Clinical trial NCT03037385
Conditions: RET-altered Non Small Cell Lung Cancer Medullary Thyroid Cancer RET-altered Papillary Thyroid Cancer RET-altered Colon Cancer RET-altered Solid Tumors Lung Neoplasm Carcinoma, Non-Small-Cell Lung Thyroid Diseases Thyroid Neoplasm Thyroid Cancer, Papillary Carcinoma, Neuroendocrine Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Disease Carcinoma, Bronchogenic Bronchial Neoplasms Endocrine System Diseases Endocrine Gland Neoplasm Head and Neck Neoplasms Adenocarcinoma, Papillary Adenocarcinoma Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Colonic Neoplasms Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasm Digestive System Disease Gastrointestinal Disease Colonic Diseases Intestinal Disease
Keywords: RET Lung RET Thyroid RET fusion RET alteration RET mutation RET positive RET inhibitor RET altered RET rearrangement RET NSCLC RET medullary thyroid cancer RET-rearranged NSCLC RET-rearranged thyroid M918T TRIM33-RET RET fusion lung cancer RET fusion thyroid cancer lung cancer mutation BLU 667 RET tyrosine kinase RET gene mutation RET kinase RET MTC advanced lung cancer advanced non small cell lung cancer metastatic lung cancer KIF5B-RET CCDC6-RET NCOA4-RET advance solid tumor V804L V804M thyroid cancer RET inhibitor lung cancer RET inhibitor RET PTC rearranged during transfection RET-PTC1 RET-PTC RET-PTC3 RET-PTC4 PRKAR1A-RET RET-PTC2 GOLGA5-RET RET-PTC5 ERC1-RET KTN1-RET RET-PTC8 HOOK3-RET PCM1-RET TRIM24-RET RET-PTC6 TRIM27-RET RET-PTC7 AKAP13-RET FKBP15-RET SPECC1L-RET TBL1XR1-RET BCR-RET FGRF1OP-RET RFG8-RET
Sponsor: Hoffmann-La Roche
Start date: 2017-03-17; Completion date: 2024-03-21
Enrollment: 590 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in participants with medullary thyroid cancer (MTC), RET-altered NSCLC and other RET-altered solid tumors.

Detailed description:
The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part (Phase 2). Both parts will enroll participants with advanced non-resectable NSCLC, advanced non-resectable thyroid cancer and other advanced solid tumors that have progressed following standard systemic therapy, have not adequately responded to standard systemic therapy, or the participants must be intolerant to or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.

Arms: arm 1: Multiple doses of pralsetinib (BLU-667) for oral administration. arm 2: Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.
Interventions: intervention 1: pralsetinib (BLU-667)
Intervention descriptions: intervention 1: pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants

Protocol documents:
Prot_000.pdf: 
Official Title: 
NCT Number: 
Document Date: 
A Phase 1/2 Study of the Highly-Selective RET Inhibitor, BLU-667, in 
Patients with Thyroid Cancer, Non−Small Cell Lung Cancer (NSCLC) 
and Other Advanced Solid Tumors
NCT03037385
Protocol Amendment Version 15: 01-December-2022


CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel,
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates,
including Genentech, Inc. in the United States.  The information contained in this document, especially
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that
this information will not be disclosed to others without written authorization from Roche except to the
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Pralsetinib—F. Hoffmann-La Roche Ltd
Protocol BO42863, Version 15
PROTOCOL
PROTOCOL TITLE:
A PHASE 1/2 STUDY OF THE HIGHLY-SELECTIVE
RET INHIBITOR, BLU-667, IN PATIENTS WITH
THYROID CANCER, NON−SMALL CELL LUNG
CANCER (NSCLC) AND OTHER ADVANCED
SOLID TUMORS
PROTOCOL NUMBER:
BO42863 (formerly BLU-667-1101)
STUDY NAME
ARROW
VERSION NUMBER:
15
TEST COMPOUND:
Pralsetinib (RO7499790, BLU-667)
STUDY PHASE:
Phase I/II
EUDRACT NUMBER:
2016-004390-41
IND NUMBER:
131825
NCT NUMBER:
NCT 03037385
MEDICAL MONITOR:
, M.D.
SPONSOR NAME AND
LEGAL REGISTERED
ADDRESS:
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL DATE:
See electronic signature and date stamp on the final 
page of this document.


Pralsetinib—F. Hoffmann-La Roche Ltd
2/Protocol BO42863, Version 15
PROTOCOL HISTORY
Protocol
Associated Country and/or Region-Specific Protocols
Version
Date Final
Country and/or Region
Version
Date Final
15 
See electronic date stamp 
on the final page of this 
document. 
14
28 March 2022 


13
8 July 2020




China
12
4 February 2020
9
3 July 2019
France
China
11
10
4 February 2020
26 July 2019

20 December 2018
China
8
20 December 2018
7
12 December 2018




27 August 20218
France
6
27 August 2018


Republic of Korea
5
25 July 2018
4.1
25 July 2018





Republic of Korea
3
8 February 2018
2
2 February 2018



1
9 January 2017





Pralsetinib—F. Hoffmann-La Roche Ltd
3/Protocol BO42863, Version 15
PROTOCOL AMENDMENT, VERSION 15
RATIONALE
Study BO42863 has been amended to align the protocol with pralsetinib Investigator's
Brochure, Version 6.  Substantive changes to the protocol, along with a rationale for
each change, are summarized below.
•
A benefit−risk assessment and guidance on concomitant administration of
coronavirus 2019 vaccines with pralsetinib has been added (Section 1.5.4).  This
was not included in the previous version of this protocol (Version 14) due to an
oversight though the rationale for inclusion was added.
•
Contraception requirements for females of childbearing potential have been
amended as per pralsetinib Investigator's Brochure (Version 6) to indicate that
non‑hormonal contraception should be used during treatment with pralsetinib, as
pralsetinib may render hormonal contraceptives ineffective (Sections 5.3 and 9.6.1).
•
A description of the technical and organizational security measures taken to protect
personal data has been added to align with CTR requirements (Section 17).
•
Previous protocol amendment rationales were moved to Appendix 5.
Additional minor changes have been made to improve clarity and consistency.
Substantive new information appears in italics.  This amendment represents cumulative
changes to the original protocol.


Pralsetinib—F. Hoffmann-La Roche Ltd
4/Protocol BO42863, Version 15
PROTOCOL AMENDMENT ACCEPTANCE FORM
PROTOCOL TITLE:
A PHASE 1/2 STUDY OF THE HIGHLY-SELECTIVE
RET INHIBITOR, BLU-667, IN PATIENTS WITH
THYROID CANCER, NON-SMALL CELL LUNG
CANCER (NSCLC) AND OTHER ADVANCED SOLID
TUMORS
PROTOCOL NUMBER:
BO42863 (formerly, BLU-667-1101)
STUDY NAME:
ARROW
VERSION NUMBER:
15
TEST COMPOUND:
Pralsetinib (RO7499790, previously known as
BLU-667)
MEDICAL MONITOR:
, M.D.
SPONSOR NAME:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files. Please return a copy of
the signed form as instructed by the contract research organization, Labcorp/Covance.


 
Pralsetinib—F. Hoffmann-La Roche Ltd 
5/Protocol BO42863, Version 15 
STUDY SUMMARY 
Title: 
A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in 
Patients with Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and 
Other Advanced Solid Tumors 
Study 
Centers: 
The study will be conducted at multiple centers in the United States (US), 
Asia, and Europe. 
 
 
Rationale: 
RET is a receptor tyrosine kinase expressed in several neural, 
neuroendocrine and genitourinary tissues types that normally requires 
ligand and co-receptor binding for activation.  Oncogenic activation of 
rearranged during transfection (RET) kinase activity has been observed in 
thyroid cancers where activating RET fusions (papillary thyroid cancer 
[PTC]) and RET mutations (medullary thyroid cancer [MTC]) occur. RET 
fusions have been found in tumors including non-small cell lung 
carcinomas (NSCLC), colon, breast, ovary, salivary carcinomas, and 
inflammatory myofibroblastic tumors, suggesting that RET fusions may be 
oncogenic in many tumor types. 
RET activating mutations are observed in 50% to 80% of MTC patients 
and to a lesser extent in other cancers. RET fusions have been identified 
in approximately 1-2% of patients with NSCLC. Patients with NSCLC, 
thyroid cancer, or other tumors, and whose disease has relapsed after 
initial treatment with chemotherapy or multikinase inhibitors (MKIs) have 
limited treatment options, and National Clinical Practice Guidelines in 
Oncology (NCCN) guidelines recommend evaluation for clinical trials. 
Pralsetinib (previously known as BLU-667) is a potent and selective 
inhibitor of RET and oncogenic RET mutants. In vivo, dose dependent 
antitumor efficacy with pralsetinib was demonstrated in several RET-driven 
tumor models. Antitumor efficacy was correlated with pralsetinib 
exposures and pharmacodynamics modulation of tumor biomarkers, 
including direct inhibition of RET activity. Pralsetinib has been shown to be 
tolerable at active doses in in vivo pharmacology and safety pharmacology 
studies. Given the strong genetic and preclinical evidence that activated 
RET is an oncogenic disease driver and the poor prognosis of many 
patients with RET-driven tumors, the potential benefit/risk profile of 
pralsetinib suggests study in humans is warranted. This study is the first 
study to evaluate the maximum tolerated dose and investigate clinical 
activity of pralsetinib. 
Number of 
Patients: 
Approximately 647 patients will be enrolled in this study, including: 
• 
A total of 62 patients were enrolled in Phase 1 (Dose Escalation) 
• 
Approximately 585 patients in Phase 2 (Dose Expansion) 
Objectives: 
Phase 1, Dose Escalation Objectives 
Primary Objectives 
• 
To determine the maximum tolerated dose (MTD) and recommended 
Phase 2 dose (RP2D) of pralsetinib 
• 
To determine the safety and tolerability of pralsetinib 
Secondary Objectives 
• 
To determine the overall response rate (ORR) by (Response 
Evaluation Criteria in Solid Tumors) RECIST v1.1 (or Response 
Assessment in Neuro-Oncology [RANO] criteria, if appropriate for 
tumor type) according to patients’ disease type, and/or RET-altered 
status if applicable, and/or prior treatment status, if appropriate 


 
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6/Protocol BO42863, Version 15 
• 
To assess baseline RET gene status in plasma and/or tumor tissue 
and correlate with measures of antineoplastic activity including, but not 
limited to ORR, clinical benefit rate (CBR), disease control rate (DCR), 
and duration of response (DOR) 
• 
To characterize the PK profile of pralsetinib and correlate drug 
exposure with safety assessments 
• 
To characterize the pharmacodynamics of pralsetinib, including, but 
not limited to, changes in blood calcitonin and carcinoembryonic 
antigen (CEA) in MTC patients only, and changes in tumor dual 
specificity phosphatase 6 (DUSP6) and sprout receptor tyrosine 
kinase (RTK) signaling antagonist 4 (SPRY4) levels in all patients 
Exploratory Objectives 
• 
To identify potential new blood and tumor tissue biomarkers (e.g., 
deoxyribonucleic acid [DNA], ribonucleic acid [RNA], and/or protein 
markers) of pharmacodynamic activity, antineoplastic activity, and/or 
toxicity. 
Phase 2, Dose Expansion Objectives 
Primary Objectives 
• 
To determine the ORR by RECIST v1.1 (or RANO criteria, if 
appropriate for tumor type) according to patients’ disease type, and/or 
RET-altered status if applicable, and/or prior treatment status if 
appropriate. 
• 
To further define the safety and tolerability of pralsetinib. 
Secondary Objectives 
• 
To assess additional measures of clinical benefit including DOR, CBR, 
DCR, PFS, and overall survival (OS) in all patients according to 
patients’ disease type, and/or RET-altered status if applicable, and/or 
prior treatment status if appropriate. 
• 
To assess baseline RET gene status (i.e., gene fusion partner or 
primary mutation and, for MTC, whether hereditary or sporadic) in 
plasma and/or tumor tissue and correlate with measures of 
antineoplastic activity including, but not limited to ORR, CBR, DOR, 
and DCR. 
• 
To characterize the PK profile of pralsetinib and correlate drug 
exposure with safety assessments, including changes in ECG 
intervals, and efficacy. 
• 
To characterize the pharmacodynamics of pralsetinib, including, but 
not limited to, changes in blood calcitonin and CEA in MTC patients 
only. 
• 
To assess brain activity in patients with NSCLC. 
Exploratory Objectives 
• 
To identify potential new blood and tumor tissue biomarkers (e.g., 
DNA, RNA, and/or protein markers) of pharmacodynamic activity, 
antineoplastic activity, and/or toxicity. 
• 
To assess changes in quality of life (QoL) questionnaire. 
• 
To explore disease-related symptoms, as measured by bowel 
movement history (MTC patients only). 
• 
To explore clinical benefit including ORR, CBR, DCR, PFS for patients 
previously treated with a selective RET tyrosine kinase inhibitor. 
• 
To assess brain activity in patients with tumor types other than 
NSCLC. 


 
Pralsetinib—F. Hoffmann-La Roche Ltd 
7/Protocol BO42863, Version 15 
Study Design: 
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to 
evaluate the safety, tolerability, PK, pharmacodynamics, and 
antineoplastic activity of pralsetinib, a potent and selective RET inhibitor, 
administered orally in patients with medullary thyroid cancer, RET-altered 
NSCLC and other RET-altered solid tumors. 
The study consists of 2 parts, a dose-escalation part (Phase 1) and an 
expansion part (Phase 2). Both parts will enroll patients with advanced 
non-resectable NSCLC, advanced non-resectable thyroid cancer and 
other advanced non-resectable solid tumors. Prior to Amendment 9, all 
patients were required to have progressed following standard systemic 
therapy, have not adequately responded to standard systemic therapy, or 
be intolerant to or the Investigator has determined that treatment with 
standard therapy is not appropriate, or there must be no accepted 
standard therapy for their disease. 
The dose-escalation portion of the study (Phase 1) completed on 
03 April 2018. It employed the Bayesian optimal interval (BOIN) design to 
find the MTD of pralsetinib. Dose escalation continued to enroll in cohorts 
of 3-6 (1-3 for the first 3 dose levels) patients until 12 patients were treated 
and evaluable for dose-limiting toxicity (DLT) at one dose level, at which 
time the MTD or RP2D could be determined. The total number of patients 
to be enrolled during the dose escalation part of the study could vary 
depending on the toxicity profile of pralsetinib and the number of dose 
levels tested prior to reaching the MTD. 
All patients treated at doses > 120 mg per day were required to have 
MTC, or a RET-altered solid tumor per local assessment of tumor tissue 
and/or blood. Additionally, these patients could be enrolled into an 
enrichment cohort, if it previously included less than 12 patients evaluable 
for DLT, was reviewed at a dose-escalation meeting, and did not exceed 
the MTD. Data from these patients allows for an improved assessment of 
safety, PK, and pharmacodynamics. 
In Phase 2, patients will enroll into 1 of 9 groups based on their tumor type 
and prior therapy status (if applicable): 
Group 1: NSCLC with a RET fusion previously treated with a 
platinum‑based chemotherapy (N ~80). 
Group 2: NSCLC with a RET fusion not previously treated with a platinum-
based chemotherapy, including those who have not had any systemic 
therapy. Prior platinum chemotherapy in the neoadjuvant and adjuvant 
setting is permitted if the last dose of platinum was 4 months or more 
before the first dose of study drug (N~200, including approximately 
30 patients with prior systemic therapy). 
Group 3: MTC previously treated with cabozantinib and/or vandetanib 
(N ~65). 
Group 4: MTC not previously treated with cabozantinib or vandetanib 
(N ~40) 
Group 5: Other solid tumors with a RET fusion not eligible for any of the 
other groups (N ~100). Patients should have previously received SOC 
appropriate for their tumor type, unless there is no accepted standard 
therapy for the tumor type, or the Investigator has determined that 
treatment with standard therapy is not appropriate. As the intent of this 
cohort is to enroll a variety of RET-fusion tumor types, Blueprint will notify 
sites if/when sufficient data are available, and accrual should cease for 
a particular tumor type. 
Group 6: Any solid tumors with a RET alteration (fusion or mutation) 
previously treated with a selective RET tyrosine kinase inhibitor (TKI) 
(N ~20). 


 
Pralsetinib—F. Hoffmann-La Roche Ltd 
8/Protocol BO42863, Version 15 
Group 7: Other solid tumors with a RET mutation previously treated with 
SOC appropriate for the tumor type (N ~20). 
Group 8: NSCLC with a RET fusion previously treated with a platinum-
based chemotherapy (China only; N ~30) 
Group 9: MTC not previously treated with systemic therapy (except prior 
cytotoxic chemotherapy is allowed) for advanced or metastatic disease 
extension cohort (China only; N ~30) 
Determination of RET status, as required for enrollment of all patients 
except those with MTC, is based on local assessment, or central 
assessment if local testing is not available. All patients enrolled in Phase 2 
(all 9 groups) must submit tumor tissue (archived or new) for retrospective 
assessment of RET status and other pathway biomarkers. Patients 
enrolled into Group 6 (previous treatment with a selective RET-inhibitor) 
are required to have a new tumor biopsy prior to enrollment. 
All study visits are intended to be conducted on an outpatient basis, but 
may be conducted on an inpatient basis, as needed. After provision of 
written informed consent (within 8 weeks before study drug 
administration), patients will be evaluated for study eligibility during the 
screening period within 28 days before study drug administration on 
Cycle 1, Day 1 (C1D1). 
On C1D1, eligible patients will present to the study center approximately 
2 hours before the first dose of study drug and will remain at the study 
center for at least 8 hours for serial PK sampling, pharmacodynamic 
sample collection, vital signs measurement, electrocardiogram (ECG) 
monitoring, safety laboratory tests, and safety monitoring. In Phase 2, 
patients will complete a QoL assessment (European Organization for 
Research and Treatment of Cancer Core Quality of Life Questionnaire 
[EORTC QLQ-C30]). Additionally, in Phase 2 only, continuous ECG Holter 
monitoring will be performed approximately 1 hour before dosing until after 
collection of the 8-hour PK sample for approximately 20 evaluable patients 
at select study centers. At these study centers, replicate 12 lead ECGs will 
be extracted from the continuous recording at the same timepoints as the 
PK blood draws. Approximately 72 patients (including ~12 patients in 
Groups 8 and 9) in Phase 2 will complete the serial PK sampling during 
Cycle 1; otherwise, patients enrolled in Phase 2 will only have predose PK 
samples collected. See Table 10, Table 11, and Table 12 and Section 7 
for a detailed description of study assessments. 
A treatment cycle is 28 days in duration. Initially, patients returned to the 
study center on C1D2 for PK sampling (24 hours after the C1D1 dose), 
C1D8 and C1D22 for safety monitoring, and on C1D15 and C1D16 for 
serial PK sampling and safety monitoring (including continuous Holter 
monitoring for 20 patients in Phase 2 at select study centers). Following 
Protocol Amendment 9, visits on C1D2 and C1D16 are no longer required, 
except for patients in Groups 8 and 9, who will undergo serial PK sampling 
in China according to the country-specific Protocol Amendment 10. 
Patients will also attend study center visits on C2D1 and C2D15, on Day 1 
of C3 through C13, C15, C17, C21, and every 4 cycles thereafter for 
additional safety monitoring; PK and pharmacodynamic sampling; and 
disease response assessment by computed tomography (CT) or magnetic 
resonance imaging (MRI). In Phase 2 only, the EORTC QLQ-C30 will be 
administered on D1 of every cycle through C12. A tumor biopsy will be 
performed within 2 weeks (±4 days) of C2D1 (Phase 1 only) and upon 
disease progression (both Parts), if the patient consents and the 
procedure is deemed to be safe and medically feasible by the Investigator. 
All patients will attend an End-of-treatment (EOT) visit approximately 
14 days (±7 days) after the last dose of study drug. A Follow-up telephone 
contact for resolution of any residual adverse event (AE) will be made on 


 
Pralsetinib—F. Hoffmann-La Roche Ltd 
9/Protocol BO42863, Version 15 
Day 30 (+7 days) after the last dose of study drug, or at the time the 
patient initiates another antineoplastic therapy.  All patients will 
subsequently be contacted every 3-4 months for PFS (until progression or 
start of new therapy) and every 3 months for overall survival. 
In the event that, due to unforeseen circumstances, a patient is unable to 
travel to the investigative site for a planned study visit, elements of that 
visit may be performed remotely (e.g., phone/video calls) or at outside 
facilities with notification and agreement from the Sponsor.  Appropriate 
guidance documents may be put in place to support these unforeseen 
circumstances. All efforts should be made to ensure the safety and 
wellbeing of the patient prior to continuation of study drug and altered 
study visits (as above) should be appropriately documented in the source. 
Duration of 
Treatment: 
It is anticipated that patients will receive at least 1 cycle of pralsetinib; no 
maximum treatment duration has been set. After C1, patients may 
continue to receive pralsetinib until precluded by toxicity, noncompliance, 
withdrawal of consent, death, or closure of the study by the Sponsor. 
Duration of 
Patient 
Participation: 
The minimum duration of patient participation is approximately 3 months, 
including a screening period to assess study eligibility up to 4 weeks 
(28 days); a treatment period of at least 1 cycle (28 days); an EOT visit at 
least 14 ± 7 days following the last dose of study drug; and a Follow-up 
telephone contact for resolution of any AEs 30 days (+ 7 days) after the 
last dose of study drug, or at the time the patient initiates another 
antineoplastic therapy; and PFS and OS follow-up until withdrawal of 
consent, death, or loss to follow-up. 
Duration of 
Study: 
The expected enrollment period is approximately 60 months, and the 
expected duration of the study is approximately 84 months. 
Target 
Population: 
Key Inclusion Criteria: 
• 
Patient is ≥ 18 years of age. 
• 
Diagnosis during dose escalation (Phase 1) – Pathologically 
documented, definitively diagnosed non-resectable advanced solid 
tumor. 
o 
All patients treated at doses > 120 mg per day must have MTC, 
or a RET-altered solid tumor per local assessment of tumor 
tissue and/or blood. 
o 
Phase 1 enrichment patients must have MTC or a RET-altered 
solid tumor per local assessment of tumor tissue and/or blood. 
• 
Diagnosis during dose expansion (Phase 2) – All patients (with the 
exception of patients with MTC enrolled in Groups 3, 4, and 9) must 
have an oncogenic RET fusion or mutation (excluding synonymous, 
frameshift, and nonsense mutations) solid tumor, as determined by 
local testing of tumor or circulating tumor nucleic acid in blood as 
detailed below. 
o 
Group 1 – patients must have pathologically documented, 
definitively diagnosed locally advanced or metastatic NSCLC 
with a RET fusion previously treated with a platinum-based 
chemotherapy. 
o 
Group 2 – patients must have pathologically documented, 
definitively diagnosed locally advanced or metastatic NSCLC 
with a RET fusion not previously treated with a platinum-based 
chemotherapy, including those who have not had any systemic 
therapy. Prior platinum chemotherapy in the neoadjuvant and 
adjuvant setting is permitted if the last dose of platinum was 
4 months or more before the first dose of study drug. 
o 
Group 3 – patients must have pathologically documented, 
definitively diagnosed advanced MTC that has progressed 


 
Pralsetinib—F. Hoffmann-La Roche Ltd 
10/Protocol BO42863, Version 15 
within 14 months prior to the screening visit and was previously 
treated with cabozantinib and/or vandetanib. 
o 
Group 4 – patients must have pathologically documented, 
definitively diagnosed advanced MTC that has progressed 
within 14 months prior to the screening visit and was not 
previously treated with cabozantinib or vandetanib. 
o 
Group 5 - patients must have a pathologically documented, 
definitively diagnosed advanced solid tumor with an oncogenic 
RET fusion, have previously received SOC appropriate for their 
tumor type (unless there is no accepted standard therapy for the 
tumor type or the Investigator has determined that treatment 
with standard therapy is not appropriate), and must not eligible 
for any of the other groups. 
o 
Group 6 - patients must have a pathologically documented, 
definitively diagnosed advanced solid tumor with an oncogenic 
RET fusion or mutation, previously treated with a selective TKI 
that inhibits RET, such as selpercatinib. 
o 
Group 7 - patients must have a pathologically documented, 
definitively diagnosed advanced solid tumor with an oncogenic 
RET mutation previously treated with SOC appropriate for the 
tumor type and not eligible for any of the other groups. 
o 
Group 8 - patients must have pathologically documented, 
definitively diagnosed locally advanced or metastatic NSCLC 
with a RET fusion that was previously treated with a platinum-
based chemotherapy (China only). 
o 
Group 9 - patients must have pathologically documented, 
definitively diagnosed advanced MTC that has progressed 
within 14 months prior to the screening visit and was not 
previously treated with systemic therapy (except prior cytotoxic 
chemotherapy is allowed) for advanced or metastatic disease 
(China only). 
• 
Patients must have non-resectable disease. Prior to Protocol 
Amendment 9, patients must have progressed following standard 
therapy or have not adequately responded to standard therapy, or the 
patient must be intolerant to, or the Investigator has determined that 
treatment with standard therapy is not appropriate, or there must be no 
accepted standard therapy for their disease. 
• 
Dose expansion (Phase 2) patients in all groups (except Group 7) 
must have measurable disease per RECIST v1.1 (or RANO criteria, if 
appropriate). 
• 
Patient agrees to provide tumor tissue (archived, if available or a fresh 
biopsy) for RET status confirmation and is willing to consider an 
on-treatment tumor biopsy, if considered safe and medically feasible 
by the treating Investigator. For Phase 2, Group 6, patients are 
required to undergo a pretreatment biopsy to define baseline RET 
status in tumor tissue. 
• 
Patient has Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0-1. 
Primary 
Endpoints: 
Phase 1, Dose Escalation 
• 
MTD and RP2D of pralsetinib. 
• 
Overall safety profile of pralsetinib, as assessed by the type, 
frequency, severity, timing, and relationship to study drug of any AEs, 
serious adverse events (SAEs), changes in vital signs, ECGs, and 
safety laboratory tests. 


 
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Phase 2, Dose Expansion 
• 
ORR by disease type, and/or RET-altered status if applicable, and/or 
prior treatment status, if appropriate, including patients treated at the 
MTD/RP2D in Phase 1. 
• 
Overall safety profile of pralsetinib, as assessed by the type, 
frequency, severity, timing, and relationship to study drug of any AEs, 
SAEs, changes in vital signs, ECGs, and safety laboratory tests. 
Secondary 
Endpoints: 
Phase 1, Dose Escalation 
• 
ORR for all patients according to patients’ disease type and/or 
RET‑altered status if applicable, and/or prior treatment status, if 
appropriate. 
• 
RET gene status and correlation between RET gene status and ORR, 
DOR, CBR, and DCR, and other measures of antineoplastic activity (in 
plasma and/or tissue) in all patients according to their disease type 
and/or RET-altered status, if applicable, and/or prior treatment status, 
if appropriate. 
• 
PK parameters of pralsetinib: PK parameters of interest will include, as 
appropriate, maximum plasma drug concentration (Cmax), time to 
maximum plasma drug concentration (Tmax), time of last quantifiable 
plasma drug concentration (Tlast), area under the plasma 
concentration versus time curve from time 0 to 24 hours postdose 
(AUC0-24), plasma drug concentration at 24 hours postdose (C24); 
apparent volume of distribution (Vz/F), terminal elimination half-life 
(t½), apparent oral clearance (CL/F), and accumulation ratio (R). 
• 
Pharmacodynamic parameters of pralsetinib: changes in tumor/blood 
including, but not limited to, changes in blood calcitonin and CEA 
(MTC patients); and changes in tumor biomarker levels (DUSP6 and 
SPRY4) levels (all patients). 
Phase 2, Dose Expansion 
• 
DOR, CBR, DCR, PFS, and OS in all patients, including patients 
treated at MTD/RP2D in Phase 1, according to their disease type 
and/or RET-altered status, if applicable, and/or prior treatment status, 
if appropriate. 
• 
RET gene status (i.e., gene fusion partner or primary mutation and, for 
MTC, whether hereditary or sporadic) and correlation between RET 
gene status and ORR, DOR, CBR, DCR, and other measures of 
antineoplastic activity (in plasma and/or tissue) in all patients, including 
patients treated at MTD/RP2D in Phase 1, according to their disease 
type and/or RET-altered status if applicable, and/or prior treatment 
status, if appropriate. 
• 
PK parameters of pralsetinib: PK parameters of interest will include, as 
appropriate, maximum plasma drug concentration (Cmax), time to 
maximum plasma drug concentration (Tmax), time of last quantifiable 
plasma drug concentration (Tlast), area under the plasma 
concentration versus time curve from time 0 to 24 hours postdose 
(AUC0-24), plasma drug concentration at 24 hours postdose (C24); 
apparent volume of distribution (Vz/F), terminal elimination half-life 
(t½), apparent oral clearance (CL/F), and accumulation ratio (R). 


 
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• 
ECG Assessment: The effects of pralsetinib on ECG parameters will 
be evaluated for approximately 20 evaluable patients using 12-lead 
ECGs extracted from continuous recordings (12-lead Holter) on C1D1 
and C1D15. Individual ECGs will be extracted in replicate from the 
12‑lead Holter recordings at specified timepoints and will be evaluated 
by a central laboratory. QT intervals will be measured from lead II and 
will be corrected for heart rate (QTc) using Fridericia’s correction 
factors (QTcF). The primary QTc parameter will be QTcF. Secondary 
parameters (heart rate, PR, and QRS, and T-wave morphology) will 
also be evaluated. Potential effects of pralsetinib will be evaluated as 
change from predose baseline heart rate, PR, QRS, and QTcF by 
postdose timepoint. For the purpose of QT assessment, 
exposure‑response analysis will be performed on the relationship 
between pralsetinib systemic levels and change in QTcF. 
• 
Pharmacodynamic parameters of pralsetinib: changes in tumor/blood 
including, but not limited to, changes in blood calcitonin and CEA and 
biochemical response rate (MTC patients only). 
• 
Intracranial response rate among patients with NSCLC who have 
measurable (target by RECIST v1.1) lesions in the brain, and time to 
intracranial progression among all patients with NSCLC. 
Exploratory 
Endpoints 
Phase 1, Dose Escalation 
• 
Levels of exploratory blood and tumor markers (DNA, RNA and 
protein) as compared to antineoplastic activity, and/or toxicity. 
Phase 2, Dose Expansion 
• 
Changes in patient-reported outcomes as assessed by the EORTC 
QLQ-C30 instruments. 
• 
Changes in disease-related symptoms as reported by bowel 
movement history for MTC patients. 
• 
ORR, CBR, DCR, PFS for patients previously treated with a selective 
RET tyrosine kinase inhibitor. 
• 
Intracranial response rate among patients with tumor types other than 
NSCLC who have measurable (target by RECIST v1.1) lesions in the 
brain, and time to intracranial progression among all patients with 
tumor types other than NSCLC. 


 
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STUDY SCHEMATIC 
 
BID = twice daily; BOIN =Bayesian optimal interval; MKI = multikinase inhibitor; MTC =medullary 
thyroid cancer; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; P =oral; 
QD = once daily; RET = rearranged during transfection; RP2D =recommended Phase 2 dose; 
TKI = tyrosine kinase inhibitor. 
 
