A Phase 2, Subprotocol of DAY101 Monotherapy for Patients With Recurrent, Progressive, or Refractory Solid Tumors With MAPK Pathway Aberrations
Phase: PHASE2
Conditions: Melanoma, Solid Tumor, CRAF Gene Amplification, RAF1 Gene Amplification, BRAF Gene Fusion, BRAF Fusion, CRAF Gene Fusion, CRAF Fusion, RAF1 Gene Fusion, RAF1 Fusion, Thyroid Cancer, Papillary, Spitzoid Melanoma, Pilocytic Astrocytoma, Pilocytic Astrocytoma, Adult, Non Small Cell Lung Cancer, Non-Small Cell Adenocarcinoma, Colorectal Cancer, Pancreatic Acinar Carcinoma, Spitzoid Malignant Melanoma, Bladder Cancer, Bladder Urothelial Carcinoma, MAP Kinase Family Gene Mutation, RAF Mutation
Sponsor: Day One Biopharmaceuticals, Inc.

 
CLINICAL SUBPROTOCOL DAY101-102A 
A Phase 2, Subprotocol of DAY101 Monotherapy for 
Patients with Recurrent, Progressive, or Refractory Solid 
Tumors with MAPK Pathway Aberrations 
 
Investigational Product: 
DAY101 
Protocol Number: 
DAY101-102a 
IND #: 
108340 
EudraCT #: 
2021-003768-29 
Development Phase: 
2 
Sponsor: 
Day One Biopharmaceuticals, Inc. (Day One) 
2000 Sierra Point Parkway, Suite 501 
Brisbane, CA 94005 
Original Protocol  
09 February 2021 
Protocol Amendment 1.0 
Protocol Amendment 2.0 
01 September 2021 
19 October 2022 
 
 
Confidentiality Statement 
This document contains confidential information that is the property of Day One and may not be disclosed to 
anyone other than the recipient clinical investigator, research staff, and respective members of the Institutional 
Review Board//Research Ethics Board/Independent Ethics Committee/Human Research Ethics Committee. This 
information cannot be used for any purpose other than the evaluation of conduct of the clinical investigation 
without the prior written consent of Day One. 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
19 October 2022 
Protocol Amendment 2.0 Final 
Confidential & Proprietary 
Page 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Protocol DAY101-102a has been amended to incorporate the following major changes. 
The changes and rationale for each change are summarized in the table below. 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
19 October 2022 
Protocol Amendment 2.0 Final 
Confidential & Proprietary 
Page 4 
Section(s) 
Description of Change  
Brief Rationale 
Title page 
Updated Sponsor address. 
Administrative. 
Title page, 
Approval page 
Protocol versions will be referred to as 
protocol amendments. 
Revised to align with company formatting. 
List of 
Abbreviations and 
Definition of 
Terms 
Revised list of abbreviations. 
Align with current version of protocol 
Synopsis, 3.1 
Removed sentence: Patients ages 12 up to 
< 18 years will be included in the study 
provided their BSA is ≥ 1.5 m2. 
Updated study design schema. 
 
Correction. Sentence was removed as weight-
based dosing was added.  
Synopsis, 3.1.1 
Revised end of study to reflect 
approximately 25 months after last patient 
is enrolled. 
Corrected study duration.  
Synopsis, 4.1, 4.2 
Moved all eligibility criteria into 
sub- protocols. 
Restructured eligibility criteria between 
DAY101-102 and sub- protocols. 
Synopsis; 4.1 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
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Synopsis; 4.2 
• 
Clarified cardiac arrythmias. Added 
ischemia, ventricular hypertrophy, 
cardiomyopathy, or conduction 
disorder 
• 
Added electrolyte imbalances in serum 
potassium, magnesium, or calcium that 
are not currently adequately managed 
• 
Added patients with history of acute 
neurological events (such as 
intracranial or subarachnoid 
hemorrhage, stroke, intracranial 
trauma) within the past 6 months 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
19 October 2022 
Protocol Amendment 2.0 Final 
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Schedule of 
Activities (Table 1) 
• Addition of Tanner Stage 
• Addition of bone age 
• Addition of HIV/hepatitis serology 
assessments 
• Removed DAY101 dosing at 
 
 
• Removed AEs and concomitant 
medication on
 
• Corrected vital sign footnote 
• Added: Neurological Examination 
assessment and timepoints 
• Removed footnote “c” for 
ECHO/MUGA assessment; removed 
assessment at 
 
• Removed footnote “q” at 
 for 
freshly acquired tumor tissue 
• Added DAY101 Drug Dispensation/ 
Return assessment at 
 
• Clarified footnote “s”: tumor tissue 
archival sample collected preferably 
within the last 3 years  
• Clarified that assessments will be 
performed by an ophthalmologist or a 
qualified site clinical personnel. 
• Added “All patients: A baseline 
complete neurologic examination should 
be performed by the Investigator and/or 
a neurologist. Symptom directed 
neurologic examinations may be 
completed at subsequent visits. Tissue 
Agnostic Cohort: Patients with CNS 
tumors will have complete neurologic 
examinations performed at baseline and 
at 
 as indicated.” 
• Added: Triplicate ECGs on 
 
 
Editorial changes and corrections throughout 
Schedule of Activities and footnotes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per ANSM recommendation, included regular 
neurologic examinations for patients with 
CNS tumors who enroll in the Tissue 
Agnostic Cohort.  
 
 
 
 
 
Per ANSM recommendation, modified 
protocol to add requested triplicate ECGs. 
1.3.1 
Added results from Study 
FIREFLY-1/PNOC026 and Study 
 
5.2.1, Table 6 
Clarified dosing instructions. 
General dosing instructions revised to align 
with DAY101 programs. 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
19 October 2022 
Protocol Amendment 2.0 Final 
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5.2.3 
Added guideline for dose modification, 
inclusive of edema-associated adverse 
events (AEs). 
Per ANSM request, added dose modification 
guidelines for edema-associated AEs. 
5.2.4.1 
Clarified assessments will be performed by 
an ophthalmologist or a qualified site 
clinical personnel.  
 
Clarified discontinuation of DAY101 in 
the event of retinal detachment diagnosis. 
Provided guidance on who may perform 
ophthalmology examinations and visual 
symptom assessments. 
 
Per ANSM recommendation, revised guidance 
for retinal detachment. 
5.2.4.2 (Table 9) 
Added: If a Grade 4 rash recurs at a 
reduced dose, a second dose reduction is 
not acceptable, and discontinuation of 
treatment is required. 
Per ANSM recommendations, revised course 
of action in the case of a Grade 4 rash 
recurrence. 
5.2.4.3  
Added text to clarify sunglasses should be 
worn when exposed to sunlight/UV light. 
Increased skin protection factor (SPF) to 
≥50. 
 
Updated the recommendation for 
prophylactic skin care regimen. 
Per ANSM recommendations, added guidance 
on wearing sunglasses and increased SPF to 
≥50. 
 
 
To clarify all patients receiving DAY101 
should follow the prophylactic skin care 
regimen recommendations. 
5.2.4.4 (Table 9) 
Added: If a Grade 3 or 4 creatine 
phosphokinase (CPK) elevation is 
symptomatic, discontinuation of treatment 
is required. 
Per ANSM recommendations, clarified course 
of action if second occurrence of increase 
CPK occurs. 
5.2.4.4, Table 10 
Added bilirubin parameters. 
 
 
 
 
Removed “asymptomatic” for ≥ Grade 3 
adverse event grading. 
 
Clarified if Grade 3 or 4 liver function test 
(LFT) elevation recurs, a second dose 
reduction may be considered if 
asymptomatic and isolated. 
Per PCL-Canada recommendations, revised 
section to include bilirubin assessment 
guidance. 
 
 
Per ANSM recommendations, revised 
definition of Grade 3 increased liver 
transaminases. Also clarified course of action 
in the case of Grade 3 or 4 LFT elevation. 
5.2.4.5 
Added QTc prolongation guidance. 
Per ANSM recommendation, added guidelines 
for dose modification and ECG monitoring in 
the event of QTc prolongation. 
5.3.1 
Clarified window for recording 
medications in electronic case report form. 
Revised to align between studies. 
5.3.2; 5.3.3 
Revised text to advise medications that 
may cause hypomagnesemia or 
hypermagnesemia and hypophosphatemia 
should be used with caution. 
Per ANSM request, modified concomitant 
medications.  

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
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19 October 2022 
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5.3.4 
Added palliative radiotherapy.  
To provide guidance on palliative 
radiotherapy.   
5.5.3 
Clarified concomitant medications and 
recommendation of prohibited 
concomitant medications. 
To provide guidance and clarify medications 
that may not be used when receiving 
DAY101. 
6.6.2 
Addition of Tanner Stage 
To assess Tanner Stage for patients 12 to <18 
years of age at screening and yearly thereafter. 
6.6.7 
Clarified when neurological examinations 
should be performed for patients in the 
Tissue Agnostic Cohort. 
Per ANSM recommendation, added 
neurological examinations more frequently for 
patients with neurological tumors.  
6.7, 6.10, 6.15 
Added subheadings to align with DAY101 
Master study. 
Administrative. 
6.17 
Modified protocol to include justification 
of sample blood volumes in the pediatric 
population 
Per Agence Nationale de Sécurité du 
Médicament et des Produits de Santé (ANSM) 
recommendation, added language in 
accordance with the European Commission 
(EC)’s recommendations for pediatric patients 
(aged < 18 years). 
7.3.3 
Clarified pharmacokinetic analyses 
method. 
To clarify validated bioanalytical method will 
be used and concentrations will be 
summarized using standard summary 
statistics. 
8.2, 8.2.1, 8.2.1 
Revised language to reflect Safety Review 
Committee and Independent Monitoring 
Committee (IDMC) will be established. 
Per Federal Agency for Medicines and Health 
Products (FAMHP) request, added the 
implementation of a IDMC for analysis of 
cumulative safety data throughout study 
conduct. 
10 
Added new citations. 
Updated to reflect current version of protocol. 
Appendix A 
Revised list of medications that have 
possible CYPs and transporters 
interactions while using DAY101. 
To provide guidance on medications that may 
have possible interactions while using 
DAY101. 
Appendix B 
Added new appendix for medications 
known to cause QTc prolongation. 
Per ANSM recommendation, added guidelines 
for dose modification and ECG monitoring in 
the event of QTc prolongation. Included list of 
medications known to cause QTc 
prolongation. 
Additional minor formatting and editorial changes (not listed in the table above) have been 
made to improve clarity and to correct grammar and typographical errors. These include 
revisions to abbreviations and literature references, as applicable. 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
19 October 2022 
Protocol Amendment 2.0 Final 
Confidential & Proprietary 
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SYNOPSIS 
TITLE: 
A Phase 2, Subprotocol of DAY101 Monotherapy for Patients with Recurrent, Progressive, or Refractory 
Solid Tumors with MAPK Pathway Aberrations 
STUDY SITES: 
Approximately 15 institutions will participate in this study. 
PHASE: 
2 
OBJECTIVES: 
See Study Protocol DAY101-102 (Master Protocol) for a complete list of objectives.  
STUDY DESIGN: 
This is a Phase 2, multi-center, open-label sub-protocol of Master Protocol DAY101-102, which will enroll 
patients ≥12 years of age with recurrent or progressive melanoma or solid tumors with BRAF fusion or 
CRAF/RAF1 fusions or amplification. Patients with these alterations will be identified through molecular 
assays as routinely performed at Clinical Laboratory Improvement Amendments of 1988 (CLIA) or other 
similarly certified laboratories. In this sub-protocol, patients will be enrolled into a melanoma cohort or a 
“tissue agnostic” cohort. 
Study DAY101-102a will consist of a screening period, a treatment period, a safety/efficacy follow-up period, 
and a long-term follow-up period where survival status, and subsequent anticancer therapies will be collected. 
DAY101 will be administered to adult patients (≥ 18 years) at 600 mg orally (PO) once weekly (QW), the 
maximum tolerated dose (MTD) as determined from Takeda Study C28001 (
 on 
 
