BOR is defined as the best response achieved at any time point on the study where response 
refers to the overall response at a given time point (e.g., overall visit response; (derived; see 
Appendix 1)) according to the following hierarchy: 
x Complete Response (CR), 
x Partial Response (PR), 
x Stable disease (SD) 
x Progressive disease (PD) 
x Not Evaluable (NE) 
per modified RECIST version 1.1 for patients with GIST. 
CR or PR responses must be confirmed by repeat imaging at no less than 4 weeks after the date 
of the initial response (See Appendix 1). To be assigned SD, patient must have met the SD 
criteria once after first dose at a minimum of 6 weeks. It should be noted that patients with no 
measurable disease at baseline should have overall visit response(s) of Non-CR/Non-PD. In 
these cases, for analysis purposes, BOR will be set to NE. Additionally, if a patient does not 
have any post-baseline overall visit response assessments, then the patient will be assigned BOR 
of NE. 
4.2.14.2 Confirmed Objective Response Rate (ORR) 
Confirmed ORR is defined as the proportion of the patients who were confirmed to have 
DFKLHYHG&5RU35SHUPRGLILHG5(&,67YHUVLRQIRUSDWLHQWVZLWK*,67FRQILUPHG
weeks after initial response with a subsequent scan) after initiation of study drug. Patients with 
no measurable disease at baseline or no evaluable post-baseline response assessment (e.g., 
RECIST) will be considered non-responders. 
 
4.2.14.3 Clinical Benefit Rate (CBR) at 16 Weeks 
CBR at 16 weeks is defined as the proportion of patients remaining on study who have not met 
criteria for progressive disease (PD) on or prior to the 16-week assessment (i.e., patients with an 
objective response or stable disease (SD) lasting 4 cycles from the start of treatment (defined as 
at least 109 days from start of treatment). Patients with no tumor assessments (e.g., scans) for 
Week 16 and later timepoints would not be counted as having clinical benefit. 
 
 
 
 
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Confidentiality Statement 
 
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Page 16 of 45 
 
 
 
 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.2.14.4 Disease Control Rate (DCR) 
DCR is defined as the proportion of patients who have achieved confirmed BOR of CR, PR, or 
SD (in the case of SD, measurements must have met the SD criteria at least 6 weeks after the 
initiation of study drug). 
4.2.14.5 Best Percent change from baseline in sum of the longest diameter of target 
lesions 
The percentage change in the sum of longest diameter for the target lesions by visit will be 
calculated. Best percent change in the sum of the longest diameter (SLD) of target lesions will 
be identified. This is defined as the biggest percent reduction from baseline or in the scenario 
where patient does not have any reduction then no change or smallest increase. 
That said post-baseline visits where the longest diameter of one or more of the identified target 
lesions(s) were not measured and the target lesion response for said visit is NE will be excluded 
for purposes of analysis (Appendix 1). 
4.2.14.6 Duration of Follow-up 
Duration of follow-up is defined as time (months) from first dose until death, lost to follow-up 
(ltfu) or withdraw from study, whichever is earliest. 
Duration of follow-up (months)= (earliest of date of death/ltfu/withdraw from study- date of first 
dose + 1)/30.4375. 
 
 
4.3 Conventions 
All data listings, summaries, figures, and statistical analyses will be generated using SAS version 
9.3 or higher1. 
Dose Escalation (Phase 1) [DE]: 
DE or DE cohort refers subjects participating in the Phase 1 dose escalation part of this study. 
Cohort for DE phase refers to dose level. 
Summaries will be presented by dose escalation phase cohorts (dose levels) and overall. 
3 mg QD 
(N=XX) 
'RVHOHYHO!
(N=XX) 
'RVHOHYHO!
(N=XX) 
'RVHOHYHO!
(N=XX) 
'RVH;OHYHO!
(N=XX) 
All Patients 
(N=XXX) 
 
 
 
 
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Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Listings will be sorted in the following order: Cohort number, patient (if applicable, backfill 
patients should be listed after non-backfill patients), parameter, and visit unless otherwise stated. 
All data will be listed. 
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum. 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations unless otherwise specified. For each 
variable, all categories will be shown. Zero frequencies (but not the percent) within a category will 
be presented. 
4.3.1 Decimal Places 
Decimal places for derived data described in section 4.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated YDOXHLVGHFLPDOSODFHZLOOEHGLVSOD\HGZKHQWKHVPDOOHVWYDOXHLVZLWKLQWKH
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement. 
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal places. 
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. 
4.4 Patient Disposition 
Patient disposition will be summarized as follows: 
x The number of patients, who are in the Screened Set, Enrolled Set, Full Analysis Set and 
DLT-Evaluable Set will be summarized by cohort and overall. 
x The number of patients who failed screening and the reasons for failure will be tabulated 
for the Screened Set 
x The number and percentage of patients who discontinued study drug along with the reason 
for discontinuing drug and those who discontinued the study along with the reason for 
discontinuing the study will be tabulated by cohort and overall for the Full Analysis Set. 
 
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Governing QMD: 
 
Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
x Duration of follow-up will be summarized by cohort and overall for the Full Analysis Set. 
 
 
4.5 Protocol Deviations 
Number (percent) of patients with Major Deviations by deviation category will be presented by 
cohort and overall for Full Analysis Set. 
 
