Conditions: KRAS Mutation-Related Tumors Metastatic Solid Tumor Advanced Solid Tumor
Keywords: KRAS KRAS-mutant Metastatic Solid Tumor Advanced Solid Tumor Advanced/metastatic disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
A Phase 1b/2 Study of Repotrectinib in Combination with Other Anticancer Therapies for the Treatment of Subjects with KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)

Detailed description:
Phase 1 Dose Escalation: To evaluate tolerability of repotrectinib at increasing dose levels in combination with other anticancer therapies for the treatment of subjects with locally advanced or metastatic KRAS-mutant solid tumors

Phase 2 Efficacy Evaluation: Investigate the anti-tumor efficacy and safety of repotrectinib in combination with other anticancer therapies for the treatment of patients with locally advanced or metastatic KRAS-mutant solid tumors.

Arms:
arm 1: TPX-0005 + Trametinib Dose Escalation and Dose Expansion

Dose escalation: KRAS G12D mutant advanced solid tumors. Dose expansion: KRAS G12D locally advanced or metastatic NSCLC

Interventions: intervention 1: TPX-0005 intervention 2: Trametinib
Intervention descriptions: intervention 1: Oral TPX-0005 capsules intervention 2: Oral trametinib tablets

Protocol document:
Prot_SAP_000.pdf: 
Protocol for 
 
Official Title of Study 
A PHASE 1B/2 STUDY OF REPOTRECTINIB IN COMBINATION WITH TRAMETINIB 
FOR THE TREATMENT OF SUBJECTS WITH KRASG12D-MUTANT ADVANCED SOLID 
TUMORS (TRIDENT-2) 
NCT05071183 
 
February  04, 2022 


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TURNING POINT THERAPEUTICS APPROVAL 
Protocol Number: 
TPX-0005-13, Subprotocol 1 
Version (Date):  
3.0 (04 February 2022) 
Subprotocol Title: 
A Phase 1b/2 Study of Repotrectinib in Combination with Trametinib for 
the Treatment of Subjects with KRASG12D-Mutant Advanced Solid Tumors 
(TRIDENT-2) 
Date: 
  
Executive Director, Clinical Development 
Turning Point Therapeutics, Inc. 
 
 
04-Feb-2022 | 14:53 PST
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PRINCIPAL INVESTIGATOR STATEMENT OF AGREEMENT 
I, the undersigned Principal Investigator, have read and understood the following subprotocol, 
TPX-0005-13, Subprotocol 1, Version 3.0, 04 February 2022, and its appendices. 
I promise to abide by the International Conference for Harmonisation (ICH) Guidelines for Good 
Clinical Practices (GCP), the Declaration of Helsinki, and all applicable laws and regulations, 
and agree that, in all cases, the most restrictive regulation related to a given aspect of research 
involving protection of human subjects will be followed. If I have a question regarding my 
obligations during the conduct of this protocol, I have ready access to these aforementioned 
regulations, as either my personal copy, or available on file from the Chairperson of the 
Institutional Review Board (IRB)/Ethics Committee (EC) or the Sponsor, via local authorities 
and, I am authorized to enter into this commitment to conduct the study outlined in this protocol, 
and my signature below signifies that I agree to conduct the study as outlined herein. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Turning Point Therapeutics, Inc. (Sponsor) 
Indication: 
Treatment of patients with locally advanced or metastatic KRAS-mutant solid tumors 
Name of Investigational Product(s): 
Repotrectinib, trametinib (Mekinist® [trametinib] USPI 2020) 
Title of Subprotocol:  
A Phase 1b/2 Study of Repotrectinib in Combination with Trametinib for the Treatment of Subjects 
with KRASG12D-Mutant Advanced Solid Tumors (TRIDENT-2) 
Phase of Development 
Phase 1b/2 
Objectives  
Phase 1b Primary Objectives 
• Evaluate the safety and tolerability of repotrectinib at increasing dose levels in combination with 
trametinib for the treatment of subjects with locally advanced or metastatic KRAS-mutant solid 
tumors. 
• Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of 
repotrectinib in combination with trametinib for the treatment of subjects with locally advanced or 
metastatic KRAS-mutant solid tumors. 
Phase 1b Secondary Objectives 
• Characterize the pharmacokinetic (PK) profile of repotrectinib in combination with trametinib. 
• Describe the preliminary efficacy of repotrectinib in combination with trametinib. 
Phase 2 Primary Objective 
• Evaluate the efficacy of repotrectinib in combination with trametinib for the treatment of subjects 
with locally advanced or metastatic KRAS-mutant solid tumors as measured by objective response 
rate (ORR). 
Phase 2 Secondary Objectives 
• Evaluate the efficacy of repotrectinib in combination with trametinib for the treatment of subjects 
with locally advanced or metastatic KRAS-mutant solid tumors as measured by clinical benefit rate 
(CBR), progression-free survival (PFS), duration of response (DOR), time to response (TTR), and 
overall survival (OS). 
• Evaluate the safety and tolerability of repotrectinib in combination with trametinib. 
• Characterize the PK profile of repotrectinib in combination with trametinib. 
Exploratory Objectives (All Phases) 
• Evaluate biomarkers potentially predictive of response in subjects treated with repotrectinib in 
combination with trametinib.  
• Explore the potential prognostic utility of genomic alterations and characterize intrinsic or acquired 
resistance in subjects treated with repotrectinib in combination with trametinib using tissue-based 
or liquid-based biopsy samples. 
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Overall Study Design: 
This subprotocol is a Phase 1b/2 multi-center, open-label study to evaluate the efficacy, safety, 
tolerability, and PK of repotrectinib in combination with trametinib, for the treatment of subjects with 
locally advanced or metastatic KRASG12D-mutant solid tumors. The study will consist of two portions: 
Phase 1b Dose Escalation and Phase 2 Expansion. The overall study design for this subprotocol is 
shown in the figure below. 
 
Abbreviations: KRAS = Kirsten rat sarcoma viral oncogene homolog; MEK = mitogen-activated protein kinase; 
NSCLC = non-small cell lung cancer; RP2D = recommended Phase 2 dose. 
Phase 1b Dose Escalation 
Subjects with locally advanced or metastatic solid tumor malignancies harboring a KRASG12D mutation 
will be enrolled into the Phase 1b dose escalation portion of the study to determine the MTD/RP2D of 
repotrectinib in combination with trametinib. Dose escalation will follow a traditional 3+3 design. 
Phase 2 Expansion 
Once the MTD/RP2D of repotrectinib in combination with trametinib has been determined, subjects 
will be enrolled into a Phase 2 expansion portion. The Phase 2 portion is designed to explore the anti-
tumor efficacy and safety of repotrectinib in combination with trametinib for the treatment of patients 
with locally advanced or metastatic NSCLC harboring a KRASG12D mutation.  
Treatment Duration 
Subjects may receive treatment with repotrectinib in combination with trametinib until disease 
progression or unacceptable toxicity. Subjects may continue treatment with single agent repotrectinib 
or trametinib if there is continuing clinical benefit per Investigator’s judgment and in consultation with 
the Sponsor’s Medical Monitor. After discontinuation of both study drugs, subjects will continue to be 
followed on study for overall survival. 
Phase 1b Dose Escalation Study Design: 
Subjects with locally advanced or metastatic solid tumor malignancies harboring a KRASG12D mutation 
will be enrolled into the Phase 1b dose escalation portion of the study to determine the MTD/RP2D of 
repotrectinib in combination with trametinib. Initially, approximately 24 – 30 subjects with locally 
advanced or metastatic solid tumor malignancies harboring a KRASG12D mutation will be enrolled.  
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Dose escalation will follow a traditional 3+3 design. Three to six DLT-evaluable subjects at each dose 
level will be administered daily (QD) doses of repotrectinib in combination with trametinib according 
to the table below (starting with Dose Level 1) and evaluated for dose-limiting toxicities (DLTs) 
during Cycle 1 (i.e., for 28 days). After the first 3 subjects have completed their first cycle of study 
treatment (Cycle 1), a safety evaluation will be conducted by a Safety Review Committee to determine 
if enrollment of subjects in the next dose level (Dose Level 2) may begin. If no subjects experience a 
DLT within the first 28 days of Dose Level 1 treatment, then dose escalation may proceed to the next 
dose level, according to the table below. If 1 of the 3 initial subjects at Dose Level 1 experiences a 
DLT, then the next 3 subjects will be enrolled prior to escalating to the next dose level. Enrollment into 
all subsequent dose levels will follow the same procedure. If ≥ 33% of subjects at any dose level 
experience a DLT within the first 28 days of treatment, the dose levels will be de-escalated to Dose 
Level -2 or -3 according to SRC recommendation and following approval by the Sponsor, as detailed 
in the table below. If Dose Level -2 is tolerable, testing of alternate escalating dose levels (-2a, -2b) 
may occur as outlined in the table below. If Dose Level -2 is not tolerable, subjects will be de-escalated 
to Dose Level -3. If Dose Level -3 is tolerable, testing of alternate escalating dose levels (-3a, -3b) may 
occur as outlined in the table below. Alternative regimens or additional dose levels or dose level 
increments may be explored based on emergent clinical safety, efficacy, and PK data. See Section 3.2 
for further details of dose finding.  
Dose-finding Dose Levels  
Dose Level 
Repotrectinib 
Trametinib 
3 
160 mg QD/BIDa 
2 mg QD 
2 
160 mg QD 
2 mg QD 
1 (Starting Dose) 
120 mg QD 
2 mg QD 
(-2b) 
160 mg QD/BIDa 
1.0 mg QD 
(-2a) 
160 mg QD 
1.0 mg QD 
-2 
120 mg QD 
1.0 mg QD 
(-3b) 
160 mg QD/BIDa 
0.5 mg QD 
(-3a) 
160 mg QD 
0.5 mg QD 
-3 
120 mg QD 
0.5 mg QD 
Abbreviations: BID = twice daily; QD = once daily; TRAE = treatment-related adverse event. 
a 160 mg QD (once daily) for the first 14 days, after which the dose may be increased to 160 mg BID based on 
subject safety and tolerability and assuming specific criteria are met. Subjects must meet the following criteria 
while on 160 mg QD prior to dose increase to 160 mg BID: no evidence of grade ≥ 3 TRAE, unmanageable 
grade ≥ 2 dizziness, ataxia or paresthesia; or grade ≥ 3 clinically significant lab abnormalities. 
A Safety Review Committee, including study Investigators and the Sponsor Medical Monitor, will 
provide recommendations for dose escalation, confirmation of DLTs, dose de-escalation, and 
determination of the RP2D. At least 6 subjects will be treated at the RP2D prior to proceeding into the 
Phase 2 portion of the study. Additional subjects may be added at a dose level to gather more safety, 
PK, and efficacy data.  
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Criteria for Defining Dose-limiting Toxicities  
Subjects are eligible for Dose-limiting Toxicities (DLT) evaluation if they experience a DLT during 
the first cycle of treatment (i.e., 28 days), or do not experience a DLT during the first cycle of 
treatment while able to receive at least 75% of planned doses during the first cycle of treatment. 
Subjects who do not fulfill these requirements will be replaced for DLT evaluation but will remain in 
the overall safety and efficacy analyses. 
A DLT is defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to 
disease progression, intercurrent illness, or concomitant medications that meets any of the following 
criteria: 
Categorya 
Criteria 
Toxicities resulting in an 
excessive number of missed 
doses 
• 
Inability to deliver at least 75% of the planned doses of repotrectinib 
and trametinib during Cycle 1 treatment because of toxicity attributed 
to study drug (excluding toxicities clearly related to disease 
progression or intercurrent illness)  
Hematologic toxicities  
• 
Grade ≥ 4 neutropenia (ANC < 500/ mm3) lasting > 7 days 
• 
Grade ≥ 4 platelet count decrease (platelets < 25,000/mm3) or 
Grade ≥ 2 (< 75,000/mm3) associated with clinically significant 
bleeding 
• 
Grade ≥ 4 anemia  
• 
Grade ≥ 3 febrile neutropenia (defined as ANC < 1,000/mm3 with a 
single temperature of ≥ 38.3°C [≥ 101°F] or a sustained temperature of 
≥ 38°C [≥ 100.4°F] for > 1 hour) 
Renal 
• 
Grade ≥ 3 creatinine increase (> 3 × upper limit of normal [ULN]) 
Hepatic 
• 
Grade ≥ 3 total bilirubin elevation (> 3 × ULN) 
• 
Grade ≥ 2 total bilirubin elevation (> 1.5 × ULN) and grade ≥ 2 ALT 
or AST elevation (> 3 × ULN)  
• 
Grade 3 ALT elevation (> 5 × ULN) that does not resolve to grade ≤ 1 
within 7 days or any grade ≥ 4 ALT elevation 
• 
Grade 3 AST elevation (> 5 × ULN) that does not resolve to grade ≤ 1 
within 7 days or any grade ≥ 4 AST elevation 
• 
Grade 4 elevations in ALP 
Pancreatic 
• 
Grade ≥ 3 amylase or lipase elevation 
Cardiac 
• 
Grade ≥ 3 
Other AEs  
• 
Grade 3 electrolyte disturbances that require hospitalization 
• 
Grade 4 electrolytes abnormalities 
• 
Grade ≥ 3 AE, persisting after optimal treatment with standard medical 
therapy except for the exceptions noted below under “Exceptions to 
DLT criteria” 
• 
In view of the Investigators and Sponsor, any other unacceptable 
toxicity encountered 
Exceptions to DLT criteria 
• 
Grade 3 elevations in ALP  
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• 
Grade 3 electrolytes abnormalities that are adequately managed by IV 
or PO supplementation as evidenced by an improvement to grade ≤ 1 
within 3 days 
• 
Grade 3 fatigue which resolves to grade ≤ 1 in ≤ 7 days 
• 
Isolated grade 3 laboratory abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
• 
Grade 3 dizziness which resolves to grade ≤ 1 within ≤ 7 days 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute 
neutrophil count; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; DLT = 
dose-limiting toxicity; IV = intravenous; PO = per os (by mouth); ULN = upper limit of normal. 
Note: Adverse event grading based on CTCAE v5.0. 
a Toxicities clearly related to disease progression or intercurrent illness will not be considered DLTs. 
In addition, clinically important or persistent toxicities not included in the above criteria may be 
considered a DLT following review by the Sponsor and study Investigators. All DLTs should represent 
a clinically significant shift from baseline. These will be evaluated according to National Cancer 
Institute (NCI) CTCAE v5.0. 
To fully characterize the safety of repotrectinib in combination with trametinib, subjects who are 
discontinued from treatment before completing the DLT evaluation period (28 days, Cycle 1) due to 
disease progression or other event unrelated to study drugs, or who did not adequately complete the PK 
evaluations within Cycle 1, may be replaced.  
Determination of MTD 
The MTD is defined as the highest dose level of repotrectinib given in combination with trametinib 
observed to cause a DLT in fewer than 33% of the treated subjects in the first treatment cycle (i.e., 28 
days, Cycle 1).  
Recommended Phase 2 Dose (RP2D) Definition 
The RP2D is the dose chosen for further study in Phase 2 based on the Phase 1b results. RP2D dose 
selection will be based on the entirety of the safety, efficacy, and clinical pharmacology data using an 
integrated quantitative approach. The RP2D may be the MTD unless one or more of the following 
suggest an alternate dose below the MTD would be preferable:  
a. clinically significant anti-tumor effect (complete response [CR], partial response [PR], or 
prolonged stable disease [SD]) occurs below the MTD, in which case a clinically active 
dose level may be selected as the RP2D;  
b. the MTD is not achieved, in which case the highest dose level administered may become 
the RP2D; or  
c. toxicities observed beyond the DLT evaluation period (Cycle 1) require selecting the 
RP2D below the MTD level. 
Once the MTD of repotrectinib in combination with trametinib has been determined, the RP2D will be 
determined at or below the MTD.  
Phase 2 Study Design: 
Once the MTD/RP2D of repotrectinib in combination with trametinib has been determined, 
approximately 50 subjects will be enrolled into the Phase 2 expansion portion. The Phase 2 portion is 
designed to explore the anti-tumor efficacy and safety of repotrectinib in combination with trametinib 
for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
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harboring a KRASG12D mutation. 
An interim futility analysis of the ORR will be performed after approximately 15 subjects are 
evaluable for tumor response. If ≤ 2 responders (confirmed CR or PR) are observed from 15 evaluable 
subjects, the expansion cohort will be stopped for futility. If ≥ 3 responders are observed, this cohort 
may continue depending on the overall benefit and risk assessment at the interim analysis. 
Tumor assessments will include all known or suspected disease sites. All radiographic efficacy 
endpoints will be assessed using RECIST v1.1. Intracranial responses will be assessed by modified 
RECIST v1.1. For all tumor assessments, the imaging modality used at baseline should be the same 
modality used throughout the study.  
Safety will be monitored via laboratory assessments, physical examinations, electrocardiograms 
(ECG), vital signs, and TEAEs according to CTCAE v5.0. PK data will also be collected. In addition, 
safety will be monitored by a Safety Review Committee comprised of at minimum the Sponsor 
Medical Monitor and study Investigators to review all relevant safety and other relevant clinical data. 
Number of subjects (planned): 
Phase 1b Dose Escalation: approximately 24 – 30 subjects  
Phase 2 Expansion: approximately 50 subjects 
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Inclusion Criteria: 
Phase 1 AND Phase 2 
1. Subject must have a histologically or cytologically confirmed diagnosis of unresectable or 
metastatic solid tumor malignancy harboring a KRASG12D mutation. 
• 
Documented KRASG12D mutation as determined by a quantitative polymerase chain 
reaction (qPCR) or next-generation sequencing (NGS) test performed in a Clinical 
Laboratory Improvement Amendments (CLIA) laboratory or equivalently accredited 
diagnostic laboratory. Local tissue-based or liquid biopsy diagnostic testing will be 
permitted. 
• 
Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic 
laboratory for retrospective confirmation by a central diagnostic laboratory test 
selected by the Sponsor. See the Study Laboratory Manual for details. 
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0–1. 
3. Age ≥ 18 (or as required by local regulation).  
4. Willing and able to provide written institutional review board (IRB)/ethics committee (EC)-
approved Informed Consent. 
5. At least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. Subjects with central nervous system (CNS)-only measurable target lesion ≥ 5 
mm as defined by RECIST v1.1 are eligible. 
6. Required wash-out time that is related to prior therapies before starting repotrectinib 
combination treatment: 
• 
At least 14 days or 5 half-lives (whichever is shorter) must have elapsed after 
discontinuation of prior systemic therapy and all side effects from prior treatments must 
have resolved to grade ≤ 1 with the exception of alopecia. 
• 
At least 14 days must have elapsed after discontinuation of prior immunotherapy and all 
immune-related side effects from prior immunotherapy must have resolved to grade ≤ 1.  
7. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic 
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the following criteria: 
• 
Subjects requiring steroids at a stable or decreasing dose (≤ 12 mg/day dexamethasone 
or equivalent) for at least 14 days.  
• 
Subjects on stable doses of levetiracetam (same dose for 14 days). 
• 
A minimum of 14 days must have elapsed from the completion of whole brain 
radiation treatment (WBRT) before the start of treatment, and all side effects (with the 
exception of alopecia) from WBRT are resolved to grade ≤ 1. 
• 
A minimum of 7 days must have elapsed from the completion of stereotactic 
radiosurgery before the start of treatment and all side effects (with the exception of 
alopecia) from stereotactic radiosurgery are resolved to grade ≤ 1. 
8. Baseline laboratory values fulfilling the following requirements: 
Absolute Neutrophils Count  
≥ 1,500/mm3 (1.5 x 109/L) 
Platelets  
≥ 100,000/mm3 (100 x 109/L) independent of platelets transfusion support 
for at least 7 days prior to dosing 
Hemoglobin 
≥ 9.0 g/dL independent of transfusion support for at least 7 days prior to 
dosing 
Creatinine Clearance*  
> 40 mL/min 
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Total Serum Bilirubin  
< 1.5 x ULN (≤ 3.0 × ULN for patients with Gilbert’s Syndrome or liver 
metastases) 
Liver Transaminases 
(AST/ALT) 
< 2.5 x ULN; < 5 x ULN if liver metastases are present 
Alkaline Phosphatase  
< 2.5 x ULN; < 5 x ULN if liver and/or bone metastasis are present.  
Serum Calcium, Magnesium and 
Potassium  
Normal or CTCAE grade ≤ 1 with or without supplementation. 
Abbreviations: AST/ALT = aspartate aminotransferase/alanine aminotransferase, ULN = upper limit of 
normal. 
* calculated by Cockcroft and Gault’s formula: (140 - age [yr.]) x body weight [kg] x 1.23 x (0.85 if female) 
/serum creatinine [µmol/L].  
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during 
screening and be neither breastfeeding nor intending to become pregnant during study 
participation. Female patients will be considered to be of childbearing potential unless they have 
undergone permanent sterilization or are postmenopausal. Postmenopausal is defined as at least 12 
months without menses with no other medical reasons (e.g., chemical menopause due to anticancer 
treatment). For WOCBP and for men, agreement to use a highly effective contraceptive method 
from the time of screening throughout the study until 4 months (WOCBP) or 6 months (men) after 
administration of the last dose of any study drug. Highly effective contraceptive methods consist of 
prior sterilization, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
injectable or implantable contraceptives. All male study subjects must agree to use condoms 
throughout the study and 6 months after administration of the last dose. Male partners of WOCBP 
subjects must agree to condom use throughout the study and for 4 months following the last dose of 
study drug. True abstinence is acceptable if evaluated as consistent with the preferred and the usual 
lifestyle of the subject. Periodic abstinence is not an acceptable method of contraception. 
10. Ability to swallow capsules and tablets intact (without chewing, crushing, or opening). 
11. Life expectancy ≥ 3 months. 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures. 
Additional Inclusion Criteria for Phase 1 only:  
13. Subject must have received prior standard therapy appropriate for their tumor type and stage of 
disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinically 
meaningful benefit from appropriate standard of care therapy.  
• 
Subject must have received no more than 3 prior systemic regimens.  
• 
Maintenance therapy will not be counted as a separate regimen.  
• 
Adjuvant chemotherapy or chemotherapy administered as part of concurrent 
chemotherapy and radiation therapy will not count as a prior regimen of systemic 
therapy as long as recurrence occurred more than 6 months after the last day of 
chemotherapy. 
Additional Inclusion Criteria for Phase 2 only:  
14. Histologically or cytologically confirmed diagnosis of advanced or metastatic NSCLC 
harboring a KRASG12D mutation. 
• 
Subject must have a documented KRASG12D mutation as determined by a qPCR or NGS 
test performed in a CLIA laboratory or equivalently accredited diagnostic laboratory. 
Local tissue-based or liquid biopsy diagnostic testing will be permitted. 
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• 
Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic 
laboratory for retrospective confirmation by a central diagnostic laboratory test selected by 
the Sponsor. See the Study Laboratory Manual for details. 
15. Subjects must have received no more than one prior line of platinum-based chemotherapy OR 
one prior line of platinum-based chemotherapy in combination with immunotherapy OR both 
platinum-based chemotherapy and single agent anti-PD1/PDL1 therapy in two separate lines of 
therapy. 
• 
Adjuvant chemotherapy or chemotherapy administered as part of concurrent 
chemotherapy and radiation therapy for the treatment of lung cancer will not count as a 
prior regimen of systemic therapy as long as recurrence of patient's lung cancer 
occurred more than 12 months after the last day of chemotherapy.  
Exclusion Criteria:  
1. Concurrent participation in another therapeutic clinical trial. 
2. Symptomatic brain metastases or leptomeningeal involvement. 
3. History of previous cancer requiring therapy within the previous 2 years, except for squamous 
cell or basal-cell carcinoma of the skin, or any in situ carcinoma that has been completely 
resected. 
4. Major surgery within 4 weeks of start of treatment. Radiation therapy (except palliative to 
relieve bone pain) within 2 weeks of start of treatment. Palliative radiation (≤ 10 fractions) 
must have been completed at least 48 hours prior to start of treatment. 
5. Clinically significant cardiovascular disease (either active or within 6 months prior to start of 
treatment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), 
cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement 
for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of CTCAE grade ≥ 2. 
6. Any of the following cardiac criteria: 
• 
Mean resting corrected QT interval (electrocardiogram [ECG] interval measured from the 
onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec 
obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value 
• 
Any clinically important abnormalities in rhythm, conduction or morphology of resting 
ECG (e.g., complete left bundle branch block, third degree heart block, second degree 
heart block, PR interval > 250 msec) 
• 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as 
heart failure, hypokalemia, congenital long QT syndrome, family history of long QT 
syndrome, or any concomitant medication known to prolong the QT interval 
7. Known clinically significant active infections not controlled with systemic treatment (bacterial, 
fungal, viral including human immunodeficiency virus [HIV] positivity, hepatitis B [HBV], 
and hepatitis C [HCV], and acquired immunodeficiency syndrome [AIDS]-related illness).  
8. Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or 
other malabsorption syndromes that would impact drug absorption. 
9. Peripheral neuropathy, paresthesia, dizziness, dysgeusia, muscle weakness, ataxia grade ≥ 2. 
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10. Currently have or had a history of ILD, radiation pneumonitis that required steroid treatment, 
or drug-related pneumonitis.  
11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or study drug administration, or that 
may interfere with the interpretation of study results and, in the judgment of the Investigator 
and/or Turning Point Therapeutics, would make the subject inappropriate for entry into this 
study, or could compromise protocol objectives in the opinion of the Investigator and/or 
Turning Point Therapeutics. 
12. Current or anticipated use of drugs that are known to be strong CYP3A inhibitors or inducers 
as well as use of drugs that are sensitive CYP3A substrates as listed in Appendix 1. 
13. Prior exposure to repotrectinib. 
14. Prior exposure to a direct and specific inhibitor of KRAS 
15. Prior exposure to trametinib or another mitogen-activated protein kinase (MEK) inhibitor. 
16. Subjects have a history or current evidence of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR) determined by an ophthalmology exam. 
17. Current or anticipated use of drugs that are sensitive substrate with narrow therapeutic index 
for UGT1A1. 
18. Current or anticipated use of drugs that are sensitive substrate with narrow therapeutic index 
for OATP1B1, OAT3, MATE1, and MATE2-K. 
19. Current or anticipated use of drugs that are strong inhibitors of P-glycoprotein. 
Investigational Products/Dosage Formulations:  
Repotrectinib will be supplied as 40 mg capsules. 
Trametinib will be supplied as commercially available in 0.5 mg or 2 mg tablets. 
Dose Regimen and Route of Administration: 
Repotrectinib and trametinib will be administered orally as a combination treatment. For the Phase 1b 
dose escalation portion of the study, subjects will be assigned to a repotrectinib and trametinib dose 
according to the currently open dose level for 28 consecutive days in repeated four-week cycles.  
For the Phase 2 expansion portion of the study, subjects will be allocated to receive repotrectinib and 
trametinib at the RP2D combination determined during the Phase 1b dose escalation portion for 28 
consecutive days in repeated four-week cycles. 
Criteria for Evaluation 
Primary Endpoint for Phase 1: 
• Incidence of first cycle (28 days) DLTs to determine MTD and/or RP2D.  
Secondary Endpoints for Phase 1: 
• ORR assessed by  the Investigator using RECIST v1.1 
• Pharmacokinetic parameters of repotrectinib 
• Pharmacokinetic parameters of trametinib 
Phase 2 Primary Endpoint: 
• ORR assessed by Investigator per RECIST v1.1. 
Phase 2 Secondary Endpoints: 
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• DOR, TTR, and CBR by the Investigator 
• PFS and OS  
• Intracranial objective response rate (IC-ORR) assessed according to modified RECIST v1.1 in 
subjects with brain metastases. 
• Type, incidence, severity, timing, seriousness, and relatedness (to each study drug) of AEs and 
laboratory abnormalities 
• Pharmacokinetic parameters of repotrectinib 
• Pharmacokinetic parameters of trametinib 
Exploratory Endpoints (All Phases):  
• ORR and PFS by modulation of circulating tumor levels and genomic alterations observed pre- and 
post-dosing. 
Sample Size Determinations: 
Phase 1b Dose Escalation 
For dose escalation, 3 to 6 DLT-evaluable subjects will be enrolled per dose level. Therefore, it is 
expected that approximately 24 – 30 subjects will be enrolled to determine the RP2D of repotrectinib 
in combination with trametinib.  
Phase 2 Expansion 
For the Phase 2 expansion, 50 subjects will be enrolled. In addition, up to 6 locally advanced or 
metastatic KRAS-mutant NSCLC subjects treated at the RP2D in Phase 1b will be pooled for the 
efficacy analysis. If 21 subjects out of 56 subjects have a confirmed objective response (ORR = 38%; 
95% confidence interval [CI]: 25 – 51) where the lower limit of the 95% CI is > 23%, repotrectinib in 
combination with trametinib will be considered superior than the currently approved chemotherapy in 
the second-line setting for NSCLC in this expansion cohort, including the combination of docetaxel + 
ramucirumab (Cyramza® USPI, 2020) which has demonstrated a best ORR of 23% (95% CI: 20 – 26) 
in the second-line setting. 
An interim futility analysis of the ORR will be performed after approximately 15 subjects are 
evaluable for tumor response. If ≤ 2 responders (confirmed CR or PR) are observed from 15 evaluable 
subjects, the expansion cohort will be stopped for futility. If ≥ 3 responders are observed, this cohort 
may continue depending on the overall benefit and risk assessment at the interim analysis. If ≥ 3 
responders are observed, this cohort may continue depending on the overall benefit and risk assessment 
at the interim analysis. If the true ORR in this cohort is as targeted at 38%, the probability of observing 
≤ 2 responders is 3.8%. If the true ORR is significantly lower than the target ORR (i.e., 10% instead of 
38%), the probability is 81.6%. 
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11. Complete Chemistry Panel: ALT, AST, ALP, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, BUN or urea, creatinine, uric acid, glucose (nonfasted), 
lipid panel (total cholesterol, LDL, HDL, triglycerides), albumin, phosphorus or phosphate, bicarbonate, total protein, lactate dehydrogenase, amylase, lipase. On on-site dosing 
days, assessments will be performed before the dose of study drug is given. Complete Chemistry Panel is optional on C1D1 if performed within the past 7 days. 
12. Coagulation: Prothrombin time/international normalized ratio, partial thromboplastin time. On on-site dosing days, assessments will be performed before the dose of study 
drug is given. Optional on C1D1 if performed within the past 7 days. 
13. Serum Pregnancy Test: For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed during Screening, 
Cycle 1 Day 1 (optional if performed within the past 7 days.), Cycle 2 Day 1 and Day 1 of each subsequent cycle, EOT, and Safety Follow-up visit. Only subjects with 
negative serum pregnancy tests can enroll. If the results of the serum pregnancy test are not available during the clinic visits (e.g., C2D1, C3D1, C4D1, etc.), a urine pregnancy 
test may be performed. 
14. Urine Analysis: Urinalysis includes the analysis of protein, glucose, ketones, blood, and specific gravity. A microscopic (white blood cells/high-power field [HPF], red blood 
cells/HPF, and any additional findings) exam need be performed only if the urinalysis result is abnormal. Urinalysis is optional on C1D1 if performed within the past 7 days. 
15. Blood Specimens for ccfDNA Enrichment (20 mL blood specimen): In all subjects, blood samples will be collected during Screening, at Cycle 3 Day 1 (in conjunction with 
tumor assessment evaluation; may be collected at next study visit if unable to obtain at the Cycle 3 Day 1 visit), and either at the time of radiographic disease progression or at 
the EOT (whichever occurs earlier; may also be collected at Safety Follow-up visit if unable to obtain at the EOT visit) for exploratory ccfDNA molecular profiling analyses. 
Blood will be collected across two 10 mL Streck Cell-Free DNA Blood Collection Tubes (for ccfDNA analysis). Circulating cell-free DNA (ccfDNA) will be isolated from 
blood. Details for handling of these specimens including processing, storage, and shipment will be provided in the Study Manual. 
16. Triplicate 12-lead ECGs: At each timepoint, three consecutive 12-lead ECGs will be performed approximately two minutes apart to determine the mean QTc interval. 
Triplicate ECGs will be collected as follows:  
a) At Screening  
b) Day 1: at pre-dose (0 hour), at 1, 2, 4, 6, 8, and 24 hours post-dose 
c) Cycle 1 Day 8: at pre-dose (0 hour), and 2 hours post-dose 
d) Cycle 1 Day 15: at pre-dose (0 hour) 
e) Cycle 1 Day 22: at pre-dose (0 hour), at 1, 2, 4, 6, 8, and 24 hours post-dose  
f) Cycles 2-6, Day 1: at pre-dose (0 hour), and 2 hours post-dose  
g) At End of Treatment 
When coinciding with blood sample draws for PK, the ECG assessment should be performed prior to blood sample collection such that the blood sample is collected at the 
nominal time. ECGs performed within 10% of the nominal time (e.g., within 6 minutes of the 60-minute assessment) from dosing are acceptable. In addition to these 
timepoints, ECGs should be repeated as clinically indicated. Additional ECG timepoints may be included based on the emerging data. Interpretation of the tracing will be made 
by a central ECG laboratory. Each ECG tracing should be labeled with the study number, subject initials, subject number, and date, and kept in the source documents at the 
study site. Only clinically significant abnormalities will be recorded in the AE CRF page. Clinically significant abnormalities at Screening/baseline should be recorded on the 
relevant medical history/current medical conditions CRF page. Clinically significant findings must be discussed with the Sponsor’s Medical Monitor before enrolling the 
subject in the study.  
17. Echocardiography or MUGA for LVEF Assessments: Echocardiography to be performed at Screening, on Cycle 2 Day 1 (± 7 days), and after every three cycles of 
treatment (± 7 days) (Cycles 4, 7, 10, 13, and so on), and at the Safety Follow-Up visit (± 7 days).  
18. Pharmacokinetic Blood Sampling: All measurement times are relative to combination dose of repotrectinib and trametinib unless otherwise specified. Samples obtained 
within 10% of the nominal time (e.g., within 6 minutes of the 60-minute sample) from dosing will not be considered as a protocol deviation, as long as the exact time of the 
sample collection is noted on the source document and data collection tool (e.g., CRF/DCT). Blood samples will be collected on the following days: 
a) 
Day 1: at pre-dose (0 hour), at 1, 2, 4, 6, 8, and 24 hours post-dose 
b) 
Cycle 1 Day 8: at pre-dose (0 hour), and 2 hours post-dose 
c) 
Cycle 1 Day 15: at pre-dose (0 hour) 
d) 
Cycle 1 Day 22: at pre-dose (0 hour), at 1, 2, 4, 6, 8, and 24 hours post-dose  
e) 
Cycles 2-6, Day 1: at pre-dose (0 hour), and 2 hours post-dose  
f) 
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19. CT or MRI Chest/Abdomen/Pelvis Tumor Assessment: Tumor assessments will include all known or suspected disease sites. For all tumor assessments, the imaging 
modality that was used at baseline should be the same modality used throughout the study. CT or MRI scans are to be performed at Screening (≤ 28 Days from C1D1), C3D1 
(± 7 days), every 2 cycles (± 7 days) up to Cycle 19, then every 3 cycles (± 7 days) up to Cycle 37, and then every 4 cycles (± 7 days) thereafter until documented progression 
of disease regardless of treatment delays resulting from toxicity, and at the EOT if more than 4 weeks have passed since the last imaging assessment. Subject responses will be 
confirmed ≥ 4 weeks later (ideally, the confirmation scan should be scheduled at end of the next cycle, i.e., 28 days) after the initial documentation of response by the 
Investigator. Subjects may continue treatment with repotrectinib and maintain the study schedule after disease progression if there is continuing clinical benefit per 
Investigator’s judgment and in consultation with the Sponsor’s Medical Monitor. For subjects discontinuing the study treatment before documented radiographic progression, 
tumor assessments should continue on schedule approximately every two cycles or at the current scan interval at the time of treatment discontinuation until radiographic 
evidence of disease progression, the start of a subsequent anticancer therapy, withdrawal of consent, whichever is first. Every effort should be made to maintain the assessment 
scheduling relative to Cycle 1 Day 1, especially if there are dosing cycle interruptions due to toxicities. For all subjects, scans should be assessed locally by the Principal Investigator 
as per RECIST v1.1.  
20. CT or MRI of the Brain: At Screening, a CT/MRI of the brain should be obtained to rule out newly diagnosed, untreated brain metastases or to document stability of 
previously treated brain metastases. CT/MRI brain scans should be performed at every on-study tumor assessment for chest/abdomen/pelvis for subjects with brain metastases.  
21. Bone Scans: Bone scans (or bone MRI if preferred by Investigator) will be performed at baseline (28 days prior to Cycle 1 Day 1) if bone metastases are suspected. In addition, 
bone scans can be performed if clinically indicated per Investigator’s discretion. These scans are only repeated for subjects having a baseline scan, to confirm the absence of 
bone metastases in case of a Complete Response (CR). Subject responses will be confirmed ≥ 4 weeks later after the initial documentation of response by the Investigator.  
22. Adverse Events: All AEs, whether reported by the subject or noted by study personnel, will be recorded in the subject’s medical record and on the Adverse Event CRF at each 
subject contact. After informed consent for the clinical trial has been obtained but prior to initiation of study drug, only SAEs related to protocol-mandated assessments should 
be reported. After initiation of study drug, all AEs, regardless of relationship to study drug, will be reported until at least 28 days after the last dose of study treatment. Any 
SAEs occurring any time after the reporting period must be promptly reported if a causal relationship to the study drug is suspected. 
23. Concomitant Medications and Non-Drug Supportive Interventions: All concomitant medications and non-drug supportive interventions should be recorded in the CRF. 
24. Survival Follow-Up: For subjects discontinuing the study treatment due to documented radiographic progression, obtain survival status via phone call or medical chart review, 
including information about subsequent anticancer therapies (including best response) every 3 months until death, loss of follow-up, or withdrawal of consent, whichever 
comes first. For subjects discontinuing the study treatment prior to documented radiographic progression, tumor assessments should continue on the schedule approximately 
every 2 months or at the current scan interval at the time of treatment discontinuation until radiographic evidence of disease progression, the start of a subsequent anticancer 
therapy, or decision to no longer treat (e.g., supportive care only), whichever is first. 
 