. For patients ages 12 to <18 years, DAY101 will be administered at a dose of 420 mg/m2 PO QW, the 
recommended Phase 2 dose (RP2D) as determined from the 
 study (
 not to exceed 
600 mg weekly. Cycles will repeat every 28 days in the absence of disease progression or unacceptable 
toxicity, withdrawal of consent, or death. Patients will undergo radiographic evaluation of their disease at the 
end of 
 for 1 year and then 
 thereafter. Patients will continue DAY101 until 
radiographic evidence of disease progression by criteria as appropriate for their disease setting, unacceptable 
toxicity, patient withdrawal of consent, or death. Generally, response assessment will be performed according 
to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for solid tumors. Alternative criteria 
may be used in specific disease settings, such as glioma, where response assessment will be assessed by 
Response Assessment in Neuro-Oncology (RANO) criteria. Appropriate response criteria for tumors will be 
described in Appendix B and Appendix C of the Master Protocol. 
Patients who have radiographic evidence of disease progression may be allowed to continue DAY101 if, in the 
opinion of the Investigator, the patient is deriving clinical benefit from continuing study treatment, and 
continuation of treatment is approved by the Sponsor. 
See Schedule of Activities for further details. 
MAJOR ELIGIBILITY CRITERIA: 
The eligibility and exclusion criteria listed below are interpreted literally and cannot be waived. 
INCLUSION CRITERIA 
The following inclusion criteria must be met to be eligible for enrollment in this study: 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
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1. Signed informed consent by patients ≥ 12 years of age; either a Consent or an Assent Form will be 
provided to the patient based on their capacity, local regulations, and guidelines. 
2. Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a 
BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplifications obtained through a tumor or liquid 
biopsy as assessed by genomic sequencing, polymerase chain reaction (PCR), fluorescence in situ 
hybridization (FISH), or another clinically accepted molecular diagnostic method recognized by local 
laboratory or regulatory agency 
3. Patients must have radiographically documented recurrent or radiographically documented progressive 
disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1, 
RANO). Imaging must be performed within 28 days prior to the first dose of study drug .  
5. Archival tumor tissue should be preferably less than 3 years old. If unavailable, a freshly acquired tumor 
tissue or liquid biopsy obtained at baseline to confirm presence of MAPK alteration is required. 
Note: If archival tissue is unavailable, freshly acquired tumor tissue or liquid biopsy is required at 
Screening.  
See also requirements to obtain fresh tissue biopsy for pharmacodynamic testing in the Schedule of 
Activities. 
6. Previous chemotherapy and hormone therapy (excluding physiologic replacement) must be completed at 
least 4 weeks or 5 half-lives, whichever occurs first, prior to initiation of therapy. 
7. Previous immunotherapy/monoclonal antibody/targeted therapy use must be completed at least 2 weeks or 
5 half-lives (whichever is shorter) prior to initiation of therapy. In addition, radiation therapy to the target 
lesion must be completed at least 6 months prior to initiation of therapy. 
8. All associated toxicity from previous therapies must be resolved to ≤ Grade 1 or considered baseline prior 
to initiation of therapy. 
9. If brain metastases are present, they must have been previously treated and be stable by radiographic 
imaging (must have imaging taken ≥ 4 weeks from treatment of brain metastasis) AND, if receiving 
corticosteroids, the patient must be neurologically stable by clinical examination and on a stable or a 
decreasing dose of corticosteroids within 7 days prior to study start. 
10. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1; For patients <16 years of 
age, a Lansky Performance Score > 70.  
11. Acceptable end-organ function as demonstrated by the following laboratory values: 
• 
Absolute neutrophil count (ANC) ≥ 1000/μL (neutrophil count may not be supported by 
hematopoietic growth factors within 2 weeks of the laboratory test)  
• 
Platelet count ≥ 75,000/μL (platelet count may not be supported by transfusions within 2 weeks of the 
laboratory test) 
• 
Hemoglobin ≥ 9 g/dL (hemoglobin may not be supported by transfusion, erythropoietin, or other 
approved hematopoietic growth factors within 2 weeks of the laboratory test) 
• 
Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 2 × ULN if patient is known to have 
Gilbert’s Disease as the only underlying hepatic disorder; Aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) ≤ 2.5 × ULN;  
• 
Serum creatinine clearance ≥ 60 mL/min/1.73 m2 calculated according to CKD-EPI (Appendix I of 
the Master Protocol) 

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Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
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EXCLUSION CRITERIA 
Patients who meet any of the following exclusion criteria will not be eligible for enrollment in this study:  
1. Prior receipt of any RAS-, RAF-, MEK-, or ERK-directed inhibitor therapy.  
2. Known presence of concurrent activating alterations. Examples include, but are not limited, to the 
following: EGFR, ALK, MET, ROS, FGFR, RET, NTRK, PIK3CA, IDH1/2, and cKIT. Genomic 
profile of tumor under study will be reviewed by the Sponsor to confirm eligibility. 
3. Current enrollment in any other investigational treatment study. 
4. Patients with current evidence or a history of serous retinopathy (SR), retinal vein occlusion (RVO), 
or ophthalmopathy present at screening or baseline who would be considered at risk for SR or RVO. 
5. Patients who have an unstable neurological condition, despite adequate treatment (e.g., uncontrolled 
seizures). 
8. Concomitant treatment with strong cytochrome (CYP)2C8 inhibitor and/or inducers within 14 days 
before initiation of therapy.  
9. Concomitant treatment with medications that are predominantly transported by breast cancer 
resistance protein (BCRP) substrates with a narrow therapeutic index within 14 days before initiation 
of therapy. Medications that are substrates of CYP2C8 are allowed but should be used with caution.  
12. Active, uncontrolled systemic bacterial, viral, or fungal infection. 
13. History of any major disease that might interfere with safe protocol participation, as determined by 
the Investigator (e.g., allogeneic bone marrow transplantation, organ transplantation, or interstitial 
lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis). 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
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Patients with subclinical pneumonitis who have received immunotherapy previously can be included 
if his/her condition is stable without any medical intervention. 
14. History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens 
Johnsons syndrome (SJS), or hypersensitivity to the investigational medicinal product or to any drug 
with similar chemical structure or to any other excipient present in the pharmaceutical form of the 
investigational medicinal product(s). 
15. History of second malignancy within 3 years prior to study treatment except for curatively treated 
cervical cancer in situ, non-melanoma skin cancer, or superficial bladder cancer. 
PLANNED SAMPLE SIZE: 
Up to 43 patients will be enrolled. Up to 18 patients will be enrolled in the melanoma cohort and up to 25 
patients will be enrolled in the “tissue agnostic” cohort.  
INVESTIGATIONAL DRUG: 
DAY101 for oral dosing is provided as a white to off-white 
 powder as a 100 mg immediate-release 
tablet. The 100 mg tablets are red to yellowish-red oval tablets. All products are labeled DAY101. 
TREATMENT PROCEDURES: 
Patients will initiate treatment at 600 mg QW for adults ≥ 18 years. Adolescents (12 to <18 years) will initiate 
treatment at 420 mg/m2 PO QW, not to exceed 600 mg weekly. Each cycle will consist of 28 days of weekly  
dosing. 
Individual patients will continue DAY101 using QW dosing until radiographic evidence of disease progression 
by criteria as appropriate for their disease setting (e.g., RECIST v1.1, RANO), unacceptable toxicity, patient 
withdrawal of consent, or death. Patients who demonstrate radiological progression may be allowed to 
continue DAY101 if, in the opinion of the Investigator and approval by the Sponsor, the patient is deriving 
clinical benefit from continuing study treatment. Disease assessments for patients being treated beyond 
progression should continue as per regular schedule. 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
DAY101 
19 October 2022 
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STUDY ASSESSMENTS: 
See Study Protocol DAY101-102 (Master Protocol) for study assessments across all sub-protocols. Additional 
study assessments included in this sub-protocol will be specified herein. 
For this sub-study, blood for PK assessments will be collected as follows: 
 
. The complete sampling details for PK blood 
samples is described in Table 10. 
All patients taking protocol therapy will have their imaging scans reviewed by a site or local radiologist. 
Copies of all eligibility, baseline, and on-treatment patient scans, as well as historical scans from the 12-month 
period immediately prior to the eligibility scan (if available), will be transferred to the central imaging lab for 
potential future evaluation as specified in the Imaging Manual. 
End of Study and Length of Study: 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or safety follow-up 
is received from the last patient, whichever occurs later. The end of the study is expected to occur 
approximately 25 months after the last patient is enrolled. In addition, the Sponsor may decide to terminate the 
study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is expected to be 
approximately 4 years. 
STATISTICAL METHODS: 
Sample Size Considerations: 
Simon’s 2-stage design (Simon, 1989) will be used to determine whether DAY101 has sufficient anticancer 
activity to warrant further development for each biomarker selected cohort. Enrollment per cohort may be 
terminated early independently of each other. No adjustment for multiple hypothesis testing will be made if 
both cohorts complete enrollment. 
In the melanoma cohort, up to 7 patients will be enrolled in Stage 1. If no patients achieve a complete response 
(CR) or partial response (PR); confirmed or unconfirmed) within a cohort, then enrollment within that cohort 
will terminate. If at least 1 patient achieves CR or PR, 11 additional patients will be enrolled within the cohort 
in the Stage 2. The null hypothesis assumes a true overall response rate (ORR) of less than 10%, and an 
alternative hypothesis of an ORR of 10% or more.  At a 1-sided alpha of < 0.10, there is 80% power for this 
cohort, if the true ORR is 30%. 
In the “tissue agnostic” cohort, up to 10 patients will be enrolled in Stage 1. If at least 2 patients achieve a CR 
or PR, an additional 15 patients will be enrolled within the cohort in the second stage. The null hypothesis 
assumes a true ORR of less than 10% and an alternative hypothesis of an ORR of 10% or more. At a 1-side 
alpha of < 0.1, there is 81% power for this cohort, if the true ORR is 30% 
The Sponsor may consider replacing the patient if the patient is not considered evaluable for response 
assessment in the Simon Stage 1. The stage 2 will not be activated if the stage 1 minimum number of 
responses (as shown in table below) is not met and all patients have been followed for at least 6 months.  
 