 


 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT, VERSION 15  RATIONALE .................................... 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 4 
STUDY SUMMARY .............................................................................................. 5 
LIST OF ABBREVIATIONS ................................................................................ 22 
1. 
BACKGROUND AND RATIONALE ............................................... 25 
1.1 
Background on RET and RET-driven Cancers ........................ 25 
1.1.1 
RET-Altered Thyroid Cancer .................................................... 26 
1.1.2 
RET-Altered NSCLC ................................................................ 28 
1.1.3 
Other RET-Driven Cancers ...................................................... 29 
1.2 
Pralsetinib (previously known as BLU-667) ............................. 30 
1.2.1 
Preclinical Pharmacology ........................................................ 30 
1.2.2 
Toxicology................................................................................ 31 
1.3 
Study Rationale and Design .................................................... 34 
1.4 
Rationale for the Starting Dose and Dosing Regimen ............. 35 
1.5 
BLU-667-1101 Study Update ................................................... 36 
1.5.1 
Phase 1 Dose Escalation Results ............................................ 36 
1.5.1.1 
Once Daily Schedule ............................................................... 36 
1.5.1.2 
Twice Daily Schedule .............................................................. 37 
1.5.1.3 
Rationale for the RP2D ............................................................ 37 
1.5.1.4 
Pharmacokinetics .................................................................... 38 
1.5.1.5 
Pharmacodynamics ................................................................. 39 
1.5.2 
Phase 2 Dose Expansion Preliminary Data ............................. 40 
1.5.2.1 
Efficacy .................................................................................... 40 
1.5.3 
Overall Safety .......................................................................... 42 
1.5.4 
Overall Benefit-Risk Assessment ............................................. 45 
2. 
STUDY OBJECTIVES ................................................................... 46 
2.1 
Phase 1 Objectives .................................................................. 46 
2.1.1 
Primary Objectives ................................................................... 46 
2.1.2 
Secondary Objectives .............................................................. 46 
2.1.3 
Exploratory Objectives ............................................................. 47 


 
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2.2 
Phase 2 Objectives .................................................................. 47 
2.2.1 
Primary Objectives ................................................................... 47 
2.2.2 
Secondary Objectives .............................................................. 47 
2.2.3 
Exploratory Objectives ............................................................. 48 
3. 
STUDY ENDPOINTS .................................................................... 48 
3.1 
Phase 1 Endpoints ................................................................... 48 
3.1.1 
Primary Endpoints ................................................................... 48 
3.1.2 
Secondary Endpoints ............................................................... 48 
3.1.3 
Exploratory Endpoints .............................................................. 48 
3.2 
Phase 2 Endpoints ................................................................... 49 
3.2.1 
Primary Endpoints ................................................................... 49 
3.2.2 
Secondary Endpoints ............................................................... 49 
3.2.3 
Exploratory Endpoints .............................................................. 50 
4. 
STUDY PLAN................................................................................ 50 
4.1 
Study Design ........................................................................... 50 
4.1.1 
Phase 1 (Dose Escalation) ...................................................... 52 
4.1.2 
Phase 2 (Expansion) ............................................................... 53 
5. 
POPULATION ............................................................................... 55 
5.1 
Number of Patients .................................................................. 55 
5.2 
Inclusion Criteria ...................................................................... 55 
5.3 
Exclusion Criteria ..................................................................... 57 
5.4 
RET Pre-screening .................................................................. 59 
5.5 
Patient Identification and Registration ..................................... 59 
5.6 
Study Completion .................................................................... 59 
5.6.1 
Patient Withdrawal Criteria from Study Treatment ................... 60 
5.6.2 
Patient Withdrawal Criteria from the Study .............................. 60 
5.7 
Replacement of Patients .......................................................... 61 
6. 
STUDY CONDUCT ....................................................................... 61 
6.1 
General Conduct ...................................................................... 61 
6.2 
Early Termination ..................................................................... 62 
6.2.1 
Rules for Early Termination of Enrollment ............................... 62 
6.3 
Dose and Administration .......................................................... 63 


 
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6.3.1 
Dosing for Phase 1 (Dose Escalation) ..................................... 63 
6.3.1.1 
Alternate Dosing Schedule ...................................................... 64 
6.3.1.2 
Guidelines for Dose Escalation ................................................ 64 
6.3.1.3 
Intra-Patient Dose Escalation .................................................. 68 
6.3.1.4 
Dose-Limiting Toxicity .............................................................. 69 
6.3.1.5 
Dose Reduction for Adverse Events ........................................ 69 
6.3.1.6 
Maximum Tolerated Dose ........................................................ 70 
6.3.2 
Dosing for Phase 2 (Dose Expansion) ..................................... 70 
6.3.2.1 
Recommended Phase 2 Dose ................................................. 70 
6.3.2.2 
Dose Modification Recommendations for Adverse Events ...... 70 
6.3.2.3 
Dose Modification and Management of Specific 
Treatment-Related Adverse Events ......................................... 71 
6.3.2.4 
Dose Re-Escalation after Resolution of Adverse Drug 
Reactions ................................................................................. 75 
6.4 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 76 
6.5 
Prior and Concomitant Therapy ............................................... 77 
6.5.1 
Prohibited Concomitant Therapy ............................................. 77 
6.5.2 
Concomitant Therapy to Be Used with Caution ....................... 77 
6.5.3 
Permitted Concomitant Therapy .............................................. 78 
6.6 
Additional precautions ............................................................. 78 
6.7 
Schedule of Assessments........................................................ 79 
7. 
DESCRIPTION OF STUDY PROCEDURES ................................ 86 
7.1 
RET pre-screening ................................................................... 86 
7.2 
Screening................................................................................. 86 
7.3 
Safety Assessments ................................................................ 87 
7.3.1 
Physical Examination ............................................................... 87 
7.3.2 
Eastern Cooperative Oncology Group Performance Status .... 87 
7.3.3 
Vital Signs ................................................................................ 87 
7.3.4 
ECGs ....................................................................................... 87 
7.3.5 
Clinical Laboratory Tests ......................................................... 88 
7.3.6 
Adverse Events and Concomitant Medications........................ 88 
7.3.7 
Thyroid Hormone Replacement in Patients with Thyroid 
Cancer ..................................................................................... 89 


 
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7.4 
Pharmacokinetic Assessment .................................................. 89 
7.5 
Pharmacodynamic and Biomarker Assessment ...................... 89 
7.5.1 
Blood Samples for Pharmacodynamic and Biomarker 
Assessment ............................................................................. 90 
7.5.2 
Tumor Samples for RET Status and Biomarker 
Assessment ............................................................................. 90 
7.6 
Disease Response Assessment .............................................. 91 
7.7 
Patient-Reported Outcomes and Quality of Life 
Measurements ......................................................................... 91 
7.8 
End-of-Treatment and 30-Day Safety Follow-up ...................... 91 
7.9 
Progression Free Survival and Overall Survival Follow-up ...... 92 
7.10 
Sample Processing, Storage, and Shipment ........................... 92 
8. 
STUDY DRUG MANAGEMENT .................................................... 92 
8.1 
Description ............................................................................... 92 
8.1.1 
Formulation .............................................................................. 92 
8.1.2 
Storage .................................................................................... 92 
8.2 
Packaging and Shipment ......................................................... 93 
8.3 
Accountability ........................................................................... 93 
8.4 
Compliance .............................................................................. 94 
9. 
ADVERSE EVENTS ...................................................................... 94 
9.1 
Definitions ................................................................................ 94 
9.1.1 
Definition of Adverse Event...................................................... 94 
9.1.1.1 
Adverse Events of Special Interest .......................................... 95 
9.1.2 
Suspected Adverse Reaction................................................... 95 
9.1.3 
Unexpected Adverse Event ..................................................... 95 
9.2 
Documenting Adverse Events.................................................. 95 
9.3 
Assessment of Severity ........................................................... 96 
9.4 
Assessment of Causality ......................................................... 96 
9.5 
Pretreatment Events ................................................................ 96 
9.6 
Pregnancy Reporting ............................................................... 97 
9.6.1 
Contraception Requirements ................................................... 97 
9.6.2 
Gamete and Embryo Banking .................................................. 98 
10. 
SERIOUS ADVERSE EVENTS..................................................... 98 


 
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10.1 
Definition of Serious Adverse Event ........................................ 98 
10.2 
Reporting Serious Adverse Events .......................................... 99 
10.2.1 
Overdose ............................................................................... 101 
10.3 
Medical Monitors and Emergency Medical Contacts ............. 101 
11. 
STATISTICS ............................................................................... 101 
11.1 
General Procedures ............................................................... 101 
11.2 
Analysis Populations .............................................................. 102 
11.3 
Sample Size ........................................................................... 102 
11.3.1 
Phase 1 (Dose Escalation) .................................................... 102 
11.3.1.1 
Operating Characteristics ...................................................... 103 
11.3.2 
Phase 2 (Expansion) ............................................................. 104 
11.4 
Statistical Methods ................................................................. 105 
11.4.1 
Demographic and Baseline Characteristics ........................... 106 
11.4.2 
Primary Endpoints ................................................................. 106 
11.4.2.1 
Phase 1 ................................................................................. 106 
11.4.2.2 
Phase 2 ................................................................................. 106 
11.4.3 
Secondary Endpoints ............................................................. 110 
11.4.3.1 
Phase 1 ................................................................................. 110 
11.4.3.2 
Phase 2 ................................................................................. 111 
11.4.4 
Exploratory Endpoints ............................................................ 113 
11.4.4.1 
Phase 1 ................................................................................. 113 
11.4.4.2 
Phase 2 ................................................................................. 113 
12. 
ETHICS AND RESPONSIBILITIES ............................................. 114 
12.1 
Regulatory and Ethical Considerations .................................. 114 
12.2 
Data and Safety Monitoring ................................................... 114 
12.2.1 
Phase 1 Data and Safety Monitoring ..................................... 115 
12.2.2 
Phase 2 Data and Safety Monitoring ..................................... 115 
12.2.2.1 
Phase 2 Safety Review Committee ....................................... 115 
12.2.2.2 
Phase 2 Independent Data Monitoring Committee ................ 115 
12.3 
Institutional Review Board/Independent Ethics Committee ... 116 
12.4 
Informed Consent .................................................................. 117 
12.5 
Study Files, Record Retention And Management .................. 117 


 
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12.6 
Source Documentation .......................................................... 118 
12.7 
Administrative Structure ......................................................... 118 
12.8 
Financial Disclosures ............................................................. 119 
12.9 
Protocol Deviations ................................................................ 119 
13. 
AUDITING AND MONITORING .................................................. 119 
14. 
AMENDMENTS ........................................................................... 119 
15. 
STUDY REPORT AND PUBLICATIONS .................................... 119 
16. 
STUDY DISCONTINUATION ...................................................... 120 
17. 
CONFIDENTIALITY .................................................................... 121 
18. 
REFERENCES............................................................................ 122 
19. 
APPENDICES ............................................................................. 126 
19.1 
Appendix 1: Eastern Cooperative Oncology Group 
Performance Status ............................................................... 126 
19.2 
Appendix 2: List of Prohibited Medications and Food ............ 127 
19.3 
Appendix 3: List of Medications and Food to be Used with 
Caution .................................................................................. 128 
19.4 
Appendix 4: Operating Characteristics of the BOIN Design ... 129 
19.5 
Appendix 5: Previous Protocol Amendments ......................... 132 
19.6 
Appendix 6: Common Oncogenic RET Mutations .................. 142 
19.7 
Appendix 7: EORTC QLQ-C30 Assessment ......................... 143 
19.8 
Appendix 8: Examples of Implementing the Early Stopping 
Rule ....................................................................................... 145 
 
 
LIST OF TABLES 
Table 1: 
Biochemical Activity of Cabozantinib, Vandetanib, 
Regorafenib, Ponatinib, and Pralsetinib against Wild-Type 
RET, RET Mutants, and RET Fusion Proteins ............................ 30 
Table 2: 
Pralsetinib Dose Levels and Number of Patients Enrolled .......... 37 
Table 3: 
Adverse Events Occurring in ≥15% of Patients by Preferred 
Term (Safety Population, Treated at 400 mg QD) ....................... 44 
Table 4: 
Serious Adverse Events Occurring in ≥ 2% of Patients, by 
Preferred Terms (Safety Population, Treated at 400 mg QD) ..... 45 
Table 5: 
Dose-Escalation/De-Escalation Rule for the BOIN Design ......... 65 


 
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Table 6: 
Provisional Dose-Escalation Levels ............................................ 68 
Table 7: 
Dose Modification Guidelines for Pralsetinib-Related Toxicity .... 71 
Table 8: 
Pralsetinib Dose Modification Recommendations for 
Treatment-Related Pneumonitis ................................................. 73 
Table 9: 
Pralsetinib Dose Modification Recommendations for 
Treatment-Related Hyperphosphatemia ..................................... 75 
Table 10: 
Schedule of Assessments ........................................................... 79 
Table 11: 
Schedule for Pharmacokinetic Sample Collection and ECG 
Monitoring ................................................................................... 84 
Table 12: 
Schedule for Pharmacodynamic Biomarker Sample 
Collection .................................................................................... 85 
Table 13: 
Confidence Interval of Observed Response Rate for Group 
1, N = 80 ................................................................................... 107 
Table 14: 
Confidence Interval of Observed Response Rate for Group 
2, N=170 ................................................................................... 107 
Table 15: 
Confidence Interval of Observed Response Rate for Group 
3, N = 65 ................................................................................... 108 
Table 16: 
Confidence Interval of Observed Response Rate for Group 
4, N = 40 ................................................................................... 108 
Table 17: 
Probability of Observing Responses for Group 5, N = 100 ....... 108 
Table 18: 
Confidence Interval of Observed Response Rate for Group 
5, N = 100 ................................................................................. 109 
Table 19: 
Probability of Observing Responses for Groups 6 and 7, N = 
20 .............................................................................................. 109 
Table 20: 
Confidence Interval of Observed Response Rate for Groups 
8 and 9, N = 30 ......................................................................... 109 
 
 
 
LIST OF FIGURES 
Figure 1: 
RET Signaling Pathway .............................................................. 26 
Figure 2: 
Spectrum of Oncogenic RET Alterations .................................... 27 
Figure 3: 
Efficacy and Body Weight Measurements with Pralsetinib 
(BLU-667) in a KIF5B-RET NSCLC Patient-Derived 
Xenograft Model .......................................................................... 31 
Figure 4: 
Mean (+ SD) Plasma Concentration Profiles of Pralsetinib 
following Pralsetinib on C1D1 (Single Dose) and at C1D15 
(Steady State) following Once Daily Oral Administration 
(Dose Escalation) ........................................................................ 39 
Figure 5: 
Anti-Tumor Activity of Pralsetinib in RET Fusion−Positive 
NSCLC ........................................................................................ 41 
Figure 6: 
Anti-Tumor Activity of Pralsetinib in MTC Patients  
Irrespective of Prior Therapy ....................................................... 42 
Figure 7: 
Study Schematic ......................................................................... 52 


 
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Figure 8: 
Dose-Escalation Schematic ........................................................ 66 
Figure 9: 
Dose-Toxicity Scenarios ........................................................... 104 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC0-24 
area under the plasma concentration−time curve from 0 to 24 hours 
AUCinf 
area under the plasma concentration versus time curve from 0 to 
infinity 
β-hCG 
beta human chorionic gonadotropin 
BID 
twice daily 
BOIN 
Bayesian optimal interval 
CBR 
clinical benefit rate 
CEA 
carcinoembryonic antigen 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRM 
continual reassessment method 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
ctDNA 
circulating tumor deoxyribonucleic acid 
CxDx 
Cycle x Day x 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
λe 
dose escalation boundary 
λd 
dose de-escalation boundary 
DCR 
disease control rate 
DOR 
duration of response 
DTC 
differentiated thyroid cancer 
DUSP6 
dual specificity phosphatase 6 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


 
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Abbreviation or Term 
Definition 
eCRF 
electronic Case Report Form 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
end of treatment 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GDNF 
glial cell line−derived neurotrophic factors 
GFRα 
GDNF family receptors−α 
HNSTD 
highest non-severely toxic dose 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
JAK2 
Janus kinase 2 
MKI 
multikinase inhibitor 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSCLC 
non−small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PDX 
patient-derived xenograft 
P-gp 
P-glycoprotein 
PFS 
progression-free survival 
PK 
Pharmacokinetic 
PR 
partial response 
PS 
performance status 
QD 
once daily 
QTcF 
QT interval corrected using Fridericia’s formula 


 
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Abbreviation or Term 
Definition 
RAI 
radioactive iodine 
RANO 
Response Assessment in Neuro-Oncology (criteria) 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RET 
rearranged during transfection 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SOC 
standard of care 
SPRY4 
sprout RTK signaling antagonist 4 
SRC 
Safety Review Committee 
STD10 
severely toxic dose in 10% of animals 
t1/2 
terminal half-life 
T4 
Thyroxine 
TKI 
tyrosine kinase inhibitor 
TSH 
thyroid-stimulating hormone 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
VEGFR 
vascular endothelial growth factor receptor 


 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON RET AND RET-DRIVEN CANCERS 
Increasing evidence implicates aberrant activation of the receptor tyrosine kinase (RTK), 
RET (rearranged during transfection), as a critical driver of tumor growth and 
proliferation across a broad number of solid tumors (Mulligan 2014).  RET along with 
glial cell line-derived neurotrophic factors (GDNF) and GDNF family receptors−α 
(GFRα), normally mediates development, maturation and maintenance of several neural, 
neuroendocrine and genitourinary tissue types.  The RET signaling pathway is shown 
below in Figure 1.  In contrast, oncogenic RET activation occurs via gain of function 
mutation which constitutively activates RET and promotes ligand-independent tumor 
growth.  Oncogenic RET activation was initially described in hereditary and sporadic 
thyroid cancers and subsequently in non−small cell lung cancer (NSCLC) 
adenocarcinoma.  However, as next-generation deoxyribonucleic acid (DNA) 
sequencing has become more prevalent, it has become apparent that oncogenic RET 
mutations occur in a variety of solid tumors. 


 
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Figure 1: 
RET Signaling Pathway 
 
DUSP6  dual-specificity phosphatase 6, ERK  extracellular signal-related kinase, GDNF  glial 
cell linederived neurotrophic, GRF  glial cell linederived neurotrophic factor alpha, 
PI3K  phosphotidylinositol-3-kinase, RET  rearranged during transfection, SPRY4  sprout RTK 
signaling antagonist 4, STAT3  signal transducer and activator of transcription 3. 
Note:  Binding of GDNF-GRF to RET promotes receptor dimerization and activation of RET 
kinase activity, which initiates downstream signaling and phenotypic effects by means of the 
ERK, PI3K, and STAT3 pathways. Feedback inhibition of ERK signaling occurs via DUSP6 and 
SPRY4. 
 
1.1.1 
RET-Altered Thyroid Cancer 
Thyroid cancer, which consists primarily of differentiated thyroid cancer (DTC; ~90% of 
cases), medullary thyroid cancer (MTC; ~5% of cases) and anaplastic thyroid cancer 
(< 5% of cases), is the most common endocrine malignancy with ~64,000 new cases per 
year and ~2,000 deaths in the United States (Surveillance, Epidemiology and End 
Results 2018).  DTC arises sporadically from thyroid follicular cells and consists of 
papillary thyroid cancer (PTC) (~85% of cases) and follicular thyroid cancer (FLC) 
(~5%10%).  In contrast, MTC arises from parafollicular C-cells and occurs in both 
hereditary and sporadic forms.  Oncogenic RET activation has been implicated as 
a driver in both MTC and DTC. 


 
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Recurrent gene rearrangements involving RET and a dimerization domain-encoding 
gene have been identified in ~10% of sporadic papillary tumors in adults and in 
~50%80% of papillary tumors that occur after radiation exposure or arise in childhood 
(Figure 2).  The dimerization domain provided by the fusion partner allows constitutive 
association of RET kinase domains, leading to aberrant kinase activation that promotes 
tumorigenesis. Kinase-activating RET alterations also occur in nearly all cases of 
hereditary and approximately 50% of sporadic MTC.  RET alterations are found in about 
90% of cases of unresectable or metastatic MTC (Romei et al. 2018). Hereditary MTC is 
associated with 3 subtypes of multiple endocrine neoplasia (MEN) syndrome, Type 2 
(MEN2), which are variably associated with other endocrine tumors (e.g., MEN2A MTC, 
pheochromocytoma, parathyroid hyperplasia; MEN2B – MTC, pheochromocytoma, 
marfinoid habitus, neurofibromatosis; FMTC MTC without pheochromocytoma or 
parathyroid hyperplasia).  RET alterations occur in > 95% of hereditary MTC and these 
include extracellular domain mutations (primarily at the C634 position), which promote 
ligand-independent activation of RET, and kinase domains mutations (primarily M918T, 
A883F or V804L/M), which promote RET auto-activation and consequent oncogenic 
signaling (Romei et al. 2018).  RET mutations are also oncogenic drivers in 
approximately 50% of sporadic MTCs, especially the M918T mutation as it accounts for 
~70% of the RET alterations in sporadic MTC. 
Figure 2: 
Spectrum of Oncogenic RET Alterations 
 
MTC  medullary thyroid cancer, NSCLC  nonsmall cell lung cancer, PTC  papillary thyroid 
cancer, RET  rearranged during transfection. 
 
 


 
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Both DTC and MTC are treated with surgery when localized (Fagin and Wells 2016). 
Ablative therapy with radioactive iodine (RAI) is effective in DTC patients with
recurrence; however, patients eventually become refractory to RAI.  As MTC arises from 
follicular C-cells, RAI is not effective.  Once advanced, RAI-refractory DTC and MTC are 
poorly responsive to chemotherapy and systemic treatment with a small molecule 
multikinase inhibitor (MKI) is the standard of care (SOC) for both. Sorafenib and 
lenvatinib are approved MKIs for progressive and/or symptomatic RAI-refractory DTC. 
Cabozantinib and vandetanib are approved MKIs for advanced MTC.  Note that there
are no approved diagnostics for assessment of RET status and MKIs are used
regardless of RET mutational status.  Importantly, MKIs poorly inhibit RET with germline 
mutations at the “gatekeeper” residue of the kinase domain (V804L/M) and these 
substitutions arise when cells are screened for drug resistance mutations to MKIs, such 
as vandetanib (Carlomagno et al. 2004).  Multikinase inhibitors used to treat thyroid 
cancer have broad activity against many kinases (e.g., RAF, MET, EGFR, vascular 
endothelial growth factor receptors [VEGFRs] 1−3, PDGFR, RET. and others), and are 
associated with significant dermatologic, cardiovascular, and gastrointestinal side
effects.  Therefore, National Clinical Practice Guidelines in Oncology (NCCN 2018) 
recommends careful monitoring and dose interruption and/or dose modification for drug-
related side effects with these agents.  In Dec 2020, pralsetinib received
accelerated approval from the US Food and Drug Administration (FDA) for the treatment 
of adult and pediatric patients 12 years of age and older with advanced or metastatic 
RET fusion‑positive thyroid cancer who require systemic therapy and who are
radioactive iodine‑refractory (if radioactive iodine is appropriate) and for advanced or 
metastatic RET‑mutant MTC who require systemic therapy (Gavreto [pralsetinib] U.S 
Prescribing Information).  In May 2020, the selective RET inhibitor selpercatinib received 
accelerated approval from the US FDA for the treatment of adult and pediatric patients 
≥12 years of age with advanced or metastatic RET-mutant MTC who require systemic 
therapy and adult and pediatric patients ≥12 years of age with advanced or metastatic 
RET fusion-positive thyroid cancer who require systemic therapy and who are
radioactive iodine-refractory (if radioactive iodine is appropriate) (Retevmo
[selpercatinib] U.S. Prescribing Information).  In Feb 2021, the European commission 
granted a conditional approval for the treatment of adults with advanced
RET fusion-positive thyroid cancer who require systemic therapy following prior
treatment with sorafenib and/or lenvatinib and for the treatment of adults and
adolescents 12 years and older with advanced RET mutant MTC who require systemic 
therapy following prior treatment with cabozantinib and/or vandetanib (Retsevmo 
[selpercatinib] E.U. Product Information).
1.1.2 
RET-Altered NSCLC
Oncogenic RET rearrangements have been identified in 1%−2% of NSCLC (Lin et al. 
2015).  These rearrangements typically produce chimeric transcripts that encode
a fusion protein consisting of the RET kinase domain coupled to a protein with
a dimerization domain (e.g., KIF5B, CCDC6, NCOA4).  This generates a constitutively


 
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active kinase that promotes tumorigenesis (Figure 2).  As with anaplastic lymphoma 
kinase (ALK) and ROS1-rearranged NSCLC, RET-rearranged NSCLC is typically 
adenocarcinoma histology (though occasionally squamous) and occurs in young, 
non‑smoking patients.  Because diagnostic testing for RET is not SOC, patients with 
advanced RET-rearranged NSCLC are treated per NCCN guidelines for EGFR- and 
ALK-negative adenocarcinoma.  This usually includes first-line chemotherapy with 
a platinum doublet and second-line therapy with single-agent cytotoxic chemotherapy or 
a checkpoint inhibitor; however, clinical response and overall survival (OS) with these 
agents remains poor.  Subsequent therapy for refractory patients per NCCN guidelines 
is best supportive care or a clinical trial. 
Initial case reports and single-arm studies with the MKIs cabozantinib, vandetanib, 
sorafenib, and alectinib in patients with known RET-rearranged NSCLC have 
demonstrated clinical activity, suggesting that RET may be a valid target in NSCLC. 
Although encouraging response rates (~12%−60%) (Horiike et al. 2016; Lin et al. 2016; 
Gautschi et al. 2017) have been observed in these early studies, duration of response 
(DOR) is typically less than a year.  MKI treatment was associated with significant 
toxicity, requiring dose interruption and/or dose modification as similarly observed in 
thyroid cancer, which likely limit exposures required to effectively inhibit RET.  Thus, 
RET-rearranged NSCLC remains an unmet need that requires new therapeutic 
approaches, particularly those that can selectively and potently inhibit RET in vivo 
(Drilon et al. 2018). 
In September 2020, pralsetinib received accelerated approval from the US FDA for the 
treatment of adult patients with locally advanced or metastatic RET fusion-positive 
NSCLC as detected by an FDA approved test (Gavreto [pralsetinib] U.S Prescribing 
Information).  In November 2021, the European commission granted a conditional 
approval for the treatment of adult patients with RET fusion-positive advanced NSCLC 
not previously treated with a RET inhibitor (Gavreto [pralsetinib] E.U. Product 
Information). 
In September 2022, the selective RET inhibitor selpercatinib received full approval from 
the US FDA for the treatment of adult patients with locally advanced or metastatic RET 
fusion−positive NSCLC (Retevmo [selpercatinib] U.S. Prescribing Information) and in 
September 2022 the European commission granted a conditional approval for the 
treatment of adults with advanced RET fusion-positive NSCLC not previously treated 
with a RET inhibitor (Retsevmo [selpercatinib] E.U. Product Information). 
1.1.3 
Other RET-Driven Cancers 
Emerging genomic and functional data implicate RET as a potential driver in several 
cancers beyond thyroid cancer and NSCLC (Borrello et al. 2013; Mulligan 2014).  For 
example, RET rearrangements and potentially activating point mutations have been 
observed at low frequency in colorectal cancer, breast cancer, and other solid tumors, as 
well as in chronic myelomonocytic leukemia (Ballerini et al. 2012; Stransky et al. 2014; 


 
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Medico et al. 2015).  Additionally, upregulation of RET, GDNF, and GFRαs has also 
been detected across solid tumor indications and this may promote RET activation, 
tumorigenesis and drug resistance (Nakashima et al. 2007; Yang and Horten 2014; 
Platt et al. 2015).  Thus, it is possible that other advanced solid tumors are dependent on 
RET activity and could respond to RET inhibition. 
To date, clinical activity attributable to RET inhibition has been uncertain for these 
approved MKIs, likely due to insufficient inhibition of RET and off-target toxicities.  There 
is a need for precision therapies that provide durable clinical benefit by selectively 
targeting RET alterations and anticipated resistance mutations. 
1.2 
PRALSETINIB (PREVIOUSLY KNOWN AS BLU-667) 
1.2.1 
Preclinical Pharmacology 
Pralsetinib (also known as BLU-667, BLU123244, or X581238) is a potent and selective 
inhibitor of RET and oncogenic RET mutants.  In cellular systems, pralsetinib inhibits the 
kinase activity of RET oncogenic mutants and RET fusion proteins with low nanomolar 
potency.  In vivo, dose dependent antitumor efficacy with pralsetinib was demonstrated 
in several RET-driven models, including a RET C634W mutant-driven MTC xenograft, 
a CCDC6-RET fusion expressing colorectal cancer patient-derived xenograft (PDX) and 
a KIF5B-RET fusion−driven NSCLC PDX.  Antitumor efficacy was correlated with 
pralsetinib exposures and pharmacodynamic modulation of tumor biomarkers, including 
direct inhibition of RET activity.  Repeat dose administration to mice at doses, ranging 
from 10 mg/kg twice a day (BID) to 30 mg/kg BID and 60 mg/kg once a day (QD), were 
well tolerated and resulted in complete tumor growth inhibition or tumor regression.  
At doses required for complete tumor growth inhibition in these models, a 90% decrease 
in RET kinase activity was observed. 
Table 1: Biochemical Activity of Cabozantinib, Vandetanib, Regorafenib, 
Ponatinib, and Pralsetinib against Wild-Type RET, RET Mutants, 
and RET Fusion Proteins 
Mean IC50 (nM) 
RET 
RET 
V804L 
RET 
V804M 
RET 
M918T 
CCDC6- 
RET 
VEGFR-2 
Pralsetinib 
0.43 
0.33 
0.38 
0.40 
0.45 
35 
Cabozantinib 
11 
45 
162 
8 
34 
2 
Vandetanib 
4 
3597 
726 
7 
20 
4 
Regorafenib 
12 
53 
70 
25 
15 
14 
Ponatinib 
0.6 
4 
2 
0.8 
0.8 
2 
CCDC6  = coiled-coil domain-containing 6; IC50  =half-maximal inhibitory concentration of enzyme 
activity; RET  =rearranged during transfection; VEGFR  =vascular endothelial growth factor. 
Source: BPM-0015. 
 


 
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Figure 3: Efficacy and Body Weight Measurements with Pralsetinib 
(BLU-667) in a KIF5B-RET NSCLC Patient-Derived Xenograft 
Model 
T re a tm e n t D a y
T u m o r V o lu m e  (m m 3)
0
1 0
2 0
3 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
V e h ic le  C o n tr o l
C a b o z a n t in ib  6 0  m g /k g  Q D
B L U -6 6 7  - 3  m g /k g  B ID
B L U -6 6 7  - 1 0  m g /k g  B ID
B L U -6 6 7  - 3 0  m g /k g  B ID
B L U -6 6 7  - 6 0  m g /k g  Q D
 
BID  twice daily; NSCLC  nonsmall cell lung cancer; PDX  patient-derived xenograft; 
QD  once daily. 
Note:  Mice bearing KIF5B-RET fusion lung adenocarcinoma PDXs were dosed orally, once or 
twice daily as indicated with 3, 10, 30 mg/kg BID or 60 mg/kg QD BLU-667 (pralsetinib) for 
28 days.  Tumor size was measured twice weekly for the 28-day dosing period. BLU-667 
antitumor activity was highly statistically significant (p  0.01 for 3 mg/kg BID BLU-667, p  0.001 
for 10 and 30 mg/kg BID and 60 mg/kg QD dosing by one way analysis of variance followed by 
Dunnett’s multiple comparison test).  Datapoints represent the group mean and error bars 
represent the standard error of the mean for 9 mice per cohort. 
Source: 1110-003. 
 
The selectivity of pralsetinib on RET versus other human targets was characterized. 
Pralsetinib had a high degree of selectivity for RET over 450 kinases, including  25-fold 
selectivity for RET over VEGFR2 and FGFR1, two kinases inhibited by several MKIs. 
Pralsetinib also demonstrated high selectivity when tested in a panel of 
55 transmembrane or soluble receptors, ion channels, and monoamine transporters. 
Safety pharmacology studies revealed that pralsetinib inhibits the human  
ether-à-go-gorelated gene (hERG) channel activity in vitro with an average IC50 of 
5.18 M, suggesting low potential for prolonging the QT interval.  In the cardiovascular 
safety pharmacology study in radiotelemetry-implanted rats, doses of 150 mg/m2 
(25 mg/kg) and higher were associated with reduced heart rate and increased systolic 
and diastolic blood pressure, all without clinical signs. However, no electrocardiogram 
(ECG) changes were noted in toxicology studies. 
Additional information can be found in the Pralsetinib Investigator’s Brochure (IB). 
1.2.2 
Toxicology 
Sprague-Dawley rats and cynomolgus monkeys were chosen as the nonclinical test 
species for assessing chemical structure- and pharmacology-mediated toxicity of 
pralsetinib on the basis of the following criteria: a) these species have historically been 


 
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used to assess potential human adverse effects, b) these species are qualitatively 
similar in hepatocyte metabolism profiles to humans, c) these species contain identical 
or highly homologous amino acids surrounding the pralsetinib binding site compared 
with human RET, and d) these species are pharmacologically responsive to the effects 
of pralsetinib. 
In the 28-day Good Laboratory Practice (GLP)-compliant repeated-dose toxicology study 
in Sprague-Dawley rats, the toxicities defining the severely toxic dose in 10% of animals 
(STD10; 180 mg/m2/day) were inanition and metabolic abnormalities, which included 
reduced food consumption, reduced weight, dermal atonia, and chemistry alterations, 
including increased blood phosphorus. 
Adverse, non−dose-limiting toxicity (DLT) and non-severely toxic effects were 
considered secondary to off-target pharmacology.  These effects were characterized by 
thickened physeal cartilage (femur), hyperphosphatemia with corresponding 
mineralization in the glandular stomach, incisor tooth degeneration, and decreased bone 
marrow cellularity with corresponding decrease in red blood cell counts.  These effects 
were either resolving or resolved after the 14-day recovery period with the exception of 
incisor tooth degeneration.  The primary vascular effects on the physeal cartilage in the 
femur and on the teeth are attributed to impaired angiogenesis secondary to VEGFR 
inhibition (Patyna et al. 2008; Chen and Cleck 2009; Fletcher et al. 2010).  The primary 
tissue mineralization effects are attributed to the pharmacologic effect of inhibiting FGFR 
signaling, which has been observed with other compounds in development (Brown et al. 
2005; Yanochko et al. 2013).  The primary cellular effects are on the bone marrow and 
are attributed to Janus kinase 2 (JAK2) inhibition (Quelle et al. 1994; Parganas et al. 
1998; Broxmeyer 2013; Springuel et al. 2015). 
In the 28-day GLP-compliant repeated-dose toxicology study in cynomolgus monkeys, 
the lethal dose (480 mg/m2/day) was associated with erosion and ulceration of the 
gastrointestinal mucosa, and sepsis.  The DLT defining the highest non-severely toxic 
dose (HNSTD; 90 mg/m2/day) were inanition, reduced food consumption, reduced body 
weight, and alterations in chemistry and hematology values. 
Other effects in monkeys included decreased bone marrow cellularity, physeal 
dysplasia, and decreased cellularity of lymphoid organs with decreased lymphocytes.  
All effects in the HNSTD group were resolving or resolved after the 14-day recovery 
period.  No functional effects on the cardiovascular system were noted based on ECG 
analyses and in-life examinations.  Gastrointestinal ulcerations and sepsis in monkeys 
are attributed to the pharmacologic effect of inhibiting VEGFR.  Reduced bone marrow 
cellularity was attributed to the pharmacologic effect of inhibiting JAK2.  Decreased 
cellularity of lymphoid organs, corresponding with decreased lymphocytes with 
increased neutrophils and monocytes, were collectively attributed to stress. 


 
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Pralsetinib was negative for mutagenic activity in the GLP-compliant 5 strain Ames test, 
with and without metabolic activation.  Pralsetinib was classified as non-phototoxic 
following in vitro phototoxicity evaluation in 3T3 fibroblasts using the neutral red uptake 
assay. 
Results from the repeated dose GLP-compliant 28-day toxicology studies in rats and 
monkeys, the non-GLP cardiovascular safety pharmacology studies in 
radiotelemetry‑implanted rats, and other toxicology studies all inform the clinical program 
of potential risks to humans in the first-in-human (FIH) study.  Overall, results from these 
studies indicate an acceptable benefit-risk profile for the clinical testing of pralsetinib. 
Two 13-week GLP-compliant repeated-dose toxicology studies were conducted in 
Sprague Dawley rats and cynomolgus monkeys.  In the 13-week rat study, adverse dose 
effects at 20 mg/kg/day (120 mg/m2/day) in both males and females included tooth 
degeneration (dentin matrix alteration, ameloblast degeneration, odontoblast 
degeneration, and odontoblast necrosis), subsequent tooth fractures, decreased 
hematopoiesis in the bone marrow in the sternum and femur, and decreased lymphoid 
cellularity in the thymus that corresponded with lower mean thymus weights and gross 
observation of small thymus.  Additional adverse effects at 20 mg/kg/day included 
tubular degeneration/atrophy in the testis with secondary cellular debris and reduced 
sperm in the lumen of the epididymis, which corresponded with lower mean testis and 
epididymis weights, respectively, and gross observations of soft and small testes, and 
degeneration of the corpus luteum in the ovary at 20 mg/kg/day.  The NOAEL was 
10 mg/kg/day.  This dosage level corresponded to mean area under the 
concentration−time curve (AUC) to the last measurable concentration (AUC[0-t]) values of 
33,300 and 42,300 ng•hr/mL and mean Cmax values of 2360 and 3580 ng/mL for males 
and females, respectively, on Day 91. 
In the 13-week monkey study, pralsetinib was well-tolerated at all dosage levels (i.e., 
2, 5, and 10 mg/kg/day). Therefore, the NOAEL was considered to be 10 mg/kg/day.  
This dosage corresponded to mean AUC(0-t) values of 43,200 and 31,900 ng•hr/mL and 
mean Cmax values of 2790 and 2850 ng/mL for males and females, respectively, on 
Day 91. 
A GLP-compliant repeat-dose embryofetal toxicology study was conducted to 
characterize the toxicity of pralsetinib in pregnant female Sprague-Dawley rats when 
dosed at 5, 10, 20, and 30 mg/kg/day (30, 60, 120, and 180 mg/m2/day) via oral gavage 
QD during gestation on Days 6–17.  All females in the 20- and 30-mg/kg/day groups had 
100% post-implantation losses (all early resorptions).  A higher mean litter proportion of 
post-implantation loss and lower mean litter proportion of viable fetuses were noted in 
the 10-mg/kg/day group.  Multiple visceral malformations and developmental variations 
(primarily of the kidney and ureter) and skeletal malformations (vertebral, rib, costal 
cartilage, and vertebral centra anomalies) and developmental variations (reduced 
ossification of ribs) were noted at 5 and/or 10 mg/kg/day.  Based on the adverse effects 


 
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on intrauterine survival and/or fetal morphology at all dosage levels, a NOAEL for 
embryo/fetal development could not be determined. 
Additional information can be found in the Pralsetinib IB. 
1.3 
STUDY RATIONALE AND DESIGN 
Pralsetinib potently and selectively targets RET fusions and RET-activated mutants, 
such as M918T and V804L/M, shows potent antitumor activity in RET-driven tumor 
models, and demonstrates tolerability at pharmacologically active doses in preclinical 
toxicology species.  Together, these data provide strong rationale for exploring the 
clinical utility of pralsetinib in advanced cancer patients with RET alterations. The study 
employed a dose escalation/maximum tolerated dose (MTD) expansion design to define 
the pralsetinib MTD/recommended Phase 2 dose (RP2D) and to assess the safety, 
tolerability, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic activity 
of pralsetinib in RET-altered solid tumors. As pralsetinib demonstrates potent activity 
against RET fusions, activating mutations, and resistance mutations, the overall 
response rate (ORR) for all RET-altered tumors will be assessed. 
The dose-escalation part of the trial (Phase 1) has been completed.  It included patients 
with advanced non-resectable NSCLC, advanced non-resectable thyroid cancer, and 
other advanced non-resectable solid tumors.  The dose-escalation part employed 
a Bayesian optimal interval (BOIN) design to define the MTD of pralsetinib.  The BOIN 
design is simple to implement, similar to the traditional 3 + 3 design but is more flexible 
and possesses superior operating characteristics that are comparable to those of the 
more complex model-based designs, such as the continual reassessment method 
(CRM).  The target toxicity rate for the MTD is 30%.  At dose levels above 120 mg, 
patients must have had a diagnosis of MTC, or the tumor must carry a RET alteration, as 
per local assessment of tumor tissue and/or blood. 
The MTD and RP2D were determined to be 400 mg QD in Phase 1, and enrollment to 
the dose expansion part of the trial (Phase 2) is ongoing.  The dose expansion part will 
permit a more complete assessment of safety, pharmacokinetics, pharmacodynamics, 
and antitumor activity in patients with different types of RET-driven malignancies treated 
with pralsetinib at the RP2D.  During the expansion part, patients will be enrolled in 
9 groups: 
• 
NSCLC patients with a RET fusion who have previously been treated with 
a platinum-based chemotherapy (Group 1) 
• 
NSCLC patients with a RET fusion not previously treated with a platinum-based 
chemotherapy, including those who have not had any systemic treatment 
Prior platinum chemotherapy in the neoadjuvant and adjuvant settings are 
permitted if the last dose of platinum was 4 months or more before the first dose 
of study drug (Group 2). 