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TABLE OF CONTENTS 
TURNING POINT THERAPEUTICS APPROVAL ......................................................................2 
PRINCIPAL INVESTIGATOR STATEMENT OF AGREEMENT ..............................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
SCHEDULE OF ACTIVITIES......................................................................................................15 
ABBREVIATIONS AND DEFINITION OF TERMS..................................................................27 
1. 
INTRODUCTION ......................................................................................................32 
1.1. 
Repotrectinib Mechanism of Action and Indication ...................................................32 
1.2. 
Background .................................................................................................................32 
1.2.1. 
KRAS as a Driver of Cancer ......................................................................................32 
1.2.2. 
KRAS-Mutant NSCLC and Treatment Approaches ....................................................33 
1.3. 
Repotrectinib Combination Approaches and Rationales ............................................34 
1.3.1. 
Rationale for Repotrectinib in Combination with Trametinib ....................................34 
1.4. 
Summary of Nonclinical Experience ..........................................................................34 
1.4.1. 
Nonclinical Pharmacology of Repotrectinib ..............................................................34 
1.4.1.1. 
Nonclinical Pharmacology of Repotrectinib Given in Combination with 
Trametinib ...................................................................................................................35 
1.4.2. 
Nonclinical Pharmacokinetics ....................................................................................40 
1.4.3. 
Nonclinical Toxicology ..............................................................................................40 
1.5. 
Clinical Experience .....................................................................................................41 
1.5.1. 
Study TPX-0005-09: Mass Balance, Pharmacokinetics, and Metabolism of 
Repotrectinib in Healthy Male Subjects .....................................................................42 
1.6. 
Proposed Clinical Starting Dose .................................................................................42 
1.6.1. 
Repotrectinib in Combination with Trametinib ..........................................................42 
2. 
STUDY OBJECTIVES ..............................................................................................44 
2.1. 
Phase 1b Objectives ....................................................................................................44 
2.1.1. 
Primary Objectives .....................................................................................................44 
2.1.2. 
Secondary Objectives .................................................................................................44 
2.2. 
Phase 2 Objectives ......................................................................................................44 
2.2.1. 
Primary Objective .......................................................................................................44 
2.2.2. 
Secondary Objective ...................................................................................................44 
2.3. 
Exploratory Objectives (All Phases) ..........................................................................44 
3. 
STUDY DESIGN .......................................................................................................45 
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3.1. 
Overall Study Design ..................................................................................................45 
3.2. 
Phase 1b Dose Escalation Study Design ....................................................................45 
3.2.1.1. 
Dose-Limiting Toxicities ............................................................................................47 
3.2.1.2. 
Determination of MTD ...............................................................................................49 
3.2.1.3. 
Recommended Phase 2 Dose (RP2D) Definition .......................................................49 
3.2.1.4. 
Follow-Up After a Dose-Limiting Toxicity ...............................................................49 
3.2.1.5. 
Safety Review Committee ..........................................................................................49 
3.3. 
Phase 2 Expansion Study Design ...............................................................................49 
3.4. 
Study Duration ............................................................................................................50 
3.5. 
Dose Modifications .....................................................................................................50 
3.5.1. 
Dose Interruptions and Delays ....................................................................................51 
4. 
SUBJECT ELIGIBILITY CRITERIA .......................................................................56 
4.1. 
Subject Inclusion Criteria ...........................................................................................56 
4.2. 
Subject Exclusion Criteria ..........................................................................................58 
5. 
STUDY TREATMENT ..............................................................................................60 
5.1. 
Allocation to Treatment ..............................................................................................60 
5.1.1. 
Repotrectinib + Trametinib.........................................................................................60 
5.2. 
Investigational Product Supplies ................................................................................60 
5.2.1. 
Dosage Form(s) and Packaging ..................................................................................60 
5.2.1.1. 
Repotrectinib ...............................................................................................................60 
5.2.1.2. 
Trametinib ...................................................................................................................61 
5.2.2. 
Investigational Product Storage and Accountability ..................................................61 
5.2.2.1. 
Repotrectinib ...............................................................................................................61 
5.2.2.2. 
Trametinib ...................................................................................................................61 
5.2.3. 
Destruction of Investigational Product Supplies ........................................................61 
5.3. 
Dose Regimen and Route of Administration ..............................................................62 
5.3.1. 
Repotrectinib + Trametinib.........................................................................................62 
5.4. 
Concomitant Treatments .............................................................................................62 
5.4.1. 
Prohibited Concomitant Medications .........................................................................62 
5.4.1.1. 
Other Anti-Tumor or Investigational Drugs ...............................................................63 
5.4.2. 
Anti-Diarrheal, Anti-Emetic Therapy .........................................................................63 
5.4.3. 
Anti-Inflammatory Therapy ........................................................................................63 
5.4.4. 
Corticosteroids ............................................................................................................64 
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6. 
STUDY ASSESSMENTS ..........................................................................................64 
6.1. 
Informed Consent .......................................................................................................64 
6.2. 
Tumor Molecular Alteration .......................................................................................64 
6.3. 
Tumor Treatment History ...........................................................................................64 
6.4. 
Demographics .............................................................................................................64 
6.5. 
Medical History ..........................................................................................................64 
6.6. 
Physical Examination .................................................................................................64 
6.7. 
Ophthalmologic Examination .....................................................................................65 
6.8. 
Performance Status .....................................................................................................65 
6.9. 
Vital Signs ..................................................................................................................65 
6.10. 
Subject Diary and Compliance ...................................................................................65 
6.11. 
Laboratory Assessments .............................................................................................65 
6.12. 
Pregnancy Test ............................................................................................................66 
6.13. 
Cardiac Safety Monitoring .........................................................................................66 
6.13.1. 
Electrocardiogram .......................................................................................................66 
6.13.2. 
Echocardiogram/MUGA Scan ....................................................................................67 
6.14. 
Pharmacokinetics ........................................................................................................67 
6.15. 
Pharmacodynamics/Biomarkers .................................................................................68 
6.16. 
Tumor Assessments ....................................................................................................68 
6.16.1. 
CT/MRI of Chest/Abdomen/Pelvis ............................................................................69 
6.16.2. 
Brain CT or MRI ........................................................................................................69 
6.16.3. 
Bone Scan ...................................................................................................................69 
6.16.4. 
Blinded Independent Central Review (BICR) ............................................................69 
6.17. 
Other Clinical Assessments ........................................................................................69 
7. 
STUDY CONDUCT ...................................................................................................70 
7.1. 
Screening and Eligibility ............................................................................................70 
7.2. 
Timing of Clinical Procedures ....................................................................................70 
7.2.1. 
Pre-Dose Assessments ................................................................................................70 
7.3. 
Subject Discontinuation and Withdrawal from Study ................................................71 
7.4. 
Study Treatment Discontinuation ...............................................................................72 
7.5. 
Withdrawal of Consent ...............................................................................................72 
7.6. 
Lost to Follow-Up.......................................................................................................72 
7.7. 
Long-Term Follow-Up ...............................................................................................73 
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7.8. 
Restrictions .................................................................................................................73 
7.8.1. 
Concomitant Medications ...........................................................................................73 
7.8.2. 
Surgery ........................................................................................................................73 
7.8.3. 
Palliative Radiation .....................................................................................................73 
7.8.4. 
Supportive Care ..........................................................................................................73 
7.8.5. 
Contraception ..............................................................................................................73 
8. 
SAFETY ASSESSMENTS ........................................................................................75 
8.1. 
Adverse Events ...........................................................................................................75 
8.1.1. 
Serious Adverse Events (Immediately Reportable to Turning Point 
Therapeutics) ..............................................................................................................75 
8.2. 
Methods and Timing for Capturing and Assessing Safety Parameters ......................76 
8.2.1. 
Adverse Event Reporting Period ................................................................................76 
8.2.2. 
Eliciting Adverse Event Information ..........................................................................76 
8.2.3. 
Assessment of Severity of Adverse Events ................................................................76 
8.2.4. 
Assessment of Causality of Adverse Events ..............................................................77 
8.2.5. 
Procedures for Recording Adverse Events .................................................................78 
8.2.5.1. 
Diagnosis Versus Signs and Symptoms .....................................................................78 
8.2.5.2. 
Adverse Events That Are Secondary to Other Events ................................................78 
8.2.5.3. 
Persistent or Recurrent Adverse Events .....................................................................79 
8.2.5.4. 
Abnormal Laboratory Values .....................................................................................79 
8.2.5.5. 
Abnormal Vital Sign Values .......................................................................................80 
8.2.5.6. 
Abnormal Liver Function Tests ..................................................................................80 
8.2.5.7. 
Deaths .........................................................................................................................81 
8.2.5.8. 
Preexisting Medical Conditions ..................................................................................82 
8.2.5.9. 
Lack of Efficacy or Worsening of the Malignancy Under Study ...............................82 
8.2.5.10. 
Hospitalization or Prolonged Hospitalization .............................................................82 
8.2.5.11. 
Exposure During Pregnancy .......................................................................................82 
8.2.5.12. 
Occupational Exposure ...............................................................................................84 
8.2.5.13. 
Adverse Events Associated with an Overdose or Incorrect Administration of 
Study Drug ..................................................................................................................84 
8.3. 
Immediate Reporting Requirements from Investigator to Turning Point 
Therapeutics ................................................................................................................84 
8.3.1. 
SAE Reporting ............................................................................................................85 
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8.3.2. 
Immediate Reporting Requirements for Pregnancies .................................................85 
8.3.2.1. 
Pregnancies in Female Subjects ..................................................................................85 
8.3.2.2. 
Congenital Anomalies/Birth Defects and Abortions ..................................................85 
8.4. 
Follow-Up of Subjects After Adverse Events ............................................................85 
8.4.1. 
Investigator Follow-Up ...............................................................................................85 
8.4.2. 
Turning Point Therapeutics Follow-Up ......................................................................86 
8.5. 
Post-Study Adverse Events.........................................................................................86 
8.6. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees .....................................................................86 
9. 
STATISTICAL METHOD ANALYSIS ....................................................................86 
9.1. 
Analysis Sets ...............................................................................................................87 
9.1.1. 
Full Analysis Set .........................................................................................................87 
9.1.2. 
Efficacy Evaluable Analysis Set .................................................................................87 
9.1.3. 
Safety Analysis Set .....................................................................................................87 
9.1.4. 
Pharmacokinetic Concentration Analysis Set .............................................................87 
9.1.5. 
Pharmacokinetic Parameter Analysis Set ...................................................................87 
9.2. 
Sample Size Determinations .......................................................................................88 
9.2.1. 
Repotrectinib + Trametinib.........................................................................................88 
9.2.1.1. 
Phase 1b Dose Escalation ...........................................................................................88 
9.2.1.2. 
Phase 2 Expansion ......................................................................................................88 
9.3. 
Study Endpoints ..........................................................................................................88 
9.3.1. 
Primary Endpoint for Phase 1 .....................................................................................88 
9.3.2. 
Secondary Endpoints for Phase 1 ...............................................................................88 
9.3.3. 
Primary Endpoint for Phase 2 .....................................................................................88 
9.3.4. 
Secondary Endpoints for Phase 2 ...............................................................................88 
9.3.5. 
Exploratory Endpoints for Phase 1b and Phase 2 .......................................................89 
9.4. 
Statistical Analysis ......................................................................................................89 
9.4.1. 
General Considerations ...............................................................................................89 
9.4.1.1. 
Missing Data ...............................................................................................................89 
9.4.2. 
Efficacy Analyses .......................................................................................................89 
9.4.3. 
Analysis of Primary Endpoint ....................................................................................89 
9.4.3.1. 
Objective Response Rate ............................................................................................89 
9.4.4. 
Analysis of Secondary Endpoints ...............................................................................89 
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9.4.5. 
Safety Analyses ..........................................................................................................90 
9.4.6. 
Analysis of Pharmacokinetics .....................................................................................90 
9.4.6.1. 
Single-and Multiple-Dose Repotrectinib and Trametinib Pharmacokinetic 
Analysis ......................................................................................................................90 
9.5. 
Interim Analysis ..........................................................................................................90 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................91 
11. 
DATA HANDLING AND RECORD KEEPING ......................................................91 
11.1. 
Case Report Forms/Electronic Data Record ...............................................................91 
11.2. 
Study Monitoring, Audits, and Inspections ................................................................91 
11.3. 
Inspection of Records .................................................................................................92 
11.4. 
Record Retention ........................................................................................................92 
12. 
ETHICS ......................................................................................................................92 
12.1. 
Ethics Review .............................................................................................................92 
12.2. 
Protocol Compliance ..................................................................................................93 
12.3. 
Ethical Conduct of the Study ......................................................................................93 
12.4. 
Written Informed Consent ..........................................................................................93 
12.5. 
Subject Confidentiality ...............................................................................................93 
13. 
PUBLICATION OF STUDY RESULTS ...................................................................94 
14. 
REFERENCES ...........................................................................................................95 
APPENDIX 1. STRONG CYP3A INHIBITORS OR INDUCERS, SENSITIVE 
CYP3A SUBSTRATES AND MEDICATIONS THAT CAUSE QTC 
PROLONGATION .....................................................................................................99 
APPENDIX 2. SUMMARY OF CHANGES ...........................................................................101 
 
 
 
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LIST OF TABLES 
Table 1: 
Schedule of Activities: Repotrectinib + Trametinib ...................................................15 
Table 2: 
Dose-finding Dose Levels ..........................................................................................46 
Table 3: 
CTCAE Dose-Limiting Toxicities ..............................................................................48 
Table 4: 
Repotrectinib Dose Modification Guidelines for Adverse Events (CTCAE 
v5.0) ............................................................................................................................53 
Table 5: 
Investigational Product: Repotrectinib Product and Dosage Information ..................60 
Table 6: 
Investigational Product: Trametinib Product and Dosage Information ......................61 
Table 7: 
Safety Laboratory Tests ..............................................................................................66 
Table 8: 
Grading of Severity of Adverse Events ......................................................................77 
Table 9: 
Causation Attribution ..................................................................................................78 
Table 10: Stopping Rule for Interim Futility Analysis of ORR in Phase 2 ................................91 
 
LIST OF FIGURES 
Figure 1: 
Patient Derived KRASG12D Lung Spheroid Model LU5178 ........................................36 
Figure 2: 
Cell Viability Assay with Repotrectinib and Trametinib Combination in 
A427 KRASG12D Lung Cancer Model .........................................................................36 
Figure 3: 
Bliss Synergy Analysis for Repotrectinib and Trametinib Combination in 
A427 KRASG12D Lung Cancer Model .........................................................................37 
Figure 4: 
Repotrectinib and Trametinib Combination Suppresses Downstream 
Oncogenic Signaling in A427 KRASG12D Lung Cancer Model ..................................38 
Figure 5: 
Repotrectinib and Trametinib Combination Increases Cell Cycle Arrest and 
Induction of Apoptosis ...............................................................................................38 
Figure 6: 
In Vivo GEMM KRASG12D mLU6045 Syngeneic Murine Lung Model TGI 
Study ...........................................................................................................................39 
Figure 7: 
In Vivo Patient Derived KRASG12D LU0876 Xenograft Lung Model TGI 
Study ...........................................................................................................................39 
Figure 8: 
In Vivo Pharmacodynamic Evaluation of Signal Modulation by 
Repotrectinib and Trametinib treatment in KRASQ61K Calu6 Lung Model ................40 
Figure 9: 
Subprotocol 1 Study Design .......................................................................................45 
 