 
Null/Alternative 
Hypotheses 
Study Power 
 
Study Alpha 
(1-sided) 
Stage 1 n 
(Minimum Number of 
Responses to Move to 
Stage 2) 
Melanoma cohort 
 
 
 
 
Tissue agnostic 
cohort 
 
 
 
 
 
 

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Analysis Methods: 
For the primary analysis of the primary endpoint, for both cohorts, a 90% exact confidence interval (CI) will 
be calculated. See Study Protocol DAY101-102 (Master Protocol) for a description of analysis methods, 
including efficacy, safety, and pharmacokinetic analyses. 
Efficacy Analyses 
See Study Protocol DAY101-102 (Master Protocol) for a description of analysis methods for efficacy. 
Safety Analyses 
See Study Protocol DAY101-102 (Master Protocol) for a description of analysis methods for safety. 
Pharmacokinetic Analyses 
Plasma concentrations of DAY101 will be analyzed at specified time points using validated bioanalytical 
methods. Plasma concentrations will be summarized by nominal sample time using standard summary 
statistics for PK concentrations. 
 

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Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
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SCHEDULE OF ACTIVITIES 
Scheduled activities will be performed in Study DAY101-102a (Monotherapy Sub-protocol) 
as outlined in Table 1. Every effort should be made to ensure that each protocol-specific 
procedure is completed as described. Additional details regarding study procedures are 
included in Section 6 of the Master Protocol. 
 

Day One Biopharmaceuticals, Inc.  (Day One) 
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Table 1: 
Schedule of Activities 
Assessment 
Informed consent/ assentb 
Demographics  
Medical History 
ECOG or Lansky (for patients 
<16 years of age) 
Physical examinationc 
Neurologic Examinationd 
Dermatologic Examinationd 
Bone Agee 
Tanner Stagingf 
Vital signsg 
12-lead ECG in triplicateg 
Hematologyh 
Chemistryh 
Creatine phosphokinaseh 
Coagulation Panel 
(APTT/INR)i 

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Assessment 
Thyroid function testi 
HBcAb, HBsAg, HCV RNAj 
HIV-1 Ab, HIV-2 Ab, HIV 
viral load and CD4+ T cell 
countj 
Echocardiogram/MUGAk 
Ophthalmologic examl 
Visual symptom assessmentm 
Pregnancy testn 
Adverse eventso 
Concomitant medicationp 
Tumor assessment 
CT/MRIq 
Archival tumor tissue 
samplesr 
Freshly acquired tumor tissue 
sample (PD analysis) s,t 
PK Sampleu, v 
ctDNAv 
Additional anticancer 
treatment and survival statusw 
DAY101 dosingx 

Day One Biopharmaceuticals, Inc.  (Day One) 
Clinical Protocol DAY101-102a (Monotherapy Sub-study) 
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Assessment 
DAY101 Drug Dosing Diaryy 
DAY101 drug 
Dispensation/Returnz 
a Results of screening assessments must be reviewed by Investigator before patient enrollment to confirm that the patient meets the eligibility criteria. 
b Informed consent may be obtained greater than 
 but must be provided before any study-specific procedures are performed; 
however, evaluations performed as part of routine care prior to informed consent can be utilized as screening evaluations if permitted by site IRB/IEC policies. 
Assessments will be performed at the end of
 
 Assessments are to be performed on or up to 7 
days before the next cycle. For CT/MRI, assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is discontinued. 
To ensure image consistency, the same imagine modalities and acquisition protocols used at Screening are to be used for subsequent tumor assessments.   
c A complete physical examination, including weight, height, and vital signs will be performed 
 for all subjects. At subsequent physical exams only 
patients ages 12 to <18 should have height and weight collected. The physical exams will take place prior to the start of dosing of each 
 
; otherwise, a symptom-directed physical examination will be done.  
d All patients: A baseline complete neurologic examination should be performed by the Investigator and/or a neurologist. Symptom directed neurologic 
examinations will be completed at subsequent visits as indicated. A baseline complete dermatologic examination should be performed by the Investigator and/or a 
dermatologist. Symptom directed dermatologic examinations will be completed at subsequent visits as indicated. Tissue Agnostic Cohort: Patients with CNS 
tumors will have complete neurologic examinations performed at baseline and at subsequent visits as indicated. 
e All patients aged 18 years or less should have an assessment of bone age at baseline via bone age radiograph of the left wrist. For patients aged 12-18 years of age 
without epiphyseal closure at baseline, bone age via radiograph should be assessed 
 thereafter. 
f For patients 12 to < 18 years of age, pubertal stage will be measured 
 thereafter. For female patients, age at 
menarche will be recorded. Assessments will occur while on active treatment through sexual maturity. Refer to Study Protocol DAY101-102 (Master Protocol 
Section 6.9) for Tanner Staging details. 
g Vitals performed on days where pharmacokinetic (PK) collection occurs should be performed prior to collection. ECGs should be collected immediately before 
PK sample collections on days/timepoints when PK sampling occurs (within 15 minutes prior to the PK collection). Patients will rest at least 5 minutes prior to 
obtaining ECGs. Refer to Section 6.18 for PK sampling details. 
h Assessment will be performed at 
i Assessment will be performed at 
 and as 
clinically indicated. 
j Serology testing as defined according to local guidelines. 
k An echocardiogram or MUGA will be performed at screening, prior to DAY101 dosing at 
, or 
more frequently if clinically indicated. If the LVEF is found to have declined below the lower limit of normal or have declined ≥ 10% during the study, a re-
examination needs to be performed within 2 weeks. Must use the same assessment (ECHO or MUGA) at screening and throughout the study. 

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l For ophthalmologic examinations, a full examination by an opthalmologist or other qualified site clinical personnel will be conducted at screening and as 
clinically indicated if changes in visual symptoms occur throughout the study.  
m Investigator or qualified site staff will inquire for changes in visual symptoms at every visit (from 
). If change and/or abnormality is 
reported, this should be recorded as an adverse event and the patient should be referred to an ophthalmologist or other qualified site clinical personnel for further 
examination.  
n Assessment will be performed predose at all in-clinic visits and at other timepoints indicated in the Schedule of Activities, or if clinically indicated on patients of 
child-bearing potential only. 
o See Study Protocol DAY101-102 (Master Protocol) Section 8.1.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) for instructions regarding AE collection.   
p Document concomitant medication taken from 
 
q Assessments will be performed at the end of
 
 Assessments are to be performed on or 
up to 7 days before the next cycle. For CT/MRI, assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is 
discontinued. To ensure image consistency, the same imagine modalities and acquisition protocols used at Screening are to be used for subsequent tumor 
assessments.  For patients who discontinue study treatment before radiographic progressive disease, tumor assessment will progress accordingly as if on study 
treatment and these patients will be requested to return to site for continued monitoring and assessment.  
r A tumor tissue archival sample which preferably has been collected within the last 3 years. See Section 6.4 and Laboratory Manual for specific instructions. 
s A freshly acquired tumor tissue sample collected at screening may also be used for assessment of ERK phosphorylation status (as part of the PD analysis) and 
ERK-regulated gene expression. If no fresh tumor tissue sample was collected at 
 a sample will be taken 
 if accessible and can be safely 
performed. An additional on-treatment tumor sample will be collected 
, if accessible and can be safely 
performed. Fresh tumor tissue collection is considered optional for patients 12 to < 18 years of age. 
t Refer to Table 10 for PK blood sample schedule. The complete sampling details for PK blood samples will be described in the Laboratory Manual. 
u PK samples will also be collected if a serious adverse event (SAE) or suspected unexpected serious adverse reaction (SUSAR) occurs. 
v Additional patient blood samples will be collected by blood draw prior to start of any new therapy. 
w Patients will be contacted every 
 after Safety Follow-up visit until death, these data may be obtained by phone. 
x DAY101 will be administered in-clinic on
. On days not in-clinic, DAY101 will be taken once weekly at home until study 
treatment is discontinued.  In the event that the in-clinic visit does not occur on the exact Visit Day as shown in Schedule of Activities 
 
, dosing should be withheld until patient is in the clinic and completes necessary predose visit activities. Note: Within the Schedule of Activities table 
above at 
, dosing is indicated at 
, however, DAY101 will continued to be taken weekly at home unless instructed otherwise by the 
Investigator. Patients will return unused drug at the start of each cycle. No dosing will occur at the EOT visit, only study drug return will take place.  
y The study diary will be provided at 
. The study diary will be completed by the patient, or patient’s parent or legal guardian, for every dose of 
study drug administered starting at 
 The Investigator or study staff should review diary entries for compliance, in particular for any potential 
missed doses, at every in-clinic, or remote visit. Study diary from last cycle should be returned and reviewed at 
 
z DAY101 is to be dispensed to patients 
 and unused drug should be returned at the start of the following cycle. Study drug from last cycle should 
be returned at 
      

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...................................... 3 
SYNOPSIS .................................................................................................................. 9 
SCHEDULE OF ACTIVITIES .................................................................................. 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 24 
1. 
INTRODUCTION .................................................................................. 27 
1.1. 
Background on Disease .......................................................................... 27 
1.2. 
Background on DAY101 ........................................................................ 29 
1.3. 
Study Rationale and Dose Justification .................................................. 29 
1.3.1. 
Study Rationale ....................................................................................... 29 
1.3.2. 
Justification for Dose .............................................................................. 30 
1.3.3. 
Benefit/Risk ............................................................................................ 30 
2. 
STUDY OBJECTIVES .......................................................................... 31 
3. 
INVESTIGATIONAL PLAN ................................................................. 32 
3.1. 
Study Design ........................................................................................... 32 
3.1.1. 
End of Study and Length of Study ......................................................... 33 
3.1.2. 
Number of Patients ................................................................................. 33 
3.2. 
Investigational Sites ................................................................................ 33 
4. 
SELECTION OF STUDY POPULATION ............................................ 34 
4.1. 
Inclusion Criteria .................................................................................... 34 
4.2. 
Exclusion Criteria ................................................................................... 36 
5. 
TREATMENT ........................................................................................ 38 
5.1. 
Investigational Product ........................................................................... 38 
5.2. 
DAY101 Administration ........................................................................ 38 
5.2.1. 
General Dosing Instructions ................................................................... 38 
5.2.2. 
Dose-Limiting Toxicity .......................................................................... 38 
5.2.3. 
Dose Modifications ................................................................................. 39 
5.2.4. 
Management of Treatment-Related Events ............................................ 39 
5.2.4.1. 
Ocular Disturbances ................................................................................ 39 
5.2.4.2. 
Dermatologic Toxicity ............................................................................ 41 
5.2.4.3. 
Photosensitivity ....................................................................................... 42 
5.2.4.4. 
Increased Creatine Phosphokinase ......................................................... 42 
5.2.4.5. 
Increased Liver Transaminases and Bilirubin ........................................ 42 