 
4.6 Baseline Comparability 
The comparability of cohorts with respect to patient demographics and baseline characteristics will 
be assessed in a descriptive manner, but no formal statistical testing will be performed. 
The following baseline demographic variables will be summarized by cohort and overall for the 
Full Analysis Set using standard continuous or categorical variable summaries: Age at informed 
consent (years), gender, ethnicity, race, height, weight and BMI. 
4.7 Medical History 
Medical history conditions (prior and on-going) and previous surgical procedures reported at 
screening will be presented together for Full Analysis Set. Terms will be coded by Medical 
Dictionary of Regulated Activities (MedDRA) primary system organ class (SOC) and preferred 
term. 
4.8 Baseline Characteristics 
Reported mutation status history (e.g, presence of any kit mutation, type of kit Exon mutation, 
presence of any PDGRA mutation, type of PDGRFA Exon Mutation, Kit and PDGRFA wild-type 
status) will be summarized by cohort and overall for Full Analysis Set. 
Details regarding GIST history (initial diagnosis: time from first diagnosis of GIST to first dose of 
study drug (years), stage at initial diagnosis, current stage, primary tumor location, histology, any 
prior surgery related to GIST, any prior radiation therapy related to GIST and any Systemic 
Anticancer Therapy (SACT) related to GIST; current stage and location of sites of disease at 
screening) will be summarized by cohort and overall for the Full Analysis Set. 
 
 
 
 
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Governing QMD: 
 
Confidentiality Statement 
 
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Page 19 of 45 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
The ECOG performance status scale measures a patient’s level of daily functioning (scale ranges 
from grades 0-5). Descriptive statistics of baseline ECOG score will be presented by cohort and 
overall. 
Details regarding SACT related to GIST (any prior SACT, number of prior therapies, number of 
prior regimens, number of prior TKIs, type of SACT) will be summarized by cohort and overall 
for Full Analysis Set. 
Details regarding prior surgery and radiation therapy will not be summarized or listed. 
4.9 Prior and Concomitant Medications 
Data will not be summarized or listed. 
4.10 Non-Pharmacological Procedures 
Data will not be summarized or listed. 
4.11 Exposure to Study Drug 
Extent of exposure (number of days of exposure to study), actual number of days dosed, the 
cumulative amount of administered treatment, dose intensity, and relative dose intensity will be 
summarized by cohort and overall for Full Analysis Set. Additionally, the number (percent) of 
patients that had an interruption lasting 3 days or more, duration of longest interruption for those 
subjects with an interruption lasting at least 3 days, number (percent) of patients that had an 
interruption due to an AE, number (percent) of patients that had a dose reduction due to an AE or 
dose increase will also be summarized by cohort and overall. 
4.12 Treatment Compliance 
Compliance for Cycle 1 will be summarized by cohort and overall for the Full Analysis Set. 
4.13 Efficacy Analyses 
No statistical comparisons between cohorts are planned for this study. All efficacy analyses will 
be conducted on the full analysis set unless otherwise stated. 
4.13.1 Efficacy Analysis 
x ORR 
 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
ORR (confirmed) will be summarized by each cohort and overall along with corresponding exact 
binomial 2-sided 95% CI. 
Descriptive summaries will be provided for the confirmed best overall response (BOR) and time 
to response (confirmed) by cohort and overall. 
A waterfall plot of the best percentage change in the target lesion sum of longest diameters from 
baseline will be produced by cohort. Additionally, swimmer’s plots of the duration of treatment 
overlayed with overall timepoint response will be produced. 
x DCR and CBR 
DCR and CBR at 16 weeks will be summarized by each cohort and overall along with 
corresponding exact binomial 2-sided 95% CI. 
4.14 Pharmacokinetic Analyses 
Pharmacokinetic analyses will be analyzed and reported in a separate report. 
4.15 Safety Analyses 
The safety analyses will be presented by the treatment received for the Full Analysis Set. 
4.15.1 Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as: 
x Any AE that has an onset on or after the first dose of study drug and before last dose + 30 
days 
x Any pre-existing AE or medical history finding that has worsened in severity on or after 
the first dose of study drug 
A post-treatment AE is Any AE that has an onset greater than 30 days after last dose of study drug. 
If an AE has missing relationship it is assumed to be related to the study drug for analysis purposes. 
If a toxicity grade is missing, then the toxicity grade will be reported as missing. 
The following tables will be presented for AEs: 
x 2YHUDOOLQFLGHQFHDQGQXPEHURI7($(7($(V*UDGH7UHDWPHQW-Related TEAEs, 
Treatment-5HODWHG 7($(V  *UDGH , Serious Treatment Emergent Adverse Events 
(Treatment-Emergent SAEs), Serious Treatment-Related TEAEs (Treatment Emergent, 
 