 
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ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
AKT 
protein kinase B 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT  
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology  
AST  
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the plasma concentration versus time curve to infinity 
AUClast 
AUC from time zero to the last quantifiable concentration point (tlast) 
BCRP 
breast cancer resistance protein 
BICR 
Blinded Independent Central Review 
BID 
twice a day 
CBR 
Clinical Benefit Rate 
ccfDNA 
circulating cell-free DNA 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL/F 
oral clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum observed plasma drug concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
Case Report Form 
CSR 
central serous retinopathy 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
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Term 
Definition 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic CRF 
EDC 
electronic data capture 
EE 
Efficacy Evaluable 
EGFR 
epidermal growth factor receptor 
EMT 
epithelial-mesenchymal transition 
EOT 
End of Treatment 
ERK 
extracellular signal-regulated kinase 
FAK 
focal adhesion kinase 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GAPs 
GTPase activating proteins 
GCP 
Good Clinical Practice  
GDP 
guanosine diphosphate 
GEFs 
guanine exchange factors 
GEMM 
genetically engineered mouse model 
GLP 
Good Laboratory Practice 
GTP 
Guanosine-5'-triphosphate 
HBV 
hepatitis B 
HCV 
hepatitis C 
HEK 
human embryonic kidney 
hERG 
human ether-a-go-go-related gene 
HIV 
human immunodeficiency virus 
HPF 
high-power field  
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration  
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Term 
Definition 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IC-ORR 
intracranial objective response rate 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
JAK 
janus kinase 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction  
MAF 
major allele frequency 
MAPK 
RAF-MEK-ERK transduction pathway 
MATE 
multidrug and toxin extrusion protein 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MEK 
mitogen-activated extracellular signal-regulated kinase 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NA 
not applicable 
NCI 
National Cancer Institute 
ND 
not determined 
NE 
not evaluable 
NGS 
next-generation sequencing 
NN 
non-CR/non-PD 
NOAEL 
no observable adverse effect level 
NSCLC 
non-small-cell lung cancer 
NTRK-1 
neurotrophin receptor kinase 1 
NTRK-2 
neurotrophin receptor kinase 2 
NTRK-3 
neurotrophin receptor kinase 3 
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Term 
Definition 
OATP 
organic anion-transporting polypeptide 
ORR 
objective response rate 
OS 
overall survival 
pAKT 
phospho-AKT 
PARP 
poly (ADP-ribose) polymerase 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI3K 
phosphoinositide 3-kinase 
P-gp 
p-glycoprotein 
PK 
pharmacokinetics 
PO 
per os (by mouth) 
PR 
partial response 
PS 
Performance Status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once a day 
qPCR 
quantitative polymerase chain reaction 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T 
wave 
QTc 
QT interval corrected for heart rate 
Racc 
accumulation ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
receptor tyrosine kinase encoded by the ROS1 gene 
RP2D 
Recommended Phase 2 dose 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SLP 
solute carrier 
SRC 
tyrosine kinase first identified in avian sarcoma virus 
STAT 
signal transducer and activator of transcription 
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Term 
Definition 
SOP 
standard operating procedure 
t1/2 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to reach maximum (peak) plasma drug concentration 
TRAE 
treatment-related adverse event 
TTR 
time to response 
UGT 
uridine 5’-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution  
WBRT 
whole brain radiation treatment 
WT 
wild-type 
 
 
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1. 
INTRODUCTION 
1.1. 
Repotrectinib Mechanism of Action and Indication 
Repotrectinib is an oral, adenosine triphosphate (ATP)-competitive potent kinase inhibitor with 
activity against janus kinase (JAK2), tyrosine kinase first identified in avian sarcoma virus 
(SRC), and focal adhesion kinase (FAK) at clinically relevant concentrations, providing a unique 
polypharmacology profile for combatting multiple resistance mechanisms simultaneously, 
including bypass signaling, epithelial-mesenchymal transition (EMT), cancer cell stemness, and 
metastasis.  
In this subprotocol, repotrectinib will be given in combination with trametinib for the treatment 
of subjects with locally advanced or metastatic KRASG12D-mutant solid tumors. 
1.2. 
Background 
1.2.1. 
KRAS as a Driver of Cancer 
Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small transductor GTPase protein that 
relays external growth signals and regulates a complex signaling network with multiple 
downstream pathways that are involved in tumor cell growth, survival, and proliferation (Jancík 
2010). Under normal physiological conditions, KRAS acts as a molecular regulator with guanine 
exchange factors (GEFs) facilitating its activation by exchanging guanosine diphosphate (GDP) 
with guanosine-5'-triphosphate (GTP). After activated KRAS mediates transduction of growth 
signals, its intrinsic GTPase activity hydrolyses the bound GTP to GDP to become deactivated, 
often facilitated by GTPase activating proteins (GAPs). When mutated, impaired GAP 
stimulation favors the formation of persistently GTP-bound KRAS leading to the enhanced 
activation of KRAS, promoting binding of effectors to trigger signal transduction pathways 
including the RAF–MEK–ERK (MAPK) pathway, the aberrant activation of which has been 
found to drive many human cancer types (Cox 2014; Cully 2008; Keeton 2017; Vetter 2001).  
Somatic mutations in KRAS are the most common activating lesions found in human cancer, 
with mutations at codons 12, 13, or 61 of KRAS occurring de novo in approximately one third of 
all human cancers and are especially prevalent in pancreatic adenocarcinomas, colorectal 
carcinomas, and non-small-cell lung cancer (NSCLC) (Keeton 2017; NCCN 2020). The KRAS 
oncogene is considered a prognostic biomarker, the presence of which is predictive of poor 
survival and lack of efficacy to therapy in the clinic (Lièvre 2006; NCCN 2020; Pao 2005; 
Slebos 1990). 
Since the first detection of activated KRAS in human cancers in 1982, multiple approaches to 
develop drugs to treat malignancies arising from KRAS mutations have been investigated, 
including interfering with maturation, trafficking, and localization to the plasma membrane, or 
inhibiting downstream signaling (Keeton 2017). While many of these approaches have shown 
promising preclinical activity, the majority have shown limited efficacy in clinical trials 
(Cox 2014; Keeton 2017). KRAS has often been considered an undruggable target for direct 
inhibition, in part due to the relative cellular abundance and the high affinity of KRAS for 
binding GTP as well as the lack of a suitable binding location in critical regions on the smooth 
surface of the KRAS oncoprotein (Lindsay 2018; Ostrem 2013; Ni 2019). Only recently has 
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clinical activity been observed with selective allosteric KRASG12C inhibitors, with responses 
being noted especially in patients with NSCLC (Canon 2019; Hallin 2019; Ostrem 2013).  
Over the years, research involving KRAS-mutant cancers have mainly focused on downstream 
mediators in part due to clinically-approved inhibitors of MAPK pathway proteins (e.g., 
inhibitors of MEK and BRAF), with notable successes such as combinations of MEK inhibitors 
(e.g., trametinib) with other targeted therapeutics in the case of malignant melanoma (Cox 2014). 
However, the majority of these efforts have been limited by adaptive feedback to reactivate 
MAPK signaling or compensatory upregulation of phosphoinositide 3-kinase/protein kinase B 
(PI3K/AKT) signaling (Kitai 2017; Manchado 2016; Yaeger 2019; Tsubaki 2019).  
1.2.2. 
KRAS-Mutant NSCLC and Treatment Approaches 
Lung cancer remains the leading cause of cancer-related death globally, with an estimated 
1.76 million people having died of lung cancer in 2018 (Bray 2018). NSCLC is the most 
common subtype of lung cancer, representing 80–90% of lung cancer cases (Planchard 2019). 
NSCLC is associated with a poor prognosis in the advanced or metastatic setting where the 
5-year survival rate is estimated to be approximately 7% (Howlader 2019; ACS 2020). 
KRAS mutations occur in 20–40% of lung adenocarcinomas, with the most frequent mutations 
occurring in codons 12 and 13, and the most common subtypes including G12C, G12V, 
and G12D (Cox 2014; Ricciuti 2016). The presence of KRAS mutations is prognostic of poor 
survival for patients with NSCLC when compared to the absence of KRAS, independent of 
therapy (NCCN 2020). KRAS mutations are also predictive of lack of therapeutic efficacy with 
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).  
Although there are clinically-approved inhibitors of several MAPK pathway proteins (e.g., 
inhibitors of MEK, BRAF and EGFR) for a subset of NSCLC patients, to date there have been 
no approved targeted therapies for treatment of KRAS-mutant NSCLC (NCCN 2020).  
Recently, development of selective allosteric KRASG12C inhibitors such as AMG510 and 
MRTX849 have demonstrated encouraging clinical activity in patients with KRASG12C-mutant 
NSCLC, with overall response rates (ORRs) as high as 54% (N = 13) observed with AMG510 
(Amgen 2019; Canon 2019; Hallin 2019).  However, KRASG12C mutations are only present in a 
small subset of NSCLC patients (approximately 13% of lung adenocarcinoma harbor KRASG12C 
mutations) and KRASG12C inhibitors rely on the mutant cysteine for binding and therefore do not 
affect the wild-type KRAS protein or other KRAS subtypes.  In addition, resistance to direct 
targeting of KRAS can occur and may be due to genetic alterations in downstream pathways, 
thus combination therapies are likely needed to provide greater benefit than direct targeting of 
KRAS alone (Burns 2020). 
Taken together, there is an urgent, unmet medical need for development of novel targeted 
therapeutics and novel therapeutic strategies for the treatment of patients with locally advanced 
or metastatic KRAS-mutant NSCLC. 
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1.3. 
Repotrectinib Combination Approaches and Rationales 
1.3.1. 
Rationale for Repotrectinib in Combination with Trametinib 
Trametinib (Mekinist® [trametinib] USPI 2020) is a reversible inhibitor of mitogen-activated 
extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream 
regulators of the MAPK pathway, which promotes cellular proliferation. Trametinib is indicated, 
in combination with dabrafenib, for the treatment of patients with metastatic NSCLC with BRAF 
V600E mutation. Preclinical studies demonstrated sensitivity of cell lines harboring KRAS 
mutations to MEK inhibitors, supporting clinical evaluations of MEK inhibitors for patients with 
KRAS-mutant cancers (Sebolt-Leopold 1999; Davies 2007; Okumura 2014). However, clinical 
efficacy of MEK inhibitors such as trametinib in KRAS-mutant cancers has been limited, 
attributed to adaptive feedback mechanisms that reactivate MAPK signaling (Kitai 2017; 
Manchado 2016; Yaeger 2019; Tsubaki 2019). Preclinical data has demonstrated that MEK 
inhibition in KRAS-mutant cancer models caused autocrine activation of signal transducer and 
activator of transcription (STAT3) (Lee 2014). KRAS-mutant cancer cells cultured under long-
term trametinib exposure exhibit upregulated FAK and AKT activation along with elevated S6 
protein phosphorylation and became resistant to trametinib (internal data, unpublished).  
In vitro studies have demonstrated that trametinib-mediated AKT activation is better suppressed 
in combination with repotrectinib, compared to combinations with individual SRC, FAK or JAK 
inhibitors (Murray 2020). Combination with repotrectinib represses S6, AKT and STAT3 
activation and resensitizes these cancer cells to trametinib. Repotrectinib in combination with 
trametinib has demonstrated enhanced potency in in vitro KRASG12D NSCLC cell models as well 
as in ex vivo patient-derived KRASG12D NSCLC organoid models (Section 1.4.1.1). Repotrectinib 
and trametinib combination also demonstrated greater tumor growth inhibition than either single 
agent alone in an in vivo syngeneic genetically engineered mouse model (GEMM) KRASG12D 
model as well as in a patient-derived KRASG12D mutant lung xenograft model (Section 1.4.1.1). 
Repotrectinib’s ability to simultaneously inhibit SRC/FAK/JAK2 is expected to suppress MAPK 
reactivation and compensatory bypass signaling mediated by single agent trametinib therapy, 
with potential to yield improved efficacy in the clinic. Repotrectinib given in combination with 
trametinib may provide a promising treatment option for patients with advanced NSCLC 
harboring a KRASG12D mutation.  
1.4. 
Summary of Nonclinical Experience 
Detailed overview of nonclinical pharmacology, pharmacokinetics, and safety assessment has 
been presented in the Investigator’s Brochure (IB). 
1.4.1. 
Nonclinical Pharmacology of Repotrectinib 
Kinase selectivity of repotrectinib toward 456 human kinases (wild type [WT] and mutant) was 
evaluated in kinase binding assay using the KINOMEscan® profiling platform with potent hits 
further tested for IC50 values in enzymatic kinase inhibition assays. Overall, there were ten 
kinases with less than 10-fold selectivity over anaplastic lymphoma kinase (ALK) (IC50 
1.04 nM), including JAK2, FYN, LYN, YES, FGR, TXK, ARK5, SRC, DDR1, and FAK with 
IC50 values of 1.04, 1.05, 1.66, 2.15, 3.05, 3.17, 4.46, 5.29, 5.73 and 6.96 nM, respectively. It is 
known that tyrosine kinases are responsible for only a small fraction of phosphorylation events in 
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living cells (< 1%) (Hunter 1980; Sharma 2014). However, a subset of these tyrosine kinases, 
including JAK2, SRC and FAK, contribute to cancer malignancy, stemness, EMT and metastasis 
(Lee 2014; Mohrherr 2019; Sen 2009; Zhou 2017). 
In H2228 cells, repotrectinib suppressed the phosphorylation of SRC, FAK and paxillin with 
IC50 values in a range of 80-100 nM and downregulated the expression of EGFR, CD44, and 
vimentin with IC50 values around 100 nM. In addition, repotrectinib inhibited the 
phosphorylation of the oncogenic transcription/ translation factor YB-1 with an IC50 value 
around 100 nM in H2228 cells. YB-1 regulates aspects of gene expression that lead to tumor cell 
growth and drug resistance (Lasham 2013; Kuwano 2019), including modulation of EGFR 
upregulation (Stratford 2007; Kuwano 2019), EMT (Castellana 2015; Kosnopfel 2018), and 
cancer cell stemness (Kang 2013; Yang 2017). Repotrectinib demonstrated an in vitro anti-
metastatic activity by inhibiting cell migration in both H2228 cells and HT1080 human 
fibrosarcoma cells. Aberrant upregulation of JAK2/STAT pathways has been implicated in 
multiple human pathological diseases, including cancer (Bousoik 2018). Repotrectinib inhibited 
JAK2 signaling (pSTAT5 IC50 139 nM) and cell proliferation (IC50 169 nM) of SET2 cells 
harboring oncogenic JAK2 V617F mutation. Overall, repotrectinib demonstrated inhibition of 
JAK2/SRC/FAK in cellular assays and has the potential to overcome resistance from bypass 
signaling, EMT, cancer cell stemness and metastasis.  
The secondary pharmacodynamics studies in a 44 safety-related targets screen indicated that 
repotrectinib only weakly inhibited three targets, including A2A (IC50 6300 nM), human L-type 
Ca2+ channel (IC50 3500 nM), and LCK (IC50 110 nM). Repotrectinib had minimal effects on 
human ion channels, including human ether-a-go-go-related gene (hERG) (IC50 18 µM, Chinese 
hamster ovary [CHO] cells), hNaV1.5 (IC50 > 30 µM, human embryonic kidney [HEK]293 
cells), and human L-type CaV1.2 (IC50 > 30 µM, HEK293 cells). 
1.4.1.1. 
Nonclinical Pharmacology of Repotrectinib Given in Combination with 
Trametinib 
The combination of repotrectinib with trametinib was evaluated for inhibition of cell viability 
across panels of NSCLC, colorectal cancer (CRC) and pancreatic cancer cell lines that harbor a 
spectrum of KRAS mutations.  Addition of repotrectinib (1 µM) to trametinib treatment resulted 
in a >10 fold increase in trametinib anti-cell viability efficacy in 9 out of 15 KRASG12D mutant 
cancer models screened (Murray 2020).  
The effect on cell viability by repotrectinib in combination with various MAPK pathway 
inhibitors including trametinib, selumetinib, VS-6766, TNO199 and LY31214996 was assessed 
in NSCLC patient-derived organoid models harboring KRASG12D mutations. The combination of 
repotrectinib with trametinib exhibited the greatest enhanced inhibition of cancer cell viability 
compared to other MAPK pathway inhibitor combinations in KRASG12D  mutant NSCLC cancers 
(Figure 1). Similar repotrectinib and trametinib combination benefit was demonstrated in-patient 
derived pancreatic ex vivo spheroid models harboring KRASG12D mutations. 
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Figure 3: 
Bliss Synergy Analysis for Repotrectinib and Trametinib Combination in 
A427 KRASG12D Lung Cancer Model 
 
To understand the underlying mechanisms that resulted in greater efficacy, Western immunoblot 
analyses were performed with A427 cells (NSCLC KRASG12D) treated with single agent 
repotrectinib or trametinib vs the combination of repotrectinib and trametinib. Evaluation of 
downstream signal modulation by repotrectinib in combination with trametinib in A427 cells 
demonstrated greater inhibition of SRC, STAT3 and FAK phosphorylations, which coincided 
with increased inhibition of AKT and S6 phosphorylation compared to single agent treatments 
(Figure 4). The combination of repotrectinib and trametinib increased cell cycle inhibitor 
proteins such as p27 and p21 and inhibited RB1 phosphorylation more robustly than single agent 
treatments (Figure 5A). Furthermore, the repotrectinib and trametinib combination enhanced 
induction of apoptosis in comparison to single agent treatments as indicated by elevated cleavage 
of poly(ADP-ribose) polymerase (PARP) and caspase 3 (Figure 5B). 
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Figure 4: 
Repotrectinib and Trametinib Combination Suppresses Downstream 
Oncogenic Signaling in A427 KRASG12D Lung Cancer Model 
 
 
Figure 5: 
Repotrectinib and Trametinib Combination Increases Cell Cycle Arrest and 
Induction of Apoptosis 
 
 
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Trametinib induced a rebound in phospho-AKT (pAKT) levels in a subset of KRAS-mutant 
cells which was substantially suppressed by the combination with repotrectinib. In contrast, 
suppression of the trametinib-induced pAKT rebound was not achieved by combinations of 
trametinib with dasatinib (SRCi), ruxolitinib (JAK1/2i), or defactinib (FAKi), 
suggesting that concomitant SRC/FAK/JAK2 inhibition may be necessary (Murray 2020). 
The combination efficacy of repotrectinib and trametinib was tested in two KRASG12D in vivo 
lung models.  In the syngeneic GEMM KRASG12D lung model mLU6045, the combination of 
repotrectinib with trametinib demonstrated a 78% tumor growth inhibition vs 38% and 41% by 
repotrectinib or trametinib as single agents, respectively (p-value ≤ 0.0001) (Figure 6). In a 
patient-derived KRASG12D lung xenograft model LU0876, the combination of repotrectinib and 
trametinib demonstrated a 70% tumor growth inhibition vs 50% by trametinib alone (p-value = 
0.0483); repotrectinib single agent response was similar to vehicle treatment (Figure 7). 
Figure 6: 
In Vivo GEMM KRASG12D mLU6045 Syngeneic Murine Lung Model TGI 
Study 
 
Abbreviations: BID = twice a day; GEMM = genetically engineered mouse model; PO = per os (by mouth); QD = 
once a day; SEM = standard error of the mean. 
**** p-value ≤ 0.0001 
Figure 7: 
In Vivo Patient Derived KRASG12D LU0876 Xenograft Lung Model TGI 
Study 
 
Abbreviations: BID = twice a day; PO = per os (by mouth); QD = once a day; SEM = standard error of the mean. 
* p-value = 0.0483 
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The combination of trametinib and repotrectinib in a Calu-6 (NSCLC KRASQ61K) 
murine xenograft study demonstrated in vivo that repotrectinib suppresses of SRC/FAK/STAT3 
activation (Figure 8). 
Figure 8: 
In Vivo Pharmacodynamic Evaluation of Signal Modulation by 
Repotrectinib and Trametinib treatment in KRASQ61K Calu6 Lung Model 
 
1.4.2. 
Nonclinical Pharmacokinetics 
Repotrectinib was highly bound (> 95%) to human serum albumin. The primary route of 
elimination of repotrectinib was CYP (cytochrome P450) 3A4-mediated metabolism, followed 
by glucuronidation of the oxidative metabolites, which were subsequently excreted into bile and 
urine. Repotrectinib weakly inhibited CYP enzymes with insignificant time-dependent 
inhibition. The only UGT (uridine 5’-diphospho-glucuronosyltransferase) inhibited by 
repotrectinib was UGT1A1. Human hepatocyte culture studies suggested that repotrectinib may 
induce CYP2B6 and CYP3A4(/5) enzymes. Repotrectinib was transported by P-glycoprotein 
(P-gp), and likely by breast cancer resistance protein (BCRP) and multidrug and toxin extrusion 
protein (MATE) 2-K. However, repotrectinib was not a substrate for any other human solute 
carrier (SLC) transporters evaluated. Repotrectinib inhibited P-gp, BCRP, organic 
anion-transporting polypeptide (OATP) 1B1, OAT3, MATE1 and MATE2-K. 
1.4.3. 
Nonclinical Toxicology 
In accordance with the ICH S9 Guideline “Nonclinical Evaluation for Anticancer 
Pharmaceuticals” (March 2010), the Sponsor has completed a comprehensive nonclinical safety 
program encompassing in vitro hERG assay, ECG assessment in monkeys, single- and repeat-
dose exploratory toxicology studies, and definitive 28-day and 91-day toxicology studies with 
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28-day recovery periods conducted in rat and monkey, as well as genotoxicity and phototoxicity 
studies.  
The nonclinical profile was well-characterized with adequate exposure margins to support the 
intended use of repotrectinib for patients with advanced solid tumors.  
1.5. 
Clinical Experience 
Repotrectinib is currently under evaluation in a Phase 1/2 clinical trial as a monotherapy in 
subjects with advanced or metastatic solid tumors harboring ROS1, NTRK1-3, or ALK 
rearrangements (TPX-0005-01 or TRIDENT-1). Repotrectinib is also being evaluated as a 
monotherapy in a clinical study of pediatric subjects and young adults with advanced or 
metastatic solid tumors harboring ROS1, NTRK1-3, or ALK alterations (TPX-0005-07).  
Based on the safety, preliminary efficacy, and PK data obtained in Phase 1 of TRIDENT-1 (data 
cutoff of March 2019), the recommended Phase 2 dose (RP2D) was determined to be:  
• 160 mg once daily (QD) for the first 14 days and may increase to 160 mg twice a day 
(BID) based on subject safety and tolerability. Subjects must meet the following 
criteria while on 160 mg QD prior to dose increase to 160 mg BID: no evidence of 
grade ≥ 3 treatment-related adverse event (TRAE), unmanageable grade ≥ 2 
dizziness, ataxia or paresthesia; or grade ≥ 3 clinically significant lab abnormalities.  
Repotrectinib absorption was relatively fast under fasting conditions, with a median time to reach 
maximum (peak) plasma drug concentration (Tmax) of 2 hours. Mean Cmax and AUCinf increased 
after a single dose with increasing doses from 40 mg QD to 240 mg QD. Apparent volume of 
distribution (Vz/F) was medium with geometric mean values ranging from 229 to 506 L. 
Geometric mean oral clearance (CL/F) was low compared to human liver blood flow, ranging 
from 8.9 to 16.1 L/h. Mean terminal half-life was long after a single dose, ranging from 14.6 to 
25.9 hours. The accumulation ratio (Racc) values of Cmax and AUC were lower than expected 
based on the single-dose terminal half-lives. The CL/F at steady state was higher than observed 
after a single dose at the same administered dose, suggesting a possible auto-induction of 
metabolic enzyme(s). 
Overall, at the time of the most recent safety data cutoff (30 October 2020), 185 subjects have 
received at least one dose of repotrectinib in doses ranging from 40 mg QD to 200 mg BID in the 
TRIDENT-1 study. In the Phase 1 portion, the MTD was not reached. There were 
4 dose-limiting toxicities (DLTs): 1 DLT of dizziness at 240 mg QD and 3 DLTs at 160 mg BID 
(2 DLTs of dizziness; 1 DLT of dyspnea and hypoxia).  
Of the 185 subjects enrolled in the TRIDENT-1 study as of the 30 October 2020 safety data 
cutoff date, 180 (97.3%) subjects experienced at least one treatment-emergent adverse event 
(TEAE), with approximately half of the TEAEs reported with a maximum severity of grade 1 
and 2 and the majority managed without dose modifications.  
The most common TEAEs occurring in ≥ 20% of subjects regardless of relationship to study 
drug included dizziness (58.4%); dysgeusia (43.2%); constipation (32.4%); dyspnea (31.4%); 
fatigue (27.0%); paresthesia (25.4%); anemia (22.2%); and nausea (20.0%). TEAEs (grade ≥ 3) 
were experienced by 93 (50.3%) of 185 subjects. Dizziness (grade ≥ 3) occurred in 4 subjects 
(2.2%).  
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Dizziness (9 [5%] subjects) was the most common reason for dose interruption. The majority 
(80%) of dizziness events have been grade 1, and no subjects discontinued treatment due to 
dizziness.  
In summary, safety data from the Phase 1 and Phase 2 patient populations of TRIDENT-1 
demonstrate a favorable tolerability profile for repotrectinib. 
1.5.1. 
Study TPX-0005-09: Mass Balance, Pharmacokinetics, and Metabolism of 
Repotrectinib in Healthy Male Subjects 
TPX-0005-09 was conducted as a 2-part, 2-treatment, fixed-sequence study in 7 healthy male 
volunteers to investigate the mass balance, PK, and metabolism of a single oral dose and PK of 
an intravenous tracer of [14C]repotrectinib in healthy male subjects. The treatments were 
administered after an overnight fast of at least 10 hours. Below is a summary of key findings. 
Refer to the Investigator’s Brochure for further details. 
Following concomitant administration of a single oral dose of 160-mg repotrectinib capsule 
formulation and intravenous administration of tracer [14C]repotrectinib in study TPX-0005-09 
(Period 1), the geometric mean absolute bioavailability of repotrectinib based on AUC0-∞ was 
approximately 45.7%. The geometric means t1/2 of the IV formulation and the oral capsule dose 
were 32.5 and 36.2 hours, respectively.  
Following oral administration of a 160 mg of [14C]repotrectinib (100 µCi) dose (TPX-0005-09, 
Period 2), the mean total recovery of radioactivity in excreta was 93.7% with radioactivity 
recoveries in feces and urine of 88.8% and 4.84%, respectively. No metabolite exceeded 10% of 
total circulating drug-related radioactivity. All detected metabolites had been previously detected 
in rat and/or cynomolgus monkey following oral administration; therefore, there were no unique 
human metabolites. 
1.6. 
Proposed Clinical Starting Dose 
1.6.1. 
Repotrectinib in Combination with Trametinib 
Repotrectinib is an oral, adenosine triphosphate (ATP)-competitive potent kinase inhibitor with 
activity against JAK2, SRC, and FAK. Among 185 subjects treated in the Phase 1 and Phase 2 
portions of the TRIDENT-1 study, the most common toxicities observed were dizziness (58.4%), 
dysgeusia (43.2%), constipation (32.4%), dyspnea (31.4%), fatigue (27.0%), paresthesia 
(25.4%), anemia (22.2%), and nausea (20.0%). The majority of dizziness events were grade 1 or 
grade 2 and generally occurred within the first 14 days of treatment. A titration approach was 
implemented to minimize early onset of TEAEs, including dizziness, thus the RP2D of 
repotrectinib is 160 mg QD for the first 14 days, after which the dose may be increased to 160 
mg BID based on subject safety and tolerability.  
Trametinib is a MEK inhibitor indicated as monotherapy for the treatment of patients with 
metastatic melanoma with BRAF V600E or V600K mutations and in combination with 
dabrafenib for the treatment of patients with metastatic NSCLC harboring a BRAF V600E 
mutation. The most common adverse events (≥ 20%) seen with trametinib as a single agent 
include rash, diarrhea, and lymphedema (Mekinist® [trametinib] USPI 2020). 
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Based on the known toxicity profiles of both repotrectinib and trametinib described above, 
overlapping toxicities are not anticipated. However, in clinical trials, development of 
combination therapies of targeted agents can prove to be challenging because of toxicities 
observed with combined treatments, even if individual agents do not have overlapping toxicities. 
Therefore, the starting dose of repotrectinib in combination with trametinib for the Phase 1b dose 
escalation portion of the study will be 120 mg daily (QD), and the starting dose of trametinib will 
be 2 mg QD.  
Further doses will be explored during the dose escalation, and the RP2D for repotrectinib given 
in combination with trametinib will be chosen based on the results from the Phase 1b portion of 
the study.  
 