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5.2.4.6. 
QTc Prolongation .................................................................................... 43 
5.3. 
Removal of Patients from Therapy or Assessment ................................. 44 
5.4. 
Prior and Concomitant Medications ....................................................... 44 
5.4.1. 
General .................................................................................................... 44 
5.4.2. 
Allowed Concomitant Medications ........................................................ 44 
5.4.3. 
Prohibited Concomitant Medications ..................................................... 45 
5.4.4. 
Palliative Radiotherapy ........................................................................... 45 
6. 
TESTS AND EVALUATIONS .............................................................. 46 
6.1. 
Screening ................................................................................................ 46 
6.2. 
Enrollment .............................................................................................. 46 
6.3. 
Medical History and Malignancy History .............................................. 46 
6.4. 
Archival Tumor Samples ........................................................................ 46 
6.5. 
Freshly Acquired Tumor Samples for Pharmacodynamic Analysis ....... 46 
6.6. 
ctDNA Samples: Blood .......................................................................... 46 
6.7. 
Physical Examination ............................................................................. 46 
6.8. 
Eastern Cooperative Oncology Group (ECOG) /Lansky Performance 
Status ....................................................................................................... 46 
6.9. 
Assessment of Change in Pubertal Development (Tanner Stage) .......... 47 
6.10. 
Vital Signs .............................................................................................. 47 
6.11. 
Ophthalmology Examination (All Patients) ........................................... 47 
6.12. 
Visual Symptom Assessment ................................................................. 47 
6.13. 
Dermatologic Examination ..................................................................... 47 
6.14. 
Neurologic Examination ......................................................................... 47 
6.15. 
Height and Bone Age .............................................................................. 47 
6.16. 
Cardiac Function ..................................................................................... 47 
6.16.1. 
Electrocardiograms ................................................................................. 47 
6.16.2. 
Echocardiogram/Multiple-Gated Acquisition ........................................ 47 
6.17. 
Laboratory Tests ..................................................................................... 48 
6.17.1. 
Pregnancy Test ........................................................................................ 48 
6.17.2. 
Hematology ............................................................................................. 48 
6.17.3. 
Serum Chemistries .................................................................................. 48 
6.17.4. 
Coagulation Panel ................................................................................... 48 
6.17.5. 
Thyroid Function Tests ........................................................................... 48 

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6.18. 
Pharmacokinetic Samples: Blood ........................................................... 48 
6.19. 
Disease Assessment ................................................................................ 49 
6.19.1. 
Tumor Measurements ............................................................................. 49 
6.19.1.1. 
Collection of Radiographic Studies for Independent Review ................ 49 
6.20. 
Telephone/Telemedicine Visit ................................................................ 49 
6.21. 
Survival Status ........................................................................................ 49 
6.22. 
Study Drug Administration and Dosing Diary ....................................... 49 
6.23. 
Concomitant Medication ........................................................................ 49 
6.24. 
End of Treatment Visit ........................................................................... 49 
6.25. 
Safety Follow-up Visit ............................................................................ 49 
6.26. 
Long-Term Follow-up ............................................................................ 49 
6.27. 
Force Majeure Flexibility ....................................................................... 49 
7. 
PLANNED ANALYSES ........................................................................ 50 
7.1. 
Analysis Populations .............................................................................. 50 
7.2. 
Determination of Sample Size ................................................................ 50 
7.3. 
Statistical Methods .................................................................................. 51 
7.3.1. 
Efficacy Analyses ................................................................................... 51 
7.3.2. 
Safety Analyses ...................................................................................... 51 
7.3.3. 
Pharmacokinetic Analyses ...................................................................... 51 
8. 
ADVERSE EVENTS .............................................................................. 52 
8.1. 
Stopping Rules ........................................................................................ 52 
8.2. 
Independent Data Monitoring Committee .............................................. 52 
8.2.1. 
Risk Management ................................................................................... 52 
8.2.2. 
Continuous Review of Safety Data ......................................................... 52 
9. 
STUDY ADMINISTRATION ............................................................... 53 
10. 
REFERENCES ....................................................................................... 54 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................. 16 
Table 2: 
Summary of Systemic Treatment Regimen and Outcome in Tumors with 
BRAF Fusions in Adult Patients ............................................................. 29 
Table 3: 
Dose Rounding Guidelines in Adolescents with BSA 0.9 ->1.4 m2 for 
DAY101 420 mg/m2 QW ....................................................................... 38 
Table 4: 
Dose Level Reductions for DAY101 Based on Recommend Phase 2 
Dose for Weekly Regimen in Adult and Adolescent Patients ................ 39 
Table 5: 
Serous Retinopathy (SR)/Serous Retinal Detachment (SRD)/Retinal 
Pigment Epithelium Disorder (RPED) Management Recommendations
 ................................................................................................................ 40 
Table 6: 
Rash Management Recommendations .................................................... 41 
Table 7: 
Increased Creatine Phosphokinase Management Recommendations ..... 42 
Table 8: 
Increased Liver Transaminases and Bilirubin Recommendations .......... 43 
Table 9: 
QTc Prolongation Recommendations ..................................................... 44 
Table 10: Schedule of Blood Sample Collections for DAY101 Pharmacokinetics 49 
Table 11: Sample Size Determinations ................................................................... 51 
Table 12: List of Medications with Potential Drug Interactions with DAY101 ..... 57 
Table 13: Drugs Associated with QTc Prolongation and Torsades de Pointes ...... 58 
 
 
LIST OF FIGURES 
Figure 1: 
Mechanism of Fusion Oncogene Action ................................................ 27 
Figure 2: 
Study Design Schema ............................................................................. 32 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation  
or Term 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the concentration-time curve from time zero to t 
BCRP 
breast cancer resistance protein 
BCVA 
best corrected visual acuity 
BP 
blood pressure 
BRAF 
v-raf murine sarcoma viral oncogene homolog B 
BSA 
body surface area 
BUN 
Blood urea nitrogen 
C 
cycle 
CI 
confidence interval 
CKD 
chronic kidney disease 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CR 
complete response 
CRAF 
v-raf murine sarcoma viral oncogene homolog C 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
D 
Day 
DMC 
Data Monitoring Committee 
DRESS 
drug reaction with eosinophilia and systemic symptoms 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
ERK 
extracellular signal-related kinase 
FDA 
Food and Drug Administration 

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Abbreviation  
or Term 
Definition 
FFPE 
formalin-fixed, paraffin-embedded 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practices 
HREC 
Human Research Ethics Board 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LGG 
low-grade glioma 
LTFU 
long-term follow-up 
LVEF 
left ventricular ejection fraction 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated protein kinase 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
Multiple-gated acquisition 
NCI 
National Cancer Institute 
NSCLC 
non small cell lung carcinoma 
ORR 
overall response rate 
PCR 
polymerase chain reaction 
pERK 
phosphorylated ERK 
PFS 
progression-free survival 
PK 
pharmacokinetic(s)  
pLGG 
pediatric low-grade glioma 
PO 
per os, orally 
PR 
partial response 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
Q2D 
every other day 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate by Fridericia's formula 
QW 
once weekly 
RAF1 
Raf-1 Proto-Oncogene, Serine/Threonine Kinase 
RANO 
Response Assessment in Neuro-Oncology 

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Abbreviation  
or Term 
Definition 
RDD 
rhegmatagenous retinal detachment 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RPED 
retinal pigment epithelium disorder 
R/R 
relapsed or refractory 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens Johnsons syndrome 
SPF 
Skin protection factor 
SR 
serous retinopathy 
SRD 
serous retinal detachment 
SUSAR 
suspected unexpected serious adverse reaction 
T3 
triiodothyronine 
T4 
tetraiodothyronine 
t1/2  
half-life 
TEAE 
treatment-emergent adverse event  
THC 
tetrahydrocannabinol 
tmax 
time to reach maximum drug concentration 
TPCV 
thioguanine, procarbazine, lomustine, and vincristine 
TTR 
time to response 
ULN 
upper limit of normal 
UV 
ultraviolet 
WHO 
World Health Organization 
 

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1. 
INTRODUCTION 
See Study Protocol DAY101-102 (Master Protocol). 
1.1. 
Background on Disease 
Oncogenic v-raf murine sarcoma viral oncogene homolog B (BRAF) fusions originate from 
genomic rearrangements placing the 3’ portion of the BRAF gene encoding the kinase 
domain behind another gene at the 5’ position. The rearrangements result in the expression of 
oncoproteins that are constitutively active due to loss of the auto-inhibitory domain of BRAF 
and whose expression is controlled by the promoter of the 5’ partner (Lu et al. 2017). 
Figure 1: 
Mechanism of Fusion Oncogene Action 
 
Abbreviations: BRAF, v-raf murine sarcoma viral oncogene homolog B. 
Source: Jones et al. 2012. 
BRAF fusions involving the intact and in-frame BRAF kinase domain were observed in 
approximately 0.3% of samples analyzed with Foundation Medicine’s FoundationOne™ 
comprehensive genomic profiling (55/20,537) and MSK-IMPACT™ testing (33/10,945), 
although proportion varies accordingly with tumor histology (Ross et al. 2016, Zehir et al. 
2017). BRAF fusion alterations are reported in 3% (14/531) of melanoma, 2% (3/1062) of 
glioma and approximately 1% in thyroid, pancreatic, non-small cell lung carcinoma 
(NSCLC), and colorectal cancers (Ross et al. 2016). Given their rarity, the significance of 
BRAF fusions for clinical outcome is unknown. However, these incidences of BRAF fusions 
were assessed in patients primarily with relapsed/refractory or advanced cancers whose 
overall prognostic outcome is generally poor. 
v-raf murine sarcoma viral oncogene homolog C (CRAF)/ Raf-1 Proto-Oncogene, 
Serine/Threonine Kinase (RAF1) fusions, while rare, have also been reported in low-grade 
glioma (LGG) (Jones et al. 2009, Ryall et al. 2020) and melanoma (Williams et al. 2020). 
These fusions have also been shown to upregulate the mitogen-activated protein kinase 
(MAPK) pathway signalling (Jain et al. 2017, Ryall et al. 2020).   
To date, there are no approved therapies specifically targeting treatment of adult or pediatric 
patients with oncogenic BRAF or CRAF fusion-positive tumors. The 3 Food and Drug 
Administration (FDA)-approved treatments for tumors with BRAF V600E/K mutations - 