 
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• 
MTC patients who have been previously treated with cabozantinib and/or 
vandetanib (Group 3) 
• 
MTC patients not previously treated with cabozantinib or vandetanib (Group 4) 
• 
RET-fusion solid tumors in previously treated patients with SOC or who have not 
adequately responded to standard therapy, or the patient must be intolerant to, or 
the investigator has determined that treatment with, standard therapy is not 
appropriate, or there must be no accepted standard therapy for their disease and 
the patient is not eligible for any other group 
Because the intent of this cohort is to enroll a variety of patients with RET-fusion 
tumor types, Roche will notify sites if and when sufficient data are available, and 
accrual should cease for a particular tumor type (Group 5). 
• 
RET-mutated or fusion solid tumors in previously treated patients with a selective 
RET tyrosine kinase inhibitor (an example of a previous selective RET inhibitor is 
selpercatinib) (TKI; Group 6) 
• 
Patients with RET-mutated solid tumors treated with SOC appropriate for the tumor 
type (Group 7) 
• 
NSCLC patients with a RET fusion who have previously been treated with 
a platinum-based chemotherapy extension cohort (Group 8, China only) 
• 
MTC patients who were not previously treated with systemic therapy (except prior 
cytotoxic chemotherapy is allowed) for advanced or metastatic disease extension 
cohort (Group 9, China only) 
 
1.4 
RATIONALE FOR THE STARTING DOSE AND DOSING 
REGIMEN 
Selection of the safe starting dose in clinical trials for anticancer small molecules is 
based on either one-tenth the allometrically scaled STD10 in the rat, the most 
sensitive species based on administered dose, or one-sixth the allometrically scaled 
HNSTD in monkeys if monkeys cannot tolerate one-tenth of the allometrically scaled rat 
STD10 value.  The STD10 in the rat is 30 mg/kg/day or 180 mg/m2/day, one-tenth of which 
equals 18 mg/m2/day.  The HNSTD in the monkey is 7.5 mg/kg/day or 90 mg/m2/day, 
indicating that the monkey can tolerate one-tenth of the rat STD10.  Therefore, the safe 
starting dose for the proposed Phase 1 trial will be 18 mg/m2 or a flat dose of 30 mg/day 
based on a 1.7 m2 human. 
The maximum plasma concentration (Cmax) and AUC from 0 to 24 hours (AUC0-24hr) 
values at the proposed FIH starting dose of 30 mg QD are projected to be 270 ng/mL 
and 2300 ng • hr/mL, respectively.  The starting dose provides an acceptable margin of 
safety as the predicted Cmax and AUC0-24hr values are well below the values observed at 
the STD10 in the rat (Cmax = 8150 ng/mL and AUC0-24 hr = 113000 ng/mL) and the HNSTD 
in the monkey (Cmax = 3255 ng/mL and AUC0-24 hr  = 27100 ng • hr/mL). 
Dosing commenced with QD administration, as in vivo efficacy studies in animal tumor 
models showed no advantage of BID over QD dosing of pralsetinib. However, based on 


 
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the predicted pralsetinib half-life of approximately 4−5 hours in humans, BID dosing may 
be superior.  Therefore, starting with the fourth dose level, or at a subsequent dose level, 
a BID dosing schedule could be explored, as described in Section 6.3, if supported by 
pharmacokinetic (PK) and safety data from the prior dose levels. 
1.5 
BLU-667-1101 STUDY UPDATE 
Phase 1, dose escalation was completed on 3 April 2018. Phase 2, dose expansion 
completed enrolling patients on 28 December 2021. 
1.5.1 
Phase 1 Dose Escalation Results 
1.5.1.1 
Once Daily Schedule 
The first patient, first visit of BO42863 (formerly BLU-667-1101) occurred on 
17 March 2017.  A total of 53 patients (51 with RET-altered tumors) were enrolled into 
the QD dose escalation of pralsetinib at doses ranging from 30 mg to 600 mg as outlined 
in Table 2.  Four patients were treated at 600 mg QD and 2 of the 4 patients 
experienced DLTs (Grade 3 hyponatremia and Grade 3 hypertension).  While both DLTs 
were reversible, per the protocol guidelines, 600 mg QD exceeded the MTD and the 
MTD for pralsetinib was determined to be 400 mg QD. 
 
 


 
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Table 2: Pralsetinib Dose Levels and Number of Patients Enrolled 
Cohort:  Dose 
# Patients 
Treated 
(n = 53) 
# Evaluable 
(n = 51a) 
DLT 
1:  30 mg QD 
2 
1 
0 
2:  60 mg QD 
6 
6 
0 
3:  100 mg QD 
5 
5 
1 ALT increased 
4:  200 mg QD 
5 
5 
0 
5:  300 mg QD 
5 
5 
1 tumor lysis syndrome; 1 hypertension 
6:  200 mg QD 
8 
7 
0 
7:  300 mg QD 
6 
6 
0 
8:  400 mg QD 
12 
12 
1 myositis, b 1 hypertension 
9:  600 mg QD 
4 
4 
1 hyponatremia; 1 hypertension 
ALT= alanine aminotransferase; DLT= dose-limiting toxicity; QD= once daily. 
a Two patients were not evaluable for DLT (at least 75% of Cycle 1 doses not completed and did 
not experience a DLT). 
b. This event was formerly reported by the site as asthenia. 
 
1.5.1.2 
Twice Daily Schedule 
A BID dosing schedule was also explored in Phase 1.  The BID dosing schedule started 
at a 300-mg total daily dose (200 mg in the morning, 100 mg in the evening).  A total of 
9 patients were enrolled into the BID dose escalation: 4 at the 300-mg total daily dose 
(200 mg in the morning, 100 mg in the evening) and 5 at the 200-mg total daily dose 
(100 mg BID).  Of the first 4 patients enrolled at the 300-mg total daily dose, 
2 experienced DLTs of Grade 3 hypertension and the dose was subsequently 
de-escalated to 100 mg BID.  Two of 5 patients at 100 mg BID experienced DLTs, 
including 1 patient with Grade 3 hypertension and 1 patient with tumor lysis syndrome 
(TLS).  All patients resumed treatment after resolution of DLT to Grade 1 or baseline and 
continued in the study.  Based on overall safety, exposure, tolerability, QD was the 
preferred dosing schedule and chosen for the dose expansion, Phase 2.  An MTD for 
BID dosing was not defined, and further exploration is not planned. 
1.5.1.3 
Rationale for the RP2D 
Two of the 4 patients treated with pralsetinib at 600 mg QD experienced DLTs (Grade 3 
hyponatremia and Grade 3 hypertension).  While both DLTs were reversible, per the 
protocol guidelines, 600 mg QD exceeded the MTD and the MTD of pralsetinib was 
determined to be 400 mg QD.  The overall safety across doses 60−400 mg QD was 
favorable.  Most adverse events were Grade 1; the most commonly reported adverse 
events in Phase 1 of the study were constipation (24%), ALT increased (22%), AST 
increased (20%), and hypertension (16%).  Pralsetinib demonstrated rapid absorption, 
a long t1/2, and a dose-dependent increase in exposure and pathway inhibition.  
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and brain RET IC90.  Based on this, 400 mg was selected as the recommended dose for 
expansion, which in now enrolling. 
1.5.1.4 
Pharmacokinetics 
In Phase 1 (dose escalation), the mean pralsetinib concentration−time profiles following 
single oral dose administration, showed rapid absorption into the systemic circulation 
(median Tmax: 2 to 3 hours) followed by an apparent monophasic elimination.  Results 
showed a comparable profile to that observed in healthy volunteer studies. Apparent oral 
clearance was comparable between C1D1 (mean of 6.4 to 30.9 L/hr) and C1D15 (mean 
of 8.6 to 40.2 L/hr), indicating no apparent time-dependent changes in the 
pharmacokinetics of pralsetinib.  The mean t½ of pralsetinib on C1D1 ranged from 
11.3 to 22.9 hours (for the 200- to 400-mg dose range), supporting QD dosing. 
Additionally, the mean t½ was comparable to the values reported in Phase 1 healthy 
volunteer studies (BLU-667-0101; mean: 13.2 hours and BLU-667-0102; mean: 
16.9 hours).  Following repeated QD administration, steady-state was expected to be 
reached by D4 with < 3-fold accumulation (GeoMean accumulation ratio of 1.65 
[coefficient of variation [CV: 96.8%, 400 mg] and 2.75 [CV 70.9%, 400 mg] for Cmax and 
AUC, respectively).  The steady-state (C1D15) mean plasma pralsetinib 
concentration−time profiles for each dose level are shown in Figure 4.  Furthermore, 
pralsetinib doses ≥ 400 mg on C1D15 resulted in sustained plasma concentrations 
above both plasma and brain RET IC90 values in ~30% of all patients. 


 
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Figure 4: Mean (+ SD) Plasma Concentration Profiles of Pralsetinib 
following Pralsetinib on C1D1 (Single Dose) and at C1D15 (Steady 
State) following Once Daily Oral Administration (Dose Escalation) 
 
C= cycle; D= day; h= hour; IC90= 90% inhibitory concentration; PK= pharmacokinetic; 
RET= rearranged during transfection; SD= standard deviation. 
Note:  RET IC90 measured in mouse tumor xenografts model. 
 
1.5.1.5 
Pharmacodynamics 
RET pathway inhibition was assessed by measuring expression of the RET pathway 
genes DUSP6 and SPRY4 in pre- and post-treatment tumor tissue in a subset of 
patients in Phase 1.  Pralsetinib treatment led to downregulation of DUSP6 and SPRY4 


 
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mRNAs in tumor tissue indicating RET pathway inhibition.  Increased pathway inhibition 
was observed with increasing pralsetinib dose. 
1.5.2 
Phase 2 Dose Expansion Preliminary Data 
Phase 2 enrollment at the RP2D has been completed. 
1.5.2.1 
Efficacy 
Pralsetinib has demonstrated broad and durable antitumor activity in patients with RET 
fusion-positive NSCLC and RET-altered MTC and PTC, regardless of treatment history, 
RET-fusion partner or mutation, or brain involvement. 
1.5.2.1.1 
Non−Small Cell Lung Cancer 
Efficacy data were reported as of the data cutoff of 18 November 2019 (Blueprint 
Medicines Corporation press release 2020) for NSCLC patients treated with pralsetinib 
who were evaluable for response assessment per RECIST v1.1, as determined by 
blinded independent central review.  All patients received the proposed indicated dose of 
400 mg QD in Study BLU-667-1101.  In 80 patients with RET fusion−positive NSCLC 
previously treated with platinum-based chemotherapy, the ORR was 61% 
(95% confidence interval [CI]: 50% to 72%) (2 responses pending confirmation as of the 
data cutoff date) (Figure 5).  Overall, 95% had tumor shrinkage, including 14% of 
patients with complete regression of target tumors.  The median DOR was not reached 
(95% CI: 11.3 months to not estimable).  In 26 patients with metastatic RET 
fusion−positive NSCLC who were systemic anticancer treatment naive, the ORR was 
73% (95% CI: 52% to 88%) (all responses confirmed as of the data cutoff date), with 
12% of patients achieving a complete response (CR).  All treatment-naive patients had 
tumor shrinkage. 


 
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Figure 5: Anti-Tumor Activity of Pralsetinib in RET FusionPositive NSCLC 
 
NSCLC  nonsmall cell lung cancer; RET  rearranged during transfection. 
 
1.5.2.1.2 
Thyroid Cancer 
Efficacy data were reported as of the data cutoff of 13 February 2020 (Blueprint 
Medicines Corporation press release in April 2020).  Top-line efficacy data were reported 
for patients with thyroid cancer treated with pralsetinib who were evaluable for response 
assessment per RECIST v1.1, as determined by blinded independent central review.  All 
patients received the proposed indicated dose of 400 mg QD. 
In 53 patients with RET-mutant MTC previously treated with cabozantinib or vandetanib, 
the ORR was 60% (95% CI: 46%to 74%), with one response pending confirmation 
(Figure 6). Nearly all patients (98%) had tumor shrinkage.  The median DOR was not 
reached (95% CI: not estimable to not estimable), and the 18-month DOR rate was 90% 
(95% CI: 77%to 100%). 
In addition, the top-line data showed robust clinical activity in treatment-naive patients, 
supporting the potential of pralsetinib across lines of therapy.  In 19 patients with 
RET-mutant MTC who had not received prior systemic treatment, the confirmed ORR 
was 74% (95% CI: 49%to 91%), and all patients had tumor shrinkage.  The median DOR 
was not reached (95% CI: 7 months to not estimable), with 12 of 14 responders 
remaining in response for up to 15 months as of the data cutoff date. 
In 9 patients with RET fusionpositive thyroid cancer, the confirmed ORR was 89% 
(95% CI: 52% to 100%), and all patients had tumor shrinkage.  The median DOR was 


 
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not reached (95% CI: 8 months to not estimable), with seven of eight responders 
remaining in response for up to 20 months as of the data cutoff date. 
Figure 6: 
Anti-Tumor Activity of Pralsetinib in MTC Patients  
Irrespective of Prior Therapy 
 
MTC=medullary thyroid cancer. 
 
Additionally, pralsetinib has received FDA breakthrough therapy designation in patients 
with RET fusion−positive NSCLC that has progressed following platinum-based 
chemotherapy and RET-mutated MTC requiring systemic treatment and for which there 
are no acceptable alternative treatments. 
1.5.3 
Overall Safety 
Overall, pralsetinib QD dosing schedule at dose levels ≤ 400 mg has demonstrated 
acceptable tolerability, with most adverse events being low-grade and reversible.  All 
adverse events that occurred in ≥ 15% of patients, as of the data cutoff date of 
12 April 2021, of the 532 patients who started treatment at 400 mg QD, 531 patients 
(99.8%) had experienced an adverse event.  The median treatment duration for all 
patients in the safety population, treated at 400mg QD, was 11.8 months.  The most 
frequently reported adverse events (by Preferred Term) were anemia (49.6%), AST 
increased (48.3%), constipation (43.4%), ALT increased (35.9%), hypertension (33.8%), 
and diarrhea (30.8%) Table 3.  Overall, 498 patients (93.6%) experienced an adverse 
event related to pralsetinib. 
Overall, 59.4% of patients treated at 400 mg QD experienced a SAE.  The most 
frequently reported SAEs were pneumonia (10.9%), disease progression (8.8%), 


 
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pneumonitis (4.9%), anemia (4.9%), sepsis (3.4%), urinary tract infection (3.6%), 
coronavirus infection (2.6%), pyrexia (2.6%), and pleural effusion (2.1%; Table 4).  
At the time of the 12 April 2021 data cutoff, 379 patients (71.2%) had their study 
treatment interrupted because of an adverse event, 261 patients (49.1%) had their dose 
reduced because of an adverse event, and 108 patients (20.3%) discontinued study 
treatment due to an adverse event.  Overall, 299 patients (56.2%) had their study 
treatment interrupted because of a study drug−related adverse event, 247 patients 
(46.4%) had their dose reduced because of a study drug−related adverse event, and 
40 patients (7.5%) discontinued study treatment due to a study drug−related adverse 
event.  Additional information related to the safety profile of pralsetinib can be found in 
the Pralsetinib IB.   


 
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Table 3: Adverse Events Occurring in ≥15% of Patients by Preferred Term 
(Safety Population, Treated at 400 mg QD) 
Preferred Term  
All Patients 
N=532 
Patients with AE 
531 (99.8%) 
Anaemia 
264 (49.6%) 
AST increased 
257 (48.3%) 
Constipation 
231 (43.4%) 
ALT increased 
191 (35.9%) 
Hypertension 
180 (33.8%) 
Diarrhoea 
164 (30.8%) 
White blood cell count decreased 
145 (27.3%) 
Pyrexia 
144 (27.1%) 
Fatigue 
136 (25.6%) 
Neutrophil count decreased 
134 (25.2%) 
Blood creatinine increased 
128 (24.1%) 
Cough 
122 (22.9%) 
Neutropenia 
120 (22.6%) 
Hypocalcaemia 
119 (22.4%) 
Dyspnoea 
97 (18.2%) 
Hyperphosphataemia 
96 (18.0%) 
Headache 
93 (17.5%) 
Nausea 
91 (17.1%) 
Decreased appetite 
88 (16.5%) 
Blood creatine phosphokinase increased 
88 (16.5%) 
Oedema peripheral 
85 (16.0%) 
Dry mouth 
85 (16.0%) 
Dysgeusia 
84 (15.8%) 
Pneumonia 
83 (15.6%) 
Hypokalaemia 
82 (15.4%) 
Notes:  Adverse Events (AEs) are coded using MedDRA 19.1. AEs refer to treatment-emergent 
adverse events (TEAEs).  All TEAEs including treatment-emergent SAEs are included in 
summary statistics. If a patient has multiple occurrences of an AE, the patient is presented only 
once in the respective patient count. Adjacent AEs for the same preferred term are linked per 
patient. 


 
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Table 4: Serious Adverse Events Occurring in ≥ 2% of Patients, by 
Preferred Terms (Safety Population, Treated at 400 mg QD) 
Preferred Term  
All Patients  
N=532 
Patients with SAE 
316 (59.4%) 
Pneumonia 
58 (10.9%) 
Disease progression 
47 (8.8%) 
Pneumonitis 
26 (4.9%) 
Anaemia 
26 (4.9%) 
Urinary tract infection 
19 (3.6%) 
Sepsis 
18 (3.4%) 
Coronavirus infection 
14 (2.6%) 
Pyrexia 
14 (2.6%) 
Pleural effusion 
11 (2.1%) 
Notes:  Adverse Events (AEs) are coded using MedDRA 19.1. AEs refer to treatment-emergent 
adverse events (TEAEs).  All TEAEs including treatment-emergent SAEs are included in 
summary statistics.  If a patient has multiple occurrences of an AE, the patient is presented only 
once in the respective patient count.  Adjacent AEs for the same preferred term are linked per 
patient. 
 
1.5.4 
Overall Benefit-Risk Assessment 
Conclusions regarding the benefits and risks of pralsetinib should be taken in the context 
of its stage of development.  Thus far, pralsetinib has demonstrated broad and durable 
antitumor activity in patients with RET fusion−positive NSCLC and RET-mutated MTC, 
regardless of treatment history, RET fusion partner or mutation, or central nervous 
system (CNS) involvement.  The ORRs in these unmet need populations ranged from 
58% up to 83%.  The overall safety experience suggests that pralsetinib has a favorable 
tolerability profile in advanced cancer patients and that most adverse events and serious 
adverse events are readily detected and managed with current safety monitoring 
procedures.  Taken together, available information indicates that the benefit−risk ratio for 
pralsetinib therapy is acceptable for further development. 
COVID-19 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are a more vulnerable population.  Infection 
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses.  It is unclear whether or how cancer therapies, such as 
chemotherapy, targeted therapy, or immunotherapy, affect the incidence or severity of 
COVID-19.  It is not known whether treatment with pralsetinib will increase the risk of 
infection with SARS-CoV-2.  Patients with a serious infection requiring IV antibiotics or 
any active infection that, in the opinion of the investigator, could affect patient safety will 
be taken off treatment and will be carefully monitored for infections during the study. 


 
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Based on a specific benefit-risk assessment, taking into account the available relevant 
information, the approved non-live COVID-19 vaccines should be administered in 
participants who are in the study, as long as there is no other contraindication (e.g., 
known hypersensitivity to a vaccine component).  Although there is no specific 
requirement regarding the timing of vaccine administration, the vaccination should 
ideally be at least commenced before study enrollment and initiation of study drug, 
whenever possible.   
Details of any COVID-19 vaccination received before study enrollment should be 
captured in the medical history section, at screening, whereas details regarding the 
COVID-19 vaccine received during the study should be recorded in the concomitant 
medication section.  Investigators should share with participants' primary healthcare 
providers relevant information regarding any potential effect of respective study drugs 
on the response to COVID-19 vaccination, as applicable.  Also, participants should 
contact the investigators or site staff, when they are invited to receive a COVID-19 
vaccine deployed in their region.  
The decision to vaccinate a participant should be based on a participant’s SARS-CoV-2 
infection/complication risk, general health condition, severity of underlying 
malignancy, and regional epidemiology of COVID-19.  COVID-19 vaccines should be 
administered in accordance with their respective prescribing information and applicable 
immunization guidelines.  After COVID-19 vaccination, one should continue to 
observe the applicable epidemiologic/public health and hygiene measures during the 
pandemic, along with per protocol safety measures and assessments in order to 
minimize the risk and to appropriately identify and assess potential adverse reactions 
(e.g., nausea, diarrhea, myalgia) possibly shared by vaccines and study drugs.  Based on 
the published mechanism of action of the COVID-19 vaccines and the known 
mechanism of action of pralsetinib, there is no scientific rationale to expect that 
COVID‑19 vaccines will affect the efficacy of pralsetinib. 
2. 
STUDY OBJECTIVES 
2.1 
PHASE 1 OBJECTIVES 
2.1.1 
Primary Objectives 
• 
To determine the MTD and RP2D of pralsetinib 
• 
To determine the safety and tolerability of pralsetinib 
 
2.1.2 
Secondary Objectives 
• 
To determine the ORR by RECIST v1.1 (or Response Assessment in 
Neuro-Oncology [RANO] criteria, if appropriate for tumor type) for all patients 
treated with BLU‑667 according to their disease type, and/or RET-altered status if 
applicable, and/or prior treatment status, if appropriate 
Data from patients initially treated with MTD/RP2D will be pooled with data from 
Phase 2 patients. 


 
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• 
To assess baseline RET gene status in plasma and/or tumor tissue and correlate 
with measures of antineoplastic activity including, but not limited to ORR, clinical 
benefit rate (CBR), disease control rate (DCR), and DOR 
• 
To characterize the PK profile of pralsetinib and correlate drug exposure with safety 
assessments 
• 
To characterize the pharmacodynamics of pralsetinib, including, but not limited to, 
changes in blood calcitonin and carcinoembryonic antigen (CEA) in MTC patients 
only, and changes in tumor dual specificity phosphatase (DUSP6) and sprout RTK 
signaling antagonist 4 (SPRY4) levels in all patients 
 
2.1.3 
Exploratory Objectives 
• 
To identify potential new blood and tumor tissue biomarkers (e.g., DNA, RNA, 
and/or protein markers) of pharmacodynamic activity, antineoplastic activity, and/or 
toxicity 
 
2.2 
PHASE 2 OBJECTIVES 
Data from Phase 1 patients treated at the MTD/RP2D will be pooled with data from 
Phase 2 patients for Phase 2 objectives. 
2.2.1 
Primary Objectives 
• 
To determine the ORR by RECIST v1.1 (or RANO criteria, if appropriate for tumor 
type) by disease type, and/or RET-altered status (including patients treated at 
MTD/RP2D in Phase 1), and/or prior treatment status specified in enrollment group 
definition, if appropriate 
• 
To further define the safety and tolerability of pralsetinib 
2.2.2 
Secondary Objectives 
• 
To assess additional measures of clinical benefit, including DOR, CBR, DCR, PFS, 
and OS in all patients by disease type and/or RET-altered status, and/or prior 
treatment status explained in enrollment group definition, if appropriate 
Data from patients treated at MTD/RP2D in Phase 1 will be pooled with data from 
Phase 2 patients for this analysis. 
• 
To assess baseline RET gene status (i.e., gene fusion partner or primary mutation 
and, for MTC, whether hereditary or sporadic) in plasma and/or tumor tissue and 
correlate with measures of antineoplastic activity including, but not limited to ORR, 
CBR, DOR, and DCR in all patients, including patients treated at MTD/RP2D in 
Phase 1, by disease type, and/or RET-altered status if applicable, and/or prior 
specified treatment status if appropriate 
• 
To characterize the PK profile of pralsetinib and correlate drug exposure with safety 
assessments, including changes in ECG intervals, and efficacy 
• 
To characterize the pharmacodynamics of pralsetinib, including, but not limited to, 
changes in blood calcitonin and CEA in MTC patients only 
• 
To assess brain activity in patients with NSCLC 
 


 
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2.2.3 
Exploratory Objectives 
• 
To identify potential new blood and tumor tissue biomarkers (e.g., DNA, RNA, 
and/or protein markers) of pharmacodynamic activity, antineoplastic activity, and/or 
toxicity 
• 
To assess changes in quality-of-life (QoL) questionnaire 
• 
To explore disease-related symptoms, as measured by bowel movement history 
(MTC patients only) 
• 
To explore clinical benefit including ORR, CBR, DCR, PFS for patients previously 
treated with a selective RET TKI 
• 
To assess brain activity in patients with tumor types other than NSCLC 
 
3. 
STUDY ENDPOINTS 
3.1 
PHASE 1 ENDPOINTS 
3.1.1 
Primary Endpoints 
• 
MTD and RP2D of pralsetinib 
• 
Overall safety profile of pralsetinib, as assessed by the type, frequency, severity, 
timing, and relationship to study drug of any adverse events, serious adverse 
events, changes in vital signs, ECGs, and safety laboratory tests 
 
3.1.2 
Secondary Endpoints 
• 
ORR for all pralsetinib treated patients according to patients’ disease type and/or 
RET-altered status if applicable, and/or prior treatment status if appropriate 
Data from patients initially treated with MTD/RP2D in Phase 1 will be pooled with 
data from Phase 2 patients accordingly. 
• 
RET gene status and correlation between RET gene status and ORR, CBR, DOR, 
and DCR, and other measures of antineoplastic activity (in plasma and/or tissue) in 
all patients according to their disease type and/or RET-altered status, if applicable, 
and/or prior treatment status, if appropriate 
• 
PK parameters of pralsetinib: PK parameters of interest will include, as appropriate, 
Cmax, time to maximum plasma drug concentration (Tmax), time of last quantifiable 
plasma drug concentration (Tlast), AUC0-24hr, plasma drug concentration at 24 hours 
postdose (C24hr); apparent volume of distribution (Vz/F), terminal elimination half‑life 
(t½), apparent oral clearance (CL/F), and accumulation ratio (R) 
• 
Pharmacodynamic parameters of pralsetinib: changes in tumor/blood including, but 
not limited to, changes in blood calcitonin and CEA (MTC patients) and changes in 
tumor biomarker levels (DUSP6 and SPRY4) levels (all patients) 
 
3.1.3 
Exploratory Endpoints 
• 
Levels of exploratory blood and tumor markers (DNA, RNA and protein) as 
compared to antineoplastic activity, and/or toxicity. 


 
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3.2 
PHASE 2 ENDPOINTS 
Data from Phase 1 patients treated at MTD/RP2D will be pooled with data from Phase 2 
patients for Phase 2 endpoints accordingly. 
3.2.1 
Primary Endpoints 
• 
ORR by patients’ disease type and/or RET-altered status if applicable, and/or prior 
treatment status if appropriate 
• 
Overall safety profile of pralsetinib, as assessed by the type, frequency, severity, 
timing, and relationship to study drug of any adverse events, serious, changes in 
vital signs, ECGs, and safety laboratory tests 
 
3.2.2 
Secondary Endpoints 
• 
DOR, CBR, DCR, PFS, and OS in all patients by disease type and/or RET-altered 
status, if applicable, and/or prior treatment status, if appropriate 
• 
RET gene status (i.e., gene fusion partner or primary mutation and, for MTC, 
whether hereditary or sporadic) and correlation between RET gene status and ORR, 
CBR, DOR, DCR, and other measures of antineoplastic activity (in plasma and/or 
tissue) in all patients according to their disease type and/or RET-altered status, if 
applicable, and/or prior treatment status, if appropriate 
• 
PK parameters of pralsetinib: PK parameters of interest will include, as appropriate, 
maximum plasma drug concentration (Cmax), time to maximum plasma drug 
concentration (Tmax), time of last quantifiable plasma drug concentration (Tlast), area 
under the plasma concentration versus time curve from time 0 to 24 hours postdose 
(AUC0-24), plasma drug concentration at 24 hours postdose (C24); apparent volume of 
distribution (Vz/F), terminal elimination half-life (t½), apparent oral clearance (CL/F), 
and accumulation ratio (R). 
• 
ECG assessment:  In Phase 2, the effects of pralsetinib on ECG parameters will be 
evaluated for approximately 20 patients using 12-lead ECGs extracted from 
continuous recordings (12-lead Holter) on C1D1 and C1D15.  Individual ECGs will be 
extracted in replicate from the 12-lead Holter recordings at specified timepoints and 
will be evaluated by a central laboratory.  QT intervals will be measured from lead II 
and will be corrected for heart rate (QTc) using Fridericia’s correction factors (QTcF).  
The primary QTc parameter will be QTcF.  Secondary parameters (heart rate, PR, 
and QRS, and T-wave morphology) will also be evaluated. Potential effects of 
pralsetinib will be evaluated as change from predose baseline heart rate, PR, QRS, 
and QTcF by postdose timepoint.  For the purpose of QT assessment, 
exposure−response analysis will be performed on the relationship between 
pralsetinib systemic levels and change in QTcF. 
• 
Pharmacodynamic parameters of pralsetinib:  changes in tumor/blood, including, but 
not limited to, changes in blood calcitonin and CEA and biochemical response rate 
(MTC patients only) 
• 
Intracranial response rate among patients with NSCLC who have measurable (target 
as assessed according to RECIST v1.1) lesions in the brain, and time to intracranial 
progression among all patients with NSCLC 
 


 
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3.2.3 
Exploratory Endpoints 
• 
Changes in patient-reported outcomes, as assessed by the European Organization 
for Research and Treatment of Cancer Core QoL Questionnaire (EORTC QLQ-C30) 
instruments 
• 
Changes in disease-related symptoms as reported by bowel movement history for 
MTC patients 
• 
ORR, CBR, DCR, PFS in  patients previously treated with a selective RET TKI 
• 
Intracranial response rate among patients with tumor types other than NSCLC who 
have measurable (target by RECIST v1.1) lesions in the brain, and time to 
intracranial progression among all patients with tumor types other than NSCLC 
 
4. 
STUDY PLAN 
4.1 
STUDY DESIGN 
This is a Phase 1/2, open-label, FIH study designed to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics, and antineoplastic activity of pralsetinib, a potent 
and selective RET inhibitor, administered orally in patients with medullary thyroid cancer, 
RET-altered NSCLC, and other RET-altered solid tumors (Figure 7). 
The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part 
(Phase 2).  Both parts will enroll patients with advanced non-resectable NSCLC, 
advanced non-resectable thyroid cancer and other advanced non-resectable solid 
tumors.  Prior to Amendment 9, all patients were required to have progressed following 
standard systemic therapy, have not adequately responded to standard systemic 
therapy, or be intolerant to or the investigator has determined that treatment with 
standard therapy is not appropriate, or there must be no accepted standard therapy for 
their disease.  RET gene status is assessed locally before enrollment and tissue 
submission. 
All study visits are intended to be conducted on an outpatient basis, but may be 
conducted on an inpatient basis, as needed.  After provision of written informed consent 
(within 8 weeks before study drug administration), patients will be evaluated for study 
eligibility during the screening period within 28 days before study drug administration on 
Cycle 1, Day 1 (C1D1). 
On C1D1, eligible patients will present to the study center approximately 2 hours before 
the first dose of study drug and will remain at the study center for 8 hours for serial PK 
sampling, pharmacodynamic sample collection, vital signs measurement, ECG 
monitoring, safety laboratory tests, and safety monitoring.  In Phase 2, patients will 
complete a QoL assessment (EORTC QLQ-C30).  Additionally, in Phase 2 only, 
continuous ECG Holter monitoring will be performed approximately 1 hour before dosing 
until after collection of the 8-hour PK sample for 20 patients at selected study centers.  
At these study centers, replicate 12-lead ECGs will be extracted from the continuous 
recording at the same timepoints as the PK blood draws.  Approximately 72 patients 


 
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(including ~12 patients in Groups 8 and 9) in Phase 2 will complete the serial PK 
sampling during Cycle 1; otherwise, patients enrolled in Phase 2 will have only predose 
PK samples collected.  See Table 10, Table 11, and Table 12 and Section 7 for 
a detailed description of study assessments. 
A treatment cycle is 28 days in duration.  Initially, patients returned to the study center 
on C1D2 for PK sampling (24 hours after the C1D1 dose), C1D8 and C1D22 for safety 
monitoring, and on C1D15 and C1D16 for serial PK sampling and safety monitoring 
(including continuous Holter monitoring for 20 patients in Phase 2 at selected study 
centers).  Following Protocol Amendment 9, visits at C1D2 and C1D16 were no longer 
required, except for patients in Groups 8 and 9, who will undergo serial PK sampling in 
China according to the country-specific Protocol Amendment 10.  Patients will also 
attend study center visits on C2D1 and C2D15, on Day 1 of C3 through C13, C15, C17, 
C21, and every 4 cycles thereafter for additional safety monitoring; PK and 
pharmacodynamic sampling; and disease response assessment by computed 
tomography (CT) or magnetic resonance imaging (MRI).  In Phase 2 only, the EORTC 
QLQ-C30 will be administered on D1 of every cycle through C12.  A tumor biopsy will be 
performed within 2 weeks (± 4 days) of C2D1 (Phase 1 only) and upon disease 
progression (both parts), if the patient consents and the procedure is deemed to be safe 
and medically feasible by the investigator. 
All patients will attend an end-of-treatment (EOT) visit approximately 14 days (±7 days) 
after the final dose of study drug.  A follow-up telephone contact for resolution of any 
residual adverse event will be made on Day 30 (+ 7 days) after the final dose of study 
drug, or at the time the patient initiates another antineoplastic therapy.  All patients will 
subsequently be contacted every 3−4 months for PFS (until progression or start of new 
therapy) and every 3 months for OS follow-up until closure of the study by the Sponsor.   
In the event that, due to unforeseen circumstances, a patient is unable to travel to the 
investigative site for a planned study visit, elements of that visit may be performed 
remotely (e.g., phone/video calls) or at outside facilities with notification and agreement 
from the Sponsor.  Appropriate guidance documents may be put in place to support 
these unforeseen circumstances.  All efforts should be made to ensure the safety and 
wellbeing of the patient prior to continuation of study drug and altered study visits (as 
above) should be appropriately documented in the source. 