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2. 
STUDY OBJECTIVES 
2.1. 
Phase 1b Objectives 
2.1.1. 
Primary Objectives 
• Evaluate the safety and tolerability of repotrectinib at increasing dose levels in 
combination with trametinib for the treatment of subjects with locally advanced or 
metastatic KRAS-mutant solid tumors. 
• Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose 
(RP2D) of repotrectinib in combination with trametinib for the treatment of subjects 
with locally advanced or metastatic KRAS-mutant solid tumors. 
2.1.2. 
Secondary Objectives 
• Characterize the pharmacokinetic (PK) profile of repotrectinib in combination with 
trametinib. 
• Describe the preliminary efficacy of repotrectinib in combination with trametinib. 
2.2. 
Phase 2 Objectives  
2.2.1. 
Primary Objective 
• Evaluate the efficacy of repotrectinib in combination with trametinib for the treatment 
of subjects with locally advanced or metastatic KRAS-mutant solid tumors as 
measured by objective response rate (ORR). 
2.2.2. 
Secondary Objective 
• Evaluate the efficacy of repotrectinib in combination with trametinib for the treatment 
of subjects with locally advanced or metastatic KRAS-mutant solid tumors as 
measured by clinical benefit rate (CBR), progression-free survival (PFS), duration of 
response (DOR), time to response (TTR), and overall survival (OS). 
• Evaluate the safety and tolerability of repotrectinib in combination with trametinib. 
• Characterize the PK profile of repotrectinib in combination with trametinib. 
2.3. 
Exploratory Objectives (All Phases) 
• Evaluate biomarkers potentially predictive of response in subjects treated with 
repotrectinib in combination with trametinib.  
• Explore the potential prognostic utility of genomic alterations and characterize 
intrinsic or acquired resistance in subjects treated with repotrectinib in combination 
with trametinib using tissue-based or liquid-based biopsy samples. 
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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This subprotocol is a Phase 1b/2 multi-center, open-label study to evaluate the efficacy, safety, 
tolerability, and PK of repotrectinib in combination with trametinib, for the treatment of subjects 
with locally advanced or metastatic KRASG12D-mutant solid tumors. The study will consist of two 
portions: Phase 1b Dose Escalation and Phase 2 Expansion (Figure 9). 
Figure 9: 
Subprotocol 1 Study Design 
 
Abbreviations: KRAS = Kirsten rat sarcoma viral oncogene homolog; MEK = mitogen-activated extracellular 
signal-regulated kinase; NSCLC = non-small cell lung cancer; RP2D = recommended Phase 2 dose. 
3.2. 
Phase 1b Dose Escalation Study Design 
The Phase 1b dose escalation portion of the study will follow a traditional 3+3 design, where 
three to six DLT-evaluable subjects with locally advanced or metastatic KRASG12D -mutant solid 
tumors will be enrolled at each dose level to determine the MTD/RP2D of repotrectinib in 
combination with trametinib through assessment of DLTs. 
Initially, approximately 24 – 30 subjects with locally advanced or metastatic solid tumor 
malignancies harboring a KRASG12D mutation will be enrolled into the Phase 1b dose escalation 
portion. Three to six DLT-evaluable subjects at each dose level will be administered daily (QD) 
doses of repotrectinib in combination with trametinib according to Table 2 (starting with Dose 
Level 1) and evaluated for DLTs during Cycle 1 (i.e., for 28 days). After the first 3 subjects have 
completed their first cycle of study treatment (Cycle 1), a safety evaluation will be conducted by 
a Safety Review Committee to determine if enrollment of subjects in the next dose level (Dose 
Level 2) may begin. If no subjects experience a DLT within the first 28 days of Dose Level 1 
treatment, then dose escalation may proceed to the next dose level, according to Table 2. If 1 of 
the 3 initial subjects at Dose Level 1 experiences a DLT, then the next 3 subjects will be enrolled 
prior to escalating to the next dose level. Enrollment into all subsequent dose levels will follow 
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the same procedure. If ≥ 33% of subjects at any dose level experience a DLT within the first 28 
days of treatment, the dose levels will be de-escalated to Dose Level -2 or -3 according to SRC 
recommendation and following approval by the Sponsor, as detailed in Table 2. If Dose Level -2 
is tolerable, testing of alternate escalating dose levels (-2a, -2b) may occur as outlined in Table 2. 
If Dose Level -2 is not tolerable, subjects will be de-escalated to Dose Level -3. If Dose Level -3 
is tolerable, testing of alternate escalating dose levels (-3a, -3b) may occur as outlined in Table 2. 
Alternative regimens or additional dose levels or dose level increments may be explored based 
on emergent clinical safety, efficacy, and PK data. See Section 3.2.1.1 for criteria for 
determining DLTs. The decision to escalate to the next dose level will be based on the incidence 
of DLTs and the totality of clinical data including overall PK, safety, and preliminary efficacy 
observed within each dose level.  
Table 2: 
Dose-finding Dose Levels  
Dose Level 
Repotrectinib 
Trametinib 
 3 
160 mg QD/BIDa 
2 mg QD 
 2 
160 mg QD 
2 mg QD 
1 (Starting Dose) 
120 mg QD 
2 mg QD 
(-2b) 
160 mg QD/BIDa 
1.0 mg QD 
(-2a) 
160 mg QD 
1.0 mg QD 
-2 
120 mg QD 
1.0 mg QD 
(-3b) 
160 mg QD/BIDa 
0.5 mg QD 
(-3a) 
160 mg QD 
0.5 mg QD 
-3 
120 mg QD 
0.5 mg QD 
Abbreviations: BID = twice daily; QD = once daily. 
a 160 mg QD (once daily) for the first 14 days, after which the dose may be increased to 160 mg BID based on 
subject safety and tolerability and assuming specific criteria are met. Subjects must meet the following criteria 
while on 160 mg QD prior to dose increase to 160 mg BID: no evidence of grade ≥ 3 TRAE, unmanageable grade 
≥ 2 dizziness, ataxia or paresthesia; or grade ≥ 3 clinically significant lab abnormalities. 
A Safety Review Committee, including study Investigators and the Sponsor Medical Monitor, 
will provide recommendations for dose escalation, confirmation of DLTs, dose de-escalation, 
and determination of the RP2D (Section 3.2.1.3). At least 6 subjects will be treated at the RP2D 
prior to proceeding into the Phase 2 portion of the study. Additional subjects may be added at a 
dose level to gather more safety, PK, and efficacy data (Section 3.2.1.3).  
To fully characterize the safety of the combination of repotrectinib and trametinib, subjects who 
are discontinued from treatment before completing the DLT evaluation period (28 days, Cycle 1) 
due to disease progression or other event unrelated to repotrectinib or trametinib, or who did not 
adequately complete the PK evaluations within Cycle 1, may be replaced.  
Tumor assessments will include all known or suspected disease sites. All radiographic efficacy 
endpoints will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Intracranial responses will be assessed by modified RECIST v1.1. For all tumor assessments, the 
imaging modality used at baseline should be the same modality used throughout the study.  
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Safety will be monitored via laboratory assessments, physical examinations, ECGs, vital signs, 
and TEAEs according to CTCAE v5.0. PK data will also be collected. 
An end of treatment (EOT) visit will be conducted within 7 days of the last dose of both study 
drugs. A safety follow-up visit will be conducted within 28 days of last dose of both study drugs. 
Additionally, to assess overall survival status, each subject will be contacted via phone call (or 
medical chart review), including information about subsequent anticancer therapies (including 
best response), every three months after discontinuation of study drugs until death, loss to 
follow-up, or withdrawal of consent, whichever occurs first. 
3.2.1.1. 
Dose-Limiting Toxicities 
Subjects are eligible for DLT evaluation if they experience a DLT during the first cycle of 
treatment (i.e., 28 days) or do not experience a DLT during the first cycle of treatment while able 
to receive at least 75% of planned doses during the first cycle of treatment. Subjects who do not 
fulfill these requirements will be replaced for DLT evaluation but will remain in the overall 
safety and efficacy analyses. 
A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease 
progression, intercurrent illness, or concomitant medications that meets any of the criteria in 
Table 3. 
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Table 3: 
CTCAE Dose-Limiting Toxicities  
Categorya 
Criteria 
Toxicities resulting in an 
excessive number of 
missed doses 
• 
Inability to deliver at least 75% of the planned doses of repotrectinib and 
trametinib during Cycle 1 treatment because of toxicity attributed to study drug 
(excluding toxicities clearly related to disease progression or intercurrent illness) 
Hematologic toxicities  
• 
Grade ≥ 4 neutropenia (ANC < 500/ mm3) lasting > 7 days 
• 
Grade ≥ 4 platelet count decrease (platelets < 25,000/mm3) or Grade ≥ 2 (< 
75,000/mm3) associated with clinically significant bleeding 
• 
Grade ≥ 4 anemia  
• 
Grade ≥ 3 febrile neutropenia (defined as ANC < 1,000/mm3 with a single 
temperature of ≥ 38.3°C [≥ 101°F] or a sustained temperature of ≥ 38°C 
[≥ 100.4°F] for > 1 hour) 
Renal 
• 
Grade ≥ 3 creatinine increase (> 3 × upper limit of normal [ULN]) 
Hepatic 
• 
Grade ≥ 3 total bilirubin elevation (> 3 × ULN) 
• 
Grade ≥ 2 total bilirubin elevation (> 1.5 × ULN) and grade ≥ 2 ALT or AST 
elevation (> 3 × ULN)  
• 
Grade 3 ALT elevation (> 5 × ULN) that does not resolve to grade ≤ 1 within 7 
days or any grade ≥ 4 ALT elevation 
• 
Grade 3 AST elevation (> 5 × ULN) that does not resolve to grade ≤ 1 within 7 
days or any grade ≥ 4 AST elevation 
• 
Grade 4 elevations in ALP 
Pancreatic 
• 
Grade ≥ 3 amylase or lipase elevation 
Cardiac 
• 
Grade ≥ 3 
Other AEs  
• 
Grade 3 electrolyte disturbances that require hospitalization 
• 
Grade 4 electrolytes abnormalities 
• 
Grade ≥ 3 AE, persisting after optimal treatment with standard medical therapy 
except for the exceptions noted below under “Exceptions to DLT criteria” 
• 
In view of the Investigators and Sponsor, any other unacceptable toxicity 
encountered 
Exceptions to DLT criteria 
• 
Grade 3 elevations in ALP  
• 
Grade 3 electrolytes abnormalities that are adequately managed by IV or PO 
supplementation as evidenced by an improvement to grade ≤ 1 within 3 days 
• 
Grade 3 fatigue which resolves to grade ≤ 1 in ≤ 7 days 
• 
Isolated grade 3 laboratory abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
• 
Grade 3 dizziness which resolves to grade ≤ 1 within ≤ 7 days 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil 
count; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events, v5.0; DLT = dose-
limiting toxicity; IV = intravenous; PO = per os (by mouth); ULN = upper limit of normal. 
 Toxicities clearly related to disease progression or intercurrent illness will not be considered DLTs. 
In addition, clinically important or persistent toxicities not included in the above criteria may be 
considered a DLT following review by the Sponsor and study Investigators. All DLTs should 
represent a clinically significant shift from baseline. These will be evaluated according to 
National Cancer Institute CTCAE v5.0. 
To fully characterize the safety of repotrectinib in combination with trametinib, subjects who are 
discontinued from treatment before completing the DLT evaluation period (28 days, Cycle 1) 
due to disease progression or other event unrelated to study drugs, or who did not adequately 
complete the PK evaluations within Cycle 1, may be replaced.  
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Dose re-escalation for subjects with DLTs is not allowed in the Phase 1b portion of the 
study. Subjects experiencing a DLT may resume dosing at the next lower dose level (if 
applicable) once adequate recovery is achieved. 
3.2.1.2. 
Determination of MTD 
The MTD is defined as the highest dose level of repotrectinib given in combination with 
trametinib observed to cause a DLT in fewer than 33% of the treated subjects in the first 
treatment cycle (i.e., 28 days, Cycle 1).  
3.2.1.3. 
Recommended Phase 2 Dose (RP2D) Definition 
The RP2D is the dose chosen for further study in Phase 2 based on the Phase 1b results. RP2D 
dose selection will be based on the entirety of the safety, efficacy, and clinical pharmacology 
data using an integrated quantitative approach. The RP2D may be the MTD unless one or more 
of the following suggest an alternate dose below the MTD would be preferable:  
a. clinically significant anti-tumor effect (complete response [CR], partial response 
[PR], or prolonged stable disease [SD]) occurs below the MTD, in which case a 
clinically active dose level may be selected as the RP2D;  
b. the MTD is not achieved, in which case the highest dose level administered may 
become the RP2D; or  
c. toxicities observed beyond the DLT evaluation period (Cycle 1) require selecting the 
RP2D below the MTD level. 
Once the MTD of repotrectinib in combination with trametinib has been determined, the RP2D 
will be determined at or below the MTD. At least 6 subjects will be treated at the RP2D prior to 
proceeding into the Phase 2 portion of the study. Additional subjects may be added at a dose 
level to gather more safety, PK, and efficacy data. 
3.2.1.4. 
Follow-Up After a Dose-Limiting Toxicity 
When treatment is interrupted due to a DLT, the subject must be followed at least once a week 
for 4 weeks, and subsequently at a maximum interval of 4 weeks, until resolution or stabilization 
of the event, whichever comes first. 
3.2.1.5. 
Safety Review Committee 
For the Phase 1b portion of the study, a Safety Review Committee comprised of at minimum the 
Sponsor Medical Monitor and study Investigators will review all relevant safety and other 
relevant clinical data and will provide recommendations on the following:  
• Confirmation of DLTs  
• Dose escalation decisions within the dose escalation portion 
• Selection of RP2D 
3.3. 
Phase 2 Expansion Study Design 
Once the MTD/RP2D of repotrectinib in combination with trametinib has been determined, 
approximately 50 subjects will be enrolled into the Phase 2 expansion portion. The Phase 2 
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portion is designed to explore the anti-tumor efficacy and safety of repotrectinib in combination 
with trametinib for the treatment of patients with locally advanced or metastatic NSCLC 
harboring a KRASG12D mutation. 
An interim futility analysis of the ORR will be performed after approximately 15 subjects are 
evaluable for tumor response. If ≤ 2 responders (confirmed CR or PR) are observed from 15 
evaluable subjects, the expansion cohort will be stopped for futility. If ≥ 3 responders are 
observed, this cohort may continue depending on the overall benefit and risk assessment at the 
interim analysis. 
Tumor assessments will include all known or suspected disease sites. All radiographic efficacy 
endpoints will be assessed using RECIST v1.1. Intracranial responses will be assessed by 
modified RECIST v1.1. For all tumor assessments, the imaging modality used at baseline should 
be the same modality used throughout the study.  
Safety will be monitored via laboratory assessments, physical examinations, electrocardiograms 
(ECG), vital signs, and TEAEs according to CTCAE v5.0. PK data will also be collected. In 
addition, safety will be monitored by a Safety Review Committee comprised of at minimum the 
Sponsor Medical Monitor and study Investigators to review all relevant safety and other relevant 
clinical data. The following study stopping rules will apply for the Phase 2 portion of the study: 
• Any death (other than disease progression) that is at least possibly related to the study 
agent. 
• Occurrence of two or more Grade 4 events that are at least possibly related to the study 
agent. 
3.4. 
Study Duration 
Subjects will remain on study treatment until confirmed radiographic disease progression, 
development of unacceptable toxicity, or withdrawal of consent. There is no limit to the number 
of cycles of treatment with repotrectinib or trametinib. 
For subjects discontinuing the study treatment due to documented radiographic progression, 
obtain survival status via phone call or medical chart review, including information about 
subsequent anticancer therapies (including best response) every 3 months until death, loss of 
follow-up, or withdrawal of consent, whichever comes first. For subjects discontinuing the study 
treatment prior to documented radiographic progression, tumor assessments should continue on 
the schedule approximately every 2 months or at the current scan interval at the time of treatment 
discontinuation until radiographic evidence of disease progression, the start of a subsequent 
anticancer therapy, or decision to no longer treat (e.g., supportive care only), whichever is first. 
3.5. 
Dose Modifications 
For subjects who experience a DLT, dose adjustments are permitted if it is considered in the best 
interest of the subject to continue therapy after discussing with the Sponsor’s Medical Monitor. 
Dose modification guidelines for repotrectinib are described in the Dose Modification Guidelines 
for Adverse Events table (Table 4). Dose reductions for repotrectinib will follow the dose levels 
provided in Table 2. The guidelines provided in the label for trametinib should be referenced and 
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followed to manage toxicities associated with trametinib (i.e., see Table 2 in Mekinist® 
[trametinib] USPI 2020).  
If toxicity is clearly attributed to one drug based on the known toxicity profile then one drug may 
be modified while the other is continued at the current dose. If the toxicity cannot clearly be 
attributed to one drug, then a dose modification for both drugs will be implemented according to 
the Dose Modification Guidelines for Adverse Events table for repotrectinib (Table 4) and per 
label for trametinib (see Table 2 in Mekinist® [trametinib] USPI 2020). 
Subjects who cannot be re-treated with study drug should have weekly follow-ups that include a 
physical examination, vital signs including weight, Eastern Cooperative Oncology Group 
(ECOG) performance status (PS), ECGs, and assessment of AEs and concomitant medication. 
Following a DLT or toxicity, hematology, renal, and liver function tests (LFTs) should be 
performed as appropriate.  
If a subject requires a dose delay of > 28 days from the intended day of the next scheduled dose 
of study drugs, then the subject must be discontinued from the study. If a subject requires more 
than two dose reductions for a either agent, then the subject must be discontinued from the study.  
Subjects who discontinue from the study for a study drug-related AE or a grade 3 or higher 
abnormal laboratory value must be followed as described in Section 7.3. 
3.5.1. 
Dose Interruptions and Delays 
Dose interruptions may occur in the event of a treatment-related toxicity or a non-treatment-
related issue (e.g., elective surgery). If toxicity is clearly attributed to one drug based on the 
known toxicity profile then one drug may be interrupted while the other is continued. If the 
toxicity cannot clearly be attributed to one drug, then dose interruption for both drugs will be 
implemented.   
Appropriate follow-up assessments should be done until adequate recovery occurs as assessed by 
the Investigator. Criteria required before treatment can resume for repotrectinib are described in 
the dose modification guidelines for adverse events table (Table 4). The guidelines provided in 
Table 4 are general guidelines for dose modifications due to toxicities that may arise from 
repotrectinib. The guidelines provided in the label for trametinib should be referenced and 
followed to manage toxicities (i.e., see Table 2 in Mekinist® [trametinib] USPI 2020). 
Doses may be held as needed until toxicity resolution. Depending on when the AE is resolved, a 
treatment interruption may lead to the subject missing all subsequent planned doses within that 
same cycle or even to delay the initiation of the subsequent cycle.  
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant laboratory assessments may be increased as clinically indicated. 
If the AE that led to the treatment interruption recovers within the same cycle, then re-dosing in 
that cycle is allowed. Doses omitted for toxicity are not replaced within the same cycle. The need 
for a dose reduction at the time of treatment resumption should be based on the criteria defined 
in Table 4 unless otherwise agreed to following discussion between the Investigator and the 
Medical Monitor. 
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In the event of a treatment interruption for reasons other than treatment-related toxicity (e.g., 
elective surgery) lasting ≥ 14 days, treatment resumption must be discussed with the Medical 
Monitor. 
All study visits (visit date calculations) are based off the Cycle 1 Day 1 visit date, regardless of 
dose interruptions, and evaluations are to be performed according to the Schedule of Activities 
(Table 1). Every effort should be made to maintain the tumor assessments scheduling as 
described in the Schedule of Activities. 
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Table 4: Repotrectinib Dose Modification Guidelines for Adverse Events (CTCAE v5.0) 
Toxicity 
CTCAE Grade 1* 
CTCAE Grade 2* 
CTCAE Grade 3 
CTCAE Grade 4 
Hematologic 
Continue at same dose level. 
Continue at same dose level. 
Withhold dose until toxicity 
is grade ≤ 2, or has returned 
to baseline, then resume 
treatment at the same dose 
level or reduce by one dose 
level1,2 as per the 
Investigator’s discretion. 
Grade 3 lymphopenia 
without other dose-limiting 
events (e.g., opportunistic 
infection) may continue 
study treatment without 
interruption. 
Withhold dose until toxicity is 
grade ≤ 2, or has returned to 
baseline, reduce the dose by one 
dose level1,2 and resume 
treatment. 
Grade 4 lymphopenia without 
other dose-limiting events (e.g., 
opportunistic infection) may 
continue study treatment without 
interruption. 
Non-Hematologic 
excluding dizziness, 
ataxia, and 
paresthesia 
Continue at same dose level. 
Continue at same dose level.  
For prolonged or intolerable 
CNS toxicity, withhold dose 
until toxicity is grade ≤ 1 or has 
returned to baseline, then 
reduce by one dose level1,2 and 
resume treatment. 
Withhold dose until toxicity 
is grade ≤ 1 or has returned 
to baseline. 
Withhold dose until toxicity is 
grade ≤ 1 or has returned to 
baseline, then reduce by one dose 
level1,2 and resume treatment; or 
discontinue treatment as per the 
Investigator’s discretion. 
ILD/Pneumonitis  
(occurred in the 
absence of disease 
progression, 
pulmonary embolism, 
positive cultures or 
radiation effect) 
Asymptomatic, radiographic 
findings only: No need for 
dose adjustment. Initiate 
appropriate monitoring. 
 
Symptomatic: Withhold 
current dose until toxicity has 
returned to baseline. Rule out 
infection and consider 
initiating treatment with 
corticosteroids. Then resume 
treatment at the same dose. 
Discontinue permanently if 
pneumonitis recurs or if 
failure to recover after 28 days 
Withhold current dose until 
toxicity has returned to 
baseline. Rule out infection and 
consider initiating treatment 
with corticosteroids. Then 
resume treatment at one dose 
level lower. 
Discontinue permanently if 
pneumonitis recurs or if failure 
to recover after 28 days of 
study treatment hold and 
steroid treatment. 
Discontinue treatment 
permanently. 
Discontinue treatment 
permanently. 
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Toxicity 
CTCAE Grade 1* 
CTCAE Grade 2* 
CTCAE Grade 3 
CTCAE Grade 4 
of study treatment hold and 
steroid treatment. 
AST or ALT 
elevation 
Continue at same dose level. 
Continue at same dose level. 
Withhold current dose if 
concurrent CTCAE grade ≥ 2 
total bilirubin elevation (> 1.5 x 
ULN). 
Withhold current dose until 
resolves to Grade ≤ 1. 
Discontinue treatment 
permanently. 
Prolonged QTc 
Assess electrolytes and 
concomitant medications. 
 
Correct any electrolyte 
abnormalities, or hypoxia. 
 
Continue at the same 
dose level. 
Assess electrolytes and 
concomitant medications. 
 
Correct any electrolyte 
abnormalities, or hypoxia. 
 
Continue at the same 
dose level. 
Withhold dose 
 
Assess electrolytes and 
concomitant medications. 
 
Correct any electrolyte 
abnormalities, or hypoxia. 
 
Upon recovery to grade ≤ 1: 
if no other cause for QTc 
prolongation is found or is 
considered drug-related 
resume treatment at 1 dose 
level lower. 
Discontinue treatment. 
Dizziness, ataxia, or 
muscular weakness 
Continue at same dose level. 
Withhold current dose until 
toxicity is grade ≤ 1 or has 
returned to baseline OR reduce 
by 1 dose level immediately1,2 
 
Withhold dose until toxicity 
is grade ≤ 1 or has returned 
to baseline, then reduce by 1 
dose level1,2 and resume 
treatment 
Withhold dose until toxicity is 
grade ≤ 1 or has returned to 
baseline, then reduce by 1 dose 
level1,2 and resume treatment; or 
discontinue treatment as per the 
Investigator’s discretion after 
discussion with Medical Monitor. 
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Toxicity 
CTCAE Grade 1* 
CTCAE Grade 2* 
CTCAE Grade 3 
CTCAE Grade 4 
Weight gain 
Continue at same dose level. 
Implement effective weight 
management strategy (dietary 
advice from a nutritionist and 
food intake counseling). 
Dose interrupt or dose 
reduce1,2, if required. 
Dose interrupt or dose 
reduce1,2, if required. 
Not applicable. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; CTCAE = Common Terminology Criteria for 
Adverse Events, v5.0; ILD = interstitial lung disease; QTc = QT interval corrected for heart rate; ULN = upper limit of normal. 
*Cycle will not be extended to cover for the missing doses. In cases where no specific dose adjustments for CTCAE Grade 1 or Grade 2 treatment-related 
toxicity are provided, Investigators should always manage their subjects according to their medical judgment, which may include dose reduction or interruption 
based on the particular clinical circumstances. 
1 If subjects are assigned to the Dose Level -3 dose level, further dose reductions will not be implemented. Subjects will be discontinued if a dose reduction is 
required. 
2 Dose reductions for repotrectinib will follow the dose levels provided in Table 2. 
 