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vemurafenib, dabrafenib, and encorafenib (Type-I BRAF inhibitors) are inappropriate for use 
in treatment of BRAF or CRAF fusions due to the potential for paradoxical activation of the 
MAPK pathway associated with dimerization with RAF in wild-type BRAF settings 
(Sanchez et al. 2008). Type-I BRAF inhibitors have been shown to result in paradoxical 
activation of pediatric low-grade glioma (pLGG) models driven by the KIAA1549:BRAF 
fusion and accelerate the growth of tumor models driven by the KIAA1549:BRAF fusion. 
Clinical proof of concept for this phenomenon occurred in 2014 when the multikinase 
inhibitor sorafenib, which blocks BRAF V600 in a manner similar to other Type-I BRAF 
inhibitors, was studied in children with pLGGs and produced unexpected and unprecedented 
acceleration in tumor growth. This effect was later found to be related to paradoxical 
extracellular signal-related kinase (ERK) activation (Karajannis et al. 2014). Although 
currently approved mitogen-activated protein kinase (MEK) inhibitors (cobimetinib, 
trametinib, and binimetinib) can block MAPK signalling resulting from BRAF or CRAF 
fusions, they do not directly inhibit RAF, and are associated with significant cardiac, 
dermatologic, and ophthalmologic toxicities. Use of these MEK inhibitors is still considered 
investigational in BRAF or CRAF fusion tumors. 
Standard of care for adult patients with advanced cancer varies across tumor types. Most 
commonly, BRAF fusions have been reported in melanoma, LGG, and thyroid cancer. CRAF 
fusions, while rare, have been reported in melanoma and LGG. As an example, a summary 
table of systemic treatment regimen and outcome for adult patients based on literature and 
National Comprehensive Cancer Network (NCCN) Guidelines 2020 is provided in Table 2. 
Treatment for advanced cancers in pediatric patients are poorly studied given the rarity of 
these cancers in general and carcinoma histology. Of the targeted therapies approved for 
treatment of melanoma and thyroid carcinoma in adults, only ipilimumab, selpercatinib, 
dabrafenib/trametenib are indicated for treatment of certain pediatric patients. After 
standard-of-care treatment is exhausted for adults, new therapies are required for this rare 
population with limited treatment options. 
Recurrent rearrangements in RAF have been found to occur in advanced prostate cancers, 
gastric cancers and melanoma (Palanisamy et al. 2010). Beyond BRAF fusions, CRAF/RAF1 
fusions have also been detected in melanoma and LGG and while rare, these can also 
constitutively activate the MAPK pathway (Williams et al. 2020, Ryall et al. 2020).  Thus, 
inhibition of CRAF/RAF1 fusions with a Type II pan-RAF inhibitor such as DAY101 could 
be a therapeutic strategy to target tumors harboring CRAF/RAF1 fusions.  
Lastly, emerging research has identified a unique subset of urothelial tumors with focal 
amplification of the RAF1 kinase gene. RAF1-amplified tumors have activation of the 
RAF/MEK/ERK signaling pathway and exhibit a luminal gene expression pattern. Genetic 
studies demonstrate that RAF1-amplified tumors are dependent upon RAF1 activity for 
survival. These data identify RAF1 as a novel dependency in a subset comprising nearly 12% 
of urothelial tumors and suggest that targeting RAF1-mediated signaling represents a 
rationale therapeutic strategy (Bekele et al. 2021). 

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Table 2: 
Summary of Systemic Treatment Regimen and Outcome in Tumors with 
BRAF Fusions in Adult Patients 
Tumor 
Type 
Systemic 
Therapy 
Regimen 
Outcome 
Melanoma 
1st line  
Nivolumaba, Pembrolizumabb,e 
ORR (range): 32.9–45% 
Median OS (range): 36.9 mo1 –NR5 
Nivolumab and Ipilimumabc  
ORR, 58% (95% CI: 53−64)1 
Median OS > 60 mo (95% CI: 38.2 to NR)1 
2nd line  
Nivolumab3, Pembrolizumabd, f 
ORR (range): 21–32% 
Median OS (range): 13.4 mo–15.7 mo  
Low-Grade 
Glioma 
1st lineg 
 
Temozolomide (TMZ), or 
Procarbazine, Lomustine, and 
Vincristine (PCV) 
ORR: (range) 
- 
TMZ (43–54%),  
- 
PCV (59–63%) 
Median PFS: (range) 
- 
TMZ (11.5 mo, 31 mo),  
- 
PCV (20 mo, 30.7 mo) 
RAFi 
Refractory 
Thyroid 
Carcinoma 
1st lineh 
Tyrosine Kinase Inhibitor: 
- 
MTC - Vandetanib, 
Cabozatinib, Praseltinib, 
Selpercatinib; 
- 
DTC - Sorafenib, 
Lenvatinib 
ORR: (range) 
- 
MTC (28–69%), 
- 
DTC (12.2–64.8%) 
Median PFS: (range) 
- 
MTC (11.2 mo, 30.5 mo), 
- 
DTC (10.8 mo, 18.3 mo) 
2nd linei 
Chemotherapy: bleomycin, 
doxorubicin, platinum 
compound, etoposide 
Limited to no response. ORR 37% observed in a 
small study with doxorubicin based on WHO 
criteria. 
Abbreviations: CI, confidence interval; DTC, differentiated thyroid carcinoma; mo, months; MTC, medullary 
thyroid cancer; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; WHO, World Health Organization. 
Source: aOpdivo Prescribing Information, bRobert et al. 2019, cWeber et al. 2014, dRibas et al. 2015, eSchacter 
et al. 2017, fHamid et al. 2017, g Taal et al. 2011 (no treatment considered standard), hLirov et al. 2017, 
iSherman et al. 2010 
1.2. 
Background on DAY101 
See Study Protocol DAY101-102 (Master Protocol). 
1.3. 
Study Rationale and Dose Justification 
1.3.1. 
Study Rationale 
The Type-II BRAF inhibitors have been shown preclinically to inhibit both BRAF V600 
mutations, BRAF fusions, and CRAF (Botton et al. 2019, Sun et al 2017).  
Case reports have demonstrated that inhibitors of the MAPK pathway have anti-tumor  
activity against different BRAF fusions and tumor histology (Spitzoid melanoma patient with 
ZKSCAN1:BRAF, malignant spindle cell tumor with KIAA1549:BRAF) (Subbiah et al. 
2014, Menzies et al. 2015).  
 
. Centrally reviewed radiographic assessments are available from 9 
patients enrolled into the dose escalation portion of the study (Wright et al. 2020). Eight of 
the 9 patients harbored a RAF fusion (7 harbored the canonical KIAA1549:BRAF fusion and 

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one harbored a SRGAP3-RAF1 gene fusion). Five of 8 (63%) patients with a RAF fusion 
have achieved a complete response (CR) or partial response (PR) with a median time to 
response (TTR) of 10.5 weeks. In addition, 77 pLGG patients have been dosed with DAY101 
in Arm 1 of the FIREFLY-1/PNOC026 study (
 Preliminary efficacy and 
safety data have been noted in the master protocol. 
The purpose of this study is to additionally evaluate the efficacy and safety of DAY101 as 
monotherapy in the treatment of adults and adolescents with relapsed, refractory solid tumors 
and BRAF or RAF1 fusions or RAF1 amplifications who have exhausted standard of care 
treatments available, including locally directed therapy, such as surgery or radiotherapy.  
1.3.2. 
Justification for Dose 
See Study Protocol DAY101-102 (Master Protocol). 
1.3.3. 
Benefit/Risk 
See Study Protocol DAY101-102 (Master Protocol). 

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2. 
STUDY OBJECTIVES 
See Study Protocol DAY101-102 (Master Protocol) for a complete list of objectives and 
endpoints. 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is a Phase 2, multi-center, open-label sub-protocol of Master Protocol DAY101-102, 
which will enroll patients ≥12 years of age with recurrent or progressive melanoma or solid 
tumors with BRAF fusion or CRAF/RAF1 fusions or amplification. Patients with these 
alterations will be identified through molecular assays performed at Clinical Laboratory 
Improvement Amendments of 1988 (CLIA) or other similarly certified laboratories. Patients 
will be enrolled into either a melanoma cohort or a “tissue-agnostic” cohort. 
The study design will consist of a screening period, a treatment period, a safety follow-up 
period, and a long-term follow-up (LTFU) period where survival status, and subsequent 
anticancer therapies will be collected. 
DAY101 will be administered to adult patients (≥ 18 years) at 600 mg orally (PO) once 
weekly (QW), the maximum tolerated dose (MTD) as determined from Takeda Study 
C28001 (
 on 
. For patients ages 12 to <18 years, 
DAY101 will be administered at a dose of 420 mg/m2 PO QW, the recommended Phase 2 
dose (RP2D) as determined from the 
 study (
 not to exceed 600 mg 
weekly. Treatment cycles will repeat every 28 days in the absence of disease progression, 
unacceptable toxicity, withdrawal of consent, or death. Patients will undergo radiographic 
evaluation of their disease at baseline, and then at the end of 
 for 1 year and 
then 
 thereafter.  
Patients who have radiographic evidence of disease progression may be allowed to continue 
DAY101 if, in the opinion of the Investigator, the patient is deriving clinical benefit from 
continuing study treatment, and continuation of treatment is approved by the Sponsor. 
Generally, response assessment will be performed according to Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 for solid tumors and Response Assessment in Neuro-
Oncology (RANO) for central nervous system (CNS) tumors. Appropriate response criteria 
for tumors are described in Appendix B and Appendix C of the Master Protocol DAY101-
102. 
See Schedule of Activities for further details. The study design schema is shown in Figure 2. 
Figure 2: 
Study Design Schema 
 
Abbreviations: FU, follow-up; PO, by mouth or orally; QW, once weekly 

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3.1.1. 
End of Study and Length of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or 
safety follow-up is received from the last patient, whichever occurs later. The end of Study 
DAY101-102a is expected to occur 25 months after the last patient is enrolled. In addition, 
the Sponsor may decide to terminate this study at any time. 
The total length of this study, from screening of the first patient to the end of study, is 
expected to be approximately 4 years. 
3.1.2. 
Number of Patients 
Up to 43 patients will be enrolled. Up to 18 patients will be enrolled in the melanoma cohort, 
and up to 25 patients will be enrolled in the “tissue agnostic” cohort. 
3.2. 
Investigational Sites 
Approximately 15 institutions will participate in this study. 

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4. 
SELECTION OF STUDY POPULATION 
Potential patients and/or their parents must sign an informed consent form (ICF) and 
pediatric assent form, where applicable, before any study-specific screening tests may be 
conducted.  
The eligibility and exclusion criteria listed below are interpreted literally and cannot be 
waived. 
4.1. 
Inclusion Criteria 
The following inclusion criteria must be met to be eligible for enrollment in this study: 
1. Signed informed consent by patients ≥ 12 years of age; either a Consent or an Assent 
Form will be provided to the patient based on their capacity, local regulations, and 
guidelines.  
2. Patients must have a report of histologically confirmed diagnosis of melanoma or 
other solid tumor and a BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 
amplifications obtained through a tumor or liquid biopsy as assessed by genomic 
sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization 
(FISH), or another clinically accepted molecular diagnostic method recognized by 
local laboratory or regulatory agency. 
3. Patients must have radiographically documented recurrent or radiographically 
documented progressive disease that is measurable using the appropriate tumor 
response criteria (e.g. RECIST version 1.1, RANO). Imaging must be performed 
within 28 days prior to the first dose of study drug.  
5. Archival tumor tissue should be preferably less than 3 years old. If unavailable, a 
freshly acquired tumor tissue biopsy or liquid biopsy obtained at baseline to confirm 
presence of MAPK alteration is required . 
Note: If archival tissue is unavailable, freshly acquired tumor tissue or liquid biopsy 
is required at Screening.  
See also requirements to obtain fresh tissue biopsy for pharmacodynamic testing in 
the Schedule of Activities. 
6. Previous chemotherapy and hormone therapy (excluding physiologic replacement) 
must be completed at least 4 weeks or 5 half-lives, whichever occurs first, prior to 
initiation of therapy. 
7. Previous immunotherapy/monoclonal antibody/targeted therapy use must be 
completed at least 2 weeks or 5 half-lives (whichever is shorter) prior to initiation of 
therapy. In addition, radiation therapy to the target lesion must be completed at least 6 
months prior to initiation of therapy. 
8. All associated toxicity from previous therapies must be resolved to ≤ Grade 1 or 
considered baseline prior to initiation of therapy. 