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Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Treatment-Related SAEs), TEAEs leading to Study Drug discontinuation, TEAEs leading 
to interruption of study drug, TEAEs leading to dose reduction of study drug and Fatal 
TEAEs. 
x TEAEs by system organ class and preferred term, incidence and number of events. 
x Treatment related TEAE by system organ class and preferred term, incidence and number 
of events. 
x 7($(V*UDGHE\V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPLQFLGHQFHDQGQXPEHURI
events. 
x Treatment-UHODWHG7($(V*UDGHE\V\VWHPRUJDQFODVVDQGSUHIHUUed term, incidence 
and number of events. 
x Serious TEAE by system organ class and preferred term, incidence and number of events. 
x Serious Treatment related TEAE by system organ class and preferred term, incidence and 
number of events. 
x TEAEs Leading to Discontinuation of Study Drug b system organ class and preferred term 
x TEAEs Leading to Interruption of Study Drug by system organ class and preferred term, 
incidence and number of events. 
x TEAEs Leading to dose reduction of Study Drug by system organ class and preferred term, 
incidence and number of events. 
x TEAE by system organ class, preferred term and maximum toxicity, incidence. 
x Treatment-Related TEAE by system organ class, preferred term and maximum toxicity, 
incidence. 
x Fatal TEAEs by system organ class and preferred term, incidence 
x Post-Treatment Adverse Events by system organ class and preferred term, incidence and 
number of events. 
x Adverse Events, Dose Limiting Toxicities during Cycle 1 By Preferred Term and 
maximum toxicity, incidence (Phase 1 only; DLT-Evaluable Analysis Set) 
x Listing of Serious TEAEs 
x Listing of Fatal TEAEs 
x Listing of All Deaths 
x Listing of DLTs 
All AEs will be listed. 
4.15.2 Laboratory Data 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Laboratory samples will be analyzed by local laboratories. For reporting purposes, lab parameters 
will be reported using SI units. 
Each measurement (continuous data) will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. To identify laboratory values of potential clinical 
importance, National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) will be used to assign grades for select laboratory parameters where applicable (See 
Appendix 4). A shift table representing two-way frequency tabulation for baseline and the worst 
post-baseline value according to the CTCAE grade, by cohort and overall, will be provided. For 
analysis purpose, patients with a lab parameter value that does not meet CTCAE criteria (e.g., 
value is within normal range) at baseline or any time post-baseline, will be assigned a Grade of 0 
for said visit. 
The incidence of patients meeting Hy’s law criteria will be summarized for any time, post-baseline 
(See Appendix 5). 
A listing of any abnormal laboratory measurements recorded throughout the study will be 
presented. 
4.15.3 Vital Signs 
To identify vital signs values of potential clinical importance, the following criteria will be used 
for the following vital signs parameters: systolic blood pressure (SBP) and diastolic blood pressure 
(DBP). 
 
Parameter 
Category (levels) 
SBP (mmHg) 
PP+J 
120-139 mmHg 
140-159 mmHg 
PP+J 
DBP (mmHg) 
PP+J 
80-89 mmHg 
90-99 mmHg 
 mmHg 
 
For systolic and diastolic blood pressure, a shift table representing two-way frequency tabulation 
for baseline and the maximum post-baseline value according to the above criteria, by cohort and 
overall, will be provided along with summary of any increases in category level. 
 
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Governing QMD: 
 
Confidentiality Statement 
 
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Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.15.4 Echocardiogram/MUGA 
Standard continuous and categorical summaries will be presented for each visit by cohort and 
overall for the following parameters: 
x Test type 
x 
Left ventricular ejection 
x Fraction (LVEF) % value (observed; change from baseline) 
x 
If LVEF was clinically significant 
4.15.5 ECOG Performance Status 
Baseline ECOG performance status scale scores will be summarized by cohort and overall 
(Section 4.8). 
4.15.6 Electrocardiogram Data 
The number (%) of patients meeting the following criteria at any time, post-baseline will be 
summarized by cohort and overall: 
x QT interval (ms) 
o >500 & baseline  
x QTcF maximum increase (on treatment defined as any assessment on or after first dose 
up to last dose + 30 days) 
o No increase 
o !WR ms 
o 30 to 60 ms 
o >60 ms 
x QTcF (ms) 
o >500 & baseline  
o >480 & baseline  
o >450 & baseline  
x Heart Rate (bpm) 
o  bpm 
o  bpm 
o >100 bpm 
o >100 bpm and 25% increase from baseline 
o ESPDQGGHFUHDVHIURP baseline 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
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Page 24 of 45 
 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
4.15.7 Physical Examination 
Data will not be summarized or listed. 
4.15.8 Tissue/Blood Samples for Biomarkers 
Data will not be summarized or listed. 
5 INTERIM ANALYSIS 
No formal pre-specified interim analyses are planned as this is a single arm, open-label, phase 1/2 
study, however data may be summarized periodically throughout the study based on a separate 
plan(s). 
6 DATA SAFETY MONITORING BOARD ANALYSIS 
No data safety monitoring board (DSMB) analyses are planned. 
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
Due to the termination of this study, the scope of reporting has changed. This amendment 
documents the analyses to be performed, which are generally consistent with the protocol, but 
reflects the reduction in the scope of reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Confidentiality Statement 
 
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Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
8 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
9 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods maybe 
used: 
x Independent programming of numbers and manual review of format (IP) 
x Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
x Manual review (MR) 
x Code review (CR) 
Phase 1 (Dose escalation (DE)) versions of displays will be created. Please note that in titles 
ZKHUHWH[W³SKDVH!´DSSHDUVWKLVWH[WVKRXOGEHUHSODFHGZLWK³3KDVH´ 
 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
Items in bold are not table titles but references to the section headings within eCTD. 
 
14.1 
Demographics Data 
 
 
14.1.1 
Disposition 
 
 
14.1.1.1 
DE 
Analysis Sets – 6FUHHQHG6HW3KDVH! 
IP 
 
14.1.1.2 
DE 
Screen Failures – 6FUHHQHG6HW3KDVH! 
IP 
 
14.1.1.3 
DE 
Inclusion/Exclusion Violations– 6FUHHQHG6HW3KDVH! 
IP 
 
14.1.1.4 
DE 
Discontinuation – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.1.1.5 
DE 
Duration of Follow-Up (months)– Full Analysis Set 
3KDVH! 
IP 
 
14.1.1.6 
DE 
Major Deviations-)XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.1.2 
Demographics 
 
 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.1.2 
DE 
Demographics – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1 
DE 
Medical or Surgical History – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.1.3.2 
DE 
Reported Mutation Status History- Full Analysis Set 
3KDVH! 
IP 
 