 
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4. 
SUBJECT ELIGIBILITY CRITERIA 
Each subject must meet all of the following inclusion criteria and none of the exclusion criteria 
to be enrolled in the study. 
4.1. 
Subject Inclusion Criteria 
Phase 1 AND Phase 2: 
1. Subject must have a histologically or cytologically confirmed diagnosis of unresectable 
or metastatic solid tumor malignancy harboring a KRAS mutation. 
• Documented KRASG12D mutation as determined by a quantitative polymerase chain 
reaction (qPCR) or next-generation sequencing (NGS) test performed in a Clinical 
Laboratory Improvement Amendments (CLIA) laboratory or equivalently accredited 
diagnostic laboratory. Local tissue-based or liquid biopsy diagnostic testing will be 
permitted. 
• Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic 
laboratory for retrospective confirmation by a central diagnostic laboratory test 
selected by the Sponsor. See the Study Laboratory Manual for details. 
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0–1 
3. Age ≥ 18 (or as required by local regulation).  
4. Willing and able to provide written institutional review board (IRB)/ethics committee 
(EC)-approved Informed Consent. 
5. At least 1 measurable target lesion according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1. Subjects with central nervous system (CNS)-only measurable 
target lesion ≥ 5 mm as defined by RECIST v1.1 are eligible. 
6. Required wash-out time that is related to prior therapies before starting repotrectinib 
combination treatment: 
• At least 14 days or 5 half-lives (whichever is shorter) must have elapsed after 
discontinuation of prior systemic therapy and all side effects from prior treatments 
must have resolved to grade ≤ 1 with the exception of alopecia. 
• At least 14 days must have elapsed after discontinuation of prior immunotherapy and 
all immune-related side effects from prior immunotherapy must have resolved 
to grade ≤ 1.  
7. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic 
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the following criteria: 
• Subjects requiring steroids at a stable or decreasing dose (≤ 12 mg/day 
dexamethasone or equivalent) for at least 14 days.  
• Subjects on stable doses of levetiracetam (same dose for 14 days). 
• A minimum of 14 days must have elapsed from the completion of whole brain 
radiation treatment (WBRT) before the start of treatment, and all side effects (with the 
exception of alopecia) from WBRT are resolved to grade ≤ 1. 
• A minimum of 7 days must have elapsed from the completion of stereotactic 
radiosurgery before the start of treatment and all side effects (with the exception of 
alopecia) from stereotactic radiosurgery are resolved to grade ≤ 1. 
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8. Baseline laboratory values fulfilling the following requirements: 
Absolute Neutrophils Count  
≥ 1,500/mm3 (1.5 x 109/L) 
Platelets  
≥ 100,000/mm3 (100 x 109/L) independent of platelets transfusion support 
for at least 7 days prior to dosing 
Hemoglobin 
≥ 9.0 g/dL independent of transfusion support for at least 7 days prior to 
dosing 
Creatinine Clearance*  
> 40 mL/min 
Total Serum Bilirubin  
< 1.5 x ULN (≤ 3.0 × ULN for patients with Gilbert’s Syndrome or liver 
metastases) 
Liver Transaminases (AST/ALT) 
< 2.5 x ULN; < 5 x ULN if liver metastases are present 
Alkaline Phosphatase  
< 2.5 x ULN; < 5 x ULN if liver and/or bone metastasis are present.  
Serum Calcium, Magnesium and 
Potassium  
Normal or CTCAE grade ≤ 1 with or without supplementation. 
Abbreviations: AST/ALT = aspartate aminotransferase/alanine aminotransferase, ULN = upper limit of normal. 
* calculated by Cockcroft and Gault’s formula: (140 - age [yr.]) x body weight [kg] x 1.23 x (0.85 if female) 
/serum creatinine [µmol/L].  
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
during screening and be neither breastfeeding nor intending to become pregnant during study 
participation. Female patients will be considered to be of childbearing potential unless they 
have undergone permanent sterilization or are postmenopausal. Postmenopausal is defined as 
at least 12 months without menses with no other medical reasons (e.g., chemical menopause 
due to anticancer treatment). For WOCBP and for men, agreement to use a highly effective 
contraceptive method from the time of screening throughout the study until 4 months 
(WOCBP) or 6 months (men) after administration of the last dose of any study drug. Highly 
effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), injectable or implantable contraceptives. All 
male study subjects must agree to use condoms throughout the study and 6 months after 
administration of the last dose. Male partners of WOCBP subjects must agree to condom use 
throughout the study and for 4 months following the last dose of study drug. True abstinence 
is acceptable if evaluated as consistent with the preferred and the usual lifestyle of the 
subject. Periodic abstinence is not an acceptable method of contraception. 
10. Ability to swallow capsules and tablets intact (without chewing, crushing, or opening). 
11. Life expectancy ≥ 3 months. 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
Additional Inclusion Criteria for Phase 1 Only: 
13. Subject must have received prior standard therapy appropriate for their tumor type and 
stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or 
derive clinically meaningful benefit from appropriate standard of care therapy. 
• Subject must have received no more than 3 prior systemic regimens.  
• Maintenance therapy will not be counted as a separate regimen.  
• Adjuvant chemotherapy or chemotherapy administered as part of concurrent 
chemotherapy and radiation therapy will not count as a prior regimen of systemic 
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therapy as long as recurrence occurred more than 6 months after the last day of 
chemotherapy. 
 
Additional Inclusion Criteria for Phase 2 Only: 
14. Histologically or cytologically confirmed diagnosis of advanced or metastatic NSCLC 
harboring a KRASG12D mutation. 
• Subject must have a documented KRASG12D mutation as determined by a qPCR or 
NGS test performed in a CLIA laboratory or equivalently accredited diagnostic 
laboratory. Local tissue-based or liquid biopsy diagnostic testing will be permitted. 
• Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic 
laboratory for retrospective confirmation by a central diagnostic laboratory test 
selected by the Sponsor. See the Study Laboratory Manual for details. 
15. Subjects must have received no more than one prior line of platinum-based chemotherapy 
OR one prior line of platinum-based chemotherapy in combination with immunotherapy 
OR both platinum-based chemotherapy and single agent anti-PD1/PDL1 therapy in two 
separate lines of therapy. 
• Adjuvant chemotherapy or chemotherapy administered as part of concurrent 
chemotherapy and radiation therapy for the treatment of lung cancer will not count as 
a prior regimen of systemic therapy as long as recurrence of patient's lung cancer 
occurred more than 12 months after the last day of chemotherapy.  
4.2. 
Subject Exclusion Criteria 
1. Concurrent participation in another therapeutic clinical trial. 
2. Symptomatic brain metastases or leptomeningeal involvement. 
3. History of previous cancer requiring therapy within the previous 2 years, except for 
squamous cell or basal-cell carcinoma of the skin, or any in situ carcinoma that has been 
completely resected. 
4. Major surgery within 4 weeks of start of treatment. Radiation therapy (except palliative to 
relieve bone pain) within 2 weeks of start of treatment. Palliative radiation (≤ 10 
fractions) must have been completed at least 48 hours prior to start of treatment. 
5. Clinically significant cardiovascular disease (either active or within 6 months prior to 
start of treatment): myocardial infarction, unstable angina, coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure (New York Heart Association 
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, 
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac 
dysrhythmias of CTCAE grade ≥ 2. 
6. Any of the following cardiac criteria: 
• Mean resting corrected QT interval (ECG interval measured from the onset of the 
QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained 
from 3 ECGs, using the screening clinic ECG machine-derived QTc value 
• Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block, second 
degree heart block, PR interval > 250 msec) 
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• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome, or any concomitant medication known to prolong the QT interval 
7. Known clinically significant active infections not controlled with systemic treatment 
(bacterial, fungal, viral including human immunodeficiency virus [HIV] positivity, 
hepatitis B [HBV], and hepatitis C [HCV], and acquired immunodeficiency syndrome 
[AIDS]-related illness).  
8. Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) 
or other malabsorption syndromes that would impact drug absorption. 
9. Peripheral neuropathy, paresthesia, dizziness, dysgeusia, muscle weakness, ataxia grade 
≥ 2. 
10. Currently have or had a history of ILD, radiation pneumonitis that required steroid 
treatment, or drug-related pneumonitis.  
11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug 
administration, or that may interfere with the interpretation of study results and, in the 
judgment of the Investigator and/or Turning Point Therapeutics, would make the subject 
inappropriate for entry into this study, or could compromise protocol objectives in the 
opinion of the Investigator and/or Turning Point Therapeutics. 
12. Current or anticipated use of drugs that are known to be strong CYP3A inhibitors or 
inducers as well as use of drugs that are sensitive CYP3A substrates as listed in 
Appendix 1. 
13. Prior exposure to repotrectinib. 
14. Prior exposure to a direct and specific inhibitor of KRAS. 
15. Prior exposure to trametinib or another MEK inhibitor. 
16. Subjects have a history or current evidence of retinal vein occlusion (RVO) or central 
serous retinopathy (CSR) determined by an ophthalmology exam. 
17. Current or anticipated use of drugs that are sensitive substrate with narrow therapeutic 
index for UGT1A1. 
18. Current or anticipated use of drugs that are sensitive substrate with narrow therapeutic 
index for OATP1B1, OAT3, MATE1, and MATE2-K. 
19. Current or anticipated use of drugs that are strong inhibitors of P-glycoprotein. 
 
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5. 
STUDY TREATMENT 
5.1. 
Allocation to Treatment 
All subjects will be allocated to receive repotrectinib in combination with trametinib. For the 
Phase 1b dose escalation portion of the study, subjects will be assigned according to the currently 
open dose level. For the Phase 2 portion of the study, all subjects will receive repotrectinib in 
combination with trametinib at the RP2D schedule determined in the Phase 1b portion in 28-day 
cycles. 
5.1.1. 
Repotrectinib + Trametinib 
Repotrectinib and trametinib will be administered orally as a combination treatment. For the 
Phase 1b dose escalation portion of the study, subjects will be assigned to a repotrectinib and 
trametinib dose according to the currently open dose level for 28 consecutive days in repeated 
four-week cycles. For the Phase 2 expansion portion of the study, subjects will be allocated to 
receive repotrectinib and trametinib at the RP2D combination determined during the Phase 1b 
dose-finding portion for 28 consecutive days in repeated four-week cycles.  
5.2. 
Investigational Product Supplies 
5.2.1. 
Dosage Form(s) and Packaging 
5.2.1.1. 
Repotrectinib 
Repotrectinib (TPX-0005) will be supplied for oral administration as 40 mg capsules. Study drug 
will be supplied by the Sponsor. 
The investigational repotrectinib drug product is currently supplied as size 0 hard gelatin 
capsules of 40 mg dosage strength to deliver the active pharmaceutical ingredient, repotrectinib 
(TPX-0005) and has been manufactured for use in the proposed clinical study (Table 5). 
Repotrectinib capsules are contained in round high-density polyethylene (HDPE) bottles with an 
induction seal and child resistant cap closure. The bottle does not contain a desiccant or a 
pharmaceutical coil.  
Table 5: 
Investigational Product: Repotrectinib Product and Dosage Information 
 
Investigational Product 
Product Name: 
Repotrectinib 
Dosage Form: 
Capsules 
Unit Dose: 
Capsules (40 mg) 
Route of Administration: 
Oral 
Physical Description: 
Size 0 hard gelatin capsules 
 
 
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5.2.1.2. 
Trametinib  
As per label (Mekinist® [trametinib] USPI 2020), trametinib will be supplied as commercially 
available in 0.5 mg or 2 mg tablets. Study drug will be supplied by the Sponsor. 
Trametinib 0.5 mg tablets are yellow, modified oval, biconvex, film-coated tablets with ‘GS’ 
debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 
0078-0666-15). Trametinib 2 mg tablets are pink, round, biconvex, film-coated tablets with ‘GS’ 
debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 
0078-0668-15). 
Table 6: 
Investigational Product: Trametinib Product and Dosage Information 
 
Investigational Product 
Product Name: 
Trametinib 
Dosage Form: 
Tablet 
Unit Dose: 
Tablets (0.5 mg and 2 mg) 
Route of Administration: 
Oral 
Physical Description (0.5 mg): 
Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ 
debossed on one face and ‘TFC’ on the opposing face 
Physical Description (2 mg): 
Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one 
face and ‘HMJ’ on the opposing face 
5.2.2. 
Investigational Product Storage and Accountability 
5.2.2.1. 
Repotrectinib 
Repotrectinib is currently stored at controlled ambient room temperature between 15°C to 30°C. 
Subjects should be instructed to keep their medication in its original container and stored at 15°C 
to 30°C (59°F to 86°F). Returned medication should be stored separately from medication that is 
yet to be dispensed. The repotrectinib capsule bottle must be stored as indicated. Deviations from 
the storage requirements, including any actions taken, must be documented, and reported to the 
Sponsor. 
5.2.2.2. 
Trametinib 
The trametinib bottles are stored at controlled refrigerated temperature at 2°C to 8°C (36°F to 
46°F) (Mekinist® [trametinib] USPI 2020). Trametinib is dispensed in the original bottle; do not 
remove desiccant. Protect from moisture and light. Do not place study drug in pill boxes. 
Returned medication should be stored separately from medication that is yet to be dispensed. The 
trametinib bottles must be stored as indicated. Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor. 
5.2.3. 
Destruction of Investigational Product Supplies 
At each cycle visit, and at the end of the treatment study, all unused or partially used bottles must 
be returned by subjects to the Investigator and the Sponsor will provide instructions for 
disposition of any unused repotrectinib or trametinib. If the Sponsor authorizes destruction at the 
study site, the Investigator must ensure that the materials are destroyed in compliance with 
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applicable environmental regulations, institutional policy, and any special instructions provided 
by the Sponsor. Destruction must be adequately documented. 
5.3. 
Dose Regimen and Route of Administration 
5.3.1. 
Repotrectinib + Trametinib 
Repotrectinib and trametinib will be administered orally as a combination treatment.  
For the Phase 1b dose escalation portion of the study, subjects will be assigned to a repotrectinib 
and trametinib dose level according to the currently open dose level (i.e., Dose Level 1, Dose 
Level 2, etc.) for 28 consecutive days in repeated four-week cycles.  
For the Phase 2 expansion portion of the study, subjects will be allocated to receive repotrectinib 
and trametinib at the RP2D determined during the Phase 1b dose escalation portion for 
28 consecutive days in repeated four-week cycles. 
Repotrectinib and trametinib should be taken with at least 8 oz (240 mL) of water, either 1 hour 
before or at least 2 hours after a meal. Each dose should be taken at the same time each day. If 
the study drug is given BID, then the study drug should be taken in the morning, and again in the 
evening approximately 12 hours later. 
For subjects taking repotrectinib and trametinib QD: if the subject is more than 12 hours late 
taking the study drug, the dose should be skipped, and the subject should continue taking 
repotrectinib and trametinib the next day as scheduled. 
For subjects taking repotrectinib and trametinib BID: if the subject is more than 6 hours late 
taking the study drug, the dose should be skipped, and the subject should continue with the next 
scheduled dose. 
5.4. 
Concomitant Treatments 
Any concomitant medications, blood products, as well as non-drug supportive interventions (e.g., 
paracentesis) received by subjects from the date of signed informed consent until the EOT visit 
should be recorded on the appropriate electronic Case Report Form (eCRF). The Investigator 
should be alerted if the subject is taking any agent known to affect or with the potential for drug 
interactions. 
Note on COVID-19 Vaccination: The use of vaccines is not a restriction for this study. 
Currently enrolled and potential adult clinical trial subjects are allowed to receive the COVID-19 
vaccine with no impact on their eligibility or ability to remain on study treatment. This guidance 
will also apply to pediatric and adolescent patients once vaccine approval is available for these 
populations. In addition, there is not a required wash-out period for the vaccine. The risk-benefit 
for COVID-19 vaccination while on study should be determined by the treating physician. 
Administration of the COVID-19 vaccine will be recorded in the medical history or the 
concomitant medications CRF, as applicable, as well as any adverse events related to the 
vaccine. 
5.4.1. 
Prohibited Concomitant Medications  
The concomitant use of known strong CYP3A4 inhibitors is prohibited including their 
administration at least within 2 weeks prior to the first study drug dose and throughout the study. 
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Subjects should avoid grapefruit juice or grapefruit/grapefruit-related citrus fruits (Seville 
oranges, pomelos). Coadministration of study drug in combination with strong CYP3A4 inducers 
is prohibited including their administration at least within 2 weeks prior to the first study drug 
dose and throughout the study. See Appendix 1 for a list of known CYP3A4 inhibitors and 
inducers. 
Current or anticipated use of drugs that are sensitive CYP3A4 substrates should be avoided 
including their administration at least within 2 weeks prior to the first study drug dose and 
throughout the study.  Concomitant medication suspected of being a sensitive CYP3A4 substrate 
must be approved by the Sponsor.   
 
Current or anticipated use of drugs that are sensitive substrate with narrow therapeutic index for 
UGT1A1 should be avoided, including their administration within at least 2 weeks prior to the 
first study drug dose and throughout the study. Concomitant medication suspected of being a 
sensitive UGT1A1 substrate with narrow therapeutic index must be approved by the Sponsor. 
Concomitant use of drugs that are known to be sensitive substrates with narrow therapeutic index 
for OATP1B1, OAT3, MATE1, and MATE2-K should be avoided including their administration 
at least within 2 weeks prior to the first study drug dose and throughout the study. Concomitant 
medication suspected of being a sensitive OATP1B1, OAT3, MATE1 and MATE2-K substrate 
with narrow therapeutic index must be approved by the Sponsor.  
Current or anticipated use of drugs that are strong inhibitors of P-gp should be avoided, including 
their administration within at least 2 weeks prior to the first study drug dose and throughout the 
study. Concomitant medication with suspected strong P-gp inhibitory effect must be approved by 
the Sponsor.  
If there is a question about a particular concomitant medication, discuss with the Medical 
Monitor. 
5.4.1.1. 
Other Anti-Tumor or Investigational Drugs 
Additional systemic anti-tumor therapy is not permitted while subjects are receiving study 
therapy. 
5.4.2. 
Anti-Diarrheal, Anti-Emetic Therapy  
Primary prophylaxis of diarrhea, nausea, and vomiting is not permitted in the first cycle in the 
Phase 1b portion of the study. Primary prophylaxis in subsequent cycles is at the Investigator’s 
discretion. The choice of the prophylactic drug as well as the duration of treatment is up to the 
Investigator with Sponsor approval assuming there is no known or expected drug-drug 
interaction and assuming the drug is not included in the Prohibited Concomitant Medications 
section. 
5.4.3. 
Anti-Inflammatory Therapy 
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no known 
or expected drug-drug interaction and assuming the drug is not included in the Concomitant 
Treatments section. 
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5.4.4. 
Corticosteroids 
Chronic systemic corticosteroid use (prednisone ≥ 12.5 mg/day or dexamethasone ≥ 2 mg/day) 
for palliative or supportive purpose is not permitted (unless administered for adrenal 
insufficiency). Acute emergency administration, topical application, inhaled sprays, eyedrops or 
local injections are permitted. 
6. 
STUDY ASSESSMENTS  
6.1. 
Informed Consent 
Prior to conducting any protocol-specific procedures for Phase 1b and Phase 2, written informed 
consent and any other authorizations must be signed and dated by the subject or subject’s legal 
representative (Section 12.4).  
6.2. 
Tumor Molecular Alteration  
Perform molecular testing as per Section 4.1 and the Schedule of Activities (Table 1). 
Molecular testing to determine eligibility can be performed in advance with no time limit (e.g., 
the subject can be tested while being treated on another anticancer therapy). 
Source documents (molecular pathology report detailing the specific test that confirms KRAS 
mutational status) should be submitted for the Sponsor’s approval of eligibility. 
Adequate archival tissue should be available for shipment to the Sponsor’s designated central 
laboratory. A fresh biopsy is required if no adequate previously taken and stored tumor sample is 
not available. 
6.3. 
Tumor Treatment History 
All prior therapies, including duration and best response of targeted therapies, prior 
chemotherapy, and/or immunotherapy regimens and will be recorded in the applicable eCRF. If 
brain metastases are present, prior radiation and methods of radiation (e.g., whole brain radiation, 
stereotactic radiosurgery) should also be recorded. 
6.4. 
Demographics 
Demographic information (e.g., date or year of birth and race) will be recorded at Screening, as 
allowed per local country privacy law regulations. 
6.5. 
Medical History 
Relevant medical history, including history of current disease, other pertinent clinical conditions, 
and information regarding underlying disease will be recorded at Screening. 
6.6. 
Physical Examination 
A complete physical examination, including neurological examination will be performed by 
either the Investigator or a sub-Investigator according to the Schedule of Activities (Table 1). 
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The neurological examination will include assessments of the following symptoms: dizziness, 
dysgeusia, paresthesia, ataxia, headache, neuralgia, extrapyramidal disorder, memory 
impairment, concentration impairment, somnolence, and cognitive disturbance. 
Height and weight will be collected as part of the physical exam. Height will be collected at 
Screening only.  
Clinically significant abnormal findings must be recorded in the applicable eCRF and followed 
by the Investigator, sub-Investigator, or other qualified site staff at the next scheduled visit or 
earlier as clinically indicated. 
6.7. 
Ophthalmologic Examination 
All subjects must undergo a baseline, standard ophthalmologic exam at Screening. The exam 
will include direct and indirect fundoscopic exams, visual acuity (corrected), visual field 
examination, and tonometry, with special attention to any retinal abnormalities that are 
predisposing factors for RVO or CSR. After Screening, additional ophthalmologic exams will be 
performed only as symptomatically warranted. 
6.8. 
Performance Status 
The ECOG performance status will be assessed at Screening and according to the Schedule of 
Activities (Table 1). 
6.9. 
Vital Signs 
Body temperature, blood pressure, heart rate, and respiratory rate will be performed at timepoints 
outlined in the Schedule of Activities (Table 1).  
6.10. 
Subject Diary and Compliance 
All doses of study drugs (i.e., repotrectinib and trametinib) and dosing diaries will be dispensed 
by the appropriately designated study staff at the investigational site. 
Subjects will be required to bring the dosing diary and all empty and partially used study drug 
bottles and any leftover study drug to every visit. The number of capsules and/or tablets returned 
by the subject will be counted, documented, and recorded. Treatment compliance will be 
evaluated by noting the discrepancy among the assigned dose, the dose administered, and the 
reason for the discrepancy will be recorded in the source documents. 
6.11. 
Laboratory Assessments 
Laboratory assessments as described in Table 7 below will be performed per the Schedule of 
Activities (Table 1). 
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Table 7: 
Safety Laboratory Tests 
Hematology 
Complete blood count with differential: hemoglobin, platelets, WBC, absolute neutrophils, 
absolute lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils 
Chemistry 
ALT, AST, ALP, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, 
BUN or urea, creatinine, uric acid, glucose (nonfasted), lipid panel (total cholesterol, LDL, 
HDL, triglycerides), albumin, phosphorus or phosphate, bicarbonate, total protein, lactate 
dehydrogenase, amylase, lipase 
Coagulation 
PT or INR, PTT 
Urinalysis 
Urine dipstick for urine protein: If positive and clinically significant, microscopic (Reflex 
Testing) 
Urinalysis includes the analysis of protein, glucose, ketones, blood, and specific gravity. A 
microscopic (white blood cells/high-power field [HPF], red blood cells/HPF, and any 
additional findings) exam need be performed only if the urinalysis result is abnormal. 
Pregnancy Test 
Serum pregnancy test for female subjects of childbearing potential (Section 6.12) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; HDL = high-density lipoprotein; INR = International normalized ratio; LDL = low-density lipoprotein; 
PT = prothrombin time; PTT = partial thromboplastin time; WBC = white blood cell. 
Note: For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, alkaline phosphatase, total 
bile acids and acetaminophen drug and/or protein adduct levels.  
6.12. 
Pregnancy Test 
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at least 
25 mIU/mL, will be performed as per the Schedule of Activities (Table 1). Only subjects with 
negative serum pregnancy test results can enroll in the study. 
Following a negative pregnancy test result at Screening, appropriate contraception must be 
commenced, and another negative pregnancy test result will then be required at the baseline visit 
before a subject may receive study drug. Additional pregnancy tests may also be undertaken if 
requested by Institutional Review Boards/Ethics Committees or if required by local regulations. 
In case of a confirmed pregnancy, the subject will be withdrawn from study drug but may remain 
in the study.  
6.13. 
Cardiac Safety Monitoring 
6.13.1. 
Electrocardiogram 
Triplicate 12-lead (with a 10-second rhythm strip) tracings will be used for all ECGs. It is 
preferable that the machine used has a capacity to calculate the standard intervals automatically. 
At each timepoint, 3 consecutive ECGs will be performed at approximately 2 minutes apart to 
determine the mean QTc interval. See the Schedule of Activities (Table 1). 
When coinciding with blood sample draws for PK, the ECG assessment should be performed 
prior to blood sample collection such that the blood sample is collected at the nominal time.  
If the mean QTc is prolonged (> 500 msec [i.e., CTCAE Grade 3]), then the ECGs should be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate. If manual reading verifies a QTc of 
> 500 msec, immediate correction for reversible causes (including electrolyte abnormalities, 
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hypoxia, and concomitant medications with the potential to prolong the QTc interval) should be 
performed. Study drug will be held until the QTc interval decreases to ≤ 500 msec. Subjects will 
then re-start the study drug if no other cause for QTc prolongation is found or is considered drug-
related resume treatment at 1 dose level lower (Table 4). If the QTc interval has still not 
decreased to < 500 msec after 2 weeks, or if at any time a subject has a QTc interval > 515 msec 
or becomes symptomatic, the subject will be removed from the study. Additional triplicate ECGs 
may be performed as clinically indicated. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (e.g., change in subject 
clinical condition, effect of concurrent medication, electrolyte disturbance) including possible 
evaluation by a specialist. If subject experiences a cardiac or neurologic AE (specifically 
syncope, dizziness, seizures, or stroke), an ECG (triplicate) should be obtained at the time of the 
event. 
Additional ECG timepoints may be included based on the emerging data. Interpretation of the 
tracing will be made by a central ECG laboratory. Each ECG tracing should be labeled with the 
study number, subject initials, subject number, and date, and kept in the source documents at the 
study site. Only clinically significant abnormalities will be recorded in the AE CRF page. 
Clinically significant abnormalities at Screening/baseline should be recorded on the relevant 
medical history/current medical conditions CRF page and must be discussed with the Sponsor’s 
Medical Monitor before enrolling the subject in the study.  
6.13.2. 
Echocardiogram/MUGA Scan 
To monitor potential left ventricular ejection fraction dysfunction, an echocardiogram or 
multigated acquisition (MUGA) scan will be performed at timepoints specified in the Schedule 
of Activities (Table 1). The same method of evaluation should be utilized throughout the study. 
6.14. 
Pharmacokinetics 
For the determination of study drug (i.e., repotrectinib and trametinib) plasma concentrations, 
5 mL of blood will be collected for each PK sample. Plasma PK samples will be analyzed using 
a validated bioanalytical method at a Good Laboratory Practice (GLP) compliant bioanalytical 
laboratory designated by the Sponsor.  
Blood samples for PK assessments during the Phase 1b and Phase 2 potions of the study will be 
collected as specified in the Schedule of Activities (Table 1).  
Additional PK samples may be collected from subjects when experiencing unexpected and/or 
serious AEs and the date/time should be documented in the CRFs. In addition, the PK sampling 
scheme may be modified by the Sponsor pending emerging PK data.  
All reasonable efforts will be made to obtain the PK samples at the exact nominal time relative to 
dosing. However, samples obtained within 10% of the nominal time (e.g., within 6 minutes of 
the 60-minute sample) from dosing will not be considered as a protocol deviation, and the exact 
time of the sample collection noted on the source document and data collection tool (e.g., CRF).  
For the PK samples collected, after sample analysis, the remaining samples may be used for the 
purposes of exploratory metabolite scouting and potential exploratory protein biomarker testing. 
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Details regarding the collection, processing, storage, and shipping of the PK samples will be 
provided in the Study Manual. 
6.15. 
Pharmacodynamics/Biomarkers 
In all subjects, blood samples for circulating cell-free DNA (ccfDNA) will be collected at 
Screening, Cycle 3 Day 1 (in conjunction with tumor assessment evaluation), and either at the 
time of radiographic disease progression or at the EOT (whichever occurs earlier) as specified in 
the Schedule of Activities (Table 1).  
Circulating cell-free DNA (ccfDNA) will be isolated from blood to study changes of circulating 
tumor levels (i.e., assessed by modulations of minor allele frequency [MAF] of genomic 
alterations), and explore resistance mechanisms as well as clonal evolution.  
Blood will be collected across two 10 mL Streck Cell-Free DNA Blood Collection Tubes (for 
ccfDNA analysis). Circulating cell-free DNA (ccfDNA) will be isolated from blood.  
Details for handling of these specimens including processing, storage, and shipment will be 
provided in the Laboratory Manual. 
6.16. 
Tumor Assessments 
Imaging studies will include a computerized tomography (CT) or magnetic resonance imaging 
(MRI) scan of the brain, chest, abdomen, pelvis. For subjects diagnosed with primary brain 
tumors, only the MRI of the brain will be required at Screening and during the study. 
Tumor assessments will include all known or suspected disease sites and will be performed per 
specified timepoints according to the Schedule of Activities (Table 1). For all tumor assessments, 
the method of assessment that was used at Screening should be the same method used throughout 
the study. Tumor assessment will be assessed locally by Investigator and by BICR. 
For all subjects, radiographic confirmation of objective tumor response or disease progression 
will be based on RECIST v1.1 and assessed locally by Investigator (Section 6.16.4). 
At the EOT visit, the subject must undergo an EOT tumor assessment evaluation CT or MRI (if 
more than 4 weeks have passed since the last imaging assessment) to evaluate for radiologic 
disease progression if treatment is being discontinued for an alternate reason other than 
confirmed radiographic disease progression.  
For subjects demonstrating radiographic response (PR or CR) during treatment, subject 
responses will be confirmed ≥ 4 weeks later (ideally, the confirmation scan should be scheduled 
at end of the next cycle, i.e., 28 days) after the initial documentation of response by the 
Investigator.  
For subjects discontinuing study treatment before documented radiographic progression, tumor 
assessments should continue at the current scan interval at the time of treatment discontinuation 
until radiographic evidence of disease progression, the start of a subsequent anticancer therapy, 
withdrawal of consent, or decision to no longer treat (e.g., supportive care only), whichever is 
first. 
For subjects discontinuing the study treatment due to documented radiographic progression, 
survival status will be obtained via a phone call or medical chart review, including information 
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about subsequent anticancer therapies (including best response) every three months until death, 
loss of follow-up, or withdrawal of consent, whichever comes first. 
6.16.1. 
CT/MRI of Chest/Abdomen/Pelvis 
Intravenous (IV) contrast is required when not medically contraindicated. Subjects who have a 
contraindication to IV contrast may have MRI exams of the abdomen, and pelvis performed in 
lieu of CTs and a non-contrast CT of the chest. Positron emission tomography (PET)/CT may be 
used to document baseline and new disease, but the CT portion of a PET/CT may not be used in 
lieu of a diagnostic CT, unless it is performed with IV contrast. Additional requirements are 
provided in the Imaging Manual. 
Every effort should be made to maintain the assessment scheduling relative to Cycle 1 Day 1, 
regardless of any dosing interruptions. 
6.16.2. 
Brain CT or MRI 
At Screening, a CT/MRI of the brain should be obtained to rule out newly diagnosed, untreated 
brain metastases or to document stability of previously treated brain metastases.  
CT/MRI brain scans should be performed at every on-study tumor assessment for subjects with 
brain metastases. 
6.16.3. 
Bone Scan 
At Screening, a bone scan should be obtained if bone metastases are suspected.  For subjects 
with bone metastases at baseline, a bone scan should only be repeated to check for residual 
disease when assessing for complete response unless the bone scan is used to determine RECIST 
v1.1 response assessment. The bone scan should be performed at the same time as the chest, 
abdomen and pelvis CT (C/A/P) scans.  If a bone scan has been performed within 28 days prior 
to Cycle 1 Day 1 the scan can be used for Screening. Radiographic confirmation of objective 
tumor response or disease progression will be based on RECIST v1.1. The same imaging 
modality should be used at Screening and on study. 
6.16.4. 
Blinded Independent Central Review (BICR) 
All scans will be submitted to a third-party central imaging laboratory for independent review of 
tumor response and disease progression during the study according to an Imaging Review 
Charter to be prepared by the core imaging laboratory in consultation with Turning Point 
Therapeutics Medical Monitor. 
It is important to the integrity of the study that all imaging studies are forwarded to the central 
imaging laboratory in a timely manner throughout the study, within 1 week of collection 
whenever possible. Further details can be found in the Imaging Manual. 
6.17. 
Other Clinical Assessments 
All AEs, whether reported by the subject or noted by study personnel, will be recorded in the 
subject’s medical record and on the Adverse Event CRF at each subject contact. After the 
informed consent for the clinical trial has been obtained but prior to initiation of study drug, only 
SAEs related to protocol-mandated assessments should be reported. After initiation of study 
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drug, all AEs, regardless of relationship to study drug, will be reported until at least 28 days after 
the last dose of study treatment. AEs will be graded according to CTCAE version 5.0. The type, 
incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities will 
be reported. Refer to Section 8 for a description of procedures for AE assessments. 
Refer to Section 5.4 for information regarding concomitant treatments and Section 7.7 (Long-
Term Follow-up) for survival follow-up procedures. 
7. 
STUDY CONDUCT 
Scheduled protocol-related activities will be performed at specified timepoints and within 
windows as outlined in the Schedule of Activities (Table 1). If a visit is missed for any reason, 
the next scheduled visit should occur as originally planned. 
7.1. 
Screening and Eligibility 
All subjects being considered for screening must provide informed consent prior to completing 
any study-specific procedures. A subject number will be assigned. After signing informed 
consent, subjects will be screened to confirm eligibility.  
The following items must be completed as part of the screening procedures: 
• An eligibility checklist must be completed for each subject and sent to the Sponsor 
for eligibility confirmation before enrollment  
• Source documents of molecular pathology report, detailing the specific test that 
confirms KRAS mutational status, should be submitted for the Sponsor’s approval of 
eligibility (refer to Section 6.2 for additional information) 
• Imaging studies (CT or MRI of the chest, abdomen, and pelvis and MRI of the brain) 
should be submitted for BICR assessment 
7.2. 
Timing of Clinical Procedures 
On visits that require in-clinic dosing, clinical assessments should be conducted as described in 
Section 7.2.1.  
7.2.1. 
Pre-Dose Assessments 
• Record any AEs  
• Review and record concomitant medications and non-drug supportive interventions 
taken since the time of Informed Consent Form (ICF) signing  
• Assess study drug compliance  
• Perform a complete physical examination and record vital signs and body weight  
• Perform ECOG performance status  
• Collect blood for clinical laboratory assessments, (hematology, chemistry, and 
coagulation profile) 
• Collect blood for ccfDNA 
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• For WOCBP, collect blood for pregnancy test 
• Collect urine for urine analysis  
• Perform and record pre-dose triplicate 12-lead ECGs approximately 2 minutes apart 
• Collect pre-dose PK sample  
7.3. 
Subject Discontinuation and Withdrawal from Study 
A subject may be discontinued from study treatment at any time if the subject, the Investigator, 
or the Sponsor Medical Monitor determine that it is not in the subject's best interest to continue 
on study. The following is a list of possible reasons for early discontinuation of study treatment: 
• Disease progression (unless there is reasonable evidence of clinical benefit to justify 
continuation on treatment - which must be previously discussed with the Sponsor) 
− Subjects should remain on study treatment until there is confirmed radiographic 
progression 
− Subject may be allowed to continue repotrectinib or trametinib beyond RECIST-
defined progression if, in the clinical judgment of the Investigator, the subject 
continues to derive clinical benefit from the study drug(s) (with approval from 
Turning Point Therapeutics; see Section 7.4) 
• Any adverse event (AE) that cannot be adequately managed with dose modifications, 
including dose interruption > 28 days (unless there is reasonable evidence of clinical 
benefit to justify continuation on the protocol–which must be previously discussed 
with Turning Point Therapeutics) (Section 3.5) 
• Protocol violation requiring discontinuation of study treatment 
• Subject is not compliant with study procedures 
• Lost to follow-up 
• Subject withdrawal of consent for further treatment 
• Turning Point Therapeutics' early termination of study. Reasons for terminating the 
study may include, but are not limited to, the following: 
− All enrolled subjects have discontinued study treatment 
− The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to subjects 
− Subject enrollment is unsatisfactory 
Data to be collected for the EOT visit are described in the Schedule of Activities (Table 1). 
Subjects will be followed for at least 28 calendar days after the last dose of study drug (i.e., 
repotrectinib and trametinib). If a subject is discontinued from treatment due to an AE, the 
subject will be followed until the AE has resolved or stabilized as per Section 8.4. 
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7.4. 
Study Treatment Discontinuation 
For subjects discontinuing the study treatment prior to documented radiographic progression, 
tumor assessments should continue on the schedule approximately every 2 months or at the 
current scan interval at the time of treatment discontinuation until radiographic evidence of 
disease progression, the start of a subsequent anticancer therapy, or decision to no longer treat 
(e.g., supportive care only), whichever is first. At this time, subjects should transition into 
long-term follow-up (see Section 7.7). 
7.5. 
Withdrawal of Consent 
A subject may withdraw consent for any further contact with him or her or persons previously 
authorized by the subject to provide this information. Subjects should notify the Investigator in 
writing of the decision to withdraw consent from future follow-up, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the Investigator, as 
to whether the withdrawal is only from further receipt of the investigational product or also from 
study procedures and/or post-treatment study follow-up and entered on the appropriate CRF 
page. If vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law. 
7.6. 
Lost to Follow-Up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of 2 documented phone 
calls, faxes, or emails as well as lack of response by the subject to 1 registered mail letter. All 
attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death. If the Investigator’s use of a third-party representative to assist in the follow-up part of the 
study has been included in the subject’s informed consent, then the Investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining the subject’s contact 
information or other public vital status data necessary to complete the follow-up part of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, to obtain updated contact information. If, after all attempts, the 
subject remains lost to follow up, then the last known alive date as determined by the 
Investigator should be reported and documented in the subject’s medical records. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record. In any circumstance, every effort should be 
made to document subject outcome, if possible. The Investigator should inquire about the reason 
for withdrawal, request that the subject return all unused investigational product, request that the 
subject return for a final visit, if applicable, and follow up with the subject regarding any 
unresolved AEs. 
If the subject refuses further visits, the subject should continue to be followed for survival (if 
applicable) unless the subject withdraws consent for disclosure of future information or for 
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further contact. In this case, no further study-specific evaluations should be performed, and no 
additional data should be collected. The Sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
7.7. 
Long-Term Follow-Up 
For subjects discontinuing the study treatment due to documented radiographic progression, 
survival status will be obtained via phone call or medical chart review, including information 
about subsequent anticancer therapies (including best response) every 3 months until death, lost 
to follow-up, or withdrawal of consent, whichever comes first. 
7.8. 
Restrictions 
7.8.1. 
Concomitant Medications 
Please refer to Section 5.4.1 for Prohibited Concomitant Medications. 
7.8.2. 
Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time passed between surgery and study drug required to minimize the risk 
of impaired wound healing and bleeding has not been determined. Stopping study drug is 
recommended for at least 2 days prior to surgery. Postoperatively, the decision to reinitiate study 
drug treatment should be based on a clinical assessment of satisfactory wound healing and 
recovery from surgery. 
7.8.3. 
Palliative Radiation 
Palliative radiotherapy on study is permitted, following agreement with the Sponsor, for the 
treatment of painful bony lesions provided the lesions were known at the time of study entry and 
the Investigator clearly indicates that the need for palliative radiotherapy is not indicative of 
disease progression. In view of the current lack of data about the interaction of study drug with 
radiotherapy, study drug treatment should be interrupted during palliative radiotherapy, stopping 
1 day before palliative radiotherapy and resuming treatment 1 day after completion of palliative 
radiotherapy and recovery from any acute radiation toxicities to baseline. 
7.8.4. 
Supportive Care 
Palliative and supportive care for disease-related symptoms may be administered at the 
Investigator’s discretion and according to available American Society of Clinical Oncology 
(ASCO) guidelines. 
7.8.5. 
Contraception 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during 
Screening and be neither breast feeding nor intending to become pregnant during study 
participation. A female will be considered to be of childbearing potential unless they have 
undergone permanent sterilization or are postmenopausal. Postmenopausal is defined as at least 
12 months without menses with no other medical reasons (e.g., chemical menopause due to 
anticancer treatment).  
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For WOCBP, agreement must be provided to use a highly effective contraceptive method from 
the time of screening throughout the study until 4 months (WOCBP) after administration of the 
last dose of any study drug. Highly effective methods of contraception are those that, alone or in 
combination, result in a failure rate of less than 1% per year when used consistently and correctly 
(i.e., perfect use) and include the following: 
• Established use of combined (estrogen and progestogen containing) hormonal 
methods of contraception (intravaginal, or transdermal) provided the subject remains 
on the same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure inhibition of ovulation. 
• Progestogen-only hormonal contraception (injectable, or implantable) provided the 
subject remains on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure inhibition of 
ovulation. 
• Correctly placed copper containing intrauterine device (IUD). 
• Intrauterine hormone-releasing system (IUS). 
• Vasectomized partner with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate. 
• Bilateral tubal ligation or bilateral salpingectomy. 
• Sexual abstinence is acceptable if evaluated as consistent with the preferred and the 
usual lifestyle of the subject. Periodic abstinence is not an acceptable method of 
contraception.  
All male study subjects must agree to condom use throughout the study and for 6 months 
following the last dose of study drug. Male partners of WOCBP subjects must agree to condom 
use throughout the study and for 4 months following the last dose of study drug.  
 