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9. If brain metastases are present, they must have been previously treated and be stable 
by radiographic imaging (must have imaging taken ≥ 4 weeks from treatment of brain 
metastasis) AND, if receiving corticosteroids, the patient must be neurologically 
stable by clinical examination and on a stable or a decreasing dose of corticosteroids 
within 7 days prior to study start. 
10. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1; For 
patients < 16 years of age, a Lansky Performance Score > 70.  
11. Acceptable end-organ function as demonstrated by the following laboratory values: 
• Absolute neutrophil count (ANC) ≥ 1000/μL (neutrophil count may not be 
supported by hematopoietic growth factors within 2 weeks of the laboratory test)  
• Platelet count ≥ 75,000/μL (platelet count may not be supported by transfusions 
within 2 weeks of the laboratory test) 
• Hemoglobin ≥ 9 g/dL (hemoglobin may not be supported by transfusion, 
erythropoietin, or other approved hematopoietic growth factors within 2 weeks of 
the laboratory test) 
• Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 2 × ULN if patient is 
known to have Gilbert’s disease as the only underlying hepatic disorder; 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × 
ULN.  
• Serum creatinine clearance ≥ 60 mL/min/1.73 m2 calculated according to chronic 
kidney disease (CKD)-EPI (Appendix I of the Master Protocol) 

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4.2. 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible for enrollment 
in this study:  
1. Prior receipt of any RAS-, RAF-, MEK-, or ERK-directed inhibitor therapy.  
2. Known presence of concurrent activating alterations. Examples include, but are not 
limited, to the following: EGFR, ALK, MET, ROS, FGFR, RET, NTRK, PIK3CA, 
IDH1/2, and cKIT. Genetic profile of tumor under study will be reviewed by the 
Sponsor to confirm eligibility. 
3. Current enrollment in any other investigational treatment study. 
4. Patients with current evidence or a history of serous retinopathy (SR), retinal vein 
occlusion (RVO), or ophthalmopathy present at screening or baseline who would be 
considered at risk for SR or RVO. 
5. Patients who have an unstable neurological condition, despite adequate treatment 
(e.g., uncontrolled seizures). 
8. Concomitant treatment with strong cytochrome (CYP)2C8 inhibitor and/or inducers 
within 14 days before initiation of therapy.  
9. Concomitant treatment with medications that are predominantly transported by breast 
cancer resistance protein (BCRP) substrates with a narrow therapeutic index within 
14 days before initiation of therapy. Medications that are substrates of CYP2C8 are 
allowed but should be used with caution. 
12. Active, uncontrolled systemic bacterial, viral, or fungal infection. 
13. History of any major disease that might interfere with safe protocol participation, as 
determined by the Investigator (e.g., allogeneic bone marrow transplantation, organ 
transplantation, or interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis). Patients with subclinical pneumonitis 

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who have received immunotherapy previously can be included if his/her condition is 
stable without any medical intervention. 
14. History of drug reaction with eosinophilia and systemic symptoms (DRESS) 
syndrome, Stevens Johnsons syndrome (SJS), or hypersensitivity to the 
investigational medicinal product or to any drug with similar chemical structure or to 
any other excipient present in the pharmaceutical form of the investigational 
medicinal product(s). 
15. History of second malignancy within 3 years prior to study treatment except for 
curatively treated cervical cancer in situ, non-melanoma skin cancer, or superficial 
bladder cancer. 

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5. 
TREATMENT 
5.1. 
Investigational Product 
See Study Protocol DAY101-102 (Master Protocol). 
5.2. 
DAY101 Administration 
5.2.1. 
General Dosing Instructions 
Dosing for an individual should be at a consistent day and time (± 12 hours) each week. 
There is no restriction with regard to intake of food (patients can be fed or fasted). Tablets 
should not be cut or crushed.  
If the patient vomits the tablets and they are still recognizable, then the patient can be 
re-dosed. If the patient vomits within 30 minutes of ingesting tablets and the tablets are not 
recognizable, the patient or parent/legal guardian should be instructed to call the Investigator 
or study nurse to discuss whether the patient should take any additional tablets. If it has been 
longer than 30 minutes or the Investigator or study nurse is not reachable, the patient should 
not be re-dosed. 
The patient or the patient’s parent/legal guardian will complete a study drug administration 
diary to record dosing compliance. The study drug administration diary will be reviewed at 
each clinic visit by the Investigator or study staff. The study drug administration diary will 
also be assessed at each clinic visit. 
Late doses (i.e., between 12 and 72 hours of regularly scheduled dose) should be noted in the 
diary. Doses that are late by more than 72 hours (3 days) should be skipped and recorded in 
the dosing diary as missed. A minimum of 4 days should occur between doses. Any dose that 
cannot be given within 3 days of the scheduled dose should be recorded as missed. 
For adolescent patients, dose rounding guidelines by body surface area (BSA) are provided in 
Table 3. Any questions regarding dose rounding should be directed to the Sponsor Medical 
Monitor. BSA should be calculated and an updated dose should be provided on Day 1 of 
each cycle (See Appendix J of Master Protocol DAY101-102). 
Table 3: 
Dose Rounding Guidelines in Adolescents with BSA 0.9 ->1.4 m2 for 
DAY101 420 mg/m2 QW 
BSA (m2) 
420 mg/m2 (mg) 
Abbreviations: BSA, body surface area; QW, every week. 
5.2.2. 
Dose-Limiting Toxicity 
Not applicable. 

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5.2.3. 
Dose Modifications 
Patients who experience a treatment-emergent adverse event (TEAE) that is clinically or 
medically intolerable, such as peripheral/facial/periorbital edema, hematotoxicity, 
hyperbilirubinemia, or cardiac, pulmonary, or renal toxicity, should have DAY101 dosing 
interrupted until adverse events (AEs) are resolved to Grade 1 or baseline level. Patients 
should be reevaluated at least weekly for resolution of the AE. Upon resolution, dosing may 
be restarted at the original dose of DAY101 if toxicity resolves in 2 weeks. Otherwise 
consider dose reduction(s) as shown in Table 4.  
For patients who experience a TEAE that is clinically or medically intolerable more than 
once, a second dose reduction may be considered as shown in Table 4.  
For specific instructions on dose reduction for ocular disturbances, rashes, photosensitivity, 
increased creatine phosphokinase (CPK), increased liver transaminases, and QTc 
prolongation please see dose modification recommendations in Section 5.2.4 .     
All patients who experience drug-related toxicity requiring a recovery period longer than 
28 days will be withdrawn from study drug administration unless there is evidence of benefit 
and no alternative treatment available as determined by the Investigator and approved by the 
Sponsor. 
Table 4: 
Dose Level Reductions for DAY101 Based on Recommend Phase 2 Dose 
for Weekly Regimen in Adult and Adolescent Patients 
Patient Age 
Starting Dose 
First Dose Reduction a 
(reduce or discontinue 
dose) 
Second Dose Reduction a  
(reduce or discontinue 
dose) 
≥ 18 years 
600 mg QW 
500 mg QW 
400 mg QW 
≥ 12 up to <18 
years 
420 mg/m2 QW 
350 mg/m2 QW 
280 mg/m2 QW 
Abbreviations: eCRF, electronic case report form; QW, every week. 
a All dose reductions must be recorded on the eCRF. 
5.2.4. 
Management of Treatment-Related Events 
Included below are toxicity management guidelines.  
5.2.4.1. 
Ocular Disturbances 
Patients must be instructed to report visual symptoms as soon as they occur. An eye 
examination will be performed by an ophthalmologist or other qualified site clinical 
personnel while on study and at any time visual abnormalities are described by the patient. 
Regular monitoring and management of visual symptoms may avoid more serious ocular 
complications.   
Retinal Detachment 
Ocular toxicities are graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) v. 5.0 and follow those definitions. Retinal detachment is commonly graded in two 
ways. Rhegmatagenous retinal detachment (RDD) refers to a tear in the retina most 

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commonly due to trauma or age-related vitreous retraction. In contrast, serous retinopathy 
(SR) results in retinal detachment through the buildup of fluid behind the retinal layer. 
Serous retinopathy (SR), serous retinal detachment (SRD), and retinal pigment epithelium 
disorder (RPED), all refer to the same process and are graded in CTCAE v5 under 
Retinopathy (Grade 1–4). If SR/SRD/RPED are diagnosed, monitor, and manage under the 
care of the clinical expert (e.g., ophthalmologist) according to Table 5  If symptoms do not 
resolve within 4 weeks after DAY101 is held, discontinue treatment with DAY101. 
Table 5: 
Serous Retinopathy (SR)/Serous Retinal Detachment (SRD)/Retinal 
Pigment Epithelium Disorder (RPED) Management Recommendations 
AE Grade 
Event Description 
Recommendation 
Grade 1  
Asymptomatic; clinical or diagnostic 
observations only 
Monitor closely with weekly 
ophthalmologic examinations. No 
change in DAY101 dose or schedule.  
Grade 2 
Mildly symptomatic; moderate 
decrease in visual acuity (best 
corrected visual acuity 20/40 and 
better or 3 lines or less decreased 
vision from known baseline); limiting 
instrumental ADL 
Monitor closely with weekly 
ophthalmologic examinations. Hold 
DAY101 if symptoms do not improve 
in 2 weeks. If resolution in ≤ 2 weeks, 
resume DAY101 at same dose. 
Otherwise, consider a dose reduction 
(see Table 4).   
Grade 3  
Symptomatic with marked decrease in 
visual acuity (best corrected visual 
acuity worse than 20/40 or more than 3 
lines of decreased vision from known 
baseline, up to 20/200); limiting self-
care ADL 
Monitor closely with weekly 
ophthalmologic examinations. Hold 
DAY101 until signs and symptoms 
improve to baseline or Grade 1. Resume 
at the same dose if symptoms resolve 
within 2 weeks. Otherwise, consider a 
dose reduction (see Table 4).  
Grade 4 
Best corrected visual acuity of 20/200 
or worse in the affected eye 
Monitor closely with weekly 
ophthalmologic examinations. Hold 
DAY101 until signs and symptoms and 
visual acuity tests improve to baseline 
or Grade 1. Resume at the same dose if 
symptoms and visual acuity tests 
resolve within 2 weeks. Otherwise, 
discuss the doses of DAY101 with 
Sponsor prior to resuming treatment.  
Abbreviations: ADL, activities of daily living 
Source: Van Rijssen 2019 et. al.  
Rhegmatagenous Retinal Detachment (RDD) 
If Grade 3 or 4 RDD occurs and surgical treatment is required, immediately discontinue 
treatment with DAY101. Appropriate follow-up and treatment measures must be taken by the 
treating ophthalmologist. The Sponsor must be notified immediately.  