 
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Figure 7: 
Study Schematic 
BID= twice daily, BOIN = Bayesian optimal interval; MTC= medullary thyroid cancer; 
NSCLC= non−small cell lung cancer; PO= oral; QD= once daily; RET= rearranged during 
transfection; TKI= tyrosine kinase inhibitor. 
 
4.1.1 
Phase 1 (Dose Escalation) 
The dose escalation (Phase 1) portion of the study was completed on 3 April 2018.  The 
study enrolled patients with a pathologically documented, definitively diagnosed 
advanced non-resectable NSCLC, advanced non-resectable thyroid cancer, and other 
advanced non-resectable solid tumors that had progressed following standard systemic 
therapy, had not adequately responded to standard systemic therapy, or the patient 
must be intolerant to or the investigator has determined that treatment with standard 
therapy is not appropriate, or there must be no accepted standard therapy for their 
disease.  Patients treated at doses > 120 mg/day were required to have an MTC- or 
a RET-altered solid tumor per local assessment of tumor tissue and/or blood.  
Additionally, these patients could be enrolled into an enrichment cohort, if it previously 
included fewer than 12 patients evaluable for DLT, was reviewed at a dose-escalation 
meeting, and did not exceed the MTD.  Data from these patients allowed for an 
improved assessment of safety, pharmacokinetics, and pharmacodynamics. 
The dose-escalation part of the study employed the BOIN design (Liu and Yuan 2015) to 
find the MTD of pralsetinib.  The BOIN design is simple to implement, similar to the 
traditional 3 + 3 design but is more flexible and possesses superior operating 
characteristics that are comparable to those of the more complex model-based designs, 


 
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such as the CRM.  The target toxicity rate for the MTD is 30%.  Dose escalation 
continued to enroll in cohorts of 3−6 patients (1−3 patients for the first 3 dose levels) until 
12 patients were treated and evaluable for DLT at one dose level.  The total number of 
patients to be enrolled during the dose escalation part of the study could vary depending 
on the toxicity profile of pralsetinib and the number of dose levels tested prior to reaching 
the MTD.  Dose escalation could also be stopped before reaching the MTD based on 
safety findings (such as toxicities beyond C1 that preclude continued dosing), PK data 
(such as a plateau in drug exposure despite increasing dose), or pharmacodynamic data 
(such as persistent elimination of circulating tumor [ct] DNA).  It was originally estimated 
that dose escalation would require approximately 35 patients. 
Pralsetinib was administered QD to patients enrolled at the first three dose levels.  
Starting with the fourth dose level, or at a later dose level, a BID dosing schedule was 
allowed to be explored, if supported by PK and safety data, as described in Section 6.3.  
In addition, based on emerging data, other alternative dosing regimens, such as 
intermittent dosing (e.g., 3 weeks on, 1 week off) could be explored.  The protocol was to 
be amended prior to evaluating new dosing schedules that increase dosing frequency, 
other than BID dosing. 
During Phase 1, patient safety was reviewed on an ongoing basis (at least monthly) at 
a teleconference that includes the study investigators and the Sponsor’s clinical study 
team.  Available safety data were to be reviewed to confirm that no unexpected, 
significant, delayed, or unacceptable risks had been discovered.  Available PK, 
pharmacodynamic, and tumor response data were also to be reviewed.  Dose escalation 
decisions, the dose for subsequent dose levels, and MTD/RP2D determination were 
made at a teleconference, as described above, that was designated in advance to be 
a dose-escalation teleconference. 
Additional details on the dose-escalation process, safety monitoring, estimation of the 
MTD/RP2D, and DLTs are provided in Sections 6.3.1.2 and 11.3. 
4.1.2 
Phase 2 (Expansion) 
In Phase 2, patients will enroll into 1 of 7 groups based on their tumor type and prior 
therapy status (if applicable).  Patients will be treated with pralsetinib at the MTD/RP2D 
as determined in Phase 1 and must have at least 1 target lesion evaluable by RECIST 
v1.1 or RANO criteria, with the exception of patients enrolled in Group 7: 
• 
Group 1:  Patients with NSCLC with a RET fusion previously treated with 
a platinum-based chemotherapy (n ~80) 


 
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• 
Group 2:  Patients with NSCLC with a RET fusion not previously treated with 
a platinum-based chemotherapy, including patients who have not had any systemic 
therapy 
Prior platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted 
if the last dose of platinum was 4 months or more before the first dose of study 
drug (n~200, including approximately 30 patients with prior systemic therapy). 
• 
Group 3:  Patients with MTC previously treated with cabozantinib and/or vandetanib 
(n ~65). 
• 
Group 4:  Patients with MTC not previously treated with cabozantinib or vandetanib 
(n ~40). 
• 
Group 5:  Patients with other solid tumors with a RET fusion not eligible for any of 
the other groups (n ~100) 
Patients should have previously received SOC appropriate for their tumor type, 
unless there is no accepted standard therapy for the tumor type or the 
investigator has determined that treatment with standard therapy is not 
appropriate.  As the intent of this cohort is to enroll a variety of RET-fusion tumor 
types, Roche will notify sites if/when sufficient data are available and accrual 
should cease for a particular tumor type. 
• 
Group 6:  Patients with any solid tumor with a RET alteration (fusion or mutation) 
previously treated with a selective RET inhibitor (n~20) 
• 
Group 7:  Patients with other solid tumors with a RET mutation previously treated 
with SOC appropriate for the tumor type (n~20). 
• 
Group 8:  Patients with NSCLC with a RET fusion previously treated with 
a platinum‑based chemotherapy (China only; n ~30) 
• 
Group 9:  Patients with MTC not previously treated with systemic therapy (except 
prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease 
extension cohort (China only; n ~30) 
 
Determination of RET status, as required for enrollment of all patients except those with 
MTC, is based on local assessment or central assessment; however, patients with MTC 
are not required to have RET results before enrollment.  All patients enrolled in Phase 2 
must submit tumor tissue (archived or new) for retrospective assessment of RET status 
and other pathway biomarkers (see Section 7.5.2).  Patients enrolled in Group 6 
(previous treatment with a selective RET-inhibitor) are required to have a new tumor 
biopsy prior to enrollment. 
During Phase 2, patient safety will be reviewed on an ongoing basis through various 
safety teams. Specific details regarding safety monitoring are described in Section 12.2. 


 
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5. 
POPULATION 
5.1 
NUMBER OF PATIENTS 
Approximately 647 patients will be enrolled in this study, including: 
• 
A total of 62 patients were enrolled in Phase 1 (dose escalation) 
• 
Approximately 585 patients in Phase 2 (expansion) 
 
The total number of patients enrolled in Phase 1 was dependent upon the observed 
safety profile, which determined the number of patients per dose cohort, as well as the 
number of dose escalations required to achieve the MTD. 
5.2 
INCLUSION CRITERIA 
Patients meeting the following criteria will be eligible for participation in the study: 
• 
Age ≥ 18 years old 
• 
Diagnosis during dose escalation (Phase 1) − Pathologically documented, 
definitively diagnosed non-resectable advanced solid tumor 
– 
All patients treated at doses > 120 mg per day must have MTC or 
a RET-altered solid tumor per local assessment of tumor tissue and/or blood. 
– 
Phase 1 enrichment patients must have MTC or a RET-altered solid tumor per 
local assessment of tumor tissue and/or blood. 
• 
Diagnosis during dose expansion (Phase 2) 
All patients (with the exception of patients with MTC enrolled in Groups 3, 4, 
and 9) must have an oncogenic RET fusion or mutation (excluding synonymous, 
frameshift, and nonsense mutations) solid tumor, as determined by local testing 
of tumor or circulating tumor nucleic acid in blood; as detailed below. For a list of 
common oncogenic mutation, see Appendix 6. 
– 
Group 1:  Patients must have pathologically documented, definitively 
diagnosed locally advanced or metastatic NSCLC with a RET fusion 
previously treated with a platinum-based chemotherapy. 
– 
Group 2:  Patients must have pathologically documented, definitively 
diagnosed locally advanced or metastatic NSCLC with a RET fusion not 
previously treated with a platinum-based chemotherapy, including those who 
have not had any systemic therapy.  Prior platinum chemotherapy in the 
neoadjuvant and adjuvant setting is permitted if the last dose of platinum 
was 4 months or more before the first dose of study drug. 
– 
Group 3:  Patients must have pathologically documented, definitively 
diagnosed advanced MTC that has progressed within 14 months prior to the 
screening visit and was previously treated with cabozantinib and/or 
vandetanib. 
– 
Group 4:  Patients must have pathologically documented, definitively 
diagnosed advanced MTC that has progressed within 14 months prior to the 


 
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screening visit and was not previously treated with cabozantinib or 
vandetanib. 
– 
Group 5:  Patients must have a pathologically documented, definitively 
diagnosed advanced solid tumor with an oncogenic RET fusion, have 
previously received SOC appropriate for their tumor type (unless there is no 
accepted standard therapy for the tumor type or the investigator has 
determined that treatment with standard therapy is not appropriate), and 
must not eligible for any of the other groups. 
– 
Group 6:  Patients must have a pathologically documented, definitively 
diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, 
previously treated with a selective TKI that inhibits RET, such as 
selpercatinib. 
– 
Group 7:  Patients must have a pathologically documented, definitively 
diagnosed advanced solid tumor with an oncogenic RET mutation previously 
treated with SOC appropriate for the tumor type and not eligible for any of 
the other groups. 
– 
Group 8:  Patients must have pathologically documented, definitively 
diagnosed locally advanced or metastatic NSCLC with a RET fusion that 
was previously treated with a platinum-based chemotherapy (China only). 
– 
Group 9:  Patients must have pathologically documented, definitively 
diagnosed advanced MTC that has progressed within 14 months prior to the 
screening visit and was not previously treated with systemic therapy (except 
prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease 
(China only). 
• 
Patients must have non-resectable disease. 
Prior to Protocol Amendment 9, patients must have progressed following 
standard therapy or have not adequately responded to standard therapy, or the 
patient must be intolerant to, or the investigator has determined that treatment 
with standard therapy is not appropriate, or there must be no accepted standard 
therapy for their disease. 
• 
Dose expansion (Phase 2):  Patients in all groups (except Group 7) must have 
measurable disease per RECIST v1.1 (or RANO, criteria if appropriate for tumor 
type). 
• 
Patient agrees to provide tumor tissue (archived, if available or a fresh biopsy) for 
RET status confirmation and is willing to consider an on-treatment tumor biopsy, if 
considered safe and medically feasible by the treating investigator.  For Phase 2, 
Group 6, patients are required to undergo a pretreatment biopsy to define baseline 
RET status in tumor tissue. 
• 
Patient has Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 
of 0 or 1. 
• 
Patient provides informed consent to participate in the study. 
 


 
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5.3 
EXCLUSION CRITERIA 
Patients meeting any of the following criteria will not be eligible for participation in the 
study: 
• 
Patient’s cancer has a known primary driver alteration other than RET (e.g., NSCLC 
with a targetable mutation in EGFR, ALK, ROS1, or BRAF; colorectal with an 
oncogenic KRAS, NRAS, or BRAF mutation) 
Investigators should discuss enrollment with Sponsor regarding co-mutations. 
• 
Patient has any of the following within 14 days prior to the first dose of study drug: 
– 
Platelet count < 75 × 109/L. 
– 
Absolute neutrophil count (ANC) < 1.0× 109/L. 
Hemoglobin < 9.0 g/dL (red blood cell transfusion and erythropoietin may be 
used to reach at least 9.0 g/dL but must have been administered at least 
2 weeks prior to the first dose of study drug. 
– 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the 
upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if 
hepatic metastases are present 
– 
Total bilirubin > 1.5× ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence 
of Gilbert disease 
– 
Estimated (calculated using the Cockroft-Gault formula) or measured creatinine 
clearance < 40 mL/min 
– 
Total serum phosphorous > 5.5 mg/dL 
• 
Patient has a QTcF > 470 ms.  Patient has a history of prolonged QT syndrome or 
torsades de pointes.  Patient has a familial history of prolonged QT syndrome. 
• 
Patient has clinically significant, uncontrolled, cardiovascular disease, including 
congestive heart failure Grade III or IV according to the New York Heart Association 
(classification; myocardial infarction or unstable angina within the previous 
6 months, uncontrolled hypertension, or clinically significant, uncontrolled 
arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g., 
Type II second-degree heart block or third-degree heart block). 
• 
Patient has CNS metastases or a primary CNS tumor that is associated with 
progressive neurological symptoms or requires increasing doses of corticosteroids 
to control the CNS disease. 
If a patient requires corticosteroids for management of CNS disease, the dose 
must have been stable for the 2 weeks preceding C1D1. 
• 
Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, 
including radiation pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention). 
• 
Patient received the following anticancer therapy: 
– 
Any systemic anticancer therapy (except for immunotherapy or other antibody 
therapies) and all forms of radiotherapy, within 14 days or 5 half-lives prior to the 


 
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first dose of study drug. Pralsetinib may be started within these washout periods 
if considered by the investigator to be safe and within the best interest of the 
patient. 
– 
Any immunotherapy or other antibody therapy within 28 days prior to the first 
dose of study drug (immune related toxicities must have resolved to Grade < 2 
prior to starting pralsetinib). 
• 
Dose expansion patients in Groups 1−5 and 7 (Phase 2): Patient has previously 
received treatment with a selective RET inhibitor such as selpercatinib. 
• 
Patient received neutrophil growth factor support within 14 days of the first dose of 
study drug. 
• 
Patient requires treatment with a prohibited medication or herbal remedy (as 
specified in Appendix 2) that cannot be discontinued at least 2 weeks before the 
start of study drug administration.  Pralsetinib may be started within 14 days or 
5 half-lives of prior therapy if considered by the investigator to be safe and within the 
best interest of the patient. 
• 
Patient has had a major surgical procedure within 14 days of the first dose of study 
drug (procedures such as central venous catheter placement, tumor needle biopsy, 
and feeding tube placement are not considered major surgical procedures). 
• 
Patient has a history of another primary malignancy that has been diagnosed or 
required therapy (except maintenance anti-hormonal therapy) within the past year. 
The following prior malignancies are not exclusionary:  completely resected basal 
cell and squamous cell skin cancer, curatively treated localized prostate cancer, 
curatively treated localized thyroid cancer, and completely resected carcinoma in 
situ of any site. 
• 
Patient is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, or other study procedures and study restrictions. 
• 
Women who are unwilling, if not postmenopausal or surgically sterile, to abstain 
from sexual intercourse or employ highly effective contraception during the study 
drug administration period and for at least 14 days after the last dose of study drug. 
• 
Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or 
employ highly effective contraception during the study drug administration period 
and for at least 7 days after the last dose of study drug.  Refer to Section 9.6.1 for 
acceptable methods of contraception. 
• 
Pregnant females, as documented by a serum beta human chorionic gonadotropin 
(β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to 
the first dose of study drug. 
Females with β-hCG values that are within the range for pregnancy but are not 
pregnant (false−positives) may be enrolled after pregnancy has been ruled out. 
Females of non-childbearing potential (postmenopausal for more than 1 year; 
bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require 
a serum β-hCG test. 


 
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• 
If female, patient is breastfeeding. 
• 
Patient has prior or ongoing clinically significant illness, medical condition, surgical 
history, physical finding, or laboratory abnormality that, in the investigator’s or 
Sponsor’s opinion, could affect the safety of the patient; alter the absorption, 
distribution, metabolism, or excretion of the study drug; or impair the assessment of 
study results. 
 
5.4 
RET PRE-SCREENING 
Sites may identify patients with a RET-mutated or RET-fusion solid tumor using local 
identification methods. 
5.5 
PATIENT IDENTIFICATION AND REGISTRATION 
Patients who are candidates for enrollment into the study will be evaluated for eligibility 
by the investigator to ensure that the inclusion and exclusion criteria (see Sections 5.2 
and 5.3) have been satisfied. 
During both Parts 1 and 2, upon identification of an eligible patient, study centers 
submitted a request to the Sponsor or designee to register each patient for enrollment.  
For Phase 1, enrollment was granted based on availability in each escalation cohort. 
For Phase 2, enrollment will be closed to a particular group when the target enrollment 
has been reached or if the Sponsor has decided to close the group once a sufficient 
number of patients have been enrolled.  Patients who have already consented for the 
study will be permitted to enroll, within a reasonable period of time, even if the group that 
they qualify for has been filled. 
The Medical Monitor or designee can be consulted by the investigator regarding the 
eligibility for all patients prior to receipt of the first dose of pralsetinib.  The decision to 
enroll a patient in the study is the responsibility of the investigator.  
Patients who have signed the main ICF and did not meet eligibility criteria should be 
entered into the clinical database as a screen failure. 
5.6 
STUDY COMPLETION 
It is anticipated that patients will receive at least 1 cycle of pralsetinib; no maximum 
treatment duration has been set.  After C1, patients may continue to receive pralsetinib 
until precluded by toxicity, noncompliance, withdrawal of consent, death, or closure of 
the study by the Sponsor.  Patients with progressive disease may remain on treatment if 
in the opinion of the investigator the patient has benefited from pralsetinib therapy, and it 
is clearly in the best medical interest of the patient to remain on treatment. 
A patient will be considered to have completed the study if he/she has completed all 
required visits shown in schedule of assessments in Section 6.7. 


 
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The end of this study is defined as the date of the last visit of the last patient in the 
study/last scheduled procedure shown in the schedule of activities for the last patient in 
the study globally, or the date at which the last data point required for statistical analysis 
or safety follow-up is received from the last patient, whichever occurs later.  See 
Section 7 for details of all study assessments. 
The expected enrollment period is approximately 60 months and the expected duration 
of the study from first the subject screened to database lock is approximately 84 months. 
The end of the study is expected to occur approximately 24 months after the last patient 
is enrolled. 
5.6.1 
Patient Withdrawal Criteria from Study Treatment 
Patients have the right to withdraw from the study at any time for any reason. 
Patients must discontinue from study treatments for any of the following reasons: 
• 
Withdrawal of consent to continue study treatment 
• 
Pregnancy 
• 
Death 
 
Patients may discontinue from study treatments for any of the following reasons: 
• 
Adverse event 
• 
Disease progression 
• 
Protocol deviation 
• 
Investigator decision 
 
5.6.2 
Patient Withdrawal Criteria from the Study 
A patient must be withdrawn from the study for any of the following reasons: 
• 
The patient withdraws consent for the study 
• 
Patient death 
• 
Loss to follow-up 
 
When a patient discontinues study drug or withdraws from the PFS/OS follow-up part of 
the study, the primary reason(s) for discontinuation or withdrawal must be recorded in 
the appropriate sections of the electronic Case Report Form (eCRF) and all efforts will 
be made to complete and report final study observations as thoroughly as possible. 
Withdrawal of consent for continued study treatment should be differentiated from 
withdrawal of consent for study follow-up, and every effort should be made within the 
bounds of safety and subject choice to have each subject complete the study follow-up.  
Patients who discontinue study drug should be seen for an EOT visit and should 
undergo additional post-treatment follow-up for safety, disease progression, and 
survival, as described in Sections 7.8 and 7.9, when feasible. 


 
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Following discontinuation of study drug, all efforts will be made to complete and report 
the protocol-defined study observations as completely as possible and to determine the 
reason for withdrawal. 
All related adverse events should be monitored until they are resolved, stabilized, have 
returned to pre-exposure baseline, determined to be due to another illness, or until 
a subsequent therapy is initiated.  For adverse events considered not related to study 
drug, similar monitoring guidelines will only be required through 30 days after the final 
dose of study drug.  If the patient withdraws from treatment because of an adverse 
event, every effort must be made to perform protocol-specified safety follow-up 
procedures, as outlined in Section 7.8. 
If there is a medical reason for withdrawal, the patient will remain under the supervision 
of the investigator or designee until the condition has returned to baseline or stabilized. 
5.7 
REPLACEMENT OF PATIENTS 
To be evaluable for DLT assessment in Phase 1, at least 1 patient in a cohort must have 
received at least 75% of their prescribed pralsetinib doses in C1 (i.e., ≥ 21 doses) and 
completed follow-up safety evaluations through C1D28 or experienced a DLT. Patients 
not evaluable for DLT assessment will be replaced if necessary to ensure that data are 
available from at least 1 evaluable patient for each cohort prior to the dose-escalation 
meeting. 
6. 
STUDY CONDUCT 
6.1 
GENERAL CONDUCT 
The study will be conducted at multiple centers in the United States, Asia, and Europe. 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and the applicable regulatory requirements. 
The schedules of assessments for the study are provided in Table 10, Table 11, and 
Table 12. 
The minimum duration of patient participation is approximately 3 months, including 
a screening period to assess study eligibility up to 4 weeks (28 days), a treatment period 
of at least 1 cycle (28 days), an EOT visit at least 14 (± 7) days following the final dose of 
study drug, and a follow-up telephone contact for resolution of any adverse events 
30 days (+ 7 days) after the final dose of study drug, or at the time the patient initiates 
another antineoplastic therapy, and PFS and OS follow-up until withdrawal of consent, 
death, or loss to follow-up. 


 
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6.2 
EARLY TERMINATION 
The study may be terminated early at the discretion of the Sponsor, if there is sufficiently 
reasonable cause.  In the event of such action, written notification documenting the 
reason for study termination will be provided to each investigator. 
Circumstances that may warrant early termination include, but are not limited to, the 
following: 
• 
Determination of unexpected, significant, or unacceptable risk to patients (see 
details in Section 6.2.1) 
• 
Insufficient adherence to protocol requirements 
• 
Plans to modify, suspend, or discontinue the development of study drug 
• 
Other administrative reasons 
 
Should the study be terminated prematurely, all study materials must be returned to the 
Sponsor or Sponsor’s designee. 
6.2.1 
Rules for Early Termination of Enrollment 
In order to further protect the safety of patients, the study incorporates an enrollment 
stopping rule that terminates further enrollment to the study if there is an excess of 
permanent treatment discontinuations due to study drug−related adverse events. 
After 10 patients have received at least 1 dose of pralsetinib, the rate of permanent 
treatment discontinuations due to drug-related adverse events will be assessed at each 
dose-escalation teleconference during Phase 1 of the study, and at least every 3 months 
during Phase 2 of the study. 
Adverse events meeting all of the following criteria will be included in the assessment: 
• 
The adverse event is considered drug related and is the reason for permanent 
discontinuation of treatment. 
• 
The adverse event is Grade ≥ 3 or meets the criteria for DLT (including events that 
meet the criteria for DLT but occur after C1 or during any cycle in Phase 2). 
• 
The adverse event occurred after the first dose of study drug but prior to initiation of 
a subsequent anticancer therapy. 
• 
The adverse event occurred while the patient was being treated at a dose that does 
not exceed the MTD. 
 
Further enrollment in this study will be terminated if the lower bound of the 1-sided 70% 
exact binomial CI of the discontinuation rate due to adverse events is > 15%. 
The operating characteristics for the early study termination assessment are presented 
in Appendix 8. 


 
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6.3 
DOSE AND ADMINISTRATION 
Patients will be dispensed the appropriate number of Sponsor-packaged, labeled bottles 
on D1 of each cycle to allow dosing for 28 days; alternatively, patients may be dispensed 
the appropriate bottle(s) until the next scheduled visit.  Patients must return all unused 
study drug (or the empty bottles) at each scheduled visit. 
Pralsetinib doses should be administered with a glass of water in a fasted state, with no 
food intake from 2 hours before until 1 hour after study drug administration.  Each dose 
should be administered at approximately the same time each day.  Patients following the 
QD schedule should take pralsetinib in the morning.  Patients following the BID schedule 
should take one dose in the morning and one dose in the evening, with approximately 
10-14 hours between doses.  Doses should always be separated by at least 8 hours. 
Patients should be instructed to swallow study drug whole and not to chew study drug. 
If a patient on the QD schedule forgets to take a dose in the morning, he/she should take 
pralsetinib until 4 p.m. that day.  If the dose has not been taken by 4 p.m., then that dose 
should be omitted, and the patient should resume treatment with the next scheduled 
dose.  If a patient on the BID schedule forgets to take a morning dose, he/she should 
take pralsetinib until 2 p.m. that day and at least 8 hours before the next dose, and if 
he/she forgets to take an evening dose he/she should take pralsetinib until 12 a.m. 
(midnight) that day, and at least 8 hours before the next dose.  Pralsetinib dose should 
always be administered with a glass of water in a fasted state, with no food intake from 
2 hours before until 1 hour after study drug administration.  If the dose has not been 
taken by the specified time, that dose should be omitted, and the patient should resume 
treatment with the next scheduled dose. 
If a patient vomits during or after taking pralsetinib, re-dosing is not permitted until the 
next scheduled dose. 
6.3.1 
Dosing for Phase 1 (Dose Escalation) 
Pralsetinib was administered QD to patients enrolled at the first 3 dose levels.  Starting 
with the fourth dose level, or at a later dose level, a BID dosing schedule could be 
explored, if supported by PK and safety data.  The highest permitted BID dose for the 
first cohort treated on a BID schedule was 50% of the QD dose at the last highest dose 
level deemed safe and did not exceed the MTD.  Thus, the total daily dose at the first 
BID dose level did not exceed the total daily dose at the highest, safe QD dose level. 
A temporary discontinuation (up to 2 weeks) in pralsetinib dosing is allowed for patients 
who require an interruption (e.g., for surgery or another procedure) during the treatment 
period.  Pralsetinib should be discontinued 48 hours before the procedure and resumed 
48 hours after the procedure is completed. 


 
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6.3.1.1 
Alternate Dosing Schedule 
Alternate dosing schedules, such as intermittent dosing (e.g., 3 weeks on, 1 week off) 
were permitted for evaluation if supported by PK, pharmacodynamic, safety, or efficacy 
data.  A decision to change the treatment schedule, including the choice of a starting 
dose for the new schedule, could only occur after agreement was reached among the 
study investigators and the Sponsor’s clinical study team.  A protocol amendment was 
required prior to evaluating dosing schedules that increase dosing frequency, other than 
BID dosing, as described above.  Enrollment in Phase 1 is complete and alternate 
schedules (other than BID) were not evaluated. 
6.3.1.2 
Guidelines for Dose Escalation 
Dose-escalation decisions will be made by the study investigators and clinical study 
team. 
The dose-escalation process is performed following the BOIN design, as follows: 
• 
Patients in the first cohort are treated at Dose Level 1. 
• 
To assign a dose to the next cohort of patients the dose escalation/de-escalation 
decision will be made according to the rules displayed in Table 5.  When using 
Table 5, “eliminate” means the removal of the current and higher doses from the trial 
to prevent treating any future patients at these doses because they are overly toxic. 
– If a dose is eliminated, automatically de-escalate the dose to the next lower level.  
Patients being treated at higher doses may continue at the higher dose if they 
are tolerating it.  If the lowest dose is eliminated, the trial will be stopped for 
safety.  In this case, no dose should be selected as the MTD. 
– If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, 
new patients will be treated at the current dose. 
– If the current dose is the lowest dose and the rule indicates dose de-escalation, 
new patients will be treated at the lowest dose unless the number of DLTs 
reaches the elimination boundary, at which point the trial will be terminated for 
safety. 
 
Repeat Step 2 and stop the trial when the number of patients treated at the current dose 
reach 12 (Table 5). 


 
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Table 5: 
Dose-Escalation/De-Escalation Rule for the BOIN Design 
Action 
Number of Patients Treated at the Current Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Escalate if 
# of DLT ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
2 
2 
De-escalate 
if # of DLT ≥ 1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
Eliminate if 
# of DLT ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
6 
6 
7 
BOIN =  Bayesian optimal interval, DLT =  dose-limiting toxicity, NA =  not applicable. 
 
 


 
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Figure 8: 
Dose-Escalation Schematic 
 
DLT= dose-limiting toxicity, λe= dose escalation boundary, λd= dose de-escalation boundary, 
MTD= maximum tolerated dose. 
 
After Phase 1 of the trial is completed, the MTD is determined based on isotonic 
regression as specified by Liu and Yuan (2015).  A lower RP2D may also be selected 
based on clinical data, including safety, PK, pharmacodynamic, and antitumor activity.  
See protocol Section 11.3 for details. 
To limit the number of patients treated at a subtherapeutic dose; the study uses a cohort 
size of 1−3 patients for the first 3 dose levels, and then transitions to a cohort size of 
3−6 patients for all subsequent dose levels. 
The first cohort of patients will receive pralsetinib at a starting dose of 30 mg QD.  The 
increment in dose between cohorts may be a maximum of 100% until 1 patient in any 
dose level experiences a DLT, or any 2 patients treated at any dose level experience 
a Grade ≥ 2 adverse event considered related to pralsetinib during C1.  All subsequent 
dose escalation increments will be a maximum of approximately 50%.  The dose may be 


 
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rounded down or up to accommodate available dosage strengths (Table 6).  Actual dose 
levels explored in Phase 1 are outlined in Table 2. 
Three to 6 patients will be enrolled initially in each cohort (1 to 3 patients for the first 
3 dose levels).  Additional patients may be enrolled into an enrichment cohort at a lower 
dose, if it previously included less than 12 patients evaluable for DLT, was reviewed at 
a dose-escalation meeting, and does not exceed the MTD.  The total number of patients 
evaluable for DLT for any given dose level should not exceed 12.  Any DLT observed in 
enrichment patients contributes to the dose escalation/de-escalation decision following 
the same rules as outlined in Table 5.  Data from these patients will allow for an 
improved assessment of safety, pharmacokinetics, and pharmacodynamics.  See 
Figure 8 for the dose escalation schematic. 
A dose escalation meeting will be held by teleconference prior to opening each 
subsequent dose cohort.  The dose escalation meeting will include the study 
investigators and the Sponsor’s clinical study team.  The meeting will occur after all 
patients in the current cohort have completed at least 28 days of observation after their 
first dose of pralsetinib or experienced a DLT.  Patients enrolled in enrichment cohorts at 
lower dose levels need not have completed 28 days of observation for a dose-escalation 
meeting to occur.  All available safety data from all patients, across all cycles of therapy 
and including all prior dose cohorts, will be reviewed to confirm that no unexpected, 
significant, delayed, or unacceptable adverse events have been discovered that may 
affect the decision to escalate the dose, or the specific dose that should be chosen.  
Available PK, pharmacodynamic, and tumor response data will also be reviewed in order 
to support dose escalation decision.  The decision to open a subsequent cohort, the 
specific dose that is chosen, and MTD/RP2D determination must be agreed to by the 
study investigator (or his or her physician designee) at each study center and the 
Sponsor’s clinical study team. 
 
 


 
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Table 6: 
Provisional Dose-Escalation Levels 
Dose Level Cohort 
Dose 
(mg) 
Schedule 
Total Daily 
Dose (mg) 
% Change from Previous 
Dose Level 
-−1 
20 
QD 
20 
−29% 
1 (starting dose level) 
30 
QD 
30 
− 
2 
60 
QD 
60 
100% 
3 
120 
QD 
120 
100% 
4 a 
60 
BID 
120 
0% (change to BID) 
5 
120 
BID 
240 
100% 
6 
240 
BID 
480 
100% 
7 b 
360 
BID 
720 
50% 
8 
500 
BID 
1000 
39% c 
9 
750 d 
BID 
1500 
50% 
BID= twice daily, QD= once daily. 
Note: Intermediate and/or additional dose levels may be considered based on the observed 
safety profile of pralsetinib. 
a Dose schedule may change from QD to BID at dose level 4, as shown here or at a higher dose 
level, or dosing may remain QD. 
b Dose interval is shown changing from 100% to 50% at dose level 7; however, this change is 
dependent on the observed safety profile, and may occur earlier or potentially later during dose 
escalation. 
c An escalation less than 50% is shown as an example, when it may make the dose choice more 
convenient. 
d  Further dose escalation will be up to approximately 1.5 × the previous dose, rounded up or 
down to accommodate available dosage strength. 
 
6.3.1.3 
Intra-Patient Dose Escalation 
To minimize the number of patients treated at potentially inactive doses, intra-patient 
dose escalation is permitted after a patient has completed ≥ 2 cycles of treatment without 
experiencing a Grade 3 or 4 adverse event related to study drug or a DLT.  A patient 
may be allowed to have his or her dose escalated after a Grade 3 or 4 related adverse 
event or a DLT if the adverse event has resolved to Grade 1 or the patient’s baseline 
value, and the investigator believes it is in the patient’s best medical interest to resume 
pralsetinib at a higher dose.  The Medical Monitor is available to advise as needed.  The 
patient’s dose may then be escalated to a dose that has been reviewed at 
a dose‑escalation meeting and does not exceed the MTD.  Additionally, patients enrolled 
to a BID schedule may transition to the QD MTD.  Any intra-patient dose-escalation 
should be done at the start of the next cycle.  The Medical Monitor is available to advise 
as needed. 


 
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6.3.1.4 
Dose-Limiting Toxicity 
DLT is defined as any Grade ≥ 3 adverse event occurring during C1 during Phase 1 
(dose escalation) that is not clearly caused by something other than pralsetinib with the 
following exceptions: 
• 
Thrombocytopenia is a DLT only if it is Grade 4. 
• 
Neutropenia is a DLT only if it is Grade 4. 
• 
Lymphopenia is a DLT only if it is Grade 4. 
• 
Anemia is a DLT only if it is Grade 4. 
• 
Abnormalities in serum calcium, magnesium, phosphorus and glucose are DLTs 
only if they are Grade 4; or if they are Grade 3 and the patient is clinically 
symptomatic, requires hospitalization, or if the specific abnormality does not return 
to baseline or Grade ≤ 2 within 7 days. 
• 
Nausea is a DLT if it is Grade 3 and persists > 3 days despite anti-emetic treatment. 
• 
Vomiting is a DLT if it is Grade 4, or if it is Grade 3 and persists >3 days despite 
antiemetic treatment. 
• 
Diarrhea is a DLT if it is Grade 4 or if it is Grade 3 and persists >3 days despite 
antidiarrheal treatment. 
• 
ALP increase is a DLT only if it is Grade 4. 
• 
Total bilirubin Grade 2 is a DLT if associated with ALT Grade ≥ 2. 
• 
Infection or fever in the absence of neutropenia are DLTs if they are Grade 4 or if 
they are Grade 3 and persist for >7 days. 
• 
Rash is a DLT if it is Grade 4 or if it is Grade 3 and persists >7 days. 
• 
Fatigue is a DLT only if it is Grade 3 and persists >7 days. 
• 
Other clinically important adverse events that do not meet the specified DLT criteria 
may be considered to be a DLT upon review at a dose-escalation meeting. 
 
6.3.1.5 
Dose Reduction for Adverse Events 
Patients who experience a DLT will have pralsetinib interrupted and be followed until the 
DLT resolves to Grade 1 or until the patient’s baseline value is achieved, if higher. 
If the DLT was thrombocytopenia or neutropenia, blood counts must have recovered to 
the following:  platelet count ≥ 75 × 109/L and ANC ≥ 1× 109/L, respectively. 
After resolution of the adverse event, with a maximum of 2 weeks’ dose interruption, the 
patient may resume therapy with a reduction of one dose level.  If the investigator 
considers it to be in the patient’s best interest, treatment may resume without dose 
reduction.  The Medical Monitor is available to advise as needed.  If the adverse event 
recurs at the same or worse severity, dosing must be interrupted as described above, 
and the dose must be reduced if the patient resumes therapy.  A maximum of three dose 
reductions are permitted for any patient. 