14.1.3.3 
DE 
Baseline Characteristics -)XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.1.3.4 
DE 
Prior Systemic Anticancer Therapy Related to GIST-Full 
$QDO\VLV6HW3KDVH! 
IP 
 
14.2 
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1 
DE 
Confirmed ORR, BOR and Time to Response-Full 
$QDO\VLV6HW3KDVH! 
Stat IP/IP 
 
14.2.2 
Secondary Efficacy Endpoints 
 
 
14.2.2.1 
DE 
DCR and CBR-)XOO$QDO\VLV6HW3KDVH! 
Stat IP/IP 
 
14.2.3 
Exploratory Endpoints 
 
 
14.3 
Safety Data 
 
 
14.3.1 
Displays of Adverse Events 
 
 
14.3.1.1 
DE 
Adverse Events, Overall Summary of Treatment- 
Emergent Adverse Events (TEAEs) – Full Analysis Set 
3KDVH! 
IP 
 
14.3.1.2 
DE 
Adverse Events, TEAEs by System Organ Class and 
Preferred Term – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.3.1.3 
DE 
Adverse Events, TEAEs  Grade 3 by System Organ Class 
and Preferred Term – )XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.4 
DE 
Adverse Events, Treatment-Related TEAEs by System 
Organ Class and Preferred Term – Full Analysis Set 
3KDVH! 
IP 
14.3.1.2 
14.3.1.5 
DE 
Adverse Events, Treatment-5HODWHG7($(V*UDGHE\
System Organ Class and Preferred Term – Full Analysis 
6HW3KDVH! 
IP 
14.3.1.2 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.3.1.6 
DE 
Adverse Events, Serious TEAEs by System Organ Class 
and Preferred Term –)XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.7 
DE 
Adverse Events, Serious Treatment-Related TEAEs by 
System Organ Class and Preferred Term – Full Analysis 
6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.8 
DE 
Adverse Events, TEAEs Leading to Discontinuation of 
Study Drug by System Organ Class and Preferred Term- 
)XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.9 
DE 
Adverse Events, TEAEs Leading to Interruptions of Study 
Drug by System Organ Class and Preferred Term-Full 
$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.10 
DE 
Adverse Events, TEAEs Leading to Dose Reductions of 
Study Drug by System Organ Class and Preferred Term- 
)XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.11 
DE 
Adverse   Events,   TEAEs   by System Organ Class, 
Preferred Term, and Maximum Toxicity-Full Analysis Set 
3KDVH! 
IP 
 
14.3.1.12 
DE 
Adverse Events, Treatment-related TEAEs by System 
Organ Class, Preferred Term, and Maximum Toxicity- 
)XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.1.17 
14.3.1.13 
DE 
Adverse Events, Fatal TEAEs by System Organ Class and 
Preferred Term- )XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.1.14 
DE 
Adverse Events, Post-Treatment Treatment Related SAEs 
by System Organ Class and Preferred Term-Full Analysis 
Set 3KDVH! 
IP 
14.3.1.2 
14.3.1.15 
DE 
Adverse Events, Dose Limiting Toxicities During Cycle 1 
by Preferred Term and Maximum Toxicity- DLT 
(YDOXDEOH$QDO\VLV6HW3KDVH! 
IP 
14.3.1.2 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events 
 
 
14.3.2.1 
DE 
Fatal TEAEs, Listing – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.3.2.2 
DE 
All Deaths, Listing – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.3.2.3 
DE 
SAE, Listing – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
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Page 29 of 45 
 
 
 
 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.3.2.4 
DE 
TEAEs Reported as Dose Limiting Toxicity, Listing – 
)XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.3.3 
Narratives of Deaths, Other Serious and Certain Other 
Significant Adverse Events 
 
 
14.3.4 
Abnormal Laboratory Values 
 
 
14.3.4.1 
DE 
Laboratory, Listing of Abnormal Values – Full Analysis 
Set 3KDVH! 
IP 
 
14.3.4.2 
DE 
Hematology, CTCAE Grade Shifts from Baseline to 
Worst Post-Baseline Grade – )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.3.4.3 
DE 
Chemistry, CTCAE Grade Shifts from Baseline to Worst 
Post-Baseline Grade – )XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.4.2 
14.3.4.4 
DE 
Coagulation, CTCAE Grade Shifts from Baseline to 
Worst Post-Baseline Grade – )XOO$QDO\VLV6HW3KDVH! 
IP 
14.3.4.2 
14..3.4.5 
DE 
Potential Hepatotoxicity based on Hy’s law – Full 
$QDO\VLV6HW3KDVH! 
IP 
 
14..3.4.6 
DE 
Laboratory, Listing of Patients with Potential 
Hepatotoxicity based on Hy’s law -Full Analysis Set 
3KDVH! 
IP 
 
14.3.5 
Extent of Exposure, Dosage Information, And 
Compliance 
 
 
14.3.5.1 
DE 
Exposure to Study Drug- )XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.3.5.2 
DE 
Compliance to Study Drug During Cycle 1 -Full 
$QDO\VLV6HW3KDVH! 
IP 
 
14.3.6 
Vital Signs and Physical Examination 
 
 
14.3.6.1 
DE 
Vital Signs: Blood Pressure Shifts from Baseline to 
Maximum Post-baseline Value – Full Analysis Set 
3KDVH! 
IP 
 