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Retinal Vein Occlusion 
If retinal vein occlusion (RVO) is diagnosed, immediately discontinue treatment with 
DAY101. Appropriate follow-up and treatment measures must be taken by the treating 
ophthalmologist or other qualified site clinical personnel. The Sponsor must be notified 
immediately.  
5.2.4.2. 
Dermatologic Toxicity 
Rashes (maculopapular and dermatitis acneiform) have been observed with DAY101 
administration. Patients should be advised to contact the Investigator immediately if they 
develop a new rash or have worsening of an existing rash while on the study. Patients should 
be referred to a dermatology department when symptoms are impairing function (e.g., cannot 
sleep, sit still) or psychosocially bothersome, and when management techniques fail to 
resolve.  
See Appendix C for recommended prophylactic skin care regimen and management options 
for rashes. It is recommended all patients receiving DAY101 follow the prophylactic skin 
care regimen. Rash management recommendations should be followed as outlined in Table 6.  
Table 6: 
Rash Management Recommendations 
AE Grade 
Event Description 
Recommendation 
Grade 1 
Papules and/or pustules 
covering < 10% BSA  
Initiate oral antihistamines or topical steroids. 
No change in DAY101 dose or schedule. 
Grade 2 
Papules and/or pustules 
covering 10–30% BSA 
 
In addition to topical antihistamines and 
steroids, treatment with minocycline or topical 
clindamycin should be considered.  
Grade 3 
Papules and/or pustules 
covering > 30% BSA with 
moderate or severe symptoms; 
limiting selfcare ADL; 
associated with local 
superinfection with oral 
antibiotics indicated 
Initiate appropriate treatment for associated 
infection in consultation with dermatologist or 
specialist. DAY101 should be held or dose 
reduced until AE resolved to Grade 1 or 
returns to baseline. DAY101 may be resumed 
at original dose if the symptoms improve 
within 2 weeks or consider dose reduction (see 
Table 4). If a Grade 3 skin toxicity recurs at a 
reduced dose, a second dose reduction may be 
considered. If a Grade 4 rash recurs at a 
reduced dose, discontinuation of treatment is 
required. 
Grade 4 
Life-threatening; papules and/or 
pustules covering any %BSA; 
extensive superinfection with 
IV antibiotics indicated 
Abbreviations: ADL, activities of daily living; AE, adverse event; BSA, body surface area; IV, intravenous. 
Source: Lemech 2012 et. al.  
Permanent discontinuation of study therapy is recommended in case a patient develops 
unexpected severe dermatologic AEs such as Stevens Johnson syndrome or toxic epidermal 
necrolysis. Additionally, permanent discontinuation of study therapy is recommended for 
patients with treatment-related skin rash associated with Grade 3 systemic organ dysfunction 

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(cardiac, hepatic, pulmonary, renal, or lymphadenopathy) possibly indicating a drug rash 
with eosinophilia and systemic symptoms (DRESS) syndrome.  
5.2.4.3. 
Photosensitivity 
Photosensitivity is a recognized class effect of RAF kinase inhibitors. For background 
information on phototoxicity in DAY101, refer to the current version of the investigator’s 
brochure (IB). Patients should avoid excess exposure to sunlight and ultraviolet (UV) light 
and use sunglasses and broad-spectrum, skin-sensitive formulation sunscreen (eg, containing 
titanium dioxide or zinc oxide) with a skin protection factor (SPF) ≥ 50. Patients should be 
instructed to monitor for signs and symptoms of photosensitivity (eg, itchy eruptions or areas 
of redness and inflammation on patches of sun-exposed skin). 
5.2.4.4. 
Increased Creatine Phosphokinase  
Consider alternative causes for increased CPK such as increased physical activity, trauma/ 
falls, muscle injury, and other causes (e.g., statins, alcohol, toxins, heat illness, seizure). Test 
for blood urea nitrogen (BUN), creatinine, urinalysis with myoglobin test, troponin I or 
troponin T as clinically indicated. 
See recommendations in Table 7 following an increase in CPK during the study. 
Table 7: 
Increased Creatine Phosphokinase Management Recommendations 
AE Grade 
Event Definition 
Recommendation 
Grade 1 
> ULN – 2.5 × ULN 
• 
Monitor closely 
• 
Adequate hydration is recommended to maintain 
fluid and electrolyte balance and tissue perfusion 
Grade 2 
> 2.5 × ULN – 
5 × ULN 
Grade 3/ 
Grade 4 
> 5 × ULN – 10 × ULN 
> 10 × ULN  
• 
Manage symptomatically 
• 
Hold DAY101, if clinically symptomatic 
• 
Resume DAY101 at original dose if symptoms return 
to Grade 1 or baseline within 2 weeks. Otherwise, 
reduce DAY101 dose (see Table 4). If an 
asymptomatic Grade 3 or 4 CPK elevation occurs at a 
reduced dose, a second dose reduction may be 
considered. If the second occurrence of Grade 3 or 4 
CPK elevation is symptomatic, discontinuation of 
treatment is required. 
Abbreviations: AE, adverse event; CPK, creatine phosphokinase; ULN, upper limit of normal. 
Source: Common Terminology Criteria for Adverse Events, version 5.0. 
5.2.4.5. 
Increased Liver Transaminases and Bilirubin  
Mild to severe increases in serum transaminases (ALT and AST) and bilirubin have been 
observed in patients treated with DAY101. 
Should an increase in AST/ALT and/or bilirubin be observed while receiving DAY101, the 
recommendations from Table 8 should be followed. 

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Table 8: 
Increased Liver Transaminases and Bilirubin Recommendations 
AE Grade 
Event Definition 
Recommendation 
Grade 1/Grade 2 
Asymptomatic, absolute 
increase in AST or ALT to 
< 5 × ULN or to 
< 5 × increase from baseline 
or bilirubin ≤ 3 × ULN or to 
≤ 3 × increase from baseline 
• 
No change in DAY101 dose. 
≥ Grade 3  
Absolute increase in AST or 
ALT to ≥ 5 x ULN 
or > 5 × increase from 
baseline or 
bilirubin > 3 × ULN or > 3 × 
increase from baseline 
• 
Withhold DAY101 until AST/ALT/or 
bilirubin abnormality resolved to < Grade 3 
AND baseline level. 
• 
Resume DAY101 at original dose if the 
AST, ALT, or bilirubin abnormality 
resolves within 8 days. 
• 
Patients whose resolution of AST, ALT, or 
bilirubin abnormality is taking longer than 8 
days may have their DAY101 dose reduced 
(see Table 4). 
• 
If a Grade 3 or 4 LFT or bilirubin elevation 
recurs at a reduced dose, a second dose 
reduction may be considered if 
asymptomatic and isolated (i.e., not 
associated with an increase in bilirubin). 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver 
function test; ULN, upper limit of normal 
5.2.4.6. 
QTc Prolongation 
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 the 
patient’s clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist. See Table 9 for QTc prolongation recommendations.  

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Table 9: 
QTc Prolongation Recommendations 
QTc Interval 
Recommendation 
> 500 msec (> 18 years) 
> 480 msec (< 18 years) 
 
• 
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 mean QTc interval of > 500 msec, 
immediate correction for reversible causes (including electrolyte 
abnormalities, hypoxia, and concomitant medications for drugs 
with the potential to prolong the QTc interval [Appendix B]) 
should be performed 
• 
Repeat ECGs should be performed hourly for at least 3 hours until 
the QTc interval falls below 500 msec. If QTc interval reverts to 
< 500 msec, and the judgment of the Investigator(s) and Sponsor is 
determined to be due to cause(s) other than study drug, treatment 
may be continued with regular ECG monitoring. 
− 
If, in that timeframe, the QTc intervals rise above 500 msec, 
the study drug will be held until the QTc interval decreases to 
< 500 msec. Patients will then re-start the study drug at the 
next lowest dose level. 
− 
If the QTc interval has still not decreased to < 500 msec after 
2 weeks, or if at any time a patient has a prolonged QTc and 
becomes symptomatic, the patient will be removed from the 
study. 
Abbreviations: ECG, electrocardiogram. 
5.3. 
Removal of Patients from Therapy or Assessment 
See Study Protocol DAY101-102 (Master Protocol). 
5.4. 
Prior and Concomitant Medications 
5.4.1. 
General 
All medications that were used from 28 days prior to enrollment through 30 days following 
the last dose of study drug will be recorded in the electronic case report form (eCRF). All 
prior anticancer treatments, regardless of when they were administered, will also be 
collected. These are to include prescription medications and transfusions. Excluded prior 
medications are those excluded via the eligibility criteria.  
5.4.2. 
Allowed Concomitant Medications 
The Investigator should instruct the patient or the patient’s parent or legal guardian to notify 
the study site about any new medications he/she takes after starting study drug. 

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Patients taking medication chronically should be maintained on the same dose and schedule 
throughout the study period, as medically feasible. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted, except as specifically prohibited in Section 5.4.3. Medications 
required to treat AEs and manage cancer symptoms and concurrent stable diseases, and 
supportive care agents, such as pain medications, antiemetics, short courses of steroids, and 
antidiarrheals, are allowed. Oral contraceptive pills are permitted. Cannabis use, including 
cannabidiol (CBD) and topical tetrahydrocannabinol (THC) products, are not prohibited 
during the course of the study, as the risk of a drug-drug interaction with DAY101 is 
assessed as low. 
As a general precaution, patients receiving concomitant medications, particularly those with 
narrow therapeutic indices, should be carefully monitored, as potential drug-drug interactions 
between DAY101 and other drugs have not been studied in humans.  
Medications known to cause hypo- or hypermagnesemia and hypophosphatemia should be 
used with caution. 
Additionally, medications known to cause QTc prolongation should be used with caution 
(refer to Appendix B). 
Patients should also be instructed to consult with the Investigator before taking any new 
medications, including over-the-counter products. 
Routine vaccinations should be administered per local institutional guidelines. 
5.4.3. 
Prohibited Concomitant Medications 
As DAY101 is a substrate of CYP2C8, patients should avoid strong inhibitors or inducers of 
CYP2C8 (refer to Appendix A), as they could alter the drug’s PK. Medications that are 
substrates of BCRP with a narrow therapeutic index are prohibited during this study. During 
this study, patients are not allowed to receive other chemotherapeutic agents (traditional 
chemotherapy, targeted agents, monoclonal antibodies, etc.), drugs with immunosuppressant 
properties (other than steroids as allowed per Section 5.4.2), or any other investigational 
agents besides DAY101. 
5.4.4. 
Palliative Radiotherapy  
In general, measurable lesions being used to measure response should not be irradiated 
without discussion with the Sponsor and may be reason for the patient to be removed from 
study for progressive disease. Irradiated non-measurable lesions will be considered not 
evaluable for response, but still can be used to assess progressive disease. The intensities, 
number, and dates of doses received for allowed palliative radiotherapy should be recorded 
on the appropriate eCRF.  
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician after discussion and approval by the Sponsor. DAY101 
must be held for 6 days before beginning radiation therapy and patients are permitted to 
restart DAY101 6 days following completion of radiation therapy.  