 
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6.3.1.6 
Maximum Tolerated Dose 
The MTD was determined to be 400 mg QD based on isotonic regression as specified 
by Liu and Yuan (2015).  Specifically, the MTD is the dose for which the isotonic 
estimate of the toxicity rate is closest to the target toxicity rate (30%).  If there are ties, 
the MTD is the higher dose level when the isotonic estimate is lower than the target 
toxicity rate, and the MTD is the lower dose level when the isotonic estimate is greater 
than the target toxicity rate. 
6.3.2 
Dosing for Phase 2 (Dose Expansion) 
6.3.2.1 
Recommended Phase 2 Dose 
The MTD and RP2D was determined to be 400 mg QD. 
All patients enrolled in Phase 2 (dose expansion) will begin treatment with pralsetinib at 
400 mg QD. 
6.3.2.2 
Dose Modification Recommendations for Adverse Events 
Dose modification guidelines for pralsetinib are summarized in Table 7.  These 
guidelines should be followed by clinical investigators; however, for an individual patient, 
dose interruptions, reductions, and treatment discontinuation should also be based on 
the clinical circumstance.  Deviation from these guidelines must be documented and 
communicated to the Sponsor. 
Adverse events are to be graded according to NCI CTCAE version 4.03. Guidance for 
re-escalation after resolution of adverse drug reactions is provided in Section 6.3.2.4. 
Pralsetinib dose reductions to below 100 mg QD are not permitted (see Table 7).  If 
a patient requires dose reduction below these dose levels, study treatment should be 
discontinued. 
Doses may be interrupted for study drug−related toxicities for up to 28 days (4 weeks). 
In general, if a study drug−related toxicity does not resolve to Grade ≤ 2 or has not 
returned to baseline after dose interruption for more than 28 days, the patient should be 
discontinued from study treatment unless after consultation with the Medical Monitor, 
resumption of treatment is considered to be in the best medical interest of the patient, 
and this is documented in writing.  Additionally, the Sponsor’s Medical Monitor must be 
contacted if an adverse event deemed unrelated to treatment requires a dose 
interruption for more 28 days; a longer recovery period is permitted after consultation 
with the Sponsor.  If a patient resumes treatment after a dose hold > 28 days, an 
unscheduled disease assessment should occur prior to restarting pralsetinib, to assess 
status of disease after the dose hold. 
For patients who require an interruption due to surgery or another major procedure, 
pralsetinib should be discontinued 48 hours before the procedure and resumed 48 hours 
after the procedure is completed. 


 
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Table 7: 
Dose Modification Guidelines for Pralsetinib-Related Toxicity 
Toxicity 
Modification 
Non-Hematologic Toxicity (except for selected AEs; see specific advice below for 
pneumonitis, hyperphosphatemia, and hypertension) 
Grade 1 
• 
No dose interruption or modification required 
Grade 2 
• 
No dose interruption or modification required, if dose interruption is 
necessary, on improvement resume dosing without dose reduction. 
Grade 3 
• 
Occurrence:  Hold until event is Grade ≤ 2, or has returned to 
baseline, and then resume by reducing the dose by 100 mg less 
than the current dose. 
• 
Occurrence at 100 mg:  Discontinue pralsetinib. 
Grade 4 
• 
Occurrence:  Hold until event is Grade ≤ 2, or has returned to 
baseline, and then resume by reducing the dose by 100 mg less 
than the current dose. 
• 
If same AE recurs at Grade 3 or higher, discontinue pralsetinib. 
Hematologic Toxicity:  Anemia, Neutropenia, Thrombocytopenia 
Grade 1 or Grade 2 
• 
No dose interruption or modification required 
Grade 3 or 4 
• 
Occurrence:  Hold until event is Grade ≤ 2, or has returned to 
baseline, and then resume by reducing the dose by 100 mg less 
than the current dose. 
• 
Occurrence at 100 mg:  Discontinue pralsetinib. 
Hematologic Toxicity:  Lymphopenia 
Grade 1 or Grade 2 
• 
No dose interruption or modification required 
Grade 3 
• 
Occurrence:  Reduce the dose by 100 mg less than the current 
dose.  Interruption of dosing can be done based on clinical 
circumstances but is not required. 
• 
Occurrence at 100 mg:  Discontinue pralsetinib. 
Grade 4 
• 
Occurrence:  Hold until event is Grade ≤ 3, or has returned to 
baseline, and then resume by reducing the dose by 100 mg less 
than the current dose. 
• 
Occurrence at 100 mg:  Discontinue pralsetinib. 
 
 
6.3.2.3 
Dose Modification and Management of Specific 
Treatment-Related Adverse Events 
Comprehensive assessments of any study drug-related adverse events (adverse drug 
reactions) experienced by the patient will be performed throughout the course of the 
study.  The severity of the event, as well as clinical judgment will be utilized to determine 
appropriate management of the patient for any adverse event experienced while 
participating in this study. 
Any medication, including those administered for therapy of symptoms considered to be 
associated with study drug administration, should be reported on the appropriate 


 
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concomitant medication page of the patient’s eCRF.  The symptoms should be reported 
on the adverse event page. 
Pneumonitis 
Pneumonitis, including interstitial lung disease, has been reported with patients treated 
with pralsetinib, including fatal events.  Pneumonitis is a known side effect of TKIs, 
particularly TKIs used in NSCLC, and has also been observed with pralsetinib.  
Drug-related pneumonitis may be associated with signs and symptoms such as 
dyspnea, hypoxia, cough, hemoptysis, and fever as well as radiologic evidence of 
parenchymal or interstitial changes. 
The diagnosis of pneumonitis and determination of causal relationship to the drug is 
often confounded by the underlying disease (especially lymphangitic carcinomatosis), 
previous therapies and other factors such as lung infection and radiation effect due to 
non-specific signs and symptoms as well as similar radiological appearance.  Most of the 
patients with the diagnosis of pneumonitis that was assessed as related to pralsetinib 
had received prior therapies (before initiation of pralsetinib) that are known to cause 
pneumonitis (e.g., pemetrexed, pembrolizumab, vandetanib, docetaxel, osimertinib).  
Pneumonitis should be suspected when such signs and symptoms develop or in 
asymptomatic patients when a new ground glass opacity or interstitial infiltration is noted 
in imaging studies.  If a patient is considered to have the potential diagnosis of 
drug-related pneumonitis, physical examination, assessment of O2 saturation, and 
evaluation for infectious etiologies, and thoracentesis, bronchoscopy, or open lung 
biopsy should be considered to reach a diagnosis.  Dose modifications, including dose 
interruption, potential dose reduction, or discontinuation, should be considered as noted 
in Table 8.  Based on the clinical picture, if pneumonitis cannot be ruled out, immediate 
dose interruption and treatment should not be delayed.  Treatment of pneumonitis may 
involve the need for corticosteroids and supportive oxygen and should be based on the 
clinical judgment and follow standard best practice guidelines. 
 
 


 
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Table 8: 
Pralsetinib Dose Modification Recommendations for 
Treatment-Related Pneumonitis 
Toxicity Grade 
Dose Modification 
Grade 1 
• Interrupt dosing for a minimum of 7 days. 
• After dose interruption if pneumonitis is improved or stable, dosing 
may be resumed without a dose reduction. 
• If pneumonitis recurs, interrupt dosing until it has resolved, then dosing 
may be resumed with a dose reduction of 100 mg less than the 
previous dose. 
• If pneumonitis recurs again, consider permanently discontinuing 
pralsetinib. Further dose interruption and dose reduction is at the 
discretion of the investigator and risk should be balanced with the need 
to treat the underlying disease. 
Grade 2 
• Interrupt dosing for a minimum of 7 days. 
• Resume dosing with a dose reduction of 100 mg when the pneumonitis 
has improved to Grade 1 or has resolved. 
• If pneumonitis recurs, consider permanently discontinuing pralsetinib.  
Further dose interruption and dose reduction is at the discretion of the 
investigator and the risk should be balanced with the need to treat the 
underlying disease. 
Grade 3 
• Permanently discontinue treatment, unless the investigator discusses 
with the Sponsor and believes the benefits and risks justify 
retreatment, and even then, the pneumonitis must be completely 
resolved and the dose must be reduced by 100 mg less than the 
current dose. 
• If restarted on a reduced dose and pneumonitis recurs, then 
permanently discontinue treatment. 
Grade 4 
• Permanently discontinue treatment. 
 
Pneumonia/Lung Infections 
The diagnosis of pneumonia and lung infections (including opportunistic infections), 
some of which have been fatal, have been reported with patients treated with pralsetinib.  
The determination of causal relationship to the drug is often confounded by immune 
suppression related to the patients underlying disease, prior therapy (such as 
immunotherapy and steroids) and other risk factors for infection such as 
myelosuppression.  Pneumonias and other lung infections should be managed with 
systemic antibiotics and other supportive management.  If the causality is at least 
possibly related to the study drug, dose interruption and potential dose reduction and/or 
discontinuation should follow the guidelines in Table 7, dose modification for 
non-hematologic toxicity. 


 
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Tumor Lysis Syndrome 
TLS has been observed following pralsetinib treatment.  Investigators should monitor 
electrolyte status and renal function via laboratory testing.  Patients with TLS may 
require supportive care with IV fluids and correction of electrolyte imbalances. 
Patients that are at risk for TLS at study entry, such as those with high tumor burden, 
should be well hydrated before initiation of pralsetinib and avoid dehydration during the 
first cycle.  If TLS is suspected, investigators should manage the adverse event(s) 
according to standard institutional practices or accepted oncology management 
guidelines (Coiffier et al. 2008; Klastersky et al. 2016). 
Hyperphosphatemia 
As hyperphosphatemia was characterized in the pralsetinib GLP toxicology study in rats 
(Section 1.2.2), dose modification guidelines have been included in Table 9 for the 
management of hyperphosphatemia (Dienstmann et al. 2014). 
 
 


 
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Table 9: 
Pralsetinib Dose Modification Recommendations for 
Treatment-Related Hyperphosphatemia 
Serum Phosphate 
Dose Modification 
≥ 5.5−7 mg/dL 
• Continue pralsetinib. 
• Dietary phosphate intake restriction 
• Phosphate binder 
− 
Sevelamer 1 tablet (800 mg) per meal (or comparable phosphate 
binder), i.e., every 8 hours 
− 
Increase dose of sevelamer up to 1200 mg (or comparable phosphate 
binder) every 8 hours if needed (phosphate levels still increasing after 
1 week). 
> 7−9 mg/dL 
• Continue pralsetinib. 
• If serum phosphate levels continue > 7−9 mg/dL despite 2 weeks of 
phosphorus-lowering therapy, the dose of pralsetinib should be reduced. If 
serum phosphate levels continue > 7−9 mg/dL despite dose reduction and 
optimal phosphorus lowering therapy for 2 weeks, temporarily discontinue 
pralsetinib.  Restart at reduced dose level when serum phosphate 
< 7 mg/dL. 
• Dietary phosphate intake restriction 
• Phosphate binder 
− 
Sevelamer 2 tablets (1600 mg) per meal (or comparable phosphate 
binder), i.e., every 8 hours 
− 
Phosphaturic agents: acetazolamide 1 tablet (250 mg) 2−3 times per 
day (or comparable agent) 
> 9 mg/dL 
• Discontinue pralsetinib. 
• Restart at reduced dose level when serum phosphate < 7 mg/dL. 
• Dietary phosphate intake restriction 
• Phosphate binder 
− 
Sevelamer 2 tablets (1600 mg) per meal (or comparable phosphate 
binder), i.e., every 8 hours 
− 
Phosphaturic agents:  acetazolamide 1 tablet (250 mg) 2−3 times per 
day (or comparable agent) 
Repeated episodes 
> 9 mg/dL or 
concurrent alteration 
in renal function 
• Permanently discontinue pralsetinib. 
  
Hypertension 
Treat with SOC antihypertension therapy.  Dose modifications are not required if 
hypertension is able to be managed with supportive medications.  If dose modification is 
necessary, please use dose medication for non-hematologic toxicity (Table 7). 
6.3.2.4 
Dose Re-Escalation after Resolution of Adverse Drug 
Reactions 
Re-escalation after dose modification for adverse events is discouraged. However, if in 
the opinion of the treating investigator re-escalation is warranted, this must be 


 
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undertaken after consultation with the Sponsor.  To be a candidate for re-escalation, the 
adverse event that led to dose modification must not have recurred, and no other 
adverse events of Grade 3 or 4 must have been observed during the preceding 28 days. 
If the criteria above are met, the daily dosing of pralsetinib may be re-escalated from the 
reduced dose level to the immediate previously administered dose level. 
Patients may receive step-wise pralsetinib dose re-escalations up to 400 mg QD 
(e.g., 100 mg QD to 200 mg QD to 300 mg QD to 400 mg QD) if the above criteria 
continue to be met. 
A patient should be treated and tolerate therapy well for at least 1 cycle at each higher 
dose level before the dose is escalated again.  In no circumstances should a patient 
receive a dose higher than 400 mg QD. 
6.4 
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY 
The Sponsor will offer continued access to pralsetinib free of charge to eligible patients 
in accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, as outlined below. 
A patient will be eligible to receive pralsetinib after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being. 
• 
There are no appropriate alternative treatments available to the patient. 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive pralsetinib after completing the study if any of the 
following conditions are met: 
• 
Pralsetinib is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient). 
• 
The Sponsor has discontinued development of pralsetinib or data suggest that the 
pralsetinib is not effective for the patient’s RET-altered solid tumor. 
• 
The Sponsor has reasonable safety concerns regarding pralsetinib as a treatment 
for the any RET-altered solid tumor. 
• 
Provision of pralsetinib is not permitted under the laws and regulations of the 
patient's country. 
 


 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
6.5 
PRIOR AND CONCOMITANT THERAPY 
All medications administered and procedures conducted within 28 days prior to C1D1 
should be recorded on the eCRF.  In addition, all prior treatments for the underlying 
malignancy should be recorded. 
6.5.1 
Prohibited Concomitant Therapy 
The following medications and procedures are prohibited during the study: 
• 
Medications that are strong dual inhibitors of P-gp and CYP3A4  
In vitro metabolism studies indicate that pralsetinib oxidation is primarily 
mediated by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C9, and 
glucuronidation by UGT1A4.  As a precaution, strong inhibitors as well as 
inducers of CYP3A4 are prohibited.  If coadministration of pralsetinib with 
a strong CYP3A inhibitor cannot be avoided, the dose of pralsetinib should be 
reduced.  Drug transporter studies in cells overexpressing P-glycoprotein (P-gp) 
indicate that pralsetinib is likely also a P-gp substrate. 
• 
Any investigational agent or device other than pralsetinib, including commercially 
available agents that are investigational for the treatment of the patient’s underlying 
malignancy 
• 
Any antineoplastic treatment other than study drug 
• 
Neutrophil growth factor support within 14 days before C1D1 and throughout C1, 
unless the patient experiences a DLT of neutropenia 
 
Please refer to Appendix 3 for the list of prohibited medications and foods. 
If radiation therapy or surgical excision of target lesion is determined to be of best clinical 
interest for the patient and cannot be avoided, the Medical Monitor should be consulted.  
Note that radiation or surgical excision of target lesions may or will render patients 
unevaluable for further response assessments. 
6.5.2 
Concomitant Therapy to Be Used with Caution 
In vitro metabolism studies in human liver microsomes have demonstrated that 
pralsetinib is a direct moderate inhibitor and inducer of multiple P450 enzymes 
(CYP2C8, CYP3A4 and CYP2C9).  Pralsetinib is also a time-dependent inhibitor of 
CYP3A4/5.  Pralsetinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, 
MATE1, and MATE2-K at clinically relevant concentrations.  In patients, pralsetinib may 
alter or increase the plasma concentration of co-administered sensitive CYP2C8, 
CYP3A4, CYP2C9, P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K 
substrates.  Hence, medications that are sensitive CYP2C8, CYP3A4, CYP2C9, P-gp, 
BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K substrates with known 


 
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drug-drug interaction potential should be used with caution.  Lists of drugs and foods to 
be used with caution are provided in Appendix 3. 
6.5.3 
Permitted Concomitant Therapy 
Medications and treatments other than those specified in Section 6.5.1 and 
Section 6.5.2, including palliative and supportive care for disease-related symptoms, are 
permitted during the study. 
Antiemetic and antidiarrheal treatments may be used at the Investigator’s discretion and 
in accordance with the local guidelines after documented nausea, vomiting or diarrhea 
has occurred without medications having been used.  Prophylaxis for nausea, vomiting 
or diarrhea may be instituted beginning on C2D1 in patients who experience these 
toxicities during C1, and during C1 for patients who have experienced nausea, vomiting, 
or diarrhea. 
6.6 
ADDITIONAL PRECAUTIONS 
None. 


 
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6.7 
SCHEDULE OF ASSESSMENTS 
Table 10: 
Schedule of Assessments 
Study Activities a 
Screening 
Study Treatment 
EOT c 
Follow-
Up 
PFS 
Follow-
Up d 
OS 
Follow-
Up 
Cycle 
 
C1 
C2 
C3-
C13, 
C15, 
C17b 
C21 and 
every 4 
cycles 
thereafter b 
Study Day(s) 
−28 to −1 
D1 
D2s 
D8 
D15 
D16s 
D22 
D1 
D15 
D1 
D1 
14 
days 
post-
last 
dose 
30 
days 
post- 
last 
dose 
Every 
3 to 4 
months 
post- 
EOT 
Every 
3 months 
post- 
EOT 
Window (days) 
 
 
 
±1 
+2 
+2 
+2 
+4 
±3 
±4 
±7 
±7 
+7 
±14 
±14 
Informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history f 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical  
examination g 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Vital signs 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Serum or urine 
pregnancy test h 
x 
 
 
 
 
 
 
x 
 
x 
x 
x 
 
 
 
ECOG PS 
x 
x 
 
 
 
 
 
x 
 
x 
x 
x 
 
 
 
12-lead ECG/ECG 
extraction from 
Holter monitor i 
Refer to Table 11 for ECG schedule. 
 
 
Hematology j 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 


 
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Study Activities a 
Screening 
Study Treatment 
EOT c 
Follow-
Up 
PFS 
Follow-
Up d 
OS 
Follow-
Up 
Cycle 
 
C1 
C2 
C3-
C13, 
C15, 
C17b 
C21 and 
every 4 
cycles 
thereafter b 
Study Day(s) 
−28 to −1 
D1 
D2s 
D8 
D15 
D16s 
D22 
D1 
D15 
D1 
D1 
14 
days 
post-
last 
dose 
30 
days 
post- 
last 
dose 
Every 
3 to 4 
months 
post- 
EOT 
Every 
3 months 
post- 
EOT 
Window (days) 
 
 
 
±1 
+2 
+2 
+2 
+4 
±3 
±4 
±7 
±7 
+7 
±14 
±14 
Coagulation j 
x 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
Serum chemistry j, k 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Urinalysis j 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Pralsetinib 
administration l 
 
X 
 
 
 
 
PK blood  
sample(s) m 
 
x 
X 
 
x 
x 
 
x 
 
x 
x 
 
 
 
 
Plasma sample for 
RET allele 
measurement and 
exploratory markers n 
 
x 
 
 
x 
 
 
x 
 
x 
x 
x 
 
 
 
Blood sample CEA, 
calcitonin (Pts with 
MTC only); central 
lab 
 
x 
 
 
 
 
 
x 
 
x 
x 
x 
 
 
 
Blood sample for 
TSH and free T4 (Pts 
with thyroid cancer 
only); local lab 
 
x 
 
 
 
 
 
x 
 
x 
x 
x 
 
 
 


 
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Study Activities a 
Screening 
Study Treatment 
EOT c 
Follow-
Up 
PFS 
Follow-
Up d 
OS 
Follow-
Up 
Cycle 
 
C1 
C2 
C3-
C13, 
C15, 
C17b 
C21 and 
every 4 
cycles 
thereafter b 
Study Day(s) 
−28 to −1 
D1 
D2s 
D8 
D15 
D16s 
D22 
D1 
D15 
D1 
D1 
14 
days 
post-
last 
dose 
30 
days 
post- 
last 
dose 
Every 
3 to 4 
months 
post- 
EOT 
Every 
3 months 
post- 
EOT 
Window (days) 
 
 
 
±1 
+2 
+2 
+2 
+4 
±3 
±4 
±7 
±7 
+7 
±14 
±14 
Tumor sample o 
x 
 
 
 
 
x 
 
 
x 
 
 
 
Tumor imaging p 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
 
x 
 
Telephone contact 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
EORTC QLQ-C30q 
 
x 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
AE monitoring r 
 
X 
 
 
SAE monitoring/ 
pretreatment event 
X 
 
 
Concomitant 
medications 
X 
 
 


 
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AE= adverse event; BID= twice a day; C= cycle; CEA= carcinoembryonic antigen; CT= computed tomography; D= day; ECG = electrocardiogram; 
ECOG PS= Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30= European Organisation for Research and Treatment of 
Cancer Core Quality of Life Questionnaire; EOT= end-of-treatment; MTC= medullary thyroid cancer; MRI= magnetic resonance imaging; 
PFS= progression-free survival; PK= pharmacokinetic; Pts= patients; QD= once a day; RANO = Response Assessment in Neuro-Oncology; 
RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SAE= serious adverse event; TSH= thyroid-stimulating hormone; 
T4= thyroxine. 
Note: Every effort should be made to keep the schedule of assessments on time for each patient. 
a In C1 and C2, all visits should be performed as noted in Table 10.  Laboratory tests, urinalysis, and physical exam performed in screening on 
Day−1 can count as C1D1 laboratory tests and do not need to be repeated on C1D1.  After C1, D1 of each subsequent cycle may be delayed up 
to 28 days to allow for resolution of toxicities.  Additional safety tests (e.g., hematology, chemistry, ECG) may be performed whenever clinically 
indicated, at the Investigator’s discretion.  Unless otherwise indicated, all tests and procedures must be performed predose at each visit. 
Whenever a test result is questionable, it should be repeated immediately. 
b Study visits will occur from C3 to C13 at 4-week intervals.  After C13, study visits will occur every 2 cycles ±4 days (every 8 weeks:  C15 and 
C17). Following C17, visit will occur every 4 cycles ±7 days (every 16 weeks: C21 ±7 days, C25 ±7 days etc.) to coincide with tumor imaging.  
Additional unscheduled visits and/or laboratory assessments should be performed as clinically indicated between formal study visits. 
c If an alternate treatment is started within 14 days of the last dose of study drug, the EOT visit should be conducted prior to the first dose of 
alternate therapy.  EOT procedures do not need to be repeated if they were completed within 7 days (or within 28 days for disease response 
assessments). 
d After completion of the EOT visit, all patients without documented progressive disease will be followed up for PFS every 3 to 4 months 
(± 14 days; as per the schedule at the time of treatment discontinuation) until documentation of progressive disease and, subsequently, all 
patients will be followed for OS every 3 months (±14 days). 
e Informed consent may be obtained up to 56 days (8 weeks) before C1D1. 
f A complete medical history will be obtained at the screening visit.  Only disease-related symptoms and changes from the previous visit need to 
be collected on C1D1. 
g A complete physical examination will be performed at the screening visit, including height.  Subsequent physical examinations will be disease 
and AE focused. 
h To be performed for women of childbearing potential within 7 days of C1D1.  A serum pregnancy test should be performed at screening; 
thereafter, a serum or urine pregnancy test should be performed monthly. 
i A single 12-lead ECG will be performed at the screening visit.  Extensive ECG sampling by means of Holter monitoring will be performed at 
selected study centers for 20 patients in Phase 2.  See Table 11 for the ECG schedule. 
j If the screening visit tests are performed within 7 days of C1D1, clinical laboratory tests do not need to be repeated on C1D1. 
k On C1D1, serum chemistry testing must be performed under fasting conditions prior to pralsetinib dosing. 


 
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l Pralsetinib will be administered QD in the morning or BID in the morning and evening (see Section 6.3) with no food intake from 2 hours before 
until 1 hour after study drug administration.  On study visit days when PK samples are collected, patients will take their morning pralsetinib dose 
at the study center. 
m Blood samples for PK assessment will be collected on C1D1, C1D2 (24 hours post C1D1 dose), C1D15, C1D16 (24 hours after the C1D15 
dose), and predose on D1 of C2 to C4.  Refer to Table 11 for PK sampling timepoints. 
n Blood samples will be collected for RET allele measurement and exploratory biomarker analyses for first 13 cycles of treatment, as detailed in 
Table 12 and in the laboratory manual. 
o Refer to Table 12.  Tumor biopsy at screening, if performed, may be obtained up to 56 days (8 weeks) prior to C1D1. 
p Disease response assessment (per RECIST v1.1 or RANO criteria, if appropriate for tumor type) will be based on local imaging scans, to be 
performed at screening, on D1 of every odd-numbered cycle from C3 ±4 days to C17 ±4 days, thereafter every 4 cycles ±7 days (16 weeks; 
i.e., C21 ±7 days, C25 ±7 days, etc.) and at EOT.  A CT scan with IV contrast of the chest (CT of the chest is preferred; however, MRI may be 
substituted), and CT or MRI with IV contrast of the abdomen, brain (MRI is preferred), and pelvis, will be performed.  In addition, for patients with 
thyroid cancer, CT with IV contrast or MRI of the neck will be performed.  At subsequent timepoints, all body regions that contained sites of 
disease (target or non-target) at screening will be imaged.  For each patient, the same method for tumor imaging used at baseline should be 
used throughout the study.  Disease response assessment will also be performed every 3 to 4 months (±14 days; as per the schedule at the time 
of treatment discontinuation) after EOT in patients without documented progressive disease. 
q Only during Phase 2, EORTC QLQ-C30 will be administered on D1 of each cycle for C1 through C12. 
r SAEs that are assessed as possibly or probably related to study treatment that occur > 30 days post-treatment will also be reported. 
s Cycle 1, Days 2 and 16, are no longer required for patients enrolled under Protocol Amendment 9, except for ~12 patients in Groups 8 and 9 
(China only) who will undergo serial PK sampling under Protocol Amendment 10 (China-specific protocol amendment). 
 
 
 


 
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Table 11: 
Schedule for Pharmacokinetic Sample Collection and ECG Monitoring 
Visit/Cycle 
Screen C1 
C2−C4 
EOT 
Day(s) 
−28 to 
−1 
D1 
D2 g 
D15 
D16 g 
D1 
Time (hr) a 
 
Pre-
dose 
0.5 
±5 
min 
1 
±5 
min 
2 
±5 
min 
4 
±10 
min 
6 
±10 
min 
8 
± 10 
min 
24 
Pre-
dose 
Pre-
dose 
0.5 
±5 
min 
1 
±5 
min 
2 
±5 
min 
4 
±10 
min 
6 
±10 
min 
8 
±10 
min 
24 
Pre-
dose 
Pre-
dose 
Parts 1 and 2b: 
PK sampling 
 
x 
x 
X 
x 
x 
x 
x 
x c 
x c 
x 
x 
x 
x 
x 
x 
x c 
x c 
 
Parts 1 and 2: 
12-lead ECG 
x 
x d 
 
 
 
x d 
 
 
x d 
x d 
 
 
 
x d 
 
 
 
x 
x 
Phase 2 only e: 
ECG extraction 
from Holter 
monitor 
 
x f 
x 
X 
x 
x 
x 
x 
x 
x f 
x 
x 
x 
x 
x 
x 
x 
 
 
C = cycle, D = day, ECG = electrocardiogram, EOT = end-of-treatment; PK = pharmacokinetic; Screen = screening. 
a The sampling window is 4 hours for the predose samples, ±5 minutes for the 0.5, 1, and 2-hour time oints, and ±10 minutes for the 4-, 6-, and 
8-hour timepoints.  Refer to Table 10 for visit windows allowances. 
b Approximately 72 patients (including ~12 patients in Groups 8 and 9) enrolled in Phase 2 will undergo serial PK sampling at C1D1 and C1D15.  
The remaining patients enrolled in Phase 2 will only have predose samples collected. 
c Record time of day that patient took their pralsetinib dose the prior day. 
d For all patients in Phase 1 and Phase 2, including those participating in continuous Holter monitoring.  Single 12-lead ECGs will be obtained. 
e For 20 patients at study centers participating in continuous Holter monitoring.  Twelve-lead ECGs are to be conducted/extracted after 5 minutes 
of recumbency or semirecumbency. 
f Three timepoints will be extracted within 1 hour prior to dosing (e.g., 45 minutes, 30 minutes, and 15 minutes prior to dosing). 
g Timepoints not required at Cycle 1 Days 2 and 16 for patients enrolled as of Protocol Amendment 9, except for the patients in Groups 8 and 9 
(China only) who will undergo serial PK sampling under Protocol Amendment 10 (China-specific protocol amendment). 
 
 


 
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Table 12: 
Schedule for Pharmacodynamic Biomarker Sample Collection 
Cycle 
Screening 
C1 
C2 and beyond 
EOT 
Day 
D1 
D15 
D1 
Time (hr) 
Predose 
Predose 
Predose 
Plasma sample for exploratory markers 
 
x 
 
x a 
x 
Plasma sample for RET allele measurement in 
ctDNAa 
 
x 
x 
x 
x 
Tumor sample b,c 
x e 
 
x c 
x d 
C = cycle, ctDNA circulating tumor DNA; D = day, EOT = end of treatment, ICF = Informed Consent Form, RANO = Response Assessment in 
Neuro-Oncology; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; RET = rearranged during transfection. 
a RET allele measurement in ctDNA and exploratory marker collection will be performed on D1 of C1, C2, C3, and every other cycle thereafter (to 
correspond with RECIST v1.1 or RANO assessments) through the first 13 cycles of treatment. 
b Tumor tissue obtained outside the 28-day screening window may be submitted for the screening timepoint upon patient consent via tissue 
screening ICF.  Pretreatment tumor tissue (archived or new tissue) will be analyzed centrally for assessment of tumor RET gene status. 
c In Phase 1 only, tumor biopsy to be obtained on the same day between C2D1 ± 2 weeks if safe and medically feasible, within 2 to 8 hours after 
pralsetinib administration.  A plasma sample for exploratory marker should also be collected as close as possible to the time of the biopsy. 
d Tumor biopsy upon disease progression, if safe and medically feasible. 
e Screening biopsy is required for all Phase 2, Group 6 patients. 


 
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7. 
DESCRIPTION OF STUDY PROCEDURES 
7.1 
RET PRE-SCREENING 
Any patient that will undergo RET testing outside of current SOC should sign the 
Pre-screening ICF prior to acquisition of tumor sample.  Pre-screening may occur any 
time prior to screening.  Patients should wait until the RET results are known before 
signing the main study ICF. 
7.2 
SCREENING 
Following informed consent, all patients will undergo screening procedures within 
28 days prior to dosing on C1D1 to determine eligibility.  Consent may be obtained up to 
56 days (8 weeks) prior to C1D1. 
During screening, either archival or new tumor biopsy samples are to be collected for 
patients for retrospective determination of the baseline RET gene alteration.  Note that 
a centrally confirmed RET gene alteration is not required for study entry; however, in the 
event that local RET testing is not available, then enrollment may be based on the 
central laboratory results. 
The following procedures will also be performed at the screening visit: 
• 
Obtain demographic data, including sex, date of birth/age, race, and ethnicity 
• 
Complete medical history, including a cancer history, and other malignancies, 
concurrent illnesses, prior treatments and the response to each treatment if 
available 
For MTC patients, information on bowel movements will also be requested.  The 
medical history obtained at C1D1, however, will be focused on disease-related 
symptoms and changes from the previous visit. 
• 
Complete physical examination, including ECOG PS 
Height and weight will also be measured. 
• 
Tumor sample (fresh biopsy or archival tumor) 
• 
Tumor imaging (MRI or CT) 
• 
Vital signs, including temperature, pulse, and systolic/diastolic blood pressure 
• 
Single 12-lead ECG 
• 
Clinical laboratory assessments (hematology, coagulation, serum chemistry, 
urinalysis) 
• 
Serum pregnancy test within 7 days prior to dosing on C1D1 (women of childbearing 
potential only) 
• 
Recording of concomitant medications and serious adverse events: Concomitant 
medications are recorded from 28 days before start of drug, while serious adverse 
events are collected from the time that Informed Consent Form is signed. 
 


 
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Patients who fail screening may be re-screened, if the investigator feels that it is in the 
best interest of the patient. 
7.3 
SAFETY ASSESSMENTS 
The schedule of safety assessments is described in Table 10.  Additional safety 
assessments may be performed when clinically indicated, at the investigator’s discretion. 
7.3.1 
Physical Examination 
A complete physical examination will be performed at the screening visit.  Subsequent 
physical examinations will be performed as outlined in Table 10 and will be disease and 
adverse event focused.   
Height and weight will also be measured. 
For MTC patients, information on bowel movements will also be requested.  Information 
should only be collected during study at subsequent physical examinations if there is 
bowel movement information available for the patient at baseline. 
7.3.2 
Eastern Cooperative Oncology Group Performance Status 
Determination of ECOG PS will be performed at the timepoints outlined in Table 10. 
Please refer to Appendix 1 for ECOG PS scoring. 
7.3.3 
Vital Signs 
Vital sign measurement will include temperature, systolic/diastolic blood pressure, and 
pulse, and will be performed at the timepoints outlined in Table 10. 
Blood pressure and pulse assessments should be conducted while the patient is seated 
or supine. 
7.3.4 
ECGs 
Single 12-lead ECG will be obtained for all patients at the timepoints outlined in Table 10 
and Table 11. 
In Phase 2 of the study only, continuous ECG Holter monitoring will be performed for 
20 patients at selected study centers.  Replicate 12-lead ECGs will be extracted from the 
continuous recording at the timepoints outlined in Table 11. 
Twelve-lead ECGs are to be conducted/extracted after 5 minutes of recumbency or 
semirecumbency. 
Instructions for acquisition of Holter ECG data will be provided in a separate ECG 
manual. 


 
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7.3.5 
Clinical Laboratory Tests 
Clinical laboratory evaluations for safety will be performed at a local laboratory.  Prior to 
starting the study, the Investigator will provide the Sponsor (or its designee) copies of all 
laboratory certifications and normal ranges for all laboratory assessments to be 
performed by that laboratory. 
Clinical laboratory evaluations will be conducted at the timepoints outlined in Table 10.  
In addition, all clinically significant laboratory abnormalities noted on testing will be 
followed by repeat testing and further investigated according to the judgment of the 
investigator. 
The following safety laboratory tests are to be evaluated by the investigator: 
Hematology: 
Hemoglobin, WBC with differential (including ANC), and platelet 
count 
Coagulation: 
Prothrombin time, international normalized ratio, and activated 
partial thromboplastin time 
Serum chemistry a: 
Sodium, potassium, blood urea nitrogen or urea, bicarbonate 
(venous) or CO2 level in blood (China only), creatinine, calcium, 
chloride, magnesium, phosphorus, glucose (screening and C1D1 
only), albumin, AST, ALT, ALP), total bilirubin (direct bilirubin if 
total > ULN) 
Thyroid tests 
Thyroid-stimulating hormone and free thyroxine (T4) (both only in 
patients with thyroid cancer [MTC and DTC]) 
Urinalysis (dipstick): 
pH, specific gravity, bilirubin, blood, glucose, ketones, leukocyte 
esterase or WBCs (China only), nitrite, protein, and urobilinogen 
Serum or urine pregnancy 
b: 
β-hCG 
β-hCG = β−human chorionic gonadotropin; DTC = differentiated thyroid cancer; MTC = medullary 
thyroid cancer; ULN = upper limit of normal. 
a On Day 1 of Cycle 1, patients must have fasted overnight prior to serum chemistry testing, all 
serum chemistry tests should be performed prior to pralsetinib administration. 
b A serum pregnancy test should be performed for women of childbearing potential within 7 days 
prior to Day 1 of Cycle 1; thereafter, a serum or urine pregnancy test should be performed 
monthly. 
  