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8. 
SAFETY ASSESSMENTS 
Safety assessments will consist of monitoring and recording AEs, including serious adverse 
events (SAEs), measurement of protocol-specified clinical laboratory assessments and vital 
signs, and other protocol-specified tests that are deemed critical to the safety evaluation of the 
study. 
Certain types of events require immediate reporting to Turning Point Therapeutics, as outlined in 
Section 8.3. 
8.1. 
Adverse Events  
According to the ICH guideline for Good Clinical Practice (GCP), an AE is any untoward 
medical occurrence in a clinical investigation subject administered a medicinal product, 
regardless of causal attribution. An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except as described in Section 8.2.5.9 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
8.1.1. 
Serious Adverse Events (Immediately Reportable to Turning Point 
Therapeutics) 
An SAE is any AE that meets any of the following criteria: 
• Fatal (i.e., the AE actually causes or leads to death) 
• Life-threatening (i.e., the AE, in the view of the Investigator, places the subject at 
immediate risk of death). This does not include any AE that, had it occurred in a more 
severe form or was allowed to continue, might have caused death 
• Requires or prolongs in-patient hospitalization (see Section 8.2.5.10) 
• Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions) 
• Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug 
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• Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to CTCAE; see 
Section 8.2.3); the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on the CRF. 
SAEs are required to be reported by the Investigator to Turning Point Therapeutics Medical 
Monitor immediately (i.e., no more than 24 hours after learning of the event; see Section 8.3 for 
reporting instructions). 
8.2. 
Methods and Timing for Capturing and Assessing Safety Parameters 
The Investigator is responsible for ensuring that all AEs are recorded on the Adverse Event CRF 
and reported to Turning Point Therapeutics. 
For each AE recorded on the Adverse Event CRF, the Investigator will make an assessment of 
seriousness (Section 8.1.1), severity (see Section 8.2.3), and causality (see Section 8.2.4). 
8.2.1. 
Adverse Event Reporting Period  
All AEs, whether reported by the subject or noted by study personnel, will be recorded in the 
subject’s medical record and on the Adverse Event CRF at each subject contact. 
After informed consent for the clinical trial has been obtained but prior to initiation of study 
drug, only SAEs related to protocol-mandated assessments should be reported. 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be reported 
until at least 28 days after the last dose of study treatment. Any SAEs occurring any time after 
the reporting period must be promptly reported if a causal relationship to the study drug is 
suspected. 
8.2.2. 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all subject evaluation timepoints. Examples of non-directive questions include the 
following: 
 
"How have you been feeling since your last clinic visit?" 
 