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6. 
TESTS AND EVALUATIONS 
6.1. 
Screening 
See Study Protocol DAY101-102 (Master Protocol). 
6.2. 
Enrollment 
See Study Protocol DAY101-102 (Master Protocol). 
6.3. 
Medical History and Malignancy History 
See Study Protocol DAY101-102 (Master Protocol). 
6.4. 
Archival Tumor Samples  
Archival tumor tissue may come from a specimen obtained at either diagnosis or recurrence 
(preferably less than 3 years old). If an archival tumor tissue sample is not available, a freshly 
acquired tumor sample or liquid biopsy obtained at baseline to confirm presence of MAPK 
alteration is required. Tumor samples may be either formalin-fixed, paraffin-embedded 
(FFPE) tissue, freshly cut FFPE slides, snap frozen tissue, or a liquid biopsy processed and 
shipped to the Central Lab as per the Laboratory Manual. 
Note: If archival tissue is unavailable, freshly acquired tumor tissue or liquid biopsy is 
required.  
Please refer to Section 6.4 for additional freshly acquired tissue requirements.  
6.5. 
Freshly Acquired Tumor Samples for Pharmacodynamic Analysis 
Freshly acquired tumor tissue samples are to be collected for pharmacodynamic analysis at 
pre- and on-treatment timepoints as per the Schedule of Activities for all patients where safe 
to obtain as determined by the Investigators. Tumor samples must be collected after drug 
dosing for that day, except for 
 in which collection must be pre-dose. 
Tumor samples must be processed and shipped to the Central Lab as per the Laboratory 
Manual. 
6.6. 
ctDNA Samples: Blood 
See ctDNA blood samples will be collected during 
.  See 
laboratory manual for ctDNA sample collection regimen.  
6.7. 
Physical Examination 
See Study Protocol DAY101-102 (Master Protocol). 
6.8. 
Eastern Cooperative Oncology Group (ECOG) /Lansky 
Performance Status 
See Study Protocol DAY101-102 (Master Protocol). 

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6.9. 
Assessment of Change in Pubertal Development (Tanner Stage) 
See Study Protocol DAY101-102 (Master Protocol). 
6.10. 
Vital Signs 
See Study Protocol DAY101-102 (Master Protocol). 
6.11. 
Ophthalmology Examination (All Patients) 
A baseline eye examination will be performed by an ophthalmologist or a qualified site 
clinical personnel. Consultation with an ophthalmologist or a qualified site clinical personnel 
is required if abnormal ocular AEs arise as specified in Section 5.2.4.1. 
The following assessments should be completed at screening: 
Fundus examination with comment on retinal abnormalities 
Best corrected visual acuity (BCVA) 
6.12. 
Visual Symptom Assessment 
Patients must be asked at each time point if they have any changes in vision. If the patient 
has noted any visual changes, an eye examination must be performed by an ophthalmologist 
or a qualified site clinical personnel prior to further dosing of DAY101 or combination 
partner. 
6.13. 
Dermatologic Examination 
See Study Protocol DAY101-102 (Master Protocol).  
6.14. 
Neurologic Examination 
See Study Protocol DAY101-102 (Master Protocol). 
6.15. 
Height and Bone Age 
See Study Protocol DAY101-102 (Master Protocol). 
6.16. 
Cardiac Function 
6.16.1. 
Electrocardiograms 
See Study Protocol DAY101-102 (Master Protocol). 
6.16.2. 
Echocardiogram/Multiple-Gated Acquisition 
See Study Protocol DAY101-102 (Master Protocol). 

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6.17. 
Laboratory Tests 
For pediatric patients (aged < 18 years), blood volumes drawn will be minimized, in 
accordance with the European Commission (EC)’s recommendations, “Ethical considerations 
for clinical trials on medicinal products conducted with the pediatric population” (2008) and 
“Ethical considerations for clinical trials on medicinal products conducted with minors” 
(2017). 
See Study Protocol DAY101-102 (Master Protocol). 
6.17.1. 
Pregnancy Test 
See Study Protocol DAY101-102 (Master Protocol). 
6.17.2. 
Hematology 
See Study Protocol DAY101-102 (Master Protocol). 
6.17.3. 
Serum Chemistries 
See Study Protocol DAY101-102 (Master Protocol). 
6.17.4. 
Coagulation Panel 
See Study Protocol DAY101-102 (Master Protocol). 
6.17.5. 
Thyroid Function Tests 
See Study Protocol DAY101-102 (Master Protocol). 
6.18. 
Pharmacokinetic Samples: Blood 
The dose of DAY101 should be taken in the clinic on pharmacokinetic (PK) sampling days 
to ensure that a PK sample is collected as scheduled related to the time of dosing. PK 
samples will be collected and handled as outlined in the Laboratory Manual. 
The blood sampling regimens for determining the PK of DAY101 is shown in Table 10.  
Blood samples for DAY101 concentration measurements will be collected on all patients in 
the study. Exact dates and clock times of drug administration and actual PK blood draw 
should be recorded on the appropriate eCRF.  
If a patient experiences an AE that fits the criteria of a serious adverse event (SAE) or 
suspected unexpected serious adverse reaction (SUSAR) as determined by the Investigator, a 
blood sample should be collected, whenever possible, for measurement of drug 
concentrations at or around that time.  
When a blood sample is taken on the same day as an ECG assessment, the ECG should be 
performed prior to sample collection (within 15 minutes prior). When a blood sample is 
taken on the same day as a vital signs assessment, the vital signs should be collected prior to 
sample collection. 

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Table 10: 
Schedule of Blood Sample Collections for DAY101 Pharmacokinetics 
Cycle 
Day 
Pharmacokinetics Timepoint 
6.19. 
Disease Assessment 
6.19.1. 
Tumor Measurements 
See Study Protocol DAY101-102 (Master Protocol). 
6.19.1.1. Collection of Radiographic Studies for Independent Review 
See Study Protocol DAY101-102 (Master Protocol). 
6.20. 
Telephone/Telemedicine Visit 
See Study Protocol DAY101-102 (Master Protocol). 
6.21. 
Survival Status 
See Study Protocol DAY101-102 (Master Protocol). 
6.22. 
Study Drug Administration and Dosing Diary 
See Study Protocol DAY101-102 (Master Protocol). 
6.23. 
Concomitant Medication 
See Study Protocol DAY101-102 (Master Protocol). 
6.24. 
End of Treatment Visit 
See Study Protocol DAY101-102 (Master Protocol). 
6.25. 
Safety Follow-up Visit 
See Study Protocol DAY101-102 (Master Protocol). 
6.26. 
Long-Term Follow-up 
See Study Protocol DAY101-102 (Master Protocol). 
6.27. 
Force Majeure Flexibility 
See Study Protocol DAY101-102 (Master Protocol). 

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7. 
PLANNED ANALYSES 
See Study Protocol DAY101-102 (Master Protocol). 
7.1. 
Analysis Populations 
See Study Protocol DAY101-102 (Master Protocol). 
7.2. 
Determination of Sample Size 
For Study DAY101-102a, Simon’s 2-stage design (Simon 1989) will be used to determine 
whether DAY101 has sufficient anticancer activity to warrant further development for each 
biomarker selected cohort. Enrollment per cohort may be terminated early independently of 
each other. No adjustment for multiple hypothesis testing will be made if both cohorts 
complete enrollment. 
 The Sponsor may consider replacing the patient if the patient is not considered evaluable for 
response assessment in the Simon stage 1. The stage 2 will not be activated if the stage 1 
minimum number of responses (as shown in table below) is not met and all patients have 
been followed for at least 6 months.    
Specific performance criteria are presented in Table 11. 

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Table 11: 
Sample Size Determinations 
  
Null/Alternative 
Hypotheses 
Study Power 
 
Study Alpha 
(1-sided) 
Stage 1 n (Minimum 
Number of Responses 
to Move to Stage 2) 
Melanoma 
cohort 
Tissue agnostic 
cohort 
7.3. 
Statistical Methods 
See Study Protocol DAY101-102 (Master Protocol). 
7.3.1. 
Efficacy Analyses 
See Study Protocol DAY101-102 (Master Protocol). 
7.3.2. 
Safety Analyses 
See Study Protocol DAY101-102 (Master Protocol). 
7.3.3. 
Pharmacokinetic Analyses 
Plasma concentrations of DAY101 will be analyzed at specified time points using validated 
bioanalytical method. Plasma concentrations will be summarized by nominal sample time 
using standard summary statistics for PK concentrations. 

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8. 
ADVERSE EVENTS 
See Study Protocol DAY101-102 (Master Protocol). 
8.1. 
Stopping Rules 
See Study Protocol DAY101-102 (Master Protocol) Section 8.3 for details regarding 
stopping rules. 
8.2. 
Independent Data Monitoring Committee 
See Study Protocol DAY101-102 (Master Protocol) Section 8.2 for details regarding the 
independent data monitoring committee (DMC). 
8.2.1. 
Risk Management 
See Study Protocol DAY101-102 (Master Protocol). 
8.2.2. 
Continuous Review of Safety Data 
See Study Protocol DAY101-102 (Master Protocol). 

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9. 
STUDY ADMINISTRATION 
See Study Protocol DAY101-102 (Master Protocol). 

Day One Biopharmaceuticals, Inc.  (Day One) 
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10. 
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Bekele RT, Samant AS, Nassar AH, et al. RAF1 amplification drives a subset of bladder 
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Botton T, Talevich E, Mishra VK, et al. Genetic Heterogeneity of BRAF Fusion Kinases in 
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Hamid O, Puzanov I, Dummer R, et al. Final analysis of a randomised trial comparing 
pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced 
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Jain P, Fierst TM, Han HJ, et al. CRAF gene fusions in pediatric low-grade gliomas define a 
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Jones DT, Gronych J, Lichter P, et al. MAPK pathway activation in pilocytic astrocytoma. 
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Jones DT, Kocialkowski S, Liu L, et al. Oncogenic RAF1 rearrangement and a novel BRAF 
mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in 
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Karajannis M, Legault G, Fisher M, et al. Phase II study of sorafenib in children with 
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Day One Biopharmaceuticals, Inc.  (Day One) 
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19 October 2022 
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Wright, K, Krzykwa, E, Greenspan, L, et al. Phase I trial of DAY101 in pediatric patients 
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Appendix A: 
List of Medications with Potential Drug  Interactions with DAY101 
Table 12: 
List of Medications with Potential Drug Interactions with DAY101 
CYP2C8 Inducers 
CYP2C8 Inhibitors 
rifampin 
gemfibrozil 
clopidogrel 
BCRP substrates with narrow therapeutic index 
 Methotrexate, topotecan, or irinotecan 
Abbreviations: BCRP=breast cancer resistance protein; CYP =cytochrome P450 
Note: The above lists are not exhaustive. See also: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers 

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Appendix B: 
List of Medications Known to Cause QTc Prolongation 
Table 13: 
Drugs Associated with QTc Prolongation and Torsades de Pointes 
Antiarrhythmics 
Antimicrobials 
Antidepressants 
Antipsychotics 
Others 
Amiodarone 
Levofloxacin 
Amitriptyline 
Haloperidol 
Cisapride 
Sotalol 
Ciprofloxacin 
Desipramine 
Droperidol 
Sumatriptan 
Quinidine 
Gatifloxacin 
Imipramine 
Quetiapine 
Zolmitriptan 
Procainamide 
Moxifloxacin 
Doxepin 
Thioridazine 
Arsenic 
Dofetilide 
Clarithromycin 
Fluoxetine 
Ziprasidone 
Dolasetron 
Ibutilide 
Erythromycin 
Sertraline 
 
Methadone 
 
Ketoconazole 
Venlafaxine 
 
 
 
Itraconazole 
 
 
 
Source: U.S. Pharmacist [Internet]. Jobson Publishing Corp. c2000-2022 [cited 2022 Feb 23]. Available from: 
https://www.uspharmacist.com/article/drug-induced-qt-prolongation 

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Appendix C: Rash Prophylaxis and Management  
Recommended Preventative Skin Care Routine