14.3.7 
Other Safety 
 
 
14.3.7.1 
DE 
Echocardiogram/MUGA, Descriptive Statistics-Full 
$QDO\VLV6HW3KDVH! 
IP 
 
14.3.7.2 
DE 
ECG, QTcF values of Potential Clinical Concern Any 
Time, Post-baseline by Category-Full Analysis Set 
3KDVH! 
IP 
 
14.3.8 
Concomitant Medication 
 
 
14.4 
PK Tables 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
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Page 30 of 45 
 
 
 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.5 
PD Tables 
 
 
14.6 
Other Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
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Page 31 of 45 
 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.1.3 
DE 
Best % Change from Baseline in Sum of the Longest 
Diameter of Target Lesion -)XOO$QDO\VLV6HW3KDVH! 
IP 
 
14.2.1.4 
DE 
Swimmers Plot, Duration of treatment -Full Analysis 
6HW3KDVH! 
IP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
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Page 32 of 45 
 
 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2 
Patient Data Listings 
 
 
16.2.1 
Discontinued Patients 
 
 
16.2.2 
Protocol Deviations 
 
 
16.2.3 
Patients Excluded from The Efficacy Analyses 
 
 
16.2.4 
Demographic Data 
 
 
16.2.5 
Compliance and / or Drug Concentration Data 
 
 
16.2.6 
Individual Efficacy Response Data 
 
 
16.2.7 
Adverse Event Listings 
 
 
16.2.8 
Individual Laboratory Measurements and Other 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Governing QMD: 
 
Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
10 APPENDIX 1: RECIST 
In this study, the overall RECIST response at a given time point (overall visit response) is 
determined by investigator based on RECIST 1.1 guidelines modified for GIST. It is based on 
investigator reported target lesion response, non-target lesion response and presence of any new 
lesions. For analysis purposes, overall visit response will be derived via programming based on 
x deriving target lesion response (via programming), 
x 
non-target lesion response (as collected) 
x presence of new lesions (as collected). 
10.1 Target Lesion Response 
For purposes of analysis, target lesion response will be derived via programming. 
Target lesion response is based on the sum of the longest diameters (SLD) of the target lesions. 
 
Target Lesion Response 
Criteria 
Complete Response (CR) 
Disappearance of all target lesions. 
Partial Response (PR) 
At least a 30% decrease in the SLD of target lesions from 
baseline (e.g., reference baseline SLD). 
Progressive Disease (PD) 
x At least a 20% increase in the SLD taking as reference 
the smallest SLD on the study (including baseline sum 
if that is the smallest on the study; reference referred to 
as nadir) 
 
x and SLD must also demonstrate an absolute increase of 
at least 0.5 cm from nadir (i.e., change from nadir in 
SLD>/=0.5cm). 
 
Or 
 
x Any re-appearance of one or more target lesions after 
an overall visit response (see 12.2) of complete 
response (CR) had been achieved at a prior visit. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
 
 
 
 
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Governing QMD: 
 
Confidentiality Statement 
 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
Sum of the longest diameter of target lesions 
Target lesions (up to 5 lesions) are identified at baseline. The longest diameter (LD) of a target 
lesion is measured in cm. The sum of the longest diameter (SLD) of all target lesions measured 
at a given tumor assessment will be calculated by summing the measurements together. At post- 
baseline tumor assessments, the same target lesions identified at baseline should be assessed 
using the same method of scan. An indicator flag will be created to flag post-tumor assessments 
where one or more identified target lesions were not assessed or marked as not evaluable and 
thus the LD measurement is missing (e.g., MTLFLG=1 for yes). An indicator flag will also be 
created to flag post-tumor assessments where the scan method does not match baseline scan 
method. 
For purposes of determining target lesion response, SLD, percent change from baseline, and 
percent change from nadir for post-baseline tumor assessments will be calculated regardless of 
missing target tumor LD measurements. That said SLD results from assessments with missing 
target lesion measurements will be excluded from other analyses (e.g., best percent change from 
baseline) if the derived target lesion response at said visit is NE. Change in method of scan of 
target lesions will not be taken into account when calculating SLD. 
Percent change from baseline in SLD/Percent change from Nadir in SLD 
The following calculations for post-baseline tumor assessments at a given visit will help with 
assigning target tumor response at given visit: 
Percent change from baseline in SLD = (SLD at a given post-baseline visit – baseline 
SLD)/(baseline SLD) x 100. 
Percent change from nadir in SLD = (SLD at a given post-baseline visit – nadir SLD)/(nadir 
SLD) x 100 where nadir represents the smallest SLD prior to the current post-baseline visit. 
Note the nadir should only be identified from assessments where all the identified target lesions 
have a LD measurement. Furthermore, the nadir may (or may not) change at every visit where 
tumor assessment occurs. 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
One or more lesions cannot be evaluated because of missing 
data or poor image quality unless a convincing argument can 
be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response 
(e.g., PD based on other findings). 
Non-Evaluable (NE) 
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Percentages should be rounded to 1 decimal place prior to assigning target lesion response. For 
example, 19.84% should be rounded to 19.8%. 
Assigning Target lesion response for a given visit 
The target lesion response will be either CR, PR, SD or PD based on what criteria is met. If the 
patient’s SLD at a given visit meets the criteria of both PR and PD (based on percent change 
from baseline and percent change from nadir respectively) then the target lesion response is PD. 
If the current tumor assessment has at least one missing target lesion LD measurement (e.g., 
MTLFLG=1) then assign the target lesion response to PD if the criteria for PD (target lesion) is 
met based on percent change from nadir. This is the only situation where it can be shown that 
the contribution of the missing lesion measurement would not change the assigned response. 
Otherwise, assign the target lesion response to NE. 
10.2 Overall Visit Response 
Overall visit response will be derived based on 
x target lesion response (derived, 10.1), 
x nontarget lesion response -(based on [investigator reported] non-target lesion response on 
the eCRF Modified RECIST v1.1 Response page, RSP01.RSPNTR) 
x presence of new lesions (based [investigator reported] “Any new lesions present?” 
(yes/no) CRF page Modified RECIST v1.1 response page, RSP01.RSNLYN). 
The following table will be used: 
 