7.3.6 
Adverse Events and Concomitant Medications 
Each patient must be carefully monitored for the development of any adverse events 
throughout the study from C1D1 (or from the time of signing informed consent, for 
serious adverse events) to 30 days after the final dose of study drug.  In addition, 
serious adverse events that are assessed as related to study treatment that occur 
> 30 days post-treatment also are to be reported. 
Complete details on adverse event and serious adverse event monitoring are provided in 
Sections 9 and 10. 


 
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Concomitant medications will be recorded from the time of signing informed consent to 
30 days after the final dose. 
7.3.7 
Thyroid Hormone Replacement in Patients with Thyroid Cancer 
Increases in TSH have been reported in studies of multitargeted kinase inhibitors in 
patients with thyroid cancer (Brose et al. 2014).  Therefore, the need to increase 
thyroid hormone replacement to maintain TSH in the target range will be recorded as an 
adverse event. 
For patients with MTC, thyroid-hormone supplementation should be used as needed to 
provide physiological replacement, and maintain TSH in the normal range for the 
institution, typically 0.4−4.0 mIU/L.  For patients with DTC, thyroid-hormone 
supplementation should be used as needed to maintain TSH suppression, as defined by 
the institution or investigator, typically TSH < 0.1 mIU/L. 
If an increase in thyroid hormone dose is required to maintain TSH in the target range, 
this should be recorded as a “Grade 1 TSH increase.” 
7.4 
PHARMACOKINETIC ASSESSMENT 
Serial blood samples will be collected at the timepoints outlined in Table 11 to determine 
circulating plasma concentrations of pralsetinib. 
When the timing of a blood sample coincides with the timing of a 12-lead ECG 
measurement or extraction, the ECG will be completed within a 1-hour timeframe to the 
collection of the blood sample.  When the timing of a blood sample coincides with the 
timing of an ECG extraction from a Holter monitor, the extraction ECG will be completed 
within 15 minutes prior to the collection of the blood sample. 
The timing of blood samples drawn for determination of pralsetinib concentrations may 
be changed if the emerging data indicate that an alternate sampling scheme is needed 
for better characterization of the pralsetinib PK profile.  Moreover, the total number of 
samples may be decreased if the initial sampling scheme is considered unnecessarily 
intensive.  Should the number of required samples increase, the protocol and ICF will be 
amended. 
7.5 
PHARMACODYNAMIC AND BIOMARKER ASSESSMENT 
The RET proto-oncogene is relevant to the pathogenesis of several cancers, with thyroid 
cancer and NSCLC being the most prominent.  RET activation mechanisms vary 
between cancer indications, with activating mutations being predominant in MTC and 
RET fusions predominant in PTC and NSCLC.  Target engagement will be monitored 
through RET pathway specific biomarkers, such as quantification of DUSP6 and SPRY4 
expression in tumors, RET allele burden in blood, as well as disease-specific secreted 
proteins (calcitonin and CEA) in blood in patients with MTC. 


 
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7.5.1 
Blood Samples for Pharmacodynamic and Biomarker 
Assessment 
Blood samples will be collected at the timepoints outlined in Table 12 to characterize the 
mutant allele fraction in plasma ctDNA of RET at baseline and during treatment with 
pralsetinib and atdisease progression to measure changes from baseline in the levels of 
RET mutant allele fraction in all patients. 
For patients with MTC, blood samples will be collected for measurement of calcitonin 
and CEA (performed by a central laboratory) as outlined in Table 12. 
A blood sample will be collected for assessment of exploratory plasma markers:  blood 
samples will be collected at the timepoints outlined in Table 12 and assayed at a central 
laboratory to identify potential markers (DNA, RNA, and/or protein) of pralsetinib activity.  
Additional exploratory biomarker research may be performed using residual blood 
samples and material derived from these samples in view of developing new genetic and 
mechanistic biomarkers of pralsetinib in patients with cancer. 
7.5.2 
Tumor Samples for RET Status and Biomarker Assessment 
To meet the secondary objectives, tumor tissue will be obtained at the timepoints 
detailed in Table 12 to assess RET gene status, pharmacodynamics effects, and 
potential mechanisms of resistance. 
Pretreatment tumor tissue (archived or new tissue) will be analyzed centrally for RET 
gene status.  Patients enrolled in Phase 2, Group 6, will be required to have a 
pre-treatment biopsy to determine baseline RET gene status in tumor tissue.  RET gene 
status will be assessed retrospectively in all patients. 
Investigators should obtain new tumor tissue via core needle biopsy according to local 
institutional practices.  Any new tumor biopsies done purely to obtain tissue for 
participation in this study should be performed using techniques and involving 
anatomical locations that are not a significant risk to the patient.  If feasible, 2 cores 
should be obtained. 
In Phase 1 only, an on-treatment tumor biopsy will be obtained to assess 
pharmacodynamic biomarker levels (e.g., DUSP6 and SPRY4).  An on-treatment biopsy 
is strongly encouraged if it is safe and medically feasible. 
A tumor biopsy obtained upon disease progression will be tested for potential 
mechanisms of resistance to pralsetinib. 
Additional exploratory biomarker research may be performed using residual tumor tissue 
samples and material derived from these samples in view of developing new genetic and 
mechanistic biomarkers of pralsetinib in patients with cancer. 


 
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7.6 
DISEASE RESPONSE ASSESSMENT 
Investigator-assessed disease response (per RECIST v1.1 or RANO criteria, if 
appropriate for tumor type) will be based on local imaging scans performed at the 
timepoints outlined in Table 10.  CT with IV contrast of the chest (CT of the chest is 
preferred to avoid respiratory artifacts; however, MRI may be substituted if necessary), 
and CT or MRI with IV contrast of the abdomen, brain (MRI is preferred for brain 
imaging), and pelvis, will be performed.  In addition, for patients with thyroid cancer, CT 
with IV contrast or MRI of the neck will be performed.  At subsequent timepoints, all body 
regions that contained sites of disease (target or non-target) at screening will be imaged; 
therefore, regions such as the pelvis and brain do not need subsequent imaging if there 
is no disease at baseline. 
If a patient is not tolerant to IV contrast, non-contrast CT or MRI may be performed.  The 
CT portion of a PET/CT scan may be used as long as it is of diagnostic quality and with 
IV contrast (if the patient is tolerant of IV contrast).  For each patient, the same method 
of tumor imaging used at baseline should be used. 
CT scans and MRI will be reviewed locally at the study center, ideally by the same 
individual at each timepoint. CT scans and MRI will also be collected and reviewed 
centrally to provide a central assessment of response and progression. 
7.7 
PATIENT-REPORTED OUTCOMES AND QUALITY OF LIFE 
MEASUREMENTS 
The EORTC QLQ-C30 is a 30-item questionnaire used to evaluate quality of life; it 
includes 5 functional domains (physical, cognitive, role, emotional, and social) and 
a global health status scale.  Each subscale is evaluated on a standardized scale of 0 to 
100 (Aaronson et al. 1993).  Patients will complete the EORTC QLQ-C30 on Day 1 of 
Cycles 1 through 12.  If a patient does not complete the questionnaire on Day 1 of 
Cycle 1 (i.e., at baseline), then it should not be completed at subsequent cycles.  A copy 
of the EORTC QLQ-C30 is provided in Appendix 7. 
7.8 
END-OF-TREATMENT AND 30-DAY SAFETY FOLLOW-UP 
All patients will attend an EOT visit approximately 14 days (± 7 days) after the final dose 
of study drug (see Table 10 for a description of EOT assessments).  If an alternate 
treatment is started within 14 days of the last dose of study drug, the EOT visit should be 
conducted prior to the first dose of alternate therapy.  EOT procedures do not need to be 
repeated if they were completed within 7 days (or within 28 days for disease response 
assessments). 
A follow-up telephone contact for resolution of any residual adverse event will be made 
30 days (+ 7 days) after the final dose of study drug or at the time the patient initiates 
another antineoplastic therapy. 


 
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7.9 
PROGRESSION FREE SURVIVAL AND OVERALL SURVIVAL 
FOLLOW-UP 
Upon discontinuation of study treatment, patients without documented progressive 
disease will be followed for PFS, which will include tumor imaging every 3 to 4 months 
(± 14 days; as per the schedule at the time of treatment discontinuation from the EOT 
visit until documentation of progressive disease, initiation of another antineoplastic 
therapy, or death. 
Patients with documented progression will be followed for survival, which will include 
subsequent antineoplastic therapy (at the least, reporting of the first therapy received 
after discontinuation of pralsetinib) and survival status approximately every 3 months 
(from the EOT visit) until death, withdrawal of consent, or closure of the study by the 
Sponsor. 
Patients who come off PFS follow-up due to progression will move on to survival 
follow-up, which can be completed by telephone. 
7.10 
SAMPLE PROCESSING, STORAGE, AND SHIPMENT 
Instructions for the processing, storage, and shipment of all study samples for central 
analysis will be provided in a separate study manual. 
Samples will be stored until analysis and remaining samples and/or tissue will be 
retained until 10 years after completion of the study, or until the research is discontinued, 
whichever occurs first.  Blood and tissue samples will be destroyed no later than 
10 years after the final Clinical Study Report has been completed. 
8. 
STUDY DRUG MANAGEMENT 
8.1 
DESCRIPTION 
8.1.1 
Formulation 
Pralsetinib will be provided as capsules or immediate release tablets (if available) for 
oral administration.  The drug produced is manufactured and formulated following 
current Good Manufacturing Practices (GMPs). 
Each capsule contains 100 mg of the active drug substance, formulated in white, 
orange, and light blue opaque hard-gelatin capsules.  Each tablet contains 100 mg of the 
active drug substance. 
All study drugs are for investigational use only and should only be used within the 
context of this study. 
8.1.2 
Storage 
Pralsetinib capsules or tablets (if available) must be stored in the container provided at 
room temperature not above 25°C (77°F). 


 
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All study drug products must be stored in a secure, limited-access location and may be 
dispensed only by the Investigator or by a member of the staff specifically authorized by 
the investigator. 
Refer to the pharmacy manual and/or the Pralsetinib IB for information on IMP 
preparation, storage, handling, and accountability. 
8.2 
PACKAGING AND SHIPMENT 
Capsules and/or tablets will be supplied in high-density polyethylene (HDPE) bottles 
containing a desiccant and a child-resistant closure. 
Packaging will meet all regulatory requirements. 
8.3 
ACCOUNTABILITY 
Accountability for the study drug at the study center is the responsibility of the 
Investigator.  The investigator will ensure that the study drug is used only in accordance 
with this protocol.  Where allowed, the investigator may choose to assign drug 
accountability responsibilities to a pharmacist or other appropriate individual.  Study drug 
dispensation will occur at the study center during each applicable visit; however, in the 
event that the patient cannot travel to the study center for resupply, shipment of study 
drug to the patient may be allowed, with Sponsor approval.  Direct to patient shipment of 
study drug from the study center should be appropriately documented by the site. 
The investigator or delegate will maintain accurate drug accountability records indicating 
the drug’s delivery date to the site, inventory at the study center, use by each patient, 
and return to the Sponsor or its designee (or disposal of the drug, if approved by the 
Sponsor).  These records will adequately document that the patients were provided the 
doses as specified in the protocol and should reconcile all study drug received from the 
Sponsor.  Accountability records will include dates, quantities, batch/serial numbers, 
expiration dates (if applicable), and patient numbers.  The Sponsor or its designee will 
review drug accountability at the study center on an ongoing basis during monitoring 
visits. 
Study drug must not be used for any purpose other than the present study.  Study drug 
that has been dispensed to a patient and returned unused must not be re-dispensed to 
a different patient. 
Patients will receive instructions for home administration of pralsetinib. 
All unused and used study drug should be retained at the center until they are 
inventoried by the study monitor.  All used, unused, or expired study drug will be 
returned to the Sponsor or its designee, or if authorized, disposed of at the study center 
per the center’s standard operating procedures and documented.  All material containing 


 
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pralsetinib will be treated and disposed of as hazardous waste in accordance with 
governing regulations. 
Refer to the pharmacy manual and/or the Pralsetinib IB for information on IMP 
preparation, storage, handling, and accountability. 
8.4 
COMPLIANCE 
Patients will be dispensed the appropriate number of study drug bottles to allow for 
dosing for at least a full cycle, or until the next scheduled visit.  Patients are to return all 
unused study drug (or the empty bottles) on D1 of each treatment cycle or at the next 
scheduled visit. Compliance with the dosing regimen will be assessed based on return of 
unused drug (or empty bottles). 
9. 
ADVERSE EVENTS 
Monitoring of adverse events will be conducted throughout the study.  Adverse events 
will be recorded on the eCRF from the time of first study drug dose through 30 days after 
the final study drug dose.  Serious adverse events and serious pretreatment events (see 
Section 9.5) will be recorded on the eCRF from the time of signing informed consent (for 
the full study, not the tissue screening ICF) through 30 days after the final study drug 
dose.  In addition, serious adverse events that are assessed as related to study 
treatment and that occur  30 days post-treatment will also be reported.  All related 
adverse events should be monitored until they are resolved, stabilized, have returned to 
pre-exposure baseline, determined to be due to another illness, or until a subsequent 
therapy is initiated.  For adverse events considered by the investigators not to be related 
to study drug, similar monitoring guidelines will only be required through 30 days after 
the final dose of study drug. 
9.1 
DEFINITIONS 
9.1.1 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug-related.  An adverse event (also 
referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a drug, without any judgment about causality.  An adverse event can arise from any 
use of the drug (e.g., off-label use, use in combination with another drug) and from any 
route of administration, formulation, or dose, including an overdose.  Overdose includes 
only clinically symptomatic doses that are at least twice the intended dose. 
An abnormal laboratory value will not be assessed as an adverse event unless that 
value leads to discontinuation or delay in treatment, dose modification, therapeutic 
intervention, or is considered by the investigator to be clinically significant. 


 
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Clinical signs/symptoms or diagnoses assessed as due to disease progression should 
not be reported as an adverse event or serious adverse event or cause of death.  
Instead, “disease progression” as an event term can be reported as an adverse event or 
serious adverse event (if meeting the definition of adverse event or serious adverse 
event as described above) or cause of death. In situations when signs/symptoms or 
a diagnosis cannot be clearly or only attributed to disease progression, it can be 
reported as an adverse event or serious adverse event.  
9.1.1.1 
Adverse Events of Special Interest 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately.  Adverse events of special interest are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
(> 3 × baseline value) in combination with either an elevated bilirubin (> 2 × ULN of 
which ≥ 35% is direct bilirubin) or clinical jaundice as defined by Hy’s Law criteria. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the 
abnormal laboratory values should be recorded on the Adverse Event eCRF and 
reported as a serious adverse event. 
• 
Suspected transmission of an infectious agent by a study treatment, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prior protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a participant exposed to a medicinal product.  This term applies only when 
a contamination of the study treatment is suspected. 
The most appropriate diagnosis should be recorded on the Adverse Event eCRF 
and reported as serious adverse event. 
 
9.1.2 
Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event that is not clearly caused by 
something other than pralsetinib. 
9.1.3 
Unexpected Adverse Event 
An unexpected adverse event is one for which the nature or severity of the event is not 
consistent with the applicable product information (e.g., the IB). 
9.2 
DOCUMENTING ADVERSE EVENTS 
Each patient must be carefully monitored for the development of any adverse events.  
This information should be obtained in the form of non-leading questions (e.g., “How are 
you feeling?”) and from signs and symptoms detected during each examination, 
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All adverse events (serious and non-serious) spontaneously reported by the patient 
and/or in response to an open question from study personnel or revealed by 
observation, physical examination, or other diagnostic procedures will be recorded in the 
appropriate section of the eCRF.  Any clinically significant value in laboratory 
assessments or other clinical findings is considered an adverse event and must be 
recorded on the appropriate pages of the eCRF.  A laboratory value may also be 
considered an adverse event when it qualifies as a serious adverse event, when it 
requires medical intervention, or when it affects dosing with study drug.  When possible, 
signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event reflecting the final clinical diagnosis. 
9.3 
ASSESSMENT OF SEVERITY 
The severity of all adverse events, including clinically significant treatment-emergent 
laboratory abnormalities, will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03.  Adverse 
events not listed in the CTCAE will be graded as follows: 
• 
Grade 1:  mild, the event is noticeable to the patient but does not interfere with 
routine activity 
• 
Grade 2:   moderate, the event interferes with routine activity but responds to 
symptomatic therapy or rest 
• 
Grade 3: severe, the event significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy 
• 
Grade 4:  life-threatening, an event in which the patient was at risk of death at the 
time of the event 
• 
Grade 5:  fatal, an event that results in the death of the patient 
 
9.4 
ASSESSMENT OF CAUSALITY 
Relationship to study drug administration will be determined by the investigator 
according to the following criteria: 
• 
Not related:  Exposure to the study treatment did not occur, or the occurrence of the 
adverse event is not reasonably related in time, or the adverse event is clearly 
caused by something other than pralsetinib. 
• 
Related:  The adverse event does not meet the criteria for “not related.” 
• 
At the time of the initial report, based on the available information and medical 
judgment, causality must be reported as either related or not related, even if there is 
insufficient information.  Once additional information is available, investigator’s 
causality assessment can be updated. 
 
9.5 
PRETREATMENT EVENTS 
A pretreatment event is any untoward occurrence in a patient who has signed informed 
consent to participate in a study but before administration of any study drug.  It does not 
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event meets the criterion of a pretreatment event and satisfies any of the six criteria 
specified for a serious adverse event as described in Section 10.
9.6 
PREGNANCY REPORTING
Pregnancy is neither an adverse event nor a serious adverse event, unless a 
complication relating to the pregnancy occurs (e.g., spontaneous abortion, which may 
qualify as a serious adverse event).
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female patient or partner of a male patient occurring while 
the patient is on study drug, or within 30 days of the patient’s final dose of study drug,
are considered immediately reportable events.  If a female partner of a male patient 
taking investigational product becomes pregnant, the male patient taking pralsetinib 
should notify the Investigator, and the pregnant female partner should be advised to call 
her healthcare provider immediately.  In pregnant female patients, study drug is to be 
discontinued immediately and the patient instructed to return any unused pralsetinib to 
the investigator.  The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported immediately using the Pregnancy Report Form.  The investigator must follow 
up and document the course and outcome of all pregnancies even if the patient was 
discontinued from the study or if the study has finished.  The female patient or partner of 
a male patient should receive any necessary counseling regarding the risks of continuing 
the pregnancy and the possible effects on the fetus.  Monitoring should continue until 
conclusion of the pregnancy.
All outcomes of pregnancy must be reported by the investigator to the Sponsor or 
Medical Monitor on a Pregnancy Outcome Report Form within 30 days after he/she has 
gained knowledge of the delivery or elective abortion.
Any serious adverse event that occurs during pregnancy must be recorded on the
Serious Adverse Event Report Form (e.g., maternal serious complications, spontaneous 
or therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, 
or birth defect) and reported within 24 hours in accordance with the procedure for 
reporting serious adverse events.
9.6.1 
Contraception Requirements
Women of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods with a failure 
rate of < 1% per year during the treatment period and for a period of a minimum of at 
least 14 days after the final dose of pralsetinib, and agreement to refrain from donating 
eggs during the same period.
Women are considered to be of childbearing potential following menarche until 
becoming postmenopausal (defined as no menses for at least 12 months without an 
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hormone (FSH) level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.  Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy (CTFG). 
Highly effective forms of non-hormonal contraception include the following (CTFG): 
• 
Intrauterine devices (IUD)  
• 
Bilateral tubal occlusion (women) 
• 
Male partner vasectomy or other method of surgical sterilization, provided that the 
partner is the sole sexual partner of trial participant, and the vasectomized partner 
has received medical assessment of the surgical success 
 
The following methods of contraception are not considered highly effective for this
study and are not acceptable:
• 
Hormonal contraceptives
• 
Barrier methods, with or without spermicide, or spermicide alone
• 
Periodic abstinence (such as calendar, symptothermal, and postovulation methods),
withdrawal (coitus interruptus), and the lactational amenorrhea method
 
Male patients with partners who are female of reproductive potential must agree that 
they will use condoms, and their partners will use a highly effective contraceptive 
method throughout the study, and for at least 7 days after the final dose of pralsetinib. 
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least 7 days after the final dose of pralsetinib to avoid 
exposing the embryo.  
Men must refrain from donating sperm during this same period.      
9.6.2 
Gamete and Embryo Banking 
Formal reproductive toxicology experiments have not been performed.  Patients should 
be informed of the possibility of gamete and embryo banking. 
10. 
SERIOUS ADVERSE EVENTS 
10.1 
DEFINITION OF SERIOUS ADVERSE EVENT 
A serious adverse event is any event that meets any of the following criteria: 
• 
Death 
• 
Life-threatening 
An adverse event is life-threatening if the patient was at immediate risk of death 
from the event as it occurred (i.e., it does not include a reaction that if it had 


 
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occurred in a more serious form might have caused death). For example, 
drug‑induced hepatitis that resolved without evidence of hepatic failure would not 
be considered life threatening even though drug-induced hepatitis can be fatal. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
Adverse events requiring hospitalization should be considered serious adverse 
events.  Hospitalization for elective surgery or routine clinical procedures that are 
not the result of adverse event (e.g., elective surgery for a preexisting condition 
that has not worsened) need not be considered adverse events or serious 
adverse events.  If anything untoward is reported during the procedure, that 
occurrence must be reported as an adverse event, either “serious” or 
“non-serious” according to the usual criteria. 
In general, hospitalization signifies that the patient has been admitted (usually 
involving at least an overnight stay) to the hospital or kept in the emergency room 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  When in doubt as to whether 
'hospitalization' occurred or was necessary, the adverse event should be 
considered serious. 
• 
Persistent or significant disability/incapacity 
An adverse event is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the patient's ability to carry out 
normal life functions. 
• 
Congenital anomaly/birth defect in the offspring of a patient or patient’s partner who 
received pralsetinib 
• 
Other: Important medical events that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse event when, based 
upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition 
Examples of such events are: 
– 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
– 
Blood abnormalities or convulsions that do not result in inpatient 
hospitalization 
– 
Development of drug dependency or drug abuse 
 
10.2 
REPORTING SERIOUS ADVERSE EVENTS 
All serious adverse events or serious pretreatment events that occur during the course 
of the study must be promptly reported by the Investigator to Roche.  Deaths and 
adverse events assessed as life threatening are to be reported immediately and serious 
adverse events that meet other criteria are to be reported within 24 hours from the point 
in time when the investigator becomes aware of the serious adverse event.  All serious 
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pralsetinib or protocol procedures.  Clinical Trial Serious Adverse Event/Adverse Event 
of Special Situations will be completed, and the information collected will include patient 
number, a narrative description of the event, and an assessment by the investigator as 
to the severity of the event and relatedness to study drug. Follow-up information on the 
serious adverse event may be requested by the Sponsor or Medical Monitor. 
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Situations 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the event), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.   
If there are serious, unexpected adverse drug reactions associated with the use of 
pralsetinib, the Sponsor will notify the appropriate regulatory agency(ies) and all 
participating investigators on an expedited basis.  The local Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) will be promptly notified based on local 
regulations where required by the IRB/IEC of all serious, unexpected adverse drug 
reactions involving risk to human patients. 
To determine reporting requirements for serious adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Pralsetinib 
Pralsetinib Investigator's Brochure  
  
All adverse events, whether serious or not, will be described in the source documents 
and in the appropriate section of the eCRF.  All new events, as well as those that worsen 
in severity or frequency relative to baseline, which occur after signing the informed 
consent through 30 days following the last dose of study drug, must be recorded.  
Adverse events that are ongoing at the time of treatment discontinuation should be 
followed through the 30-day follow-up assessment.  Serious adverse events felt by the 
investigator to be related to pralsetinib, however, must be reported any time the 
investigator becomes aware of such an event, even if this occurrence is more than 
30 days after the final dose of study drug. 
Information to be reported in the description of each adverse event includes: 
• 
A medical diagnosis of the event (if a medical diagnosis cannot be determined, 
a description of each sign or symptom characterizing the event should be recorded) 
• 
The date of onset of the event 
• 
The date of resolution of the event, if available 
• 
Whether the event is serious or not. 
• 
Severity of the event (see Section 9.3 for definitions). 


 
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• 
Relationship of the event to study treatment or protocol procedure (see Section 9.4 
for definitions). 
• 
Action taken: drug withdrawn; drug temporarily interrupted, dose reduced, dose not 
changed; unknown, or not applicable 
• 
Outcome: recovered/resolved, not recovered/not resolved, recovered/resolved with 
sequelae; fatal (notify the Medical Monitor immediately and complete the Serious 
Adverse Event Form), or unknown. 
 
10.2.1 
Overdose 
Overdose is defined as a clinically symptomatic dose that is at least twice the intended 
dose.  Any instance of overdose (suspected or confirmed and irrespective of whether or 
not it involved pralsetinib) must be communicated to Roche or a specified designee 
within 24 hours and be fully documented as a serious event.  Details of any signs or 
symptoms and their management should be recorded, including details of any 
antidote(s) administered. 
10.3 
MEDICAL MONITORS AND EMERGENCY MEDICAL CONTACTS 
Contact Information for all sites  
Medical Monitor/Emergency Medical Contact: 
, M.D. 
Mobile Telephone No.: 
 
 
To ensure the safety of study participants, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.  
11. 
STATISTICS 
11.1 
GENERAL PROCEDURES 
Statistical analyses of safety, pharmacokinetics, and pharmacodynamics will be primarily 
descriptive in nature.  Antineoplastic activity will be analyzed and presented 
descriptively.  Hypothesis testing will be performed based on the prespecified 
hypotheses for the dose expansion part (Phase 2) of the study. 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, and minimum and maximum). 
Categorical variables will be summarized showing the number and percentage of 
patients within each classification.  Appropriate CIs will also be presented. 


 
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The safety, pharmacokinetics, pharmacodynamics, and efficacy of pralsetinib will be 
assessed in the appropriate populations accordingly.  Data from patients treated at 
MTD/RP2D in Phase 1 will be pooled with data from Phase 2 patients accordingly. 
All data will be provided in by-patient listings. 
11.2 
ANALYSIS POPULATIONS 
The following analysis populations will be used for presentation of the data: 
• 
Safety population:  All patients who have received at least 1 dose of study drug 
regardless of starting dose levels.  The safety population will be the primary 
population for safety analysis, unless otherwise specified.  Patients will be analyzed 
based on the initial dose prescribed on Day 1 regardless of phase. 
• 
Efficacy population:  All patients who have been exposed to at least one dose of 
study drug at the RP2D, excluding patients previously treated with a selective RET 
inhibitor such as selpercatinib.  The efficacy population will be the primary 
population for analysis of efficacy endpoints (except for ORR, DOR, CBR, DCR).  
Patients will be analyzed based on the initial dose prescribed on Day 1 regardless of 
phase. 
• 
Dose-determining population:  All patients in the dose-escalation part who have 
received ≥ 75% (21 days) of study drug and completed safety evaluations through 
C1D28 or experienced a DLT. 
• 
“RET-altered” measurable disease population:  Patients in the efficacy population 
who have measurable (target) disease per RECIST v1.1 (or RANO criteria, if 
appropriate for tumor type) at baseline according to blinded central review and 
sufficient evidence of a RET alteration.  The RET-altered measurable disease 
population will be the primary population for analysis of ORR, DOR, CBR, and DCR. 
• 
Response-evaluable (RE) population:  Patients in the efficacy population who have 
measurable (target) disease per RECIST v1.1 (or RANO criteria, if appropriate for 
tumor type) at baseline according to blinded central review, have at least one 
evaluable post-baseline disease response assessment performed, and have no 
major protocol violations.  The RE population will be used as a sensitivity analysis 
for ORR, DOR, CBR, and DCR. 
• 
PK population:  All patients who have adequate PK samples collected so that the 
PK parameters can be estimated. 
• 
ECG population:  All patients who underwent continuous Holter monitoring and have 
sufficient ECG tracings so that QTc parameters can be evaluated. 
 
11.3 
SAMPLE SIZE 
11.3.1 
Phase 1 (Dose Escalation) 
The dose- escalation part of the study (Phase 1) employs the local BOIN design (Liu and 
Yuan 2015) to find the MTD.  The BOIN design is implemented in a simple way similar to 
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characteristics that are comparable to those of the more complex model-based designs, 
such as the CRM. 
The target toxicity rate for the MTD is 30%.  Alternatives under which decision errors are 
minimized are 18% (subtherapeutic) and 42% (overly toxic).  To avoid assigning too 
many patients to an overly toxic doses, a dose level will be eliminated (and any planned 
doses that are higher) when the posterior probability is greater than 95% that the toxicity 
rate of a dose level is > 30%, given the number of patients (≥ 3) and DLTs observed at 
the dose level.  Dose escalation will continue to enroll and treat patients in cohorts of 
3−6 patients (1−3 patients for the first three dose levels) until 12 patients are treated and 
evaluable for DLT at one dose level.  The total number of patients to be enrolled during 
the dose-escalation part of the study will vary depending on the underlining dose−toxicity 
curve and the number of dose levels tested prior to reaching MTD and is estimated to be 
approximately 20 to 50 patients. 
Dose-escalation rules are detailed in Section 6.3.1.2. 
After Phase 1 is completed, the MTD will be selected on the basis of isotonic regression 
as specified by Liu and Yuan (2015).  Specifically, the MTD will be selected as the dose 
for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.  
If there are ties, the higher dose level will be selected when the isotonic estimate is lower 
than the target toxicity rate; and the lower dose level will be selected when the isotonic 
estimate is greater than the target toxicity rate. 
11.3.1.1 
Operating Characteristics 
Appendix 4 shows the operating characteristics of the trial design based on 
100,000 simulations of the trial.  For trial simulation purposes the target toxicity rate for 
the MTD is assumed to be 30% (0.3) and the maximum sample size is 99.  Further 
assumptions include enrolling and treating 3 patients per cohort at a total of 13 dose 
levels, and that the true toxicity curves are monotonic and cover a wide range of 
possibilities (as shown in Figure 9).  The operating characteristics show that the design 
selects the true MTD with high probabilities and allocates more patients to the dose 
levels with the DLT rate closest to the target of 30%. 
 
 


 
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Figure 9: 
Dose-Toxicity Scenarios 
 
BOIN= Bayesian optimal interval, DLT= dose-limiting toxicity, MTD= maximum tolerated dose. 
Note:  Scenario numbers shown in this figure match the scenario numbers in Appendix 4, 
Operating Characteristics of the BOIN Design. 
 
11.3.2 
Phase 2 (Expansion) 
Because pralsetinib has potent activity against RET fusions, activating mutations and 
resistance mutations, the hypothesis and sample size calculation based on ORR as per 
RECIST v1.1 (or RANO criteria, if appropriate for tumor type) is specific to the 
response-evaluable RET-altered patients (excluding patients in Groups 6 and 7) treated 
at the MTD/RP2D for each Phase 2 expansion group. 
• 
Group 1:  The sample size of approximately 80 patients with RET-fusion NSCLC 
who have failed treatment with a prior platinum-based chemotherapy will 
provide >95% power at the 2-sided significance level of 0.05 for testing the 
assumption of the null hypothesis ORR= 0.23 versus the alternative ORR= 0.5. 
• 
Group 2:  The sample size of approximately 170 treatment-naive patients (1st-line) 
with RET-fusion NSCLC will provide >90% power at the 2-sided significance level of 
0.05 for testing the assumption of the null hypothesis ORR= 0.48 versus the 
alternative ORR = 0.61. 
• 
Group 3:  The sample size of approximately 65 patients with MTC who have been 
previously treated with cabozantinib and/or vandetanib will provide >90% power at 
the 2-sided significance level of 0.05 for testing the assumption of the null 
hypothesis ORR= 0.2 versus the alternative ORR= 0.4. 


 
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• 
Group 4:  The sample size of approximately 40 patients with MTC who have not 
been previously treated with cabozantinib or vandetanib will be enrolled for 
exploratory analysis; however, see Table 16 for details regarding CIs. 
• 
Group 5:  The sample size of approximately 100 patients who have solid tumors 
with a RET fusion previously treated with SOC, have previously received SOC 
appropriate for their tumor type (unless there is no accepted standard therapy for 
the tumor type or the investigator has determined that treatment with standard 
therapy is not appropriate), and must not eligible for any of the other groups.  This 
sample size will provide >90% power at the 2-sided significance level of 0.05 for 
testing the assumption of the null hypothesis ORR= 0.1 versus the alternative 
ORR= 0.3. 
• 
Group 6:  The sample size of approximately 20 patients who have RET-fusion solid 
tumors that failed a prior selective-RET inhibitor will be enrolled for exploratory 
analysis; however, see Table 19 for details regarding CIs. 
• 
Group 7:  The sample size of approximately 20 patients who have solid tumors with 
an activating RET mutation previously treated with SOC will be enrolled for 
exploratory analysis; however, see Table 19 for details regarding CIs. 
• 
Group 8:  The sample size of approximately 30 patients with RET-fusion NSCLC 
who have failed treatment with a prior platinum-based chemotherapy will be 
enrolled, see Table 20 for details regarding CIs (an observed ORR of ≥ 27% in 
30 patients will result in an exact binomial 95% CI with a lower bound greater than 
10%.) 
• 
Group 9:  The sample size of approximately 30 MTC patients that were not 
previously treated with systemic therapy (except prior cytotoxic chemotherapy is 
allowed) for advanced or metastatic disease will be enrolled, however see Table 20 
for details regarding confidence intervals (an observed ORR of ≥ 27% in 30 patients 
will result in an exact binomial 95% CI with a lower bound greater than 10%.) 
 