"Have you noticed any new or changed health problems since you were last here?" 
8.2.3. 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the CTCAE v5.0 will be used for assessing AE severity. 
Table 8 will be used for assessing severity for AEs that are not specifically listed in the CTCAE. 
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Table 8: 
Grading of Severity of Adverse Events 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not 
indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; or limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
a  Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b  Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, 
and taking medications, as performed by subjects who are not bedridden. 
c  If an event is assessed as a "significant medical event," it must be reported as a SAE per the definition of SAE. 
d  Grade 4 and 5 events must be reported as SAEs per the definition of SAE. 
8.2.4. 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the study drugs (e.g., repotrectinib-related, trametinib-related, etc.), 
indicating "yes" or "no" accordingly. The following guidance should be taken into consideration 
(see also Table 9): 
• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• Known association of the event with the study drug or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
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Table 9: 
Causation Attribution 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, science-based 
rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and administration 
of the study drug, and the adverse event cannot be readily explained by the subject's clinical state, 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
response to the study drug; and/or the adverse event abates or resolves upon discontinuation of the 
study drug or dose reduction and, if applicable, reappears upon re-challenge. 
NO 
Evidence exists that the adverse event has an etiology other than the study drug (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the 
adverse event has no plausible temporal relationship to administration of the study drug (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
8.2.5. 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on the 
Adverse Event CRF. Avoid colloquialisms and abbreviations. Only one AE term should be 
recorded in the event field on the Adverse Event CRF. 
8.2.5.1. 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event CRF rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event CRF. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be nullified and 
replaced by one AE report based on the single diagnosis, with a starting date that corresponds to 
the starting date of the first symptom of the eventual diagnosis. 
8.2.5.2. 
Adverse Events That Are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events. A medically significant secondary AE that is separated in time from the initiating event 
should be recorded as an independent event on the Adverse Event CRF. For example: 
• If vomiting results in mild dehydration with no additional treatment in a healthy 
subject, then only vomiting should be reported on the CRF 
• If vomiting results in severe dehydration, then both events should be reported 
separately on the CRF 
• If a severe gastrointestinal hemorrhage leads to renal failure, then both events should 
be reported separately on the CRF 
• If dizziness leads to a fall and consequent fracture, then all 3 events should be 
reported separately on the CRF 
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• If neutropenia is accompanied by an infection, then both events should be reported 
separately on the CRF 
All AEs should be recorded separately on the Adverse Event CRF if it is unclear as to whether 
the events are associated. 
8.2.5.3. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, across cycles. When this 
occurs, the initial severity (intensity or grade) of the event will be recorded at the time the event 
is first reported. If a persistent AE becomes more or less severe, the initial event should be closed 
and a new event with the new severity should be recorded on the Adverse Event CRF. Similarly, 
if the event becomes serious, the initial event should be closed and a new event recorded on the 
Adverse Event CRF, completing all data fields related to SAEs. The SAE should be reported to 
Turning Point Therapeutics Medical Monitor immediately (i.e., no more than 24 hours after 
learning that the event became serious). 
A recurrent AE is one that resolves between treatment cycles and subsequently recurs. Each 
recurrence of an AE should be recorded as a separate event on the Adverse Event CRF. 
8.2.5.4. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result must be reported as 
an AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• Results in more frequent follow-up assessments or further diagnostic investigation 
• Clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
increased alkaline phosphatase (ALP) and bilirubin at 5 × Upper Limit of Normal [ULN] 
associated with cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the 
Adverse Event CRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event CRF, along with a descriptor 
indicating if the test result is above or below the normal range (e.g., "elevated potassium," as 
opposed to "abnormal potassium"). If the laboratory abnormality can be characterized by a 
precise clinical term per standard definitions, the clinical term should be recorded as the AE. For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
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Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event CRF unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated as 
described in Section 8.2.5.3. 
8.2.5.5. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported as an 
AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event 
CRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event CRF unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated as 
described in Section 8.2.5.3. 
8.2.5.6. 
Abnormal Liver Function Tests  
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined below 
in the absence of other causes of liver injury are considered potential cases of drug-induced liver 
injury (potential Hy’s Law cases) and should always be considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values: 
• Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values > 3 × ULN concurrent with a 
total bilirubin value > 2 × ULN with no evidence of hemolysis and an ALP value 
≤ 2 × ULN or not available. 
• For subjects with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above: 
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− For subjects with preexisting AST or ALT baseline values above the normal 
range, AST or ALT value ≥ 2 times the baseline values and ≥ 3 × ULN, or 
≥ 8 × ULN (whichever is smaller). 
• Concurrent with 
− For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of ≥ 1 × ULN or if the value 
reaches ≥ 3 × ULN (whichever is smaller). 
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment. The possibility of hepatic 
neoplasia (primary or secondary) should be considered. In addition to repeating measurements of 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/international normalized 
ratio (INR), ALP, and total bile acids and acetaminophen drug and/or protein adduct levels. A 
detailed history, including relevant information, such as review of ethanol, acetaminophen, 
recreational drug and supplement consumption, family history, occupational exposure, sexual 
history, travel history, history of contact with a jaundiced person, surgery, blood transfusion, 
history of liver or allergic disease, and work exposure, should be collected. Further testing for 
acute hepatitis A, B, or C infection and liver imaging (e.g., biliary tract) may be warranted. All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no other 
cause for LFT abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to determine etiology 
of the abnormal LFTs. Such potential Hy’s Law cases should be reported as SAEs. 
8.2.5.7. 
Deaths 
Death due to disease progression will not be reportable as an SAE. The immediate cause of death 
will be the serious reported term. 
All deaths, regardless of relationship to study drug, must be recorded on the Death CRF and on 
the Adverse Event CRF if considered an AE and occurred within the 28-day AE reporting 
window. Deaths reported as “disease progression” are not to be reported as SAEs if they occur 
within the 28-day window. 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event CRF. Generally, only one such event should be reported. The term "sudden 
death" should be used only for the occurrence of an abrupt and unexpected death due to 
presumed cardiac causes in a subject with or without preexisting heart disease, within 1 hour 
after the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after 
the subject was last seen alive and stable. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, "unexplained death" should be recorded on the Adverse 
Event CRF. If the cause of death later becomes available (e.g., after autopsy), "unexplained 
death" should be replaced by the established cause of death. 
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8.2.5.8. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the Screening visit for this study. Such 
conditions should be recorded on the Medical History CRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on the Adverse 
Event CRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., "worsening headaches"). 
8.2.5.9. 
Lack of Efficacy or Worsening of the Malignancy Under Study 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as AEs. These data will be captured as efficacy assessment data 
only. In most cases, the expected pattern of progression will be reflected as objective 
radiographic progression according to RECIST v 1.1 criteria. In rare cases, the determination of 
disease progression will be based predominantly on symptomatic deterioration. However, every 
effort should be made to document progression through use of objective criteria. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as an AE. 
8.2.5.10. Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or prolonged 
hospitalization should be documented and reported as a SAE, except as outlined below. 
The following hospitalization scenarios are not considered to be AEs: 
• Hospitalization for respite care or social admissions (e.g., lack of housing, economic 
inadequacy, family circumstances) 
• Hospitalization solely for coordination of care, including hospice arrangements 
• Hospitalization due solely to progression of the underlying cancer 
• Hospitalization that was necessary solely because of subject requirement for 
outpatient care outside of normal outpatient clinic operating hours 
• Hospitalization for same day surgeries (as outpatient/same day/ambulatory 
procedures) 
• Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• Hospitalization for a preexisting condition, provided that the hospitalization was 
planned prior to the study or was scheduled during the study when elective surgery 
became necessary because of the expected normal progression of the disease and the 
subject has not experienced an AE 
8.2.5.11. Exposure During Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy occurs if: 
• A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (e.g., because of treatment or environmental exposure) to the investigational 
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product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product. An example of environmental exposure 
would be a case involving direct contact with investigational product in a pregnant 
woman (e.g., a nurse reports that she is pregnant and has been exposed to 
chemotherapeutic products). 
• A male subject has been exposed (e.g., because of treatment or environmental 
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the study 
subject’s treatment with the investigational product, the Investigator must submit this 
information to Premier Research Pharmacovigilance (Premier PV) on a SAE Report Form (if 
applicable) and Pregnancy Data Collection Form. In addition, the Investigator must submit 
information regarding environmental exposure to an investigational product in a pregnant 
woman (e.g., a subject reports that she is pregnant and has been exposed to a cytotoxic product 
by inhalation or spillage). This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure. The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
Pregnancy Data Collection Forms with an unknown outcome. The Investigator will follow the 
pregnancy until completion or until pregnancy termination and notify Premier PV of the outcome 
as a follow-up to the initial Pregnancy Data Collection Form. In the case of a live birth, the 
structural integrity of the neonate can be assessed at the time of birth. In the event of a 
termination, the reason(s) for the termination should be specified and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the Investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• Spontaneous abortion includes miscarriage and missed abortion. 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the Investigator assesses the infant death as related or possibly related to 
exposure to investigational product. 
Additional information regarding the exposure during pregnancy may be requested by the 
Investigator. Further follow-up of birth outcomes will be handled on a case-by-case basis 
(e.g., follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the Investigator will provide the study subject with the pregnant partner release of 
information form to deliver to his partner. The Investigator must document in the source 
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documents that the subject was given the pregnant partner release of information form to provide 
to his pregnant partner. 
8.2.5.12. Occupational Exposure 
An occupational exposure occurs when during the performance of job duties, a person (whether a 
healthcare professional or otherwise) has unplanned direct contact with the product, which may 
or may not lead to the occurrence of an AE. 
An occupational exposure is reported to safety within 24 hours of Investigator’s awareness, using 
the SAE Report Form, regardless of whether there is an associated AE/SAE. Since the 
information does not pertain to a subject enrolled in the study, the information is not reported on 
a CRF, however a copy of the completed SAE Report Form is maintained in the study master 
file. 
8.2.5.13. Adverse Events Associated with an Overdose or Incorrect Administration of 
Study Drug 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study treatment is not itself an AE, but 
it may result in an AE. All AEs associated with an overdose or incorrect administration of study 
drug should be recorded on the Adverse Event CRF. If the associated AE fulfills serious criteria, 
the event should be reported to Turning Point Therapeutics Medical Monitor immediately (i.e., 
no more than 24 hours after learning of the event). 
8.3. 
Immediate Reporting Requirements from Investigator to Turning 
Point Therapeutics 
Certain events require immediate reporting to allow Turning Point Therapeutics to take 
appropriate measures to address potential new risks in a clinical trial. The Investigator must 
report such events to Turning Point Therapeutics immediately; under no circumstances should 
reporting take place more than 24 hours after the Investigator learns of the event. The following 
is a list of events that the Investigator must report to Turning Point Therapeutics within 24 hours 
after learning of the event, regardless of relationship to study drug: 
• Serious AE (whether or not deemed drug-related or expected). 
• Pregnancy of female subject or partner of male subject of childbearing potential. 
• Occupational Exposure (regardless of whether there is an associated AE/SAE) 
The Investigator must report new significant follow-up information for these events to Premier 
Research GPV immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the event’s outcome, including recovery 
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• Additional narrative information on the clinical course of the event 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
8.3.1. 
SAE Reporting 
After informed consent has been obtained but prior to initiation of study drug, only SAEs related 
to protocol-mandated procedures should be reported. 
After initiation of study drug, SAEs will be reported until at least 28 days after the last dose of 
study drug. 
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the SAE Report Form and submit the report via fax or 
email (please refer to the Study Manual). 
8.3.2. 
Immediate Reporting Requirements for Pregnancies 
8.3.2.1. 
Pregnancies in Female Subjects 
Female subjects or partners of male subjects of childbearing potential will be instructed to 
immediately inform the Investigator if they become pregnant during the study or within 4 months 
after the last dose of study drug. A Pregnancy Data Collection Form should be completed by the 
Investigator no more than 24 hours after learning of the pregnancy and submitted using the same 
process as for SAEs. Refer to Section 8.2.5.11 for further information on reporting requirements 
for exposure during pregnancy. 
The Investigator should discontinue study drug and counsel the subject or partner of a male 
subject, discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring 
should continue until conclusion of the pregnancy. Any SAEs associated with the pregnancy 
(e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported and submitted within 24 hours. Refer to 
Section 8.2.5.11 for additional information regarding follow-up and SAE reporting requirements 
for exposure during pregnancy. 
8.3.2.2. 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female subject or partner of a male 
subject exposed to study drug should be classified as an SAE and reported as such. Any 
spontaneous abortion or miscarriage should be reported in the same fashion (therapeutic 
abortions are excluded from expedited reporting and would be captured as pregnancy outcome 
information). Refer to Section 8.2.5.11 for additional information regarding follow-up and SAE 
reporting requirements for exposure during pregnancy. 
8.4. 
Follow-Up of Subjects After Adverse Events 
8.4.1. 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or better, 
the event is assessed as stable by the Investigator, the subject is lost to follow-up, or the subject 
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withdraws consent. Every effort should be made to follow all SAEs considered to be related to 
study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the Adverse 
Event CRF and in the subject’s medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
8.4.2. 
Turning Point Therapeutics Follow-Up 
For SAEs and pregnancies, Turning Point Therapeutics or a designee may follow-up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and 
outcome information (e.g., from hospital discharge summaries, consultant reports, autopsy 
reports) in order to perform an independent medical assessment of the reported case. 
8.5. 
Post-Study Adverse Events 
Turning Point Therapeutics should be notified if the Investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 28 days after the last dose of study 
drug) if the event is believed to be related to the study drug. 
The Investigator should report these events directly to Turning Point Therapeutics or its designee 
using the SAE Report Form. 
8.6. 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees 
Turning Point Therapeutics will promptly evaluate all SAEs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators, IRBs, ECs, and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, Turning Point Therapeutics will assess 
the expectedness of these events using the IB. 
Turning Point Therapeutics will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the applicable 
reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading by Turning Point Therapeutics as needed. 
9. 
STATISTICAL METHOD ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this trial will 
be documented in a Statistical Analysis Plan (SAP), which will be maintained by the Sponsor or 
their designee. The SAP may modify the initial analysis plan outlined in the protocol; however, 
any major modifications of the primary endpoint and/or analysis methods will also be reflected 
in a protocol amendment. 
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9.1. 
Analysis Sets 
9.1.1. 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects who receive at least one full or partial dose 
of both study drugs. This will be the same as the Safety Analysis Set. The FAS set will be used 
for the summary of subject disposition, demographics, and baseline characteristics, and safety 
analysis. For Phase 2, the FAS set will also be used for primary efficacy analysis if subjects have 
received repotrectinib. 
Subjects will be classified according to the assigned treatment dose levels. Subjects who were 
screened but never started treatment will be listed in the subject data listing as screening failure, 
and reasons for screening failure will be included. 
9.1.2. 
Efficacy Evaluable Analysis Set 
Efficacy Evaluable (EE) Analysis Set will include all enrolled subjects who (1) have received at 
least one dose of study treatment with repotrectinib; (2) KRAS mutation determined by a qPCR 
or NGS test performed in a CLIA laboratory or equivalently accredited diagnostic laboratory; (3) 
have a baseline tumor assessment with measurable disease and have at least 1 on-study tumor 
assessment per RECIST v1.1; and (4) have no major protocol violations that could affect 
efficacy. 
The EE Analysis Set will be used for efficacy analyses for Phase 1b, and sensitivity analysis of 
efficacy endpoints for Phase 2. 
9.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all enrolled subjects who receive at least one dose of either 
study drug. This will be the same as the FAS. Subjects will be classified according to the actual 
treatment (dose levels or cohorts). Each subject will be classified into and analyzed consistently 
within one treatment group, unless otherwise specified. 
9.1.4. 
Pharmacokinetic Concentration Analysis Set 
The PK Concentration Analysis Set is defined as all enrolled subjects who receive at least one 
dose of study drug and have at least one concentration of study drug. 
9.1.5. 
Pharmacokinetic Parameter Analysis Set 
The PK Parameter Analysis Set is defined as all enrolled subjects who receive at least one dose 
of study drug and have sufficient information to estimate at least one of the PK parameters of 
interest. 
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9.2. 
Sample Size Determinations 
9.2.1. 
Repotrectinib + Trametinib 
9.2.1.1. 
Phase 1b Dose Escalation 
For dose escalation, 3 to 6 DLT-evaluable subjects will be enrolled per dose level. Therefore, it 
is expected that approximately 24 – 30 subjects will be enrolled to determine the RP2D of 
repotrectinib in combination with trametinib. 
9.2.1.2. 
Phase 2 Expansion 
For Phase 2 expansion, sample size will be determined using Pearson-Clopper exact confidence 
interval method. A total of approximately 50 subjects will be enrolled. In addition, up to 
6 locally advanced or metastatic KRAS-mutant NSCLC subjects treated at the RP2D in Phase 1b 
will be pooled for the efficacy analysis. If 21 subjects out of 56 subjects have a confirmed 
objective response (ORR = 38%; 95% CI: 25 – 51) where the lower limit of the 95% CI is 
> 23%, repotrectinib in combination with trametinib will be considered superior than the 
currently approved chemotherapy in the second-line setting for NSCLC in this expansion cohort, 
including the combination of docetaxel + ramucirumab (Cyramza® USPI, 2020) which has 
demonstrated a best ORR of 23% (95% CI: 20 – 26) in the second-line setting. 
9.3. 
Study Endpoints 
9.3.1. 
Primary Endpoint for Phase 1 
• Incidence of first cycle (28 days) DLTs to determine MTD and/or RP2D.  
9.3.2. 
Secondary Endpoints for Phase 1 
• ORR assessed by the Investigator using RECIST v1.1 
• Pharmacokinetic parameters of repotrectinib 
• Pharmacokinetic parameters of trametinib 
9.3.3. 
Primary Endpoint for Phase 2 
• ORR assessed by Investigator using RECIST v1.1. 
9.3.4. 
Secondary Endpoints for Phase 2 
• DOR, TTR, and CBR by the Investigator 
• Intracranial objective response rate (IC-ORR) assessed according to modified 
RECIST v1.1 in subjects with brain metastases 
• PFS and OS 
• Type, incidence, severity, timing, seriousness, and relatedness (to each study drug) of 
AEs and laboratory abnormalities 
• Pharmacokinetic parameters of repotrectinib 
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• Pharmacokinetic parameters of trametinib 
9.3.5. 
Exploratory Endpoints for Phase 1b and Phase 2 
• ORR and PFS by modulation of circulating tumor levels and genomic alterations 
observed pre- and post-dosing. 
9.4. 
Statistical Analysis 
9.4.1. 
General Considerations 
Full descriptions of analyses to be performed will be included in the SAP and will supersede any 
analysis described here.  
9.4.1.1. 
Missing Data 
All analyses and descriptive summaries will be based on the observed data. Unless otherwise 
specified, missing data will not be imputed. Partial dates for AEs and concomitant medications 
will be imputed using the most conservative rules. Further details regarding missing data will be 
included in the SAP. 
9.4.2. 
Efficacy Analyses 
9.4.3. 
Analysis of Primary Endpoint 
For Phase 1b, efficacy analysis will be performed in EE population. For Phase 2, the FAS 
analysis set will be used as the primary analysis for efficacy, and analyses using the EE 
population will be used as sensitivity analysis. Primary efficacy data will be based on the 
radiologic assessments evaluated by the Investigator. Data from BICR may be analyzed as 
supportive. 
For Phase 2, the primary efficacy endpoint is ORR of repotrectinib in combination with 
trametinib in subjects with advanced/metastatic solid tumors harboring KRAS mutations potential 
biomarkers, including genomic alterations that could predict efficacy or resistance to the study 
drugs, may be explored. 
9.4.3.1. 
Objective Response Rate 
The ORR will be defined as the proportion of subjects with a confirmed CR or PR. A confirmed 
response is a response that persists on a repeat imaging performed at least 4 weeks after initial 
documentation of response. Subjects with a confirmed objective response (CR or PR) will be 
referred to as responders. Non-responders will include subjects without a confirmed objective 
response, SD, progressive disease (PD), not evaluable (NE), or non-CR/non-PD (NN). The ORR 
will be reported as the proportion of responders by RECIST v1.1 along with the corresponding 
two-sided 95% Clopper-Pearson exact CI. 
9.4.4. 
Analysis of Secondary Endpoints 
The secondary efficacy endpoints include DOR, TTR, CBR, intracranial response, PFS, and OS 
of repotrectinib in combination with trametinib in subjects with advanced or metastatic solid 
tumors harboring KRAS mutations. Potential biomarkers, including genomic alterations that 
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could predict efficacy or resistance to the study drugs, may be explored. Further details regarding 
these secondary efficacy analyses will be included in the SAP. 
9.4.5. 
Safety Analyses 
Safety analyses will be performed using the Safety Analysis Set for each cohort, as well as for all 
cohorts combined. Further descriptions of the analyses of safety endpoints including adverse 
events coded to Medical Dictionary for Regulatory Affairs (MedDRA) version 23.0 or higher, 
deaths, laboratory results, ECG results, vital signs, and left ventricular ejection fraction (LVEF) 
will be described in the SAP. 
9.4.6. 
Analysis of Pharmacokinetics 
9.4.6.1. 
Single-and Multiple-Dose Repotrectinib and Trametinib Pharmacokinetic 
Analysis 
Repotrectinib and trametinib plasma concentration-time data will be analyzed using non-
compartmental methods to estimate the following PK parameters in individual subjects: 
maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area 
under the plasma concentration-time curve (AUC). If data permit or if considered appropriate, 
area under the plasma concentration versus time curve to infinity (AUCinf), terminal elimination 
half-life (t½), apparent plasma clearance (CL/F), apparent volume of distribution (Vz/F), and 
accumulation ratio (Racc) will be estimated. The single- and multiple-dose PK parameters will be 
summarized descriptively by dose, cycle, and day.  
Repotrectinib and trametinib concentrations will be summarized descriptively (n, mean, standard 
deviation, CV, median, minimum, maximum, geometric mean and its associated CV) by dose, 
cycle, day and nominal time. Individual, mean, and median profiles of the concentration-time 
data will be plotted by dose, cycle and day (single-dose, and multiple-dose) using nominal time. 
Median and mean profiles will be presented on both linear and log-linear scales.  
Dose normalized AUCinf, (AUCτ at steady state), AUClast, and Cmax will be plotted against dose 
(using a logarithmic scale) by cycle and day. These plots will include individual subject values 
and the geometric means for each dose. These plots will be used to help understand the 
relationship between PK exposure and dose.  
The observed Racc will be summarized descriptively. It will be analyzed after natural log 
transformation using a one-way analysis of variance with a single term for dose. The means and 
90% confidence intervals (CIs) obtained from the model will be back-transformed to provide 
means and 90% CIs for the accumulation and linearity ratios for each dose.  
Trough concentrations will be plotted for each dose using a box-whisker plot by cycle and day 
within cycle to assess the attainment of steady state. 
9.5. 
Interim Analysis 
Periodic reviews of the preliminary data may be performed for executive, regulatory, and/or 
conference presentation purposes.  
In addition, for Phase 2, an interim futility analysis of the ORR will be performed after 
approximately 15 subjects are evaluable for tumor response to safeguard future patients from 
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exposure to a potentially ineffective treatment. Depending on the enrollment rate, it is anticipated 
that approximately 20-30 subjects will be enrolled at the interim analysis.  
The interim futility stopping rule for the maximum number of responders (R) required among the 
15 (N) evaluable subjects with the cumulative probability of observing ≤ R responders under the 
targeted ORR (P1) and futility ORR (P0) is shown in Table 10. If ≤ 2 responders (confirmed CR 
or PR) are observed from 15 evaluable subjects, the expansion cohort will be stopped for futility. 
If ≥ 3 responders are observed, this cohort may continue depending on the overall benefit and 
risk assessment at the interim analysis. If the true ORR in this cohort is as targeted at 38%, the 
probability of observing ≤ 2 responders is 3.8%. If the true ORR is significantly lower than the 
target ORR (i.e., 10% instead of 38%), the probability is 81.6%. 
Table 10: 
Stopping Rule for Interim Futility Analysis of ORR in Phase 2 
N 
R 
Target ORR (P1) 
Futility ORR (P0) 
Probability Under 
P1 
Probability Under P0 
15 
2 
38% 
10% 
0.038 
0.816 
Abbreviations: EXP = expansion; ORR = overall response rate; P1 = target overall response rate; PO = futility overall response 
rate.  
Note: N is the number of evaluable patients for tumor response at the interim futility analysis and R is the maximum number of 
responders (confirmed CR or PR) for futility stop. If the number of responders is ≤ R, the cohort will be stopped for futility. 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
It is the Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported for each subject. Source documentation supporting the data should indicate the 
subject’s participation in the study and should document the dates and details of study 
procedures, AEs, and subject status. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. 
11. 
DATA HANDLING AND RECORD KEEPING 
11.1. 
Case Report Forms/Electronic Data Record 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries will be 
entered, tracked, and resolved directly through the electronic data capture (EDC) system. The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented. 
11.2. 
Study Monitoring, Audits, and Inspections 
Site visits will be conducted by an authorized Sponsor representative, who will inspect study 
data, subjects’ medical records, and CRFs according to GCP, the Food and Drug Administration 
(FDA), and the International Conference on Harmonisation (ICH) guidelines. In addition to 
monitoring by the Sponsor or its designees, the study may be audited by representatives of the 
FDA or other regulatory authorities, who will also be permitted access to study documents. The 
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Investigator should immediately notify the Sponsors’ Clinical Operations department or designee 
of any proposed or scheduled audits by regulatory authorities. 
The Investigator will permit authorized representatives of the Sponsor or designee and national 
or local health authorities to inspect facilities and records relevant to this study. 
The Investigator must obtain Institutional Review Board (IRB)/EC approval for the 
investigation. Initial IRB/IEC approval and all materials approved by the IRB/EC for this study, 
including the subject consent form and recruitment materials, must be maintained by the 
Investigator and made available for inspection. 
11.3. 
Inspection of Records 
The Sponsor and designees of the Sponsor will be allowed to conduct site visits to the 
investigational facilities for monitoring any aspect of the study. The Investigator agrees to allow 
Sponsor representatives to inspect the drug storage area, investigational product inventory, drug 
accountability records, subject charts and study source documents, and other records relative to 
the study conduct. 
11.4. 
Record Retention 
The Investigator will coordinate with the study site to ensure all documentations relating to the 
study for a period of 2 years after marketing application approval or, if not approved, 2 years 
after the notification to the FDA of the discontinuance of the investigational product for 
investigation. If it becomes necessary for the Sponsor or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 
The records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer; but at a minimum, all study 
documentation must be retained for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of repotrectinib. 
12. 
ETHICS 
12.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/IEC, as appropriate. The Investigator must submit written 
approval to the Sponsor before he or she can present informed consent and begin screening 
activities for any subject in the study. 
The Investigator is responsible for informing the IRB/IEC of any amendment(s) to the protocol 
in accordance with local requirements. In addition, the IRB/IEC must approve all advertising 
used to recruit subjects for the study, if applicable. The protocol must be re approved by the 
IRB/IEC upon receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product. 
The Sponsor will provide this information to the Investigator. 
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Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
12.2. 
Protocol Compliance 
The Investigator will conduct the trial in compliance with the protocol provided by the Sponsor. 
Modifications to the protocol may not be made without agreement of both the Investigator and 
the Sponsor. Changes to the protocol will require a written IRB/IEC approval/favorable opinion 
before implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects. The IRB/IEC may provide and expedite review, if applicable and as 
regulatory authority(ies) permit, the approval/favorable opinion for minor change(s) in ongoing 
trials that have the approval/favorable opinion of the IRB/IEC. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor/Designee and/or the Study Monitor, if 
circumstances permit, to discuss the planned course of action. Any departures from the protocol 
must be fully documented on the appropriate CRF and in the source documentation and reported 
to the IRB/IEC per institutional and/or local requirements. 
12.3. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and the Sponsors’ (or its designee’s) applicable policies and standard operating procedures 
(SOPs). 
12.4. 
Written Informed Consent 
The Investigator at the study center will ensure that the subject is given full and adequate oral 
and written information about the nature, purpose, possible risk(s), and benefit(s) of the study. 
Subjects must also be notified that they are free to withdraw from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated ICF must be obtained before conducting any study procedures 
(Section 6.1). 
The Investigator must maintain the original signed ICF. A copy of the signed ICF must be given 
to the subject. 
12.5. 
Subject Confidentiality 
To maintain subject privacy, data capture tools, investigational product accountability records, 
study reports, and communications will identify the subject only by initials and the subject 
number assigned at Screening. The Investigator will grant monitor(s) and auditor(s) from the 
Sponsor or its designee and regulatory authority(ies) access to the subject’s original medical 
records, including medical history, laboratory studies, and medication administrations, for 
verification of data gathered and to audit the data collection process. This information will be 
accessed for the duration of the research study for data reconciliation purposes. The subject’s 
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confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
13. 
PUBLICATION OF STUDY RESULTS 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for any other purposes without written consent from the 
Sponsor. It is understood that there is an obligation to provide the Sponsor with complete data 
obtained during the study. The information obtained from the clinical study will be used toward 
the development of the Sponsors' investigational product program and may be disclosed to 
regulatory authority(ies), other Investigators, corporate partners, shareholders, or consultants as 
required. 
Additionally, the Investigator should obtain authorization from the clinical trial subjects in 
writing and ensure that all 18 identifiers (outlined in the Health Insurance Portability and 
Accountability Act (HIPAA) Privacy Rule (November 26, 2012)) have been removed from the 
data. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. Investigator publication rights will be 
provided in the Clinical Trial Agreement. 
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APPENDIX 1. STRONG CYP3A INHIBITORS OR INDUCERS, 
SENSITIVE CYP3A SUBSTRATES AND MEDICATIONS 
THAT CAUSE QTC PROLONGATION 
Strong CYP3A Inhibitors or Inducers  
Strong CYP3A Inhibitors 
Strong CYP3AInducers 
Macrolide antibiotics: clarithromycin and telithromycin 
Carbamazepine 
Efavirenz 
Anti-fungal: itraconazole, ketoconazole, voriconazole, 
posaconazole 
Phenobarbital 
Phenytoin 
Anti-virals: lopinavir, indinavir, nelfinavir, ritonavir, 
saquinavir, amprenavir 
Rifampin 
Rifabutin 
Conivaptan 
Rifapentin 
Mibefradil 
St John’s wort 
Nefazodone 
 
Troleandomycin 
 
Miscellaneous: Grapefruit juice 
 
Sensitive CYP3A Substrates 
alfentanil 
avanafil 
buspirone 
conivaptan 
darifenacin 
darunavir 
ebastine 
everolimus 
ibrutinib 
lomitapide 
lovastatin 
midazolam 
naloxegol 
nisoldipine 
saquinavir 
simvastatin 
sirolimus 
tacrolimus 
tipranavir 
triazolam 
vardenafil  
budesonide 
dasatinib 
dronedarone 
eletriptan  
eplerenone 
felodipine 
indinavir 
lurasidone  
maraviroc 
quetiapine 
sildenafil 
ticagrelor  
tolvaptan  
 
 
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Medications That Cause QTc Prolongation 
Amiodarone 
Astemizole 
Azithromycin 
Chlorpromazine 
Disopyramide 
Terfenadine 
Clarithromycin 
Haloperidol 
Dofetilide 
Chloroquine 
Erythromycin 
Mesoridazine 
Flecainide 
Halofantrine 
Moxifloxacin 
Pimozide 
Ibutilide 
Probucol 
Sparfloxacin 
Thioridazine 
Procainamide 
Pentamidine 
Domperidone 
Levomethadyl 
Quinidine 
Bepridil 
Droperidol 
Methadone 
Sotalol 
Arsenic trioxide 
Vavdetanib 
Citalopram 
Cisapride 
 
 
 
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APPENDIX 2. SUMMARY OF CHANGES 
Summary of Changes for Version 2.0 to Version 3.0.  This Summary of Changes details the substantive changes to TPX-0005-13 
Subprotocol 1.  Minor changes for editorial clarifications, or for administrative corrections of typographic errors, reformatting, 
abbreviations or section/table re-numbering are not included in this summary.  Text removed from the original version (Version 2.0) is 
indicated with strikethrough text.  Text added to the new version (Version 3.0) is indicated by bold text. 
Protocol Section 
Original Text with Deletions 
Revised Text 
Justification 
Title Page 
 
Medical Monitor: 
Naseem Zojwalla, M.D. 
Vice President, Clinical Development 
Medical Monitor: 
Amit Reddy, MBBS 
Associate Medical Director, Clinical Development 
Change of Medical 
Monitor 
Sponsor 
Approval Page, 
Signatory 
Naseem Zojwalla, M.D. 
Vice President, Clinical Development 
Minal Mehta, MBBS 
Executive Director, Clinical Development 
Change of Sponsor 
Signatory 
Synopsis, 
Exploratory 
Objectives (All 
Phases) 
 
Section 2.3 
Exploratory 
Objectives (All 
Phases) 
• 
Evaluate biomarkers potentially predictive of 
response in subjects treated with repotrectinib in 
combination with other anticancer therapies.  
• 
Explore the potential prognostic utility of genomic 
alterations and characterize intrinsic or acquired 
resistance in subjects treated with repotrectinib in 
combination with other anticancer therapies using 
liquid biopsy samples 
• 
Evaluate biomarkers potentially predictive of 
response in subjects treated with repotrectinib in 
combination with other anticancer therapies.  
• 
Explore the potential prognostic utility of genomic 
alterations and characterize intrinsic or acquired 
resistance in subjects treated with repotrectinib in 
combination with other anticancer therapies using 
tissue-based or liquid-based biopsy samples 
Clarified 
acceptance of 
liquid-based biopsy 
explicitly stated as 
it allows adequate 
analytical 
performance for 
mutation testing 
Synopsis, 
Overall Study 
Design 
 
Section 3.1, 
Table 2 – 
Subprotocol 1 
Study Design 
 
Revised and 
clarified the study 
schematic to reflect 
the overall study 
design.  
Synopsis, 
Overall Study 
Design 
Phase 1b Dose Escalation 
Subjects with locally advanced or metastatic solid tumor 
malignancies harboring a KRASG12D mutation will be 
Phase 1b Dose Escalation 
Subjects with locally advanced or metastatic solid tumor 
malignancies harboring a KRASG12D mutation will be 
The study will 
utilize a more 
conservative 3+3 
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enrolled into the Phase 1b dose escalation portion of the 
study to determine the MTD/RP2D of repotrectinib in 
combination with trametinib. Dose escalation will follow 
a rolling 6 design. 
enrolled into the Phase 1b dose escalation portion of the 
study to determine the MTD/RP2D of repotrectinib in 
combination with trametinib. Dose escalation will follow 
a traditional 3+3 design 
dose escalation 
design to guide 
dose finding in 
Phase 1b.  
Synopsis, Phase 
1b Dose 
Escalation 
Study Design 
 
Section 3.2, 
Phase 1b Dose 
Escalation 
Study Design 
Initially, approximately 18  24 subjects with locally 
advanced or metastatic solid tumor malignancies 
harboring a KRASG12D mutation will be enrolled.  
Dose escalation will follow a rolling 6 design. At least 
six subjects at each dose level will be administered daily 
(QD) doses of repotrectinib in combination with 
trametinib according to the table below (starting with 
Dose Level 1 [DL1]) and evaluated for dose-limiting 
toxicities (DLTs) during Cycle 1 (i.e., for 28 days). After 
the first 3 subjects have completed their first cycle of 
study treatment (Cycle 1), a safety evaluation will be 
conducted by a Safety Review Committee to determine if 
enrollment of subjects in the next dose level (DL2) may 
begin. If no subjects experience a DLT within the first 28 
days of DL1 treatment, then dose escalation will proceed 
to the next dose level concurrent with enrollment at DL1, 
according to the table below. If 1 of the 3 initial subjects 
at DL1 experiences a DLT, then the next 3 subjects will 
be enrolled prior to escalating to the next dose level. 
Rolling enrollment into all subsequent dose levels will 
follow the same procedure. If ≥ 33% in at least 6 subjects 
at any dose level experience a DLT within the first 28 
days of treatment, the doses will be reduced according to 
the table below. If ≥ 2 of 6 subjects experience a DLT 
within the first 28 days of treatment at DL 1, then the 
study will be terminated. See Section 3.2 for further 
details of dose finding. 
 
Dose-finding Dose Levels  
 
Repotrectinib 
Trametinib 
Dose Level 3 
160 mg QD/BIDa 2 mg QD 
Initially, approximately 24  30 subjects with locally 
advanced or metastatic solid tumor malignancies 
harboring a KRASG12D mutation will be enrolled.  
Dose escalation will follow a traditional 3+3 design. 
Three to six DLT-evaluable subjects at each dose level 
will be administered daily (QD) doses of repotrectinib in 
combination with trametinib according to the table below 
(starting with Dose Level 1) and evaluated for dose-
limiting toxicities (DLTs) during Cycle 1 (i.e., for 28 
days). After the first 3 subjects have completed their first 
cycle of study treatment (Cycle 1), a safety evaluation 
will be conducted by a Safety Review Committee to 
determine if enrollment of subjects in the next dose level 
(Dose Level 2) may begin. If no subjects experience a 
DLT within the first 28 days of Dose Level 1 treatment, 
then dose escalation may proceed to the next dose level, 
according to the table below. If 1 of the 3 initial subjects 
at Dose Level 1 experiences a DLT, then the next 3 
subjects will be enrolled prior to escalating to the next 
dose level. Enrollment into all subsequent dose levels 
will follow the same procedure. If ≥ 33% of subjects at 
any dose level experience a DLT within the first 28 days 
of treatment, the dose levels will be de-escalated to 
Dose Level -2 or -3 according to SRC recommendation 
and following approval by the Sponsor, as detailed in 
the table below. If Dose Level -2 is tolerable, testing of 
alternate escalating dose levels (-2a, -2b) may occur 
as outlined in the table below. If Dose Level -2 is not 
tolerable, subjects will be de-escalated to Dose Level -
3. If Dose Level -3 is tolerable, testing of alternate 
escalating dose levels (-3a, -3b) may occur as outlined 
in the table below. Alternative regimens or additional 
dose levels or dose level increments may be explored 
Based on review of 
available safety 
and PK data from 2 
patients treated 
with repotrectinib 
and trametinib at 
Dose Level 1, the 
SRC recommended 
a dose level 
de-escalation to 
Dose Level -2 and 
recommended 
alternate dose 
finding levels. 
Furthermore, the 
study will utilize a 
more conservative 
3+3 dose escalation 
design to guide 
dose escalation 
decisions.    
 
The PK data 
showed that in 
combination with 
120 mg QD 
repotrectinib, the 
exposure of 
trametinib was 
double that of the 2 
mg trametinib 
single-agent 
exposure.   
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Dose Level 2 
160 mg QD 
2 mg QD 
Dose Level 1 (Starting 
Dose) 
120 mg QD 
2 mg QD 
Dose Level -1 
120 mg QD 
1.5 mg QD 
 
 
based on emergent clinical safety, efficacy, and PK 
data. See Section 3.2 for further details of dose finding.  
 