Target Lesion 
Nontarget Lesion 
New Lesion 
(presence) 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD (e.g. CR, 
Non-CR/non-PD) or 
NE 
No 
PR 
SD 
Non-PD (e.g. CR, 
Non-CR/non-PD) or 
NE 
No 
SD 
 
 
 
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Governing QMD: 
 
Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Not all evaluated 
(NE) 
Non-PD (e.g., CR, 
Non-CR/non-PR) or 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
10.3 BOR-confirmation of CR and PR required 
BOR is calculated based on the overall visit responses obtained up until objective disease 
progression (i.e., RECIST response = PD). In the absence of objective disease progression, the 
BOR is determined using visit responses up until the last evaluable overall visit response. 
CR : 
Overall visit response of CR confirmed at least 4 weeks later by another 
overall visit response of CR 
 
PR : 
Overall visit response of PR confirmed at least 4 weeks later by another 
overall visit response of at least PR (i.e., CR/PR) 
 
SD (t 6 weeks): 
Stable disease recorded at least 6 weeks after the date of first dose (with 
no prior evidence of progression) 
 
PD: 
Progression in the absence of CR/PR or SD 
 
NE: 
Not evaluable. 
 
 
 
Overall response first time 
point 
Overall response 
subsequent time point 
Best overall response 
CR 
CR 
&5LIVXEVHTXHQWWLPHSRLQW 
weeks after first time point) 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD-provided minimum criteria for 
SD duration are met. Otherwise, PD 
CR 
PD 
SD-provided minimum criteria for 
SD duration are met. Otherwise, PD 
CR 
NE 
SD-provided minimum criteria for 
SD duration are met. Otherwise, NE 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
PR 
CR 
PR 
PR 
PR 
35LIVXEVHTXHQWWLPHSRLQW
weeks after first time point) 
PR 
SD 
SD -provided minimum criteria for 
SD duration are met. Otherwise, PD 
PR 
PD 
SD-provided minimum criteria for 
SD duration are met. Otherwise, PD 
PR 
NE 
SD-provided minimum criteria for 
SD duration are met. Otherwise, NE 
NE 
NE 
NE 
aIf a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. 
Other considerations 
There may be cases where a patient has one or more visits that are not evaluable (NE). These 
visits may fall in between evaluable visits. This should be taken into account. Thus, subsequent 
timepoint/visit does not literally mean next time point when NE visit may be involved. 
For example, in a case where a patient had PR, NE, PR then as long as the time between the two 
visits of PR is at least 4 weeks and there is no evidence of PD between the visits with PR, the 
patient should be assigned a BOR of PR. 
Another example is where a patient has NE, NE, SD, SD, the patient can be assigned a BOR of 
SD as long as the visits with SD occur at least 6 weeks after first dose. 
Lastly, if a patient has only NE visits then BOR of NE. 
11 APPENDIX 3: SAS CODE 
11.1 ORR 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
12 APPENDIX 4: LABORATORY TESTS 
12.1 Select Laboratory Parameters-CTCAE Grades 
The following lab parameters will have CTCAE grades assigned based on numeric criteria listed for CTCAE v5.0 or v4.03. It should 
be noted that several parameters may have different set of grades based on the CTCAE term of interest (e.g., Sodium (decreased 
[CTCAE term: hyponatremia] and increased [CTCAE term: hypernatremia]), These CTCAE terms will be summarized separately. 
Grades will be derived based on numeric criteria listed in CTCAE v5.0 (or v4.03 in cases where categorization for a laboratory 
assessment based on numerical value was not possible using CTCAE v5.0) and will not take into consideration clinical signs or 
symptoms. The below table lists numeric criteria used to determine a grade for a given a parameter value in this study. Note, a semi- 
colon indicates ‘or’ within the description of the grade. 
Hematology 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
Anemia 
Decrease 
+HPRJORELQ+JE//1-10.0 
JG///1-6.2 mmol/L; 
//1-100 g/L 
+JE-8.0 g/dL; 
-4.9 mmol/L; 
-80g/L 
+JEJG/
PPRO/J/ 
N/A 
White 
Blood 
Cells (WBC) 
White Blood Cell 
Decreased 
Decrease 
//1-PP//1-3.0 
x 10e9/L 
-2000/mm3; 
-2.0 x 10e9/L 
-1000/mm3; 
-1.0 x 10e9/L 
PP[ 
10e9/L 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Platelet count 
Platelet Count 
Decreased 
Decrease 
//1-PP//1- 
75.0 x 10e9/L 
- 
PP- 
50.0 x 10e9/L 
-25,000/mm3; 
-25.0 x 10e9/L 
PP 
x 10e9/L 
Neutrophil 
count 
(absolute) 
Neutrophil Count 
Decreased 
Decrease 
//1-PP//1-1.5 
x 10e9/L 
-1000/mm3; 
-1.0 x 10e9/L 
-PP- 
0.5 x 10e9/L 
PP[ 
10e9/L 
Lymphocyte 
Lymphocyte Count 
Decrease 
//1- PP//1- 
- 500/mm3; 
- 200/mm3; 
PP[ 
count 
(absolute) 
Decreased 
 
0.8 x 10e9/L 
- 0.5 x 10e9 
/L 
- 0.2 x 10e9 /L 
10e9 /L 
ULN=Upper limit of normal 
Values in table are based on CTCAE v5.0. 
 