With approximately 590 patients in the safety population, there is > 97% probability of 
observing at least 3 adverse events that occur at a frequency of 0.5%; there is > 99% 
probability of observing at least 5 adverse events that occur at a frequency of 1%. 
11.4 
STATISTICAL METHODS 
Data from patients enrolled in Phase 1 and treated at the RP2D will be pooled together 
with data from the appropriate Phase 2 group patients for analyses.  The analyses 
based on safety population, efficacy population, RET-altered measurable disease 
population, and RE population will be conducted according to patients’ disease type, 
and/or RET-altered status if applicable, and/or prior treatment status, if appropriate.  
The analysis based on dose-determining population will be conducted according to 
patients’ initial prescribed dose level.  Efficacy endpoints will be analyzed for the efficacy 
population (PFS and OS) and RET-altered measurable disease population (ORR, DOR, 
CBR, and DCR).  Safety endpoints will be analyzed for safety population.  The RE 
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the efficacy endpoints, subgroup analyses will be completed for patients enrolled in the 
treatment-naive Group 2 (NSCLC), consisting of 1) patients enrolled prior to Protocol 
Amendment 9 (who were not candidates for standard therapies and thus may have had 
a poor prognosis) and 2) those enrolled on or after Protocol Amendment 9 (possibly 
a more typical first-line population). 
11.4.1 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized descriptively. 
11.4.2 
Primary Endpoints 
11.4.2.1 
Phase 1 
MTD and RP2D 
Tabulations of the incidence of DLTs for the DLT evaluable population at each dose 
level will be provided. 
Safety 
Safety evaluations will be based on the incidence, severity, and type of adverse events, 
and changes in the patient’s physical examination findings, vital signs, clinical laboratory 
results, and ECG findings.  Safety variables will be tabulated and presented for all 
patients of the safety population (combined Phase 1 and Phase 2), and/or by disease 
type, and/or RET-altered status, and/or prior treatment status if applicable.  
Summarization will focus on incidence of any serious adverse events, adverse events by 
System Organ Class and Preferred Term, and discontinuation rates of study drug due to 
adverse events or toxicity based on clinical laboratory results. 
Adverse events will be assessed for severity according to the NCI CTCAE, Version 4.03, 
and the verbatim adverse event term will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) for purposes of summarization. 
Treatment-emergent adverse events will be tabulated, for which treatment emergent is 
defined as any adverse event that occurs during or after administration of the first dose 
of study drug through 30 days after the final dose of study drug, any event that is 
considered by the investigator to be study drug related regardless of the start date of the 
event, or any event that is present at baseline but worsens in severity or is subsequently 
considered study drug related by the investigator. 
11.4.2.2 
Phase 2 
Data from patients enrolled in Phase 1 and treated at the RP2D will be pooled together 
with data from the appropriate Phase 2 group patients for analyses. 
Efficacy 
The ORR, defined as proportion of patients with best overall response of confirmed 
complete response (CR) or partial response (PR), will be summarized by disease type, 
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(including patients treated at the MTD/RP2D in Phase 1).  The 95% CI based on the 
exact binomial distribution will also be provided. 
An observed ORR of ≥ 35% in 80 patients will result in an exact binomial 95% CI with 
a lower bound greater than 30% (Table 13). 
Table 13: 
Confidence Interval of Observed Response Rate for Group 1, 
N = 80 
Observed ORR 
Number of  
Confirmed CRs or PRs 
Exact 95% CI 
Exact 97.5% 
35% 
28 
(24.7, 46.5) 
(23.4, 48.1) 
40% 
32 
(29.2, 51.6) 
(27.8, 53.1) 
45% 
36 
(33.8, 56.5) 
(32.4, 58.1) 
50% 
40 
(38.6, 61.4) 
(37.1, 62.9) 
CI = confidence interval; CR = complete response; ORR = overall response rate; PR = partial 
response. 
 
An observed ORR of ≥ 20% in 170 patients will result in an exact binomial 95% CI with 
a lower bound greater than 48% (Table 14). 
Table 14: 
Confidence Interval of Observed Response Rate for Group 2, 
N=170 
Observed ORR 
Number of  
Confirmed CRs or PRs 
Exact 95% CI 
Exact 97.5% 
56% 
96 
(48.7, 64) 
(47.6, 65.1) 
57% 
97 
(49.3, 64.6) 
(48.2, 65.6) 
58% 
99 
(50.4, 65.7) 
(49.4, 66.7) 
59% 
101 
(51.6, 66.9) 
(50.5, 67.9) 
60% 
102 
(52.2, 67.4) 
(51.1, 68.4) 
61% 
104 
(53.4, 68.5) 
(52.3, 69.5) 
 
An observed ORR of ≥ 20% in 65 patients will result in an exact binomial 95% CI with 
a lower bound greater than 20% (Table 15). 


 
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Table 15: 
Confidence Interval of Observed Response Rate for Group 3, 
N = 65 
Observed ORR 
Number of  
Confirmed CRs or PRs 
Exact 95% CI 
Exact 97.5% 
32% 
21 
(21.2, 45.1) 
(19.9, 46.8) 
34% 
22 
(22.6, 46.6) 
(21.2, 48.4) 
37% 
24 
(25.3, 49.8) 
(23.8, 51.5) 
40% 
26 
(28, 52.9) 
(26.5, 54.6) 
CI = confidence interval; CR = complete response; ORR = overall response rate; PR = partial 
response. 
 
An observed ORR of ≥ 28% in 40 patients will result in an exact binomial 95% CI with 
a lower bound greater than 10% (Table 16). 
Table 16: 
Confidence Interval of Observed Response Rate for Group 4, 
N = 40 
Observed ORR 
Number of  
Confirmed CRs or PRs 
Exact 95% CI 
Exact 97.5% 
28% 
11 
(14.6, 43.9) 
(13.2; 46.1) 
30% 
12 
(16.6, 46.5) 
(15.1, 48.8) 
35% 
14 
(20.6, 51.7) 
(19.0, 53.9) 
40% 
16 
(24.9, 56.7) 
(23.1, 58.8) 
45% 
18 
(29.3, 61.5) 
(27.4, 63.6) 
50% 
20 
(33.8, 66.2) 
(31.8, 68.2) 
CI = confidence interval; CR = complete response; ORR = overall response rate; PR = partial 
response. 
 
Table 17 provides the probability of observing responders for a given range of response 
rate for Group 5. 
Table 17: 
Probability of Observing Responses for Group 5, N = 100 
Number of  
Responses Observed 
True Response Rate 
20% 
30% 
40% 
50% 
≥ 10 
0.99 
>0.99 
>0.99 
1 
≥ 15 
0.87 
>0.99 
>0.99 
1 
≥ 20 
0.44 
0.98 
>0.99 
>0.99 
≥ 25 
0.08 
0.84 
>0.99 
>0.99 
≥ 30 
0.01 
0.45 
0.98 
>0.99 
 
An observed ORR of ≥ 17% in 100 patients will result in an exact binomial 95% CI with a 
lower bound greater than 10% 


 
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Table 18: 
Confidence Interval of Observed Response Rate for Group 5, 
N = 100 
Observed ORR 
Number of  
Confirmed CRs or PRs 
Exact 95% CI 
Exact 97.5% CI 
17% 
17 
(10.2, 25.8) 
(9.5, 27.1) 
20% 
20 
(12.7, 29.2) 
(11.8, 30.5) 
25% 
25 
(16.9, 34.7) 
(15.9, 36) 
30% 
30 
(21.2, 40) 
(20.2, 41.4) 
35% 
40 
(25.7, 45.2) 
(24.6, 46.6) 
40% 
45 
(30.3, 50.3) 
(29.1, 51.7) 
CI = confidence interval; CR = complete response; ORR = overall response rate; PR = partial 
response. 
 
Table 19 provides the probability of observing responders for a given range of response 
rate. 
Table 19: 
Probability of Observing Responses for Groups 6 and 7, N = 20 
Number of Responses 
Observed 
True Response Rate 
20% 
30% 
50% 
≥ 1 
0.99 
0.99 
0.99 
≥ 2 
0.93 
0.99 
0.99 
≥ 3 
0.79 
0.96 
0.99 
≥ 4 
0.59 
0.89 
0.99 
≥ 5 
0.37 
0.76 
0.99 
≥ 6 
0.20 
0.58 
0.98 
 
Table 20: 
Confidence Interval of Observed Response Rate for Groups 8 
and 9, N = 30 
Observed ORR 
Number of  
Confirmed CRs or PRs 
Exact 95% CI 
Exact 98.75% CI 
27% 
8 
(12.3, 45.9) 
(9.6, 50.8) 
30% 
9 
(14.7, 49.4) 
(11.8, 54.3) 
33% 
10 
(17.3, 52.8) 
(14.1, 57.6) 
40% 
12 
(22.7, 59.4) 
(19.0, 64.0) 
43% 
13 
(25.5, 62.6) 
(21.6, 67.1) 
50% 
15 
(31.3, 68.7) 
(27.1, 72.9) 
CI = confidence interval; CR = complete response; ORR = overall response rate; PR = parti al 
response. 
 
Safety 
See Section 11.4.2.1 for safety analysis details. 


 
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11.4.3 
Secondary Endpoints 
11.4.3.1 
Phase 1 
Efficacy 
ORR will be analyzed by disease type, and/or RET-altered status if applicable, and/or 
prior treatment status if appropriate. CBR, DCR, DOR, PFS, and OS and the correlation 
between RET gene status and antineoplastic activity will be defined as the following. 
• 
CBR is defined as the rate of CR or PR, or stable disease where stable disease has 
lasted more than 4 cycles (i.e., 16 weeks) from the first dose date. 
• 
DCR is defined as the rate of CR or PR, or stable disease, as per RECIST v1.1 (or 
RANO criteria, if appropriate). CBR, DCR will be summarized using the same 
methods as ORR. 
• 
For patients who achieve a CR or a PR per RECIST v1.1 (or RANO criteria, if 
appropriate), DOR is defined as the time from either a CR or a PR (whichever 
response is recorded first), until the first date that disease progression is objectively 
documented, or until death (if death occurs within 2 scheduled assessments of the 
last evaluable scan).  The DOR will be summarized descriptively using the 
Kaplan-Meier (KM) method.  The median (95% CI) will be provided, if estimable. 
• 
PFS is defined as the time from the first dose pralsetinib to the date of disease 
progression or death due to any cause (whichever is earlier).  Data from patients 
who initiate alternate anticancer therapy in the absence of documented progression 
will be censored at the latest disease assessment prior to the alternate therapy. 
• 
OS is defined as the time from the first dose pralsetinib to the date of death due to 
any cause.  Data from patients who are still alive or lost to follow-up will be censored 
at last known date.  The censoring date will be determined from patients’ last known 
contact date. 
 
PFS and OS will also be summarized using the KM method for the efficacy population by 
disease type, and/or RET-altered status if applicable, and/or prior treatment status if 
appropriate. KM plots will be provided.  Waterfall plots for maximum percentage of tumor 
reduction from baseline will also be provided. The probability of PFS and OS at certain 
timepoints (e.g., 3, 6, 9, and 12-months, etc.) will be estimated. 
The ORR, CBR, DCR, DOR, and other measures of antineoplastic activity by major 
RET-altered gene status will be summarized.  The correlation between RET-altered 
gene status and antineoplastic activity ORR, CBR, and DCR, will be analyzed in a same 
manner, if appropriate.  The correlation between RET gene status and DOR may be 
explored with log-rank model. 
Pharmacokinetics 
PK parameters for pralsetinib will be calculated from the plasma concentration-time data 
using standard non-compartmental methods.  PK parameters of interest will include, as 
appropriate,plasma Cmax, plasma Tmax, Tlast, AUC0-24hr, plasma drug concentration 
24 hours postdose (C24hr); Vz/F, t½) CL/F, and R.  Descriptive statistics (i.e., n, mean, 


 
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standard deviation [SD], percent coefficient of variation [%CV], minimum, median, 
maximum, geometric mean [GeoMean], GeoMean %CV, and 95% CIs) will be used to 
summarize PK parameters for each dose level as appropriate. 
Pharmacodynamics: 
PK/pharmacodynamic relationships will be descriptively analyzed within each dose level 
from paired PK/pharmacodynamic sample results for blood (e.g., calcitonin, CEA, and 
ctDNA of RET) and tumor (e.g., DUSP6/SPRY4) markers, if feasible. 
11.4.3.2 
Phase 2 
Data from patients enrolled in Phase 1 and treated at the RP2D will be pooled together 
with data from the appropriate Phase 2 group patients for analyses. 
Efficacy 
CBR, DCR, DOR, PFS, and OS and the correlation between RET gene status (i.e., gene 
fusion partner or primary mutation and, for MTC, whether hereditary or sporadic) and 
antineoplastic activity will be defined as the following. 
• 
CBR is defined as the rate of CR or PR, or stable disease which stable disease has 
been lasting more than 4 cycles (i.e., 16 weeks) from the first dose date. 
• 
DCR is defined as the rate of CR, PR, and stable disease, as per RECIST v1.1 (or 
RANO criteria, if appropriate). CBR, DCR will be summarized using the same 
methods as ORR. 
• 
For patients who achieve CR or PR per RECIST v1.1 (or RANO criteria, if 
appropriate), DOR is defined as the time from either CR or PR (whichever response 
is recorded first), until the first date that disease progression is objectively 
documented, or until death (if death occurs within 2 scheduled assessments of the 
last evaluable scan).  The DOR will be summarized descriptively using the KM 
method.  The median (95% CI) will be provided, if estimable. 
• 
PFS is defined as the time from the first dose pralsetinib to the date of disease 
progression or death due to any cause (whichever is earlier).  Patients who initiate 
alternate anticancer therapy in the absence of documented progression will be 
censored at the latest disease assessment prior to the alternate therapy. 
• 
OS is defined as the time from the first dose pralsetinib to the date of death due to 
any cause.  Patients who are still alive or lost to follow-up will be censored at last 
known date.  The censoring date will be determined from patients’ last known 
contact date. 
 
PFS and OS will also be summarized using the KM method for the safety population; KM 
plots will be provided.  Waterfall plots for maximum percentage of tumor reduction from 
baseline will also be provided.  The median of PFS and OS, as well as rates at certain 
timepoints (e.g., 3, 6, 9, and 12 months), will be estimated for all patients in the safety 
population, as well as patients in the safety population who were treated at the 
MTD/RP2D, using the KM method.  In addition, the OS follow-up analysis will be 
provided using the reverse KM method. 


 
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Antineoplastic activity, as measured by ORR, DOR, and DCR per RECIST v1.1 (or 
RANO criteria, if appropriate); PFS may be analyzed centrally and summarized 
descriptively for all NSCLC and MTC patients in Parts 1 and 2 accordingly. 
The ORR, CBR, DCR, DOR, and other measures of antineoplastic activity by major 
RET-altered gene status will be summarized. 
Pharmacokinetics 
PK parameters for pralsetinib will be calculated from the plasma concentration-time data 
using standard non-compartmental methods.  PK parameters of interest will include, as 
appropriate, plasma Cmax, Tmax, Tlast, AUC0-24hr, plasma C24hr postdose; Vz/F, t½, oral CL/F, 
and R.  Descriptive statistics (i.e., n, mean, SD, %CV, minimum, median, maximum, 
GeoMean, GeoMean %CV, and 95% CIs) will be used to summarize PK parameters for 
each dose level as appropriate. 
ECG Assessment 
In Phase 2, the effects of pralsetinib on ECG parameters will be evaluated for 
20 patients by means of12-lead ECGs extracted from continuous recordings (Holter) on 
C1D1 and C1D15. Individual ECGs will be extracted in replicate from the Holter 
recordings at specified timepoints and will be evaluated by a central laboratory. QT 
intervals will be measured from Lead II and will be corrected for heart rate (QTc) using 
Fridericia's correction factors.  The primary QTc parameter will be QTcF.  Secondary 
parameters (heart rate, PR and QRS and T-wave morphology) will also be evaluated. 
Potential effects of pralsetinib will be evaluated as change from predose baseline heart 
rate, PR, QRS and QTcF by post-dosing timepoint.  For purposes of QT assessment, 
exposure−response analysis will be performed of the relationship between pralsetinib 
plasma levels and ∆QTcF. 
Pharmacodynamics 
PK/pharmacodynamic relationships will be descriptively analyzed within each dose level 
from paired PK/pharmacodynamic sample results for blood (e.g., calcitonin, CEA, 
biochemical response rate, and ctDNA of RET).  The change and percent change from 
baseline will be summarized. Patients’ best biochemical response based on calcitonin 
and CEA will also be summarized, respectively.  The detailed definition for categorizing 
patients into biochemical CR, PR, SD, PD and NE can be found in SAP.  Patients with 
normal serum levels or missing values at baseline will not be included in the analysis. 
Time to Intracranial Progression and Intracranial Response Rate: 
• 
Intracranial progression is defined as ≥ 20% increase along with a 5-mm absolute 
increase (relative to baseline or nadir on study) in the sum of diameters of any 
intracranial lesion(s) identified as RECIST v1.1 target lesions at baseline, 
unequivocal progression of any intracranial lesion(s) identified as RECIST v1.1 
non-target lesions at baseline, or the identification of new intracranial lesion(s). 


 
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• 
Time to intracranial progression is defined as the number of weeks from first dose to 
intracranial progression.  Time to intracranial progression will be estimated using the 
same method for PFS analysis. 
• 
Detailed censoring methods will be described in the SAP. 
• 
Intracranial response is defined as ≥ 30% decrease in the sum of diameters of any 
intracranial lesion(s) identified as RECIST v1.1 target lesions at baseline if in the 
absence of unequivocal progression of any intracranial lesion(s) identified as 
RECIST v1.1 non-target lesions at baseline and the identification of new intracranial 
lesion(s).  The intracranial response rate is defined as the proportion of patients who 
experience intracranial response among those with any intracranial lesion(s) 
identified as RECIST v1.1 target lesions according to blinded central review at 
baseline. 
• 
The intracranial response rate will be analyzed with the same method used for 
ORR. 
 
11.4.4 
Exploratory Endpoints 
11.4.4.1 
Phase 1 
For all biomarker data, summary statistics and graphs will be provided as appropriate.  
Relationships between biomarker data and efficacy measures will be descriptively 
analyzed, as appropriate. 
11.4.4.2 
Phase 2 
For all biomarker data, summary statistics and graphs will be provided as appropriate.  
Relationships between biomarker data and efficacy measures will be descriptively 
analyzed, as appropriate. 
For EORTC QLQ-C-30 assessments, global health status, functional scales, and 
symptom scales will be analyzed descriptively at each timepoint.  The change from 
baseline to each timepoint will also be analyzed descriptively. 
Disease-related symptoms as reported by bowel movement history will be summarized 
and change from baseline in bowel movement history over time will be analyzed only for 
RET-mutation MTC. 
Time to intracranial progression will be analyzed in all patients with tumor types other 
than NSCLC; and intracranial response rate will be analyzed in patients with tumor types 
other than NSCLC; and measurable (target by RECIST v1.1) lesions in the brain (if 
applicable). 


 
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12. 
ETHICS AND RESPONSIBILITIES 
12.1 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
• 
Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice 
• 
Applicable laws and regulations 
 
The protocol, Informed Consent Form, Investigator's Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an Institutional Review Board or 
Ethics Committee (IRB/EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
patients. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
• 
Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures 
• 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, Clinical Trial Directive (2001/20/EC) or Regulation (E.U.) No. 
536/2014 (E.U. sites only), and all other applicable local regulations 
 
12.2 
DATA AND SAFETY MONITORING 
This is an open-label, Phase 1/2 study in which all patients receive single-agent 
pralsetinib.  The Sponsor will have access to the safety data on a regular basis.  The 
Sponsor’s clinical study team will host investigator teleconferences on a regular basis 
during the study.  Additionally, the Sponsor’s safety management team (SMT) will review 
and manage cumulative safety data at periodic intervals (approximately quarterly) and 
ad hoc, as needed.  The goal of the SMT is to evaluate and detect new safety signals or 
increased frequency or severity of known safety signals for pralsetinib.  The SMT 
members include representatives from Clinical Development, Clinical Pharmacology, 
Nonclinical Pharmacology, Regulatory Affairs, Biostatics, Clinical Operations, and 
Pharmacovigilance. 


 
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12.2.1 
Phase 1 Data and Safety Monitoring 
During the dose-escalation part of the study, the Sponsor’s clinical study team and the 
Investigators will meet at the end of each treatment cohort (and at least monthly) to 
discuss and evaluate all of the gathered safety data.  At the dose-escalation 
teleconference, safety information, including DLTs and all Grade 2 or worse adverse 
events reported during Cycle 1, and all available PK data will be described and reviewed 
for each patient in the current dose cohort.  Updated safety, PK, and other data for all 
other ongoing patients, including data from later cycles, will also be discussed. 
Dose-escalation decisions in Phase 1 was based on an evaluation of all relevant, 
available data, and not solely on DLT information.  The selection of the dose for the next 
cohort of patients was limited to a 100% increase, a 50% increase, or to the addition of 
3 patients with no dose increase, as described in Section 6.3.1.2; however, the actual 
dose level chosen could be less than the maximum permitted and was based on 
a medical review of relevant clinical and available PK data.  The Sponsor’s clinical study 
team and the investigators must have reached an agreement on whether to determine 
that the MTD has been achieved, to escalate the dose further, or to de-escalate to 
a lower dose. 
12.2.2 
Phase 2 Data and Safety Monitoring 
During the expansion part of the study (Phase 2), patient safety will be reviewed on an 
ongoing basis at a safety review meeting that includes the study investigators and the 
Sponsor’s clinical study team.  All available safety data will be reviewed to confirm that 
no unexpected, significant, or unacceptable risks have been discovered.  Available PK, 
pharmacodynamic, and tumor response data will also be reviewed. 
12.2.2.1 
Phase 2 Safety Review Committee 
In the Phase 2 part of the study (dose expansion), a Safety Review Committee (SRC) 
was established to oversee the safety aspects of the expansion portion of the study.  
The SRC consisted of, at a minimum, of the Sponsor’s Medical Monitor, a Clinical 
Operations representative, and at least our global pralsetinib investigators.  The Phase 2 
safety committee convened at a minimum of every 3 months (or more frequently 
depending on enrollment or observed safety profile) and perform ongoing review of 
serious adverse events and other safety-related data throughout the conduct of the 
study.  Meetings were held by teleconference or in person.  
In conjunction with Protocol Amendment 9, a Phase 2 independent Data Monitoring 
Committee (iDMC) is replacing the Phase 2 SRC. 
12.2.2.2 
Phase 2 Independent Data Monitoring Committee 
An IDMC has been established in conjunction with Protocol Amendment 9. The roles 
and responsibilities of the IDMC are listed below.  Refer to the IDMC Charter for 
additional information. 


 
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The aim of the Committee is to safeguard the interests of trial participants, monitor the 
main outcome measures including safety and efficacy, and monitor the overall conduct 
of the trial. 
The IDMC will receive and review information on the progress and accumulating data of 
this study and provide advice on the conduct of the study. 
The IDMC will make recommendations to the Roche and the study’s Steering Committee 
regarding the following aspects of the study, as is relevant in regard to the study design: 
a) Whether a modification should be made to the study for safety reasons, for example, 
a modification of the eligibility criteria when the risk/benefit ratio seems unfavorable 
in specific subgroups of patients 
b) At early termination of a trial when the scientific value of the trial is insufficient, either 
because of compelling external evidence regarding the hypothesis being tested or 
because the trial will not be able to produce scientifically valid results due to lack of 
accrual or lack of quality 
c) On modifications to the study sample size 
d) On actions needed to manage identified issues related to patient compliance or 
study feasibility and/or quality 
 
The role of the IDMC is to perform periodic reviews of the study’s progress, including 
adherence to protocol, follow-up assessments, and safety data.  Specifically, this role 
includes: 
a) Monitoring evidence for treatment harm (e.g., toxicity, serious adverse events, and 
deaths) 
b) Assessing the impact and relevance of external evidence 
c) Deciding whether to recommend that the study continues to recruit participants or 
whether recruitment should be terminated either for all groups or for some Phase 2 
groups and/or some participant subgroups 
d) Maintaining confidentiality of all study information that is not in the public domain 
e) Considering the ethical implications of any recommendations made by the IDMC 
f) Monitoring planned sample size assumptions 
g) Suggesting additional data analyses if necessary 
h) Advising on protocol modifications proposed by investigators or the Sponsor (e.g., to 
inclusion criteria, study endpoints, or sample size) 
i) Monitoring compliance with previous IDMC recommendations 
 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE 
Refer to Section 12.1 for details related to study conduct and submission to IRBs/ECs. 


 
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12.4 
INFORMED CONSENT 
The investigator at each study center will ensure that the patient is given full and 
adequate oral and written information about the nature, purpose, possible risk, and 
benefit of the study.  Patients must also be notified that they are free to discontinue from 
the study at any time.  The patient should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
After the study has been fully explained, written informed consent, including separate 
consent for exploratory biomarker research to be conducted on biological samples 
collected during the study, will be obtained from either the patient or his or her guardian 
or legal representative prior to study participation. 
The patient’s signed and dated informed consent must be obtained before conducting 
any study-related procedures.  The investigator must maintain the original, signed 
consent form.  A copy of the signed form must be given to the patient. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or the patient's legally authorized representative must re-consent by 
signing the most current version of the Informed Consent Form or the Addendum, in 
accordance with applicable laws and IRB/EC policy. 
The method of obtaining and documenting the informed consent and the contents of the 
consent will comply with ICH-GCP and all applicable regulatory requirement(s). 
12.5 
STUDY FILES, RECORD RETENTION AND MANAGEMENT 
All patient data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data).  The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring), are provided prior to study 
initiation, in the various functional monitoring plans (including, but not limited to, Quality 
Tolerance Limit Management Plan and Trial Monitoring Plan). 


 
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The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the Trial 
Monitoring Plan to confirm that data entered into the CRF by authorized site personnel 
are accurate, complete, and verifiable from source documents; that the safety and rights 
of patients are being protected; and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, the ICH Guideline for 
Good Clinical Practice, and all applicable regulatory requirements. 
Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party 
without written notification to the Sponsor. 
12.6 
SOURCE DOCUMENTATION 
Source documents and eCRFs will be completed for each study patient. It is the 
Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the patient’s source document/eCRF.  The source document/eCRF 
should indicate the patient’s participation in the study and should document the dates 
and details of study procedures, adverse events, and patient status. 
The investigator, or designated representative, should complete the source 
document/eCRF as soon as possible after information is collected, preferably on the 
same day that a study patient is seen for an examination, treatment, or any other study 
procedure.  Any outstanding entries must be completed immediately after the final 
examination.  An explanation should be given for all missing data. 
The investigator must sign and date the Investigator’s Statement at the end of the 
source document/eCRF to endorse the recorded data as accurate and correct. 
The Investigator will retain all completed source documents. 
12.7 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 80 sites globally will participate to enroll approximately 590 patients.  
Enrollment will occur through an interactive voice or web-based response system. 


 
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Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 6.7.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
12.8 
FINANCIAL DISCLOSURES 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study (see definition of end of study in 
Section 5.6). 
12.9 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
13. 
AUDITING AND MONITORING 
Refer to Section 12.5 for details related to study conduct and submission to auditing and 
monitoring. 
14. 
AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be made only by Roche. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
patients. 
15. 
STUDY REPORT AND PUBLICATIONS 
Roche is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. 
The publication policy of Roche is discussed in the Investigator's Clinical Research 
Agreement. 


 
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Study data, which may include imaging data, may be submitted to government or other 
health research databases or shared with researchers, government agencies, 
companies, or other groups that are not participating in this study.  These data may be 
combined with or linked to other data and used for research purposes, to advance 
science and public health, or for analysis, development, and commercialization of 
products to treat and diagnose disease.  In addition, redacted Clinical Study Reports and 
other summary reports will be provided upon request.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Roche policy on study data publication. 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
16. 
STUDY DISCONTINUATION 
Both Roche and the investigator reserve the right to terminate the study at the 
Investigator’s site at any time.  Should this be necessary, Roche or a specified designee 
will inform the appropriate regulatory authorities of the termination of the study and the 
reasons for its termination, and the Investigator will inform the IRB/IEC of the same. In 
terminating the study, Roche and the Principal Investigator will assure that adequate 
consideration is given to the protection of the patients’ interests. 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Study sites will be 
closed upon study completion.  A study site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 


 
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The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for Good Clinical Practice 
• 
Inadequate recruitment of patients by the investigator 
• 
Discontinuation of further study treatment development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigator shall promptly 
inform the patients and should ensure appropriate patient therapy and/or follow-up. 
17. 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. In the event of a data security breach, appropriate mitigation measures will be 
implemented.   
All information generated in this study is considered confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Roche.  However, authorized regulatory officials, IRB/IEC 
personnel, Roche and its authorized representatives are allowed full access to the 
records. 
Identification of patients and eCRFs shall be by initials (when permitted) and screening 
and treatment numbers only.  Any patient records or datasets that are transferred to the 
Sponsor will contain the identifier only; the patient's name or any information that would 
make the patient identifiable will not be transferred. 
Patients must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to patients, who will be required to give consent for their data to be used as 
described in the Informed Consent Form. 
Patients must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 


 
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18. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. 
The European Organization for Research and Treatment of Cancer QLQ-C30: a 
quality-of-life instrument for use in international clinical trials in oncology. J Natl 
Cancer Inst 1993;85(5):365−76. 
Ballerini P, Struski S, Cresson C, Prade N, Toujani S, Deswarte C, et al. RET fusion 
genes are associated with chronic myelomonocytic leukemia and enhance 
monocytic differentiation. Leukemia 2012;26(11):2384−9. 
Borrello MG, Ardini E, Locati LD, Greco A, Licitra L, and Pierotti MA. RET inhibition: 
implications in cancer therapy. Expert Opin Ther Targets 2013;17(4):403−19. 
Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in 
radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid 
cancer: a randomised, double-blind, phase 3 trial. Lancet 2014;384(9940):319−28. 
Brown AP, Courtney CL, King LM, Groom SC, Graziano MJ. Cartilage dysplasia and 
tissue mineralization in the rat following administration of a FGF receptor tyrosine 
kinase inhibitor. Toxicol Pathol 2005;33(4):449−55. 
Broxmeyer HE. Erythropoietin: multiple targets, actions, and modifying influences for 
biological and clinical consideration. J Exp Med. 2013;210(2):205−8. 
Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, et al. Disease 
associated mutations at valine 804 in the RET receptor tyrosine kinase confer 
resistance to selective kinase inhibitors. Oncogene 2004;23(36):6056−63. 
Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. 
Nat Rev Clin Oncol 2009;6(8):465−77. 
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of 
pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 
2008;26(16):2767−78. 
CTFG. Recommendations related to contraception and pregnancy testing in clinical 
trials. Clinical Trials Facilitation Group, 
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About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, Felip E, et al. Genomic 
aberrations in the FGFR pathway: opportunities for targeted therapies in solid 
tumors. Ann Oncol 2014;25(3):552−63. 
Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from 
evolving preclinical and clinical landscapes. Nat Rev Clin Oncol 2018;15(3): 
151−67. 
Fagin JA, and Wells SA, Jr. Biologic and clinical perspectives on thyroid cancer. N Engl 
J Med 2016;375(11):1054−67. 


 
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FDA 2016 
Drug development and drug interactions: table of substrates, inhibitors, 
and inducers. [Online], 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/dr
uginteractionslabeling/ucm093664.htm. 
Fletcher AM, Bregman CL, Woicke J, Salcedo TW, Zidell RH, Janke HE, et al. Incisor 
degeneration in rats induced by vascular endothelial growth factor/fibroblast 
growth factor receptor tyrosine kinase inhibition. Toxicol Pathol 2010;38(2): 
267−79. 
Gavreto (pralsetinib) E.U. Product Information [resource available on the internet]. 
Available at: 
https://www.ema.europa.eu/en/documents/assessment-report/gavreto-epar-public-
assessment-report_en.pdf [Cited: 17 March 2021]. 
Gavreto (pralsetinib) U.S. Prescribing Information [resource available on the internet]. 
Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213721s000lbl.pdf. 
[Cited: 17 March 2021]. 
Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, et al. Targeting RET in 
patients with RET-rearranged lung cancers: results from the global, multicenter 
RET tegistry. J Clin Oncol 2017;35(13):1403−10. 
Horiike A, Takeuchi K, Uenami T, Kawano Y, Tanimoto A, Kaburaki K, et al. Sorafenib 
treatment for patients with RET fusion-positive non-small cell lung cancer. Lung 
Cancer 2016;93:43−6. 
Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al. 
Management of febrile neutropaenia: ESMO clinical practice guidelines. Ann Oncol 
2016;27(Suppl 5):v111−8. 
Lin C, Wang S, Xie W, Chang J, Gan Y. The RET fusion gene and its correlation with 
demographic and clinicopathological features of non-small cell lung cancer: a 
meta-analysis. Cancer Biol Ther 2015;16(7):1019−28. 
Lin JJ, Kennedy E, Sequist LV, Brastianos PK, Goodwin KE, Stevens S, et al. Clinical 
activity of alectinib in advanced RET-rearranged non-small cell lung cancer. 
J Thorac Oncol 2016;11(11):2027−32. 
Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. J Royal Stat 
Soc: Series C (Applied Statistics) 2015;64(3):507−23. 
Medico E, Russo M, Picco G, Cancelliere C, Valtorta E, Corti G, et al. The molecular 
landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. 
Nat Commun 2015;6:7002. 
Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 
2014;14(3):173−86. 


 
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Nakashima M, Takamura N, Namba H, Saenko V, Meirmanov S, Matsumoto N, et al. 
RET oncogene amplification in thyroid cancer: correlations with 
radiation-associated and high-grade malignancy. Hum Pathol. 2007;38(4):621−8. 
NCCN. NCCN Guidelines®. 2018. Fort Washington, PA: National Comprehensive 
Cancer Network. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol 1982;5(6):649−55. 
Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al. Jak2 is 
essential for signaling through a variety of cytokine receptors. Cell 1998;93(3): 
385−95. 
Patyna S, Arrigoni C, Terron A, Kim T-W, Heward JK, Vonderfecht SL, et al. Nonclinical 
safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and 
RET receptors. Toxicol Pathol 2008;36(7):905−16. 
Platt A, Morten J, Ji Q, Elvin P, Womack C, Su X, et al. A retrospective analysis of RET 
translocation, gene copy number gain and expression in NSCLC patients treated 
with vandetanib in four randomized Phase III studies. BMC Cancer 2015;15:171. 
Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, et al. JAK2 associates 
with the beta c chain of the receptor for granulocyte-macrophage colony-
stimulating factor, and its activation requires the membrane-proximal region. Mol 
Cell Biol 1994;14(7):4335−41. 
Retsevmo (selpercatinib) E.U. Product Information [resource available on the internet]. 
Available at: 
https://www.ema.europa.eu/en/documents/product-information/retsevmo-epar-
product-information_en.pdf [Cited: 17 March 2021]. 
Retevmo (selpercatinib) U.S. Prescribing Information [resource available on the 
internet]. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf. 
[Cited: 17 March 2021]. 
Romei C, Ciampi R, Casella F, Tacito A, Torregrossa L, Ugolini C, et al. RET mutation 
heterogeneity in primary advanced medullary thyroid cancers and their 
metastases. Oncotarget 2018;9(11):9875−84. 
Romei C, Ciampi R, and Elisei R. A comprehensive overview of the role of the RET 
proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 2016;12(4):192−202. 
SEER 2018 Surveillance, Epidemiology, and End Results Program. National Cancer 
Institute, https://seer.cancer.gov/. 
Springuel L, Renauld JC, Knoops L. JAK kinase targeting in hematologic malignancies: 
a sinuous pathway from identification of genetic alterations towards clinical 
indications. Haematologica 2015;100(10):1240−53. 


 
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Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions 
in cancer. Nat Commun 2014;5:4846. 
Wells SA, Jr., Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American 
Thyroid Association guidelines for the management of medullary thyroid 
carcinoma. Thyroid 2015;25(6):567−610. 
Yang HS, and Horten B. Gain of copy number and amplification of the RET gene in lung 
cancer. Exp Mol Pathol 2014;97(3):465−9. 
Yanochko GM, Vitsky A, Heyen JR, Hirakawa B, Lam JL, May J, et al. Pan-FGFR 
inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and 
cardiovascular dysfunction. Toxicol Sci 2013;135(2):451−64. 


 
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19. 
APPENDICES 
19.1 
APPENDIX 1: EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Symptomatology 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care.  Totally confined to bed 
or chair 
5 
Dead 
Source: (Oken et al. 1982). 
 


 
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19.2 
APPENDIX 2: LIST OF PROHIBITED MEDICATIONS AND FOOD 
Strong Inhibitors of CYP3A4 
Strong Inducers of CYP3A4 
Boceprevir 
Apalutamide 
Conivaptan 
Carbamazepine 
Danoprevir and ritonavir 
Mitotane 
Elvitegravir and ritonavir  
Phenytoin 
Grapefruit, Grapefruit juice 
Rifampin 
Idelalisib 
St. John’s wort 
Indinavir and ritonavir 
 
Ketoconazole  
 
Nefazodone 
 
Ombitasvir and Dasabuvir 
 
Posaconazole 
 
Paritaprevir and ritonavir 
 
Ribociclib 
 
Telithromycin 
 
Troleandomycin 
 
Voriconazole 
 
Combined  P-gp and Strong CYP3A4 inhibitors: 
Clarithromycin 
Nelfinavir 
Cobicistat 
Ritonavir 
Mifebradil 
Saquinavir and ritonavir 
Itraconazole 
Telaprevir 
Lopinavir and ritonavir 
Tipranavir and ritonavir 
P-gp = P-glycoprotein. 
Note:  This list is not intended to be exhaustive.  A similar restriction will apply to other drugs that 
fall in these categories; appropriate medical judgment is required.  Please contact Roche with 
any queries relating to this issue. 
Source:  U.S. Food and Drug Administration 2015. 
 