Dose-finding Dose Levels  
Dose Level 
Repotrectinib 
Trametinib 
3 
160 mg QD/BIDa 
2 mg QD 
2 
160 mg QD 
2 mg QD 
1 (Starting Dose) 
120 mg QD 
2 mg QD 
(-2b) 
160 mg QD/BIDa 1.0 mg QD 
(-2a) 
160 mg QD 
1.0 mg QD 
-2 
120 mg QD 
1.0 mg QD 
(-3b) 
160 mg QD/BIDa 0.5 mg QD 
(-3a) 
160 mg QD 
0.5 mg QD 
-3 
120 mg QD 
0.5 mg QD 
 
Synopsis, 
Number of 
subjects 
(planned) 
 
Phase 1b Dose Escalation: approximately 18  24 
subjects  
Phase 2 Expansion: approximately 50 subjects 
Phase 1b Dose Escalation: approximately 24 – 30 
subjects  
Phase 2 Expansion: approximately 50 subjects 
To account for the 
possible alternate 
dose finding levels 
that may be 
explored. 
Synopsis, 
Inclusion 
Criteria 
Added text 
Phase 1 AND Phase 2 
Clarified that IC #1 
through #13 are 
required for Phase 
1 and Phase 2 
Synopsis, 
Inclusion 
Criteria #1  
 
Section 4.1, 
Inclusion 
1. Subject must have a histologically or cytologically 
confirmed diagnosis of unresectable or metastatic solid 
tumor malignancy harboring a KRAS mutation. 
• 
Documented KRASG12D mutation as determined 
by a quantitative polymerase chain reaction 
(qPCR) or next-generation sequencing (NGS) 
1. Subject must have a histologically or cytologically 
confirmed diagnosis of unresectable or metastatic solid 
tumor malignancy harboring a KRAS mutation. 
• 
Documented KRASG12D mutation as 
determined by a quantitative polymerase chain 
reaction (qPCR) or next-generation sequencing 
Clarification: 
Acceptance of 
tissue based or 
liquid biopsy as 
local test (was and) 
should be explicitly 
stated as there’s 
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Criteria #1  
 
test performed in a Clinical Laboratory 
Improvement Amendments (CLIA) laboratory 
or equivalently accredited diagnostic 
laboratory.  
(NGS) test performed in a Clinical Laboratory 
Improvement Amendments (CLIA) laboratory 
or equivalently accredited diagnostic 
laboratory. Local tissue-based or liquid 
biopsy diagnostic testing will be permitted. 
adequate analytical 
performance for 
mutation testing 
Synopsis, 
Inclusion 
Criteria #5 
 
Section 4.1, 
Inclusion 
Criteria #5 
5.  At least 1 measurable target lesion according to 
Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 prospectively confirmed by Blinded Independent 
Central Radiology Review (BICR) PRIOR to enrollment. 
Subjects with central nervous system (CNS)-only 
measurable target lesion ≥ 5 mm as defined by RECIST 
v1.1 are eligible. 
5.  At least 1 measurable target lesion according to 
Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1. Subjects with central nervous system (CNS)-only 
measurable target lesion ≥ 5 mm as defined by RECIST 
v1.1 are eligible. 
 
As this is a 
signal-finding 
study, radiographic 
disease 
confirmation by 
BICR is not 
needed.  
Synopsis, 
Inclusion 
Criteria #6 
 
Section 4.1, 
Inclusion 
Criteria #6 
 
6. Subject must have received prior standard therapy 
appropriate for their tumor type and stage of disease, or 
in the opinion of the Investigator, would be unlikely to 
tolerate or derive clinically meaningful benefit from 
appropriate standard of care therapy.  
• Subject must have received no more than 3 
prior systemic regimens.  
• Maintenance therapy will not be counted as 
a separate regimen.  
• Adjuvant chemotherapy or chemotherapy 
administered as part of concurrent 
chemotherapy and radiation therapy will not 
count as a prior regimen of systemic therapy as 
long as recurrence occurred more than 6 
months after the last day of chemotherapy. 
Additional Inclusion Criteria for Phase 1 only: 
13. Subject must have received prior standard therapy 
appropriate for their tumor type and stage of disease, or 
in the opinion of the Investigator, would be unlikely to 
tolerate or derive clinically meaningful benefit from 
appropriate standard of care therapy.  
• Subject must have received no more than 3 
prior systemic regimens.  
• Maintenance therapy will not be counted as 
a separate regimen.  
• 
Adjuvant chemotherapy or chemotherapy 
administered as part of concurrent 
chemotherapy and radiation therapy will not 
count as a prior regimen of systemic therapy as 
long as recurrence occurred more than 6 
months after the last day of chemotherapy. 
Clarification that 
criterion applies to 
Phase 1 only 
Synopsis, 
Inclusion 
Criteria #7 
 
Section 4.1, 
Inclusion 
Criteria #7 
7. Baseline laboratory values fulfilling the following 
requirements: 
… 
 
Total Serum 
Bilirubin 
< 1.5 x ULN 
 … 
7. Baseline laboratory values fulfilling the following 
requirements: 
… 
 
Total Serum 
Bilirubin 
< 1.5 x ULN (≤ 3.0 × ULN for patients 
with Gilbert’s Syndrome or liver 
metastases) 
 
Clarified 
requirement for 
patients with 
Gilbert’s Syndrome 
or liver metastases 
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Synopsis, 
Inclusion 
Criteria #10 
 
Section 4.1, 
Inclusion 
Criteria #10 
10. Women of childbearing potential (WOCBP) must 
have a negative serum pregnancy test during screening 
and be neither breastfeeding nor intending to become 
pregnant during study participation. Female patients will 
be considered to be of childbearing potential unless they 
have undergone permanent sterilization or are 
postmenopausal. Postmenopausal is defined as at least 
12 months without menses with no other medical reasons 
(e.g., chemical menopause due to anticancer treatment). 
For WOCBP and for men, agreement to use a highly 
effective contraceptive method from the time of 
screening throughout the study until 4 months (WOCBP) 
or 6 months (men) after administration of the last dose of 
any study drug. Highly effective contraceptive methods 
consist of prior sterilization, intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), injectable 
or implantable contraceptives. All males (study subjects 
and partners of female subjects) must agree to use 
condoms throughout the study and 6 months after 
administration of the last dose. True abstinence is 
acceptable if evaluated as consistent with the preferred 
and the usual lifestyle of the subject. Periodic abstinence 
is not an acceptable method of contraception. 
9. Women of childbearing potential (WOCBP) must 
have a negative serum pregnancy test during screening 
and be neither breastfeeding nor intending to become 
pregnant during study participation. Female patients will 
be considered to be of childbearing potential unless they 
have undergone permanent sterilization or are 
postmenopausal. Postmenopausal is defined as at least 
12 months without menses with no other medical reasons 
(e.g., chemical menopause due to anticancer treatment). 
For WOCBP and for men, agreement to use a highly 
effective contraceptive method from the time of 
screening throughout the study until 4 months (WOCBP) 
or 6 months (men) after administration of the last dose of 
any study drug. Highly effective contraceptive methods 
consist of prior sterilization, intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), injectable 
or implantable contraceptives. All male study subjects 
must agree to use condoms throughout the study and 6 
months after administration of the last dose. Male 
partners of WOCBP subjects must agree to condom 
use throughout the study and for 4 months following 
the last dose of study drug. True abstinence is 
acceptable if evaluated as consistent with the preferred 
and the usual lifestyle of the subject. Periodic abstinence 
is not an acceptable method of contraception. 
Clarify that male 
partners of 
WOCBP subjects 
only need to agree 
to 4 months of 
condom use after 
their partner has 
taken the last dose 
of study drug. 
Synopsis, 
Inclusion 
Criteria #6 
 
Section 4.1, 
Inclusion 
Criteria #6 
6. Subject must have received prior standard therapy 
appropriate for their tumor type and stage of disease, or 
in the opinion of the Investigator, would be unlikely to 
tolerate or derive clinically meaningful benefit from 
appropriate standard of care therapy.  
• 
Subject must have received no more than 3 prior 
systemic regimens.  
• 
Maintenance therapy will not be counted as a 
separate regimen.  
• 
Adjuvant chemotherapy or chemotherapy 
Additional Criteria for Phase 1 Only 
13. Subject must have received prior standard 
therapy appropriate for their tumor type and stage of 
disease, or in the opinion of the Investigator, would 
be unlikely to tolerate or derive clinically meaningful 
benefit from appropriate standard of care therapy.  
• 
Subject must have received no more than 3 prior 
systemic regimens.  
• 
Maintenance therapy will not be counted as a 
separate regimen.  
Clarified that prior 
lines of therapy 
requirement is 
different for Phase 
1 and Phase 2 
patients (ie, move 
IC#6 down to be a 
requirement for 
Phase 1 patients 
only) 
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administered as part of concurrent chemotherapy and 
radiation therapy will not count as a prior regimen of 
systemic therapy as long as recurrence occurred more 
than 6 months after the last day of chemotherapy. 
• 
Adjuvant chemotherapy or chemotherapy 
administered as part of concurrent chemotherapy 
and radiation therapy will not count as a prior 
regimen of systemic therapy as long as recurrence 
occurred more than 6 months after the last day of 
chemotherapy. 
Synopsis, 
Inclusion 
Criteria #14 
 
Section 4.1, 
Inclusion 
Criteria #14 
 
Additional Inclusion Criteria for Phase 2 only: 
14. Histologically or cytologically confirmed diagnosis 
of advanced or metastatic NSCLC harboring a 
KRASG12D mutation. 
• 
Subject must have a documented KRASG12D 
mutation as determined by a qPCR or NGS test 
performed in a CLIA laboratory or 
equivalently accredited diagnostic laboratory. 
Additional Inclusion Criteria for Phase 2 only: 
14. Histologically or cytologically confirmed diagnosis 
of advanced or metastatic NSCLC harboring a 
KRASG12D mutation. 
• 
Subject must have a documented KRASG12D 
mutation as determined by a qPCR or NGS test 
performed in a CLIA laboratory or 
equivalently accredited diagnostic laboratory. 
Local tissue-based or liquid biopsy 
diagnostic testing will be permitted. 
Clarification: 
Acceptance of 
liquid biopsy qPCR 
/ NGS as local test 
(was and) should 
be explicitly stated 
as there’s adequate 
analytical 
performance for 
mutation testing 
Synopsis, 
Exclusion 
Criteria #10 
 
Section 4.2, 
Subject 
Exclusion 
Criteria #10 
10. History of extensive, disseminated, bilateral, or 
presence of CTCAE any grade interstitial fibrosis or 
interstitial lung disease including a history of 
pneumonitis, hypersensitivity pneumonitis, interstitial 
pneumonia, interstitial lung disease, obliterative 
bronchiolitis, and pulmonary fibrosis. 
10. Currently have or had a history of ILD, radiation 
pneumonitis that required steroid treatment, or drug-
related pneumonitis 
Clarified 
exclusionary 
criteria for subjects 
who have or had a 
history of ILD. 
Synopsis, 
Criteria for 
Evaluation 
 
Section 9.3, 
Study 
Endpoints 
 
 
Secondary Endpoints for Phase 1: 
• 
ORR assessed by BICR and Investigator using 
RECIST v1.1 
Phase 2 Primary Endpoint: 
• 
ORR assessed by BICR per RECIST v1.1. 
Phase 2 Secondary Endpoints: 
• 
ORR by Investigator 
• 
DOR, TTR, and CBR by BICR and 
Investigator. 
Secondary Endpoints for Phase 1: 
• 
ORR assessed by the Investigator using 
RECIST v1.1 
Phase 2 Primary Endpoint: 
• 
ORR assessed by Investigator per RECIST 
v1.1. 
Phase 2 Secondary Endpoints: 
• 
DOR, TTR, and CBR by the Investigator 
• 
Intracranial objective response rate (IC-ORR) 
assessed according to modified RECIST v1.1 in 
Since the study is a 
signal finding 
study, radiographic 
disease assessment  
by PI per RECIST 
v1.1 is sufficient to 
assess efficacy 
signal. 
BICR assessments 
will still be 
performed and may 
be analyzed. 
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• 
Intracranial objective response rate (IC ORR) 
assessed by BICR according to modified 
RECIST v1.1 in subjects with brain metastases. 
• 
… 
Exploratory Endpoints (All Phases): 
• 
Association of circulating tumor levels and 
genomic alterations at baseline and after dosing 
with ORR and PFS 
subjects with brain metastases. 
• 
… 
Exploratory Endpoints (All Phases0 
• 
ORR and PFS by modulation of circulating 
tumor levels and genomic alterations observed 
pre- and post-dosing 
Synopsis, 
Sample Size 
Determination 
 
Section 9.2.1.1, 
Sample Size 
Determination, 
Phase 1b Dose 
Escalation 
Phase 1b Dose Escalation 
For dose escalation, at least 6 subjects will be enrolled 
per dose level. Assuming 3 dose levels to be evaluated, it 
is expected that approximately 18  24 subjects will be 
enrolled to determine the RP2D of repotrectinib in 
combination with trametinib. 
Phase 1b Dose Escalation 
For dose escalation, 3 to 6 subjects will be enrolled per 
dose level. Assuming 3 dose levels to be evaluated, it is 
expected that approximately 18 – 24 subjects will be 
enrolled to determine the RP2D of repotrectinib in 
combination with trametinib 
To account for the 
possible alternate 
dose finding levels 
that may be 
explored. 
Schedule of 
Activities, 
Tumor 
Assessment. 
Cycle 4 and 
Beyond 
 
 
 
Cycle 4 and Beyond 
Tumor Assessment 
 
CT or MRI 
(chest/abdomen/pelvis) 
X 
CT or MRI of Brain 
X 
 
 
Cycle 4 and Beyond 
Tumor Assessment 
 
CT or MRI 
(chest/abdomen/pelvis) 
 
CT or MRI of Brain 
 
 
Correction to align 
with footnote that 
CT or MRI 
assessments occur 
every 2 cycles from 
Cycle 2 
Schedule of 
Activities, 
Footnote 8 
 
Added text 
8. Dispense Repotrectinib (C1D15): For subjects 
assigned to repotrectinib BID dosing regimens (Dose 
Level 3, -2b, or -3b), repotrectinib will be dispensed 
on Day 15 following physician assessment of safety to 
confirm escalation from QD to BID dosing. 
 
Footnote added to 
Schedule of 
Activities based on 
review of available 
safety and PK data 
from 2 patients 
treated with 
repotrectinib and 
trametinib at Dose 
Level 1, the SRC 
recommended a 
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dose level 
de-escalation to 
Dose Level -2 and 
recommended 
alternate dose 
finding levels 
Schedule of 
Activities, 
Footnote 18 – 
Bone Scan 
 
Section 6.16.3, 
Bone Scan 
 
18 Bone Scans: Bone scans (or bone MRI if preferred by 
Investigator) will be performed at baseline (28 days prior 
to Cycle 1 Day 1) if bone metastases are suspected. In 
addition, bone scans can be performed if clinically 
indicated per Investigator’s discretion. These scans are 
only repeated for subjects having a baseline scan, to 
confirm the absence of bone metastases in case of a 
Complete Response (CR). Subject responses will be 
confirmed ≥ 4 weeks later after the initial documentation 
of response by the Investigator and confirmed by BICR. 
21. Bone Scans: Bone scans (or bone MRI if preferred 
by Investigator) will be performed at baseline (28 days 
prior to Cycle 1 Day 1) if bone metastases are suspected. 
In addition, bone scans can be performed if clinically 
indicated per Investigator’s discretion. These scans are 
only repeated for subjects having a baseline scan, to 
confirm the absence of bone metastases in case of a 
Complete Response (CR). Subject responses will be 
confirmed ≥ 4 weeks later after the initial documentation 
of response by the Investigator. 
Since the study is a 
signal finding 
study, radiographic 
disease 
confirmation  by 
BICR is not 
needed. 
Section 1.5.1, 
Study TPX-
0005-09: Mass 
Balance, 
Pharmacokineti
cs, and 
Metabolism of 
Repotrectinib in 
healthy Male 
Subjects 
Section added 
TPX-0005-09 was conducted as a 2-part, 2-treatment, 
fixed-sequence study in 7 healthy male volunteers to 
investigate the mass balance, PK, and metabolism of 
a single oral dose and PK of an intravenous tracer of 
[14C]repotrectinib in healthy male subjects. The 
treatments were administered after an overnight fast 
of at least 10 hours. Below is a summary of key 
findings. Refer to the Investigator’s Brochure for 
further details. 
Following concomitant administration of a single oral 
dose of 160-mg repotrectinib capsule formulation and 
intravenous administration of tracer 
[14C]repotrectinib in study TPX-0005-09 (Period 1), 
the geometric mean absolute bioavailability of 
repotrectinib based on AUC0-¥ was approximately 
Provide updated 
PK half-life 
information for the 
IV formulation 
(32.5 h) and the 
oral capsule dose 
(36.2 h) of 
repotrectinib. 
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45.7%. The geometric means t1/2 of the IV 
formulation and the oral capsule dose were 32.5 and 
36.2 hours, respectively.  
Following oral administration of a 160 mg of 
[14C]repotrectinib (100 µCi) dose (TPX-0005-09, 
Period 2), the mean total recovery of radioactivity in 
excreta was 93.7% with radioactivity recoveries in 
feces and urine of 88.8% and 4.84%, respectively. No 
metabolite exceeded 10% of total circulating drug-
related radioactivity. All detected metabolites had 
been previously detected in rat and/or cynomolgus 
monkey following oral administration; therefore, 
there were no unique human metabolites. 
Section 1.6.1, 
Repotrectinib in 
Combination 
with 
Trametinib 
Therefore, the starting dose of repotrectinib in 
combination with trametinib for the Phase 1b dose 
escalation portion of the study will be 160 mg daily 
(QD), and the starting dose of trametinib will be 1.5 mg 
QD, one dose level below the standard trametinib 
monotherapy and combination dose to minimize possible 
safety risks in the initial evaluation of the combination 
therapy. 
Therefore, the starting dose of repotrectinib in 
combination with trametinib for the Phase 1b dose 
escalation portion of the study will be 120 mg daily 
(QD), and the starting dose of trametinib will be 2 mg 
QD. 
Modify the current 
dose finding levels 
in Subprotocol 1 to 
allow assessment 
of repotrectinib 
with lower doses of 
trametinib 
 
Section 3.4, 
Study Duration 
Subjects will remain on study treatment until Blinded 
Independent Central Review (BICR) confirmed 
radiographic disease progression, development of 
unacceptable toxicity, or withdrawal of consent. There is 
no limit to the number of cycles of treatment with 
repotrectinib or trametinib. 
Subjects will remain on study treatment confirmed 
radiographic disease progression, development of 
unacceptable toxicity, or withdrawal of consent. There is 
no limit to the number of cycles of treatment with 
repotrectinib or trametinib. 
Since the study is a 
signal finding 
study, radiographic 
disease 
confirmation by 
BICR is not 
needed. 
Section 3.5.1, 
Dose 
Interruptions 
and Delays, 
1 If subjects are assigned to the DL 1 dose level, further 
dose reductions will not be implemented. Subjects will 
be discontinued if a dose reduction is required 
1 If subjects are assigned to the Dose Level -3, further 
dose reductions will not be implemented. Subjects will 
be discontinued if a dose reduction is required 
Clarified dose 
modification 
guidelines for 
subjects assigned 
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Table 4 
Repotrectinib 
Dose 
Modification 
Guidelines for 
Adverse Events 
(CTCAE v5.0), 
Footnote 1 
to Dose Level -3 
with CTCAE 
adverse events 
Section 5.4, 
Concomitant 
Medications 
Added text 
Note on COVID-19 Vaccination: The use of vaccines 
is not a restriction for this study. Currently enrolled 
and potential adult clinical trial subjects are allowed 
to receive the COVID-19 vaccine with no impact on 
their eligibility or ability to remain on study 
treatment. This guidance will also apply to pediatric 
and adolescent patients once vaccine approval is 
available for these populations. In addition, there is 
not a required wash-out period for the vaccine. The 
risk-benefit for COVID-19 vaccination while on study 
should be determined by the treating physician. 
Administration of the COVID-19 vaccine will be 
recorded in the medical history or the concomitant 
medications CRF, as applicable, as well as any 
adverse events related to the vaccine. 
Provide guidance 
regarding COVID-
19 vaccination for 
study participants. 
Section 6.15 
Pharmacodyna
mic/Biomarkers 
Circulating cell-free DNA (ccfDNA) will be isolated 
from blood to study changes of circulating tumor levels 
(i.e., assessed by modulations of major allele frequency 
[MAF] of genomic alterations), and explore resistance 
mechanisms as well as clonal evolution 
Circulating cell-free DNA (ccfDNA) will be isolated 
from blood to study changes of circulating tumor levels 
(i.e., assessed by modulations of minor allele frequency 
[MAF] of genomic alterations), and explore resistance 
mechanisms as well as clonal evolution 
Correction to 
assessment by 
modulation of 
minor allele 
frequency 
Section 6.16, 
Tumor 
Assessments 
Tumor assessments will include all known or suspected 
disease sites and will be performed per specified 
timepoints according to the Schedule of Activities 
(Table 1). For all tumor assessments, the method of 
Tumor assessments will include all known or suspected 
disease sites and will be performed per specified 
timepoints according to the Schedule of Activities 
(Table 1). For all tumor assessments, the method of 
Clarified that 
tumor assessment 
by BICR will still 
be conducted on 
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assessment that was used at Screening should be the 
same method used throughout the study.  
For all subjects, radiographic confirmation of objective 
tumor response or disease progression will be based on 
RECIST v1.1 and assessed locally by Investigator and by 
BICR (Section 6.16.4). 
At the EOT visit, the subject must undergo an EOT 
tumor assessment evaluation CT or MRI (if more than 4 
weeks have passed since the last imaging assessment) to 
evaluate for radiologic disease progression if treatment is 
being discontinued for an alternate reason other than 
BICR confirmed radiographic disease progression. 
assessment that was used at Screening should be the 
same method used throughout the study. Tumor 
assessment will be assessed locally by Investigator 
and by BICR. 
For all subjects, radiographic confirmation of objective 
tumor response or disease progression will be based on 
RECIST v1.1 and assessed locally by Investigator 
(Section 6.16.4). 
At the EOT visit, the subject must undergo an EOT 
tumor assessment evaluation CT or MRI (if more than 4 
weeks have passed since the last imaging assessment) to 
evaluate for radiologic disease progression if treatment is 
being discontinued for an alternate reason other than 
confirmed radiographic disease progression. 
study but since the 
study is a signal 
finding study, 
radiographic 
disease 
confirmation  by 
BICR is not 
needed. 
 
Section 7.1, 
Screening and 
Eligibility 
 
• 
Imaging studies (CT or MRI of the chest, abdomen, 
and pelvis and MRI of the brain) should be submitted. 
and confirmed by BICR 
• 
Imaging studies (CT or MRI of the chest, abdomen, 
and pelvis and MRI of the brain) should be submitted for 
BICR assessment. 
Clarified that 
tumor assessment 
by BICR will still 
be conducted on 
study but since the 
study is a signal 
finding study, 
radiographic 
disease 
confirmation  by 
BICR is not 
needed. 
Section 7.3, 
Subject 
Discontinuation 
and 
Withdrawal 
from Study 
Subjects should remain on study treatment until there is 
BICR confirmed radiographic progression. 
 
Subjects should remain on study treatment until there is 
confirmed radiographic progression. 
 
Since the study is a 
signal finding 
study, radiographic 
disease 
confirmation by 
BICR is not 
needed. 
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Justification 
Section 7.8.3 
Palliative 
Radiation 
Palliative radiotherapy on study is permitted for the 
treatment of painful bony lesions providing the lesions 
were known at the time of study entry and the 
Investigator clearly indicates that the need for palliative 
radiotherapy is not indicative of disease progression. In 
view of the current lack of data about the interaction of 
study drug with radiotherapy, study drug treatment 
should be interrupted during palliative radiotherapy, 
stopping 1 day before palliative radiotherapy and 
resuming treatment 1 day after completion of palliative 
radiotherapy and recovery from any acute radiation 
toxicities to baseline 
Palliative radiotherapy on study is permitted, following 
agreement with the Sponsor, for the treatment of 
painful bony lesions provided the lesions were known at 
the time of study entry and the Investigator clearly 
indicates that the need for palliative radiotherapy is not 
indicative of disease progression. In view of the current 
lack of data about the interaction of study drug with 
radiotherapy, study drug treatment should be interrupted 
during palliative radiotherapy, stopping 1 day before 
palliative radiotherapy and resuming treatment 1 day 
after completion of palliative radiotherapy and recovery 
from any acute radiation toxicities to baseline 
Clarified that 
palliative 
radiotherapy 
permitted for pre-
existing bony 
lesions following   
Sponsor agreement 
Section 7.8.5. 
Contraception 
All fertile male (study subjects and partners of female 
subjects of WOCBP) must agree to condom use 
throughout the study and for 6 months following the last 
dose of study drug. Fertile male partners of WOCBP 
must agree to condom use throughout the study and for 4 
months following the last dose of study drug.  
. 
All male study subjects must agree to condom use 
throughout the study and for 6 months following the last 
dose of study drug. Male partners of WOCBP subjects 
must agree to condom use throughout the study and for 4 
months following the last dose of study drug. 
Clarified 
contraception 
requirement for 
males partners of 
female study 
subjects. 
Aligned with the 
synopsis inclusion 
criteria. 
Section 8.2.5.11, 
Exposure 
During 
Pregnancy 
If a study subject or study subject’s partner becomes or is 
found to be pregnant during the study subject’s treatment 
with the investigational product, the Investigator must 
submit this information to Premier Research 
Pharmacovigilance (Premier PV) on a SAE Report Form 
(if applicable) and Pregnancy Data Collection Form, 
regardless of whether an SAE has occurred. 
… 
Additional information regarding the exposure during 
pregnancy may be requested by the Investigator. Further 
If a study subject or study subject’s partner becomes or is 
found to be pregnant during the study subject’s treatment 
with the investigational product, the Investigator must 
submit this information to Premier Research 
Pharmacovigilance (Premier PV) on a SAE Report Form 
(if applicable) and Pregnancy Data Collection Form. 
… 
Additional information regarding the exposure during 
pregnancy may be requested by the Investigator. Further 
follow-up of birth outcomes will be handled on a case-
by-case basis (e.g., follow-up on preterm infants to 
identify developmental delays). In the case of paternal 
Revised to clarify 
the language and 
instructions for 
reporting of 
pregnancy during 
the study. 
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Revised Text 
Justification 
follow-up of birth outcomes will be handled on a case-
by-case basis (e.g., follow-up on preterm infants to 
identify developmental delays). In the case of paternal 
exposure, the Investigator will provide the study subject 
with the Pregnancy Data Collection Form to deliver to 
his partner. The Investigator must document in the 
source documents that the subject was given the 
Pregnancy Data Collection Form to provide to his 
pregnant partner. 
exposure, the Investigator will provide the study subject 
with the pregnant partner release of information form 
to deliver to his partner. The Investigator must document 
in the source documents that the subject was given the 
pregnant partner release of information form to 
provide to his pregnant partner. 
Section 9.2.1.1, 
Phase 1b Dose 
Escalation 
For dose escalation, at least 6 subjects will be enrolled 
per dose level. Assuming 3 dose levels to be evaluated, it 
is expected that approximately 18  24 subjects will be 
enrolled to determine the RP2D of repotrectinib in 
combination with trametinib 
For dose escalation, 3 to 6 DLT-evaluable subjects will 
be enrolled per dose level. Therefore, it is expected that 
approximately 24 – 30 subjects will be enrolled to 
determine the RP2D of repotrectinib in combination with 
trametinib 
To account for the 
possible alternate 
dose finding levels 
that may be 
explored. 
Section 9.4.3, 
Analysis of 
Primary 
Endpoint 
For Phase 1b, efficacy analysis will be performed in EE 
population. For Phase 2, the FAS analysis set will be 
used as the primary analysis for efficacy, and analyses 
using the EE population will be used as sensitivity 
analysis. Primary efficacy data will be based on the 
radiologic assessments evaluated by the BICR. Data 
from the Investigator will be analyzed as supportive. 
For Phase 1b, efficacy analysis will be performed in EE 
population. For Phase 2, the FAS analysis set will be 
used as the primary analysis for efficacy, and analyses 
using the EE population will be used as sensitivity 
analysis. Primary efficacy data will be based on the 
radiologic assessments evaluated by the Investigator. 
Data from BICR may be analyzed as supportive. 
 
Clarified that 
tumor assessment 
by BICR will still 
be conducted on 
study and may be 
analyzed as 
supportive, but 
since the study is a 
signal finding 
study, radiographic 
disease 
confirmation by 
BICR is not 
needed.  
 
 
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