Chemistry 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium 
Hyponatremia 
Decrease 
//1-130 mmol/L 
125-129 mmol/L 
120-124 mmol/L 
PPRO/ 
Sodium 
Hypernatremia 
Increase 
>ULN-150 mmol/L 
>150-155 mmol/L 
>155-160 mmol/L 
>160 mmol/L 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium 
Hypokalemia 
Decrease 
//1-3.0 mmol/L 
N/A (for purpose of 
this study) 
-2.5 mmol/L 
PPRO/ 
Magnesium 
Hypomagnesemia 
Decrease 
//1-1.2 mg/dL; 
//1-0.5 mmol/L 
-PJG/- 
0.4 mmol/L 
-PJG/- 
0.3 mmol/L 
PJG/ 
mmol/L 
Magnesium 
Hypermagnesemia 
Increase 
>ULN-3.0 mg/dL; 
>ULN-1.23 mmol/L 
>3.0-8.0 mg/dL; 
>1.23-3.30 mmol/L 
>8.0 mg/dL; >3.30 
mmol/L 
N/A 
Phosphorous 
Hypophosphatemia 
Decrease 
 
 
 
 
(based 
on  
 
//1- 2.5 mg/dL; 
- PJG/ 
- PJG/ 
PJG/ 
CTCAE v4.03  
 
//1- 0.8 mmol/L 
- 0.6 mmol/L 
- 0.3 mmol/L 
mmol/L 
criteria) 
 
 
 
 
 
 
Calcium 
Hypocalcemia 
Decrease 
Corrected serum 
Corrected serum 
Corrected serum 
Corrected serum 
(Total) 
 
 
FDOFLXPRI//1-8.0 
FDOFLXPRI-7.0 
FDOFLXPRI-6.0 
FDOFLXPRI 
(correct 
 
 
PJG///1-2.0 
PJG/-1.75 
PJG/-1.5 
PJG/PPRO/ 
calcium numeric 
criteria   will  be 
 
 
mmol/L 
mmol/L 
mmol/L 
 
applied) 
 
 
 
 
 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Calcium 
Hypercalcemia 
Increase 
Corrected serum 
Corrected serum 
Corrected serum 
Corrected serum 
Total) 
 
 
calcium of >ULN-11.5 
calcium of >11.5-12.5 
calcium of >12.5-13.5 
calcium of >13.5 
(correct 
 
 
mg/dL; >ULN-2.9 
mg/dL; >2.9-3.1 
mg/dL; >3.1-3.4 
mg/dL; >3.4 mmol/L 
calcium numeric 
criteria   will  be 
 
 
mmol/L 
mmol/L 
mmol/L 
 
applied ) 
 
 
 
 
 
 
ALT 
Alanine 
Increase 
>ULN-3.0 x ULN if 
>3.0-5.0 x ULN if 
>5.0-20.0 x ULN if 
>20.0 x ULN if 
 
Aminotransferase 
 
baseline was normal; 
baseline was normal; 
baseline was normal; 
baseline was normal; 
 
Increased 
 
1.5-3.0 x baseline if 
>3.0-5.0 x baseline if 
>5.0-20.0 x baseline if 
>20.0 x baseline if 
 
 
 
baseline was high 
baseline was high 
baseline was high 
baseline was high 
 
 
 
abnormal (> ULN) 
abnormal (> ULN) 
abnormal (> ULN) 
abnormal (> ULN) 
AST 
Aspartate 
Increase 
>ULN-3.0xULN if 
>3.0-5.0xULN if 
>5.0-20.0xULN if 
>20.0xULN if baseline 
 
Aminotransferase 
 
baseline was normal; 
baseline was normal; 
baseline was normal; 
was normal; >20.0x 
 
Increased 
 
1.5-3.0x baseline if 
>3.0-5.0x baseline if 
>5.0-20.0x baseline if 
baseline if baseline 
 
 
 
baseline was high 
baseline was high 
baseline was high 
was abnormal high 
 
 
 
abnormal (i.e., > 
abnormal (i.e., > 
abnormal (i.e., > 
abnormal (i.e., > 
 
 
 
ULN) 
ULN) 
ULN) 
ULN) 
Total bilirubin 
Blood Bilirubin 
Increase 
>ULN-1.5 x ULN if 
>1.5-3.0 x ULN if 
>3.0-10.0 x ULN if 
>10.0 x ULN if 
 
Increased 
 
baseline was normal; > 
baseline was normal; 
baseline was normal; 
baseline was normal; 
 
 
 
1.0-1.5 x baseline if 
>1.5-3.0 x baseline if 
>3.0-10.0 x baseline if 
>10.0 x baseline if 
 
 
 
baseline was high 
baseline was high 
baseline was high 
baseline was high 
 
 
 
abnormal (i.e., > 
abnormal (i.e., > 
abnormal (i.e., > 
abnormal (i.e., > 
 
 
 
ULN) 
ULN) 
ULN) 
ULN) 
Albumin 
Hypoalbuminemia 
Decrease 
//1-JG///1- 
30 g/L 
-JG/-20 g/L 
JG/J/ 
 
Creatinine 
Creatinine 
Increased 
Increase 
>ULN-1.5 x ULN 
>1.5-3.0 x baseline; 
>1.5-3.0 x ULN 
>3.0 x baseline; >3.0- 
6.0 x ULN 
>6.0 x ULN 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
CCI
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CCI
CCI
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REF: 
 