REFERENCE 
U.S. Food and Drug Administration. Drug development and drug interactions: table of 
substrates, inhibitors, and inducers [resource available on the internet]. Available 
from:  
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/dr
uginteractionslabeling/ucm093664.htm. 


 
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19.3 
APPENDIX 3: LIST OF MEDICATIONS AND FOOD TO BE USED WITH CAUTION 
Sensitive CYP3A4 
Substrates 
Sensitive 
CYP2C9 
Substrates 
Sensitive 
CYP2C8 
Substrates 
Sensitive  
P-gp 
Substrates 
Sensitive P-gp 
Substrates 
Sensitive 
OATP1B1, 
OATP1B3 
Substrates 
Sensitive 
OAT1 
Substrates 
Sensitive MATE1, 
MATE2-K Substrates 
Alfentanil 
Warfarin 
with INR 
monitoring 
Repaglinide 
Digoxin 
2-amino-1-methyl-
6-
phenylimidazo[4,5-
b]pyridine (PhIP) 
Cholecysto- 
kininoctapeptide 
(CCK-8) 
Adefovir 
Metformin 
Cyclosporine 
Celecoxib 
 
Fexofenadine 
Coumestrol 
Estradiol-17β-
glucuronide 
p-
aminohippurate 
1-methyl-4-
phenylpyridinium 
(MPP+) 
Dihydroergotamine 
 
 
Loperamide 
Daidzein 
Estrone-3-sulfate 
Cidofovir 
Tetraethylammonium 
(TEA) 
Ergotamine 
 
 
Quinidine 
Dantrolene 
Pitavastatin 
Tenofovir 
 
Fentanyl 
 
 
Talinolol 
Estrone-3-sulfate 
Pravastatin 
 
 
Midazolam 
 
 
Vinblastine 
Genistein 
Telmisartan 
 
 
Pimozide 
 
 
 
Prazosin 
Rosuvastatin 
 
 
Quinidine 
 
 
 
Sulfasalazine 
 
 
 
Simvastatin 
 
 
 
 
 
 
 
Sirolimus 
 
 
 
 
 
 
 
Tacrolimus 
 
 
 
 
 
 
 
Terfenadine 
 
 
 
 
 
 
 
Source: (FDA, 2016)  
Note:  This list is not intended to be exhaustive.  A similar restriction will apply to other drugs that fall in these categories; appropriate medical 
judgment is required. Please contact Roche with any queries relating to this issue. 


 
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19.4 
APPENDIX 4: OPERATING CHARACTERISTICS OF THE BOIN DESIGN 
OPERATING CHARACTERISTICS OF THE BOIN DESIGN 
0 
Dose Level 
Number of 
Patients 
% Early 
Stopping 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Scenario 1 
True DLT rate 
0.02 
0.30 
0.90 
0.99 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
18.80 
0.0 
Selection % 
13.2 
86.8 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
# Pts Treated 
5.5 
11.2 
2.1 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
Scenario 2 
True DLT rate 
0.02 
0.09 
0.30 
0.66 
0.90 
0.98 
0.99 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
23.24 
0.0 
Selection % 
0.2 
19.1 
77.5 
3.1 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
# Pts Treated 
3.3 
6.2 
10.4 
3.2 
0.1 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
Scenario 3 
True DLT rate 
0.02 
0.05 
0.13 
0.30 
0.54 
0.77 
0.90 
0.96 
0.99 
0.99 
1.00 
1.00 
1.00 
27.07 
0.0 
Selection % 
0.1 
1.4 
24.2 
63.8 
10.5 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
# Pts Treated 
3.2 
3.8 
6.6 
9.3 
3.9 
0.3 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
Scenario_4 


 
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True DLT rate 
0.02 
0.04 
0.09 
0.17 
0.30 
0.48 
0.66 
0.81 
0.90 
0.95 
0.98 
0.99 
0.99 
30.50 
0.0 
Selection % 
0.1 
0.5 
5.4 
28.4 
50.9 
14.4 
0.4 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
# Pts Treated 
3.2 
3.5 
4.6 
6.8 
7.9 
3.9 
0.6 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
Scenario_5 
True DLT rate 
0.02 
0.04 
0.06 
0.11 
0.19 
0.30 
0.44 
0.59 
0.73 
0.83 
0.90 
0.94 
0.97 
33.89 
0.0 
Selection % 
0.1 
0.4 
1.4 
8.4 
29.4 
42.5 
16.7 
1.2 
0.0 
0.0 
0.0 
0.0 
0.0 
# Pts Treated 
3.2 
3.4 
3.8 
4.9 
6.8 
7.1 
3.8 
0.8 
0.1 
0.0 
0.0 
0.0 
0.0 
Scenario_6 
True DLT rate 
0.02 
0.03 
0.05 
0.09 
0.13 
0.21 
0.30 
0.42 
0.54 
0.66 
0.77 
0.84 
0.90 
36.93 
0.0 
Selection % 
0.0 
0.2 
0.8 
3.7 
11.9 
29.5 
35.8 
15.9 
2.1 
0.1 
0.0 
0.0 
0.0 
# Pts Treated 
3.2 
3.3 
3.6 
4.3 
5.3 
6.6 
6.2 
3.4 
0.9 
0.1 
0.0 
0.0 
0.0 
Scenario_7 
True DLT rate 
0.02 
0.03 
0.05 
0.07 
0.10 
0.15 
0.22 
0.30 
0.40 
0.51 
0.61 
0.71 
0.79 
40.06 
0.0 
Selection % 
0.0 
0.2 
0.6 
1.8 
5.2 
14.8 
28.3 
30.6 
15.4 
2.8 
0.2 
0.0 
0.0 
# Pts Treated 
3.2 
3.3 
3.6 
3.9 
4.5 
5.5 
6.3 
5.6 
3.2 
1.0 
0.1 
0.0 
0.0 
Scenario_8 
True DLT rate 
0.02 
0.03 
0.04 
0.06 
0.09 
0.12 
0.17 
0.23 
0.30 
0.39 
0.48 
0.57 
0.66 
42.89 
0.0 


 
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BOIN =  Bayesian optimal interval, DLT = dose-limiting toxicity, pts = patients 
 
Selection % 
0.1 
0.1 
0.4 
1.2 
3.4 
7.8 
17.0 
26.3 
26.6 
13.7 
3.2 
0.3 
0.0 
# Pts Treated 
3.2 
3.3 
3.5 
3.7 
4.2 
4.8 
5.5 
5.8 
4.9 
2.8 
0.9 
0.2 
0.0 
Scenario_9 
True DLT rate 
0.02 
0.03 
0.04 
0.05 
0.07 
0.10 
0.13 
0.18 
0.23 
0.30 
0.38 
0.46 
0.54 
45.95 
0.0 
Selection % 
0.0 
0.2 
0.3 
0.6 
1.8 
4.4 
9.5 
17.4 
24.5 
24.2 
13.1 
3.7 
0.5 
# Pts Treated 
3.2 
3.3 
3.4 
3.6 
3.9 
4.3 
4.9 
5.4 
5.5 
4.6 
2.7 
1.0 
0.2 
Scenario_10 
True DLT rate 
0.02 
0.03 
0.04 
0.05 
0.06 
0.09 
0.11 
0.15 
0.19 
0.24 
0.30 
0.37 
0.44 
48.47 
0.0 
Selection % 
0.0 
0.1 
0.3 
0.6 
1.2 
3.1 
5.8 
11.7 
17.9 
22.6 
20.6 
11.6 
4.3 
# Pts Treated 
3.2 
3.3 
3.4 
3.6 
3.7 
4.1 
4.5 
5.0 
5.2 
5.0 
4.0 
2.4 
1.0 


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19.5 
APPENDIX 5: PREVIOUS PROTOCOL AMENDMENTS 
AMENDMENT 14 RATIONALE
This amendment updates and supersedes Global Protocol BLU-667-1101 Amendment 
13 dated 28 March 2022. 
Major changes include the following: 
•
Marketing approval status of RET (rearranged during transfection) -inhibitors for 
the treatment of RET-altered thyroid cancer and non-small cell lung carcinoma was 
updated.
•
Safety information for pralsetinib has been updated to align with Pralsetinib 
Investigator’s Brochure, Version 6.
•
A benefit‑risk assessment and guidance on concomitant administration of 
coronavirus 2019 vaccines with pralsetinib has been added.
•
The responsibilities of the investigator and the role of the Medical Monitor in 
determining patient eligibility and during study conduct have been clarified.
•
End of study and duration of patient participation have been added.
•
Detail provided regarding reporting of serious adverse events and reference safety 
information document.
•
Medical monitor and emergency contact numbers were added.
•
Operational information has been added to align with internal Roche processes.
•
The list of prohibited medications has been updated.
AMENDMENT 13 RATIONALE 
This amendment updates and supersedes Global Protocol BLU-667-1101 Amendment 9 
dated 3 July 2019 
Major changes include the following: 
•
Group 5:  To more accurately characterize the activity of pralsetinib across various
RET fusion-positive solid tumor types, the sample size of Group 5 has increased
from N ~ 40 to N ~ 100 patients. (Increasing the study's total sample size to
647 patients). As the intent of this cohort is to enroll a variety of RET-fusion tumor
types, it is also clarified that Blueprint will notify sites if/when sufficient data are
available, and accrual should cease for a particular tumor type. Additionally, to
ensure enrollment of a population with unmet medical need, patients should have
previously received SOC appropriate for their tumor type, unless there is no
accepted standard therapy for the tumor type, or the Investigator has determined
that treatment with standard therapy is not appropriate. Finally, given the primary
endpoint of ORR, it is now required that subjects in Group 5 must have at least
1 target lesion evaluable by RECIST v1.1.


 
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• 
Phase 2 secondary objective in NSCLC patients and exploratory objective in 
patients with tumor types other than NSCLC have been updated to assess brain 
metastases activity in patients with measurable (target by RECIST v1.1) lesions in 
the brain by blinded independent central review (brain metastases sub-population) 
and assess the time to intracranial progression in all patients. 
• 
An additional analysis population, the RET-altered Measurable Disease Population, 
has been added to provide an assessment of the activity of pralsetinib in 
a mechanistically-relevant population. New language clarifies that this will be the 
primary analysis population for ORR, DOR, CBR and DCR, while the remaining 
efficacy endpoints will be examined using the Efficacy Population. 
• 
Subgroup analyses will be completed for Groups 2, consisting of: 1) patients 
enrolled prior to Protocol Amendment 9 (who were not candidates for standard 
therapies and thus may have had a poor prognosis) and 2) those enrolled on or 
after Protocol Amendment 9 (possibly a more typical first-line population).  This will 
allow examination of the activity of pralsetinib in more typical first-line populations of 
patients with NSCLC. 
• 
Pharmacodynamic parameters of pralsetinib will include changes in tumor/blood 
including, but not limited to, changes in blood calcitonin and CEA and biochemical 
response rate (MTC patients only). 
• 
Group 2: The primary intent of this cohort is to assess the activity of pralsetinib in 
the treatment-naïve patients with NSCLC; therefore, text was added to clarify that 
this group will include no more than 30 patients with prior systemic therapy. 
• 
Updated study visit frequency after Cycle 17. All study visits after Cycle 17 will occur 
at every 4 cycles (16 weeks) (e.g. Cycle 21, Cycle 25…_); study visit frequency and 
imaging was aligned within the Schedule of Assessments table. 
• 
Adjusted pralsetinib dose modification recommendations for treatment-related 
Grade 1 and Grade 2 pneumonitis. 
 
Minor changes include the following: 
• 
Name of the investigational product updated from BLU-667 to pralsetinib. 
• 
Updated background information for consistency with IB version 4.0 updates along 
with updated efficacy, PK, and safety data from interim analyses. 
• 
Deleted text to clarify the role of IDMC; IDMC review of study progress does not 
include primary efficacy outcomes. 
• 
Updated the Schedule of Assessments footnote “s” and the Schedule for PK 
Sample Collection footnote “g” to specify that Cycle1 Days 2 and 16 will only be for 
~12 patients in Groups 8 and 9 enrolled under Protocol Amendment 10. The overall 
number of patients for serial PK changed from 60 to 72. 


 
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• 
Incorporated major revisions to China-specific amendments (10 and 12). The 
updates to protocol amendment 13 include the addition of Groups 8 and 9, updates 
to the serum chemistry test panel to assess either bicarbonate (venous) or CO2 
level in blood, and updates to the urinalysis test panel updated to assess either 
leukocyte esterase or white blood cells. These changes are applicable only for 
patients in China. 
 
AMENDMENT 12 RATIONALE 
Protocol Amendment 12 was made for all investigative sites in China. Protocol 
Amendment 12 is not active outside of China. This amendment updates and supersedes 
Protocol BLU-667-1101 Amendment 10 dated 26 July 2019. 
• 
Allowed inclusion of patients in Group 9 who received prior radiotherapy, surgery, or 
systemic cytotoxic chemotherapy. 
• 
Updated contact information for reporting of serious adverse events 
Allowed white blood cells to be evaluated instead of leukocyte esterase in the urinalysis 
(dipstick) test for sites in China. 
• 
Corrected formatting, grammatical, and typos. 
 
AMENDMENT 11 RATIONALE 
This amendment updates and supersedes Global Protocol BLU-667-1101 Amendment 9 
dated 3 July 2019 for all investigative sites in France. This protocol amendment is not 
active outside of France. The following changes were made to address feedback from 
the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). 
• 
Clarified typographical errors in section 6.4.2 (concomitant therapy to be used with 
caution) introduced in Protocol Amendment 9 (3 July 2019) 
• 
Clarified that Group 4 (medullary thyroid cancer patients that do not have a RET 
mutation) will not be enrolled in the BLU-667-1101 clinical trial in France 
 
Details of all changes are presented in the “Protocol Amendment – Summary of 
Changes” document dated 23 September 2019. 
AMENDMENT 10 RATIONALE 
Amendment 10 was made for all investigative sites in China. Protocol Amendment 10 is 
not active outside of China. This amendment updates and supersedes Protocol BLU-
667-1101 Amendment 8 dated 20 December 2018. The changes were made in 
reference to Global Protocol BLU-667-1101 Amendment 9. 
AMENDMENT 9 RATIONALE 
This amendment updates and supersedes Global Protocol BLU-667-1101 Amendment 7 
dated 12 December 2018. 


 
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Major changes include the following: 
• 
The study phase was updated from a Phase 1 to a Phase 1/2 to better describe the 
study design with the increased patient population and hypothesis testing. 
– 
Throughout the protocol, Part 1 and Part 2 have been replaced with Phase 1 
and Phase 2, respectively. 
• 
Due to the encouraging initial data in treatment naïve RET fusion-positive NSCLC 
patients, the Phase 2, Group 2 sample size was increased to 200 patients to allow 
for enrollment of treatment naïve RET fusion-positive NSCLC patients (increasing 
the study's total sample size to 527 patients). 
– 
The enrollment for this group has been increased to provide >90% power to test 
the efficacy hypothesis as described in Section 11.3.2 in treatment-naïve RET 
fusion−positive NSCLC patients. 
– 
Inclusion criteria 3 and 4 were edited to allow for treatment naïve patients in 
Group 2. 
• 
Exclusion criteria 7 was edited to clarify that patients who have received previous 
immunotherapy or other antibody therapy cannot be started on BLU-667 within the 
defined washout of 28 days. 
• 
A Phase 2 independent data safety monitoring committee (Section 12.2.2) is 
replacing the Phase 2 Safety Review Committee (Section 12.2.1) to account for the 
increased number of patients in the study. 
• 
To help alleviate patient burden, Cycle 1 Days 2 and 16 were removed as serial PKs 
are no longer required. 
• 
Stopping rules were updated to account for increased sample size and move out of 
the body of the protocol to Appendix 7. 
• 
Dose modification for Grade 3 or worse pneumonitis was modified in Table 8 for 
additional safety measures that patients should be permanently discontinued from 
study treatment, unless the Investigator discusses with the Sponsor and believes 
the risk-benefit justifies retreatment. 
• 
The statistics section (Section 11) was updated to align with the statistical analysis 
plan for the study. Following changes were made: 
– 
Provided justification for increased sample size 
– 
Aligned analysis population definitions with study objectives/endpoints 
– 
Swimmer plots to display tumor burden over time and Spider plots to display 
tumor reduction will not be produced 
– 
Clarified that Patients enrolled in Phase 1 and treated at the RP2D will be 
pooled together with the appropriate Part 2 group patients for analyses. 
– 
Predefined 95% Confidence Intervals of ORR were updated based on increased 
sample size 


 
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Other minor updates include the following: 
• 
Clarified in Section 5.5 that screen failure patients need to be entered into the 
clinical database. 
• 
RET pre-screening in Section 7.1 was updated to remove the central laboratory for 
RET pre-screening as all investigational sites will use local methods. 
• 
Details regarding OS follow-up were included in Sections 5.6.2, 6.7, 7.9. 
AMENDMENT 8 RATIONALE 
Amendment 8 was made for all investigative sites in China. Protocol Amendment 8 is not 
active outside of China. 
AMENDMENT 7 RATIONALE 
This amendment updates and supersedes Global Protocol BLU-667-1101 Amendment 
4.1 dated 25 July 2018, Republic of Korea Protocol Amendment 5 dated 25 July 2018, 
and France Protocol Amendment 6 dated 27 August 2018. 
Major changes include the following: 
• 
The Part 2, dose expansion group definitions were adjusted to better account for 
current approved standard of care agents. 
– 
The study schema showing the adjustments to the Part 2 dose expansion 
groupings is found in the study schematic in the protocol synopsis and in the 
Study Plan (Section 4). Briefly, the non-small cell lung cancer (NSCLC) groups 
(Groups 1 and 2) were updated to reflect previous treatment with a regimen that 
contained platinum chemotherapy versus a multi-kinase inhibitor (MKI). The 
medullary thyroid cancer (MTC) groups (Groups 3 and 4) were updated to 
reflect previous treatment with one of the approved MKIs (cabozatinib and/or 
vandetanib) and not any MKI. Finally, the previous other RET-altered solid 
tumor group (former Group 5) was split into 2 separate groups: rearranged 
during transfection (RET) fusions (new Group 5) or RET mutations (new 
Group 7). This was done in recognition that solid tumor patients with RET-
fusions and RET-mutations may be distinct clinical and/or regulatory 
populations. 
– 
The overall enrollment for Part 2 (Dose Expansion) has been increased to 
provide >95% power in Groups 1 and 3, >90% power in Group 5, and ~68% 
power in Group 2 to test the efficacy hypothesis for each group as described in 
Section 11.3.2. The goal of each of the Part 2 groups remains to evaluate the 
safety, efficacy, and pharmacokinetics (PK) of BLU-667 in RET-altered patients 
treated at the maximum tolerated dose (MTD)/recommended Phase 2 dose 
(RP2D) in various patient populations. Specifically, the study rationale and 
design have been updated (Section 1.3); the study’s objectives (Section 2) and 
endpoints (Section 3) have been edited and split into Part 1 and Part 2 
sub‑sections for clarity and additional text has been added to justify the number 
of patients needed to test the efficacy hypothesis and the detection of adverse 
events (Section 11.3.2). 


 
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 
For additional safety precautions the following exclusion criteria were added/edited: 
added exclusion criterion 2g for patients with Grade 2 or higher serum phosphorous 
at baseline; added an exclusion criterion 6 to exclude patients with the presence of 
clinically significant interstitial lung disease or interstitial pneumonitis; and clarified 
the washout period for immunotherapy or other antibody therapy should be 28 days 
in exclusion criterion 7. 
 
Divided the dose and administration section (Section 6.3) into subsections that 
apply to Part 1 (Dose Escalation) and those that apply to Part 2 (Expansion) to 
provide additional detail and guidance on adverse event management and dose 
adjustments in Part 2 of the study. 
– 
In the dosing for Part 2 (Section 6.3.2) section edited and clarified the 
instructions for dosing and dose interruptions (Section 6.3.2.2), added dose 
modification tables for hematologic and non-hematologic adverse events 
(Table 7), and added dose modifications and management recommendations 
for specific treatment-related adverse events such as pneumonitis (Section 
6.3.2.3.1), pneumonia/lung infections (Section 6.3.2.3.2), tumor lysis syndrome 
(Section 6.3.2.3.3), hyperphosphatemia (Section 6.3.2.3.4), and hypertension 
(Section 6.3.2.3.5). 
 
Made it clear that dose re-escalation after dose modification for adverse events is 
discouraged; however, clarified under what conditions it might be considered 
appropriate to re-escalate a patient’s dose (no higher than the starting dose), after 
resolution of adverse events (Section 6.3.2.2) 
 
Created an additional Safety Review Committee (SRC) for Part 2 of the study and 
added a section to describe its membership and purpose (Section 12.2.2). 
Minor changes include the following: 
 
Incorporated the updated Part 2 Groups re-organization (inclusion criterion 3); 
clarified that all patients must have been treated with prior standard therapy unless 
the Investigator has determined that treatment with standard therapy is not 
appropriate (inclusion criterion 4); clarified that groups 1, 2, 3, 4, and 6 need to have 
measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 at baseline, but it is not required for Groups 5 and 7 (inclusion criterion 5). 
 
Updated Section 1.5 to include updated safety and efficacy data from the earlier part 
of the trial. 
 
Added sections to clarify RET Prescreening (Section 5.4 and Section 7.1) 
 
Updated the early stopping rule table (Appendix 8) to reflect the larger sample size 
 
Updated footnote “a” in the Schedule of Assessments (Section 6.7, Table 10) to 
indicate that certain labs and the physical exam required on C1D1 may be 
performed on D-1. 
 
Added a clarification that during screening and on study during physical exam 
assessments, MTC patients should be asked and have recorded information on 
bowel movements (Section 7.2 and 7.3.1). 


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•
Added that immediate release tablets of BLU-667 may be used during the trial, if
and when they become available (Section 8.1.1 and 8.1.2) and updated packaging
information (Section 8.2).
•
Clarified the definition of Response-Evaluable (RE) population (Section 11.2)
•
Moved medications that are sensitive CYP2C9 substrates with Narrow Therapeutic
Index’s such as Warfarin from the list of prohibited medications (Section 19.2
Appendix 2) to the list of Medications to be used with Caution (Section 19.3
Appendix 3).
•
Corrected formatting, grammatical, and typo corrections.
Details of the changes are presented in the “Protocol Amendment – Summary of
changes” document dated 12 December 2018
AMENDMENT 6 RATIONALE
Amendment 6 was made for all investigative sites in France. Protocol Amendment 6 is
not active outside of France.
AMENDMENT 5 RATIONALE
Amendment 5 was made for all investigative sites in the Republic of Korea. Protocol
Amendment 5 is not active outside of the Republic of Korea.
AMENDMENT 4.1 RATIONALE
This amendment updates and supersedes Global Protocol BLU-667-1101 Amendment 2
dated 02 February 2018 and Republic of Korea Protocol Amendment 3 dated
08 February 2018.
The amended protocol includes 2 major changes as follows:
•
First, based on the favorable tolerability and encouraging efficacy observed in Part 1
(dose escalation), the sample size of Part 2 (dose expansion) has been increased.
–
A summary of Part 1 including determination of the maximum tolerated dose
(MTD), overall safety, and preliminary efficacy for the dose escalation has been
added - see Section 1.5.
–
The overall enrollment for Part 2 (dose expansion) has been increased to
further evaluate the safety, efficacy, and pharmacokinetics (PK) of BLU-667 in
rearranged during transfection (RET)-altered patients treated at the
MTD/recommended Phase 2 dose (RP2D). Specifically, the study rationale and
design has been updated (Section 1.3); the stopping rules for potential drug-
related toxicity have been updated (Section 6.2.1); a primary efficacy
objective/endpoint and corresponding statistics have been added for Part 2 to
evaluate the overall response rate (ORR) in all RET-altered patients treated at
the MTD/RP2D (Section 2.1, Section 3.1.1, and Section 11.4); additional text
has been added to justify the number of patients needed to test the efficacy
hypothesis and detection of adverse events (Section 11.3.2).


 
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– 
Based on the observed efficacy in dose escalation, exploratory objectives 
regarding assessment of additional measures of clinical benefit (e.g., PFS, OS) 
and correlation of antitumor activity with RET gene status have been moved 
from exploratory objectives to secondary objectives. 
• 
Second, an expansion group has been added to assess BLU-667 safety and 
efficacy in patients previously treated with a selective RET inhibitor (Group 6). This 
is reflected in the updated study design (Section 4.1.2) and entry criteria 
(Section 5.2). In addition, the medullary thyroid cancer (MTC) expansion group has 
been split into 2: the first (Group 3) including patients with MTC previously treated 
with a multikinase inhibitor (MKI) and the second (Group 4) including patients with 
MTC not previously treated with an MKI. 
Minor changes include the following: 
• 
Section 1.2 was updated to include biochemical activity of vascular endothelial 
growth factor receptor (VEGFR) inhibition observed biochemically in MKIs as 
compared to BLU-667. 
• 
Section 1.3, Section 4.1.1, and Section 6 were revised to reflect the MTD/RP2D as 
well as the completion of Part 1. 
• 
Since a clear efficacy signal was observed in the Part 1 dose escalation, the 
secondary objectives/endpoints were updated to include the assessment of 
additional measurements of clinical benefit (e.g., duration of response [DOR], 
disease control rate [DCR], progression-free survival [PFS], and overall survival 
[OS]) and determination of potential correlations between measures of clinical 
benefit and RET gene status in plasma and tumor tissue (Section 2.1.2). 
• 
Entry criteria (Section 5) were revised to clarify oncogenic RET alterations required 
for Part 2 enrollment. An appendix was added to list common oncogenic RET 
alterations (Appendix 6). 
• 
Intra-patient dose escalation criteria were revised based on the observed 
reversibility of adverse events (AE) and overall favorable tolerability of BLU-667. 
Specifically, to achieve higher BLU-667 exposure, which may enhance the 
possibility of antitumor activity, Investigator may re-escalate to a higher dose level (≤ 
MTD) after AE resolution (Section 6.3.1.3). 
• 
The schedule of assessments (Section 6.6) was updated to limit serial PK sampling 
and remove the on-treatment biopsy for Part 2 patients, to include the quality of life 
(QoL) questionnaire administration, and to add the mandatory pretreatment biopsy 
for Part 2, Group 6 patients. 
• 
Section 7.1 was updated to reflect the changes to required screening assessments 
• 
Section 7.5 was updated to reflect the changes made to biopsy requirements in 
Part 2. 
• 
Section 7.6 was revised to clarify baseline screening scans and later timepoints. 


 
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• 
As some patients have reported subjective improvement in cancer-related 
symptoms (e.g., diarrhea), Section 7.7 (patient-reported outcomes) was added to 
reflect the exploratory objective of QoL assessment measures for Part 2 patients to 
assess potential improvements in patient symptoms. 
 
Details of the changes are presented in the “Protocol Amendment – Summary of 
changes” document dated 25 July 2018. 
AMENDMENT 3 RATIONALE 
Amendment 3 was made for all investigative sites in the Republic of Korea. Protocol 
Amendment 3 is not active outside of the Republic of Korea. 
AMENDMENT 2 RATIONALE 
This amendment updates and supersedes Protocol BLU-667-1101 Amendment 1.0 
dated 09 January 2017, as follows: 
• 
Section 1.4, Rationale for the Starting Dose and Dosing Regimen; Section 4.1.1, 
Part 1 (Dose-escalation); and Section 6.3, Dose and Administration were updated to 
clarify language regarding implementation of twice daily (BID) dose escalation to 
occur in parallel with QD dose escalation 
• 
Language in the footnote of Table 11 describing electrocardiogram (ECG) 
monitoring was updated to clarify that all patients should have a single 12-lead ECG 
for adverse event (AE) monitoring, regardless of participation in Holter monitoring 
• 
As BLU-667-1101 is a global trial, the following changes were made to address 
feedback from the French National Agency for Medicines and Health Products 
Safety (ANSM): 
– 
Exclusion criterion 1 was revised to exclude non-small cell lung cancer 
(NSCLC) patients with known BRAF mutations 
– 
Exclusion criterion 6 was revised to remove “whichever is shorter” regarding the 
washout requirements for prior anticancer therapy 
– 
Table 5 symbols were updated to reflect ≤ or ≥ 
– 
Pregnancy testing was increased from bimonthly to monthly in order to detect 
any early pregnancy while on study. Updates were reflected in both Table 10: 
Schedule of Assessments and Section 7.3.5 Clinical Laboratory Tests 
 
Details of the changes are presented in the “Protocol Amendment – Summary of 
changes” document dated 02 February 2018. 
AMENDMENT 1 RATIONALE 
This amendment updates and supersedes Protocol BLU-667-1101 Version 1.0 dated 
08 November 2016, as follows: 
• 
The Inclusion Criteria were updated to include only patients with non-resectable 
disease. 


 
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• 
Inclusion #6 was modified to make it clear that although the on-treatment tumor 
biopsy is strongly encouraged, it is not required, and the patient may decline the 
procedure. 
• 
The Exclusion Criteria were updated to exclude patients with NSCLC with a 
targetable mutation in EGFR, ALK, or ROS1. 
• 
In order to further protect the safety of patients, the study was updated to 
incorporate an enrollment stopping rule that terminates further enrollment to the 
study if there is an excess of permanent treatment discontinuations due to study 
drug−related adverse events. 
• 
An electrocardiogram measurement was added at Day 1 and Day 15, 4 hours 
postdose, to provide heart monitoring around the anticipated maximal plasma 
concentrations after the first dose and at steady state. 
• 
As a precaution, the list of prohibited medications was updated to include strong 
inhibitors of CYP1A2, CYP2D6, and CYP3A4, as well as inducers of CYP3A4. 
Strong dual P-gp and CYP3A4 inhibitors are also excluded. Appendices 2 and 3 
have been updated accordingly. 
 
Typographical errors were corrected, and minor administrative changes made. Details of 
the changes are presented in the “Protocol Amendment – Summary of changes” 
document dated 09 January 2017. 
 
 


 
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19.6 
APPENDIX 6: COMMON ONCOGENIC RET MUTATIONS 
COMMON ONCOGENIC RET MUTATIONS 
RET mutation 
Exon 
G533C 
8 
C609F/G/R/S/Y 
10 
C611F/G/S/Y/W 
10 
C618F/R/S 
10 
C620F/R/S 
10 
C630R/Y 
11 
D631Y 
11 
C634F/G/R/S/W/Y 
11 
K666E 
11 
E768D 
13 
L790F 
13 
V804L 
14 
V804M 
14 
A883F 
15 
S891A 
15 
R912P 
16 
M918T 
16 
Source: (Wells et al. 2015) 


 
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19.7 
APPENDIX 7: EORTC QLQ-C30 ASSESSMENT 
 


 
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19.8 
APPENDIX 8: EXAMPLES OF IMPLEMENTING THE EARLY 
STOPPING RULE 
Number of 
Patients 
Discontinued 
Number of 
Patients 
Treated 
70% Exact Binomial CI,  
One-Sided Lower Bound 
Action 
23 
140 
14.57% 
No Stop 
24 
140 
15.25% 
Stop 
25 
150 
14.87% 
No Stop 
26 
150 
15.51% 
Stop 
26 
160 
14.53% 
No Stop 
27 
160 
15.13% 
Stop 
28 
170 
14.8% 
No Stop 
29 
170 
15.36% 
Stop 
29 
180 
14.51% 
No Stop 
30 
180 
15.04% 
Stop 
31 
190 
14.75% 
No Stop 
32 
190 
15.26% 
Stop 
33 
200 
14.97% 
No Stop 
34 
200 
15.45% 
Stop 
34 
210 
14.71% 
No Stop 
35 
210 
15.17% 
Stop 
36 
220 
14.92% 
No Stop 
37 
220 
15.35% 
Stop 
37 
230 
14.68% 
No Stop 
38 
230 
15.1% 
Stop 
39 
240 
14.87% 
No Stop 
40 
240 
15.28% 
Stop 
40 
250 
14.66% 
No Stop 
41 
250 
15.05% 
Stop 
42 
260 
14.84% 
No Stop 
43 
260 
15.21% 
Stop 
43 
270 
14.64% 
No Stop 
44 
270 
15% 
No Stop 
45 
280 
14.81% 
No Stop 
46 
280 
15.16% 
Stop 
47 
290 
14.97% 
No Stop 
48 
290 
15.3% 
Stop 
48 
300 
14.79% 
No Stop 
49 
300 
15.11% 
Stop 
50 
310 
14.93% 
No Stop 
51 
310 
15.25% 
Stop 
51 
320 
14.77% 
No Stop 
52 
320 
15.07% 
Stop 


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Number of
Patients
Discontinued
Number of
Patients
Treated
70% Exact Binomial CI,
One-Sided Lower Bound
Action
53
330
14.91%
No Stop
54
330
15.2%
Stop
54
340
14.75%
No Stop
55
340
15.04%
Stop
56
350
14.88%
No Stop
57
350
15.16%
Stop
57
360
14.74%
No Stop
58
360
15.01%
Stop
59
370
14.86%
No Stop
60
370
15.13%
Stop
61
380
14.98%
No Stop
62
380
15.24%
Stop
62
390
14.85%
No Stop
63
390
15.1%
Stop
64
400
14.96%
No Stop
65
400
15.2%
Stop
65
410
14.83%
No Stop
66
410
15.07%
Stop
67
420
14.94%
No Stop
68
420
15.17%
Stop
68
430
14.82%
No Stop
69
430
15.05%
Stop
70
440
14.92%
No Stop
71
440
15.15%
Stop
71
450
14.81%
No Stop
72
450
15.02%
Stop
73
460
14.91%
No Stop
74
460
15.12%
Stop
74
470
14.8%
No Stop
75
470
15.01%
Stop
76
480
14.89%
No Stop
77
480
15.1%
Stop
78
490
14.99%
No Stop
79
490
15.19%
Stop
79
500
14.88%
No Stop
80
500
15.08%
Stop
81
510
14.97%
No Stop
82
510
15.16%
Stop
82
520
14.87%
No Stop


 
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CI = confidence interval. 
 
 
 
 
 
 
Number of 
Patients 
Discontinued 
Number of 
Patients 
Treated 
70% Exact Binomial CI,  
One-Sided Lower Bound 
Action 
83 
520 
15.06% 
Stop 
84 
530 
14.96% 
No Stop 
85 
530 
15.14% 
Stop 
85 
540 
14.86% 
No Stop 
86 
540 
15.04% 
Stop 
87 
550 
14.95% 
No Stop 
88 
550 
15.12% 
Stop 
88 
560 
14.85% 
No Stop 
89 
560 
15.03% 
Stop 
90 
570 
14.93% 
No Stop 
91 
570 
15.11% 
Stop 
92 
580 
15.01% 
Stop 
93 
590 
14.92% 
No Stop 
94 
590 
15.09% 
Stop 
95 
600 
15% 
No Stop 
96 
600 
15.16% 
Stop 
96 
610 
14.91% 
No Stop 
97 
610 
15.07% 
Stop 
98 
620 
14.99% 
No Stop 
99 
620 
15.15% 
Stop 