Page 42 of 45 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Amylase 
(based on 
CTCAE v4.03 
criteria) 
Serum Amylase 
Increased 
Increase 
>ULN-1.5 x ULN 
>1.5-2.0 x ULN; 
>2.0-5.0 x ULN 
>5.0 x ULN 
Lipase 
(based 
on 
CTCAE v4.03 
criteria) 
Lipase Increased 
Increase 
>ULN-1.5 x ULN 
>1.5-2.0 x ULN 
>2.0-5.0 x ULN 
>5.0 x ULN 
CK (Creatinine 
Kinase) 
CPK Increased 
Increase 
>ULN-2.5 x ULN 
>2.5 x ULN-5 x ULN 
>5 x ULN-10 x ULN 
>10 x ULN 
Alkaline 
phosphatase 
Alkaline 
Phosphatase 
increased 
Increase 
>ULN-2.5xULN if 
baseline was normal; 
2.0-2.5x baseline if 
baseline was high 
abnormal (i.e., > 
ULN) 
>2.5-5.0xULN if 
baseline was normal; 
>2.5-5.0x baseline if 
baseline was high 
abnormal (i.e., > 
ULN) 
>5.0-20.0xULN if 
baseline was normal; 
>5.0-20.0x baseline if 
baseline was high 
abnormal (i.e., > 
ULN) 
>20.0xULN if baseline 
was normal; >20.0x 
baseline if baseline 
was high abnormal 
(i.e., > ULN) 
Alkaline 
phosphatase 
Alkaline 
Phosphatase 
increased 
Increase 
>ULN-2.5xULN if 
baseline was normal; 
2.0-2.5x baseline if 
baseline was high 
abnormal (i.e., > 
ULN) 
>2.5-5.0xULN if 
baseline was normal; 
>2.5-5.0x baseline if 
baseline was high 
abnormal (i.e., > 
ULN) 
>5.0-20.0xULN if 
baseline was normal; 
>5.0-20.0x baseline if 
baseline was high 
abnormal (i.e., > 
ULN) 
>20.0xULN if baseline 
was normal; >20.0x 
baseline if baseline 
was high abnormal 
(i.e., > ULN) 
Glucose 
(based 
on 
CTCAE v4.03 
criteria) 
Hyperglycemia 
Increase 
glucose value >ULN - 
160 mg/dL; glucose 
value >ULN - 8.9 
mmol/L 
glucose value >160 - 
250 mg/dL; glucose 
value >8.9 - 13.9 
mmol/L 
>250 - 500 mg/dL; 
>13.9 - 27.8 mmol/L 
>500 mg/dL; >27.8 
mmol/L 
Glucose 
Hypoglycemia 
Decrease 
//1-55 
mg/dL; 
//1-3.0 mmol/L 
-PJG/- 
2.2 mmol/L 
-PJG/- 
1.7 mmol/L 
PJG/
mmol/L 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


REF: 
 
Page 43 of 45 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


REF: 
 
Page 44 of 45 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
Coagulation 
 
Parameter 
CTCAE Term 
Directionality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
INR 
INR Increased 
Increase 
>1.2-1.5; >1-1.5 x baseline if 
on anticoagulation** 
>1.5-2.5; >1.5-2.5 x 
baseline if on 
anticoagulation** 
>2.5; >2.5 x baseline if 
on anticoagulation** 
 
aPTT 
Activated Partial 
Thromboplastin time 
prolonged 
Increase 
>ULN-1.5 x ULN 
>1.5-2.5 x ULN 
>2.5 x ULN 
 
**A subject who is taking a medication assigned WHODrug ATC3 level code “B01A” (antithrombotic agents) will be considered to 
be on an anticoagulation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


REF: 
 
Page 45 of 45 
 
 
 
 
Sponsor: 
Theseus Pharmaceuticals, Inc. 
Protocol Number: 
THE630-21-101 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
13 APPENDIX 5: CRITERIA BASED ON HY’S LAW 
The following criteria for potential Hepatoxicity are based on Hy’s law. For criterion which 
requires multiple parameters to have a certain value (e.g., ALT>3x ULN and TBIL (total 
bilirubin)> 2xULN), all lab parameters values must be from samples with the same sample 
collection date. 
ALT exceeds thresholds 
x [8/1WR[ ULN 
x [8/1WR[ ULN 
x [8/1WR[ ULN 
x [8/1 
AST exceeds thresholds 
x [8/1WR[ ULN 
x [8/1WR[ ULN 
x [8/1WR[ ULN 
x [ ULN 
ALT or AST exceeds thresholds 
x [8/1WR[ ULN 
x [8/1WR[ ULN 
x [8/1WR[ ULN 
x [ULN 
Other criteria 
x Total Bilirubin (TBIL) >2x ULN 
x ALP> 1.5x 
x (ALT or AST> 3x ULN) and (TBIL> 2x ULN or INR >1.5)* 
x $/7RU$67![8/1DQG7%,/[8/1DQG$/3[ ULN* 
*Criterion which requires multiple parameters to have a certain value (e.g., “and”), it is assumed 
that all lab parameter values are from the same sample. 
 
 
 
 
QMD Ref: 
 
Governing QMD: 
 
Confidentiality Statement 
 
 
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Created:
2024-01-09
By: 
Status:
Transaction ID:
Signed
80046695-study-11.01.01-20240109-sap_v3.0
Final Audit Report
2024-01-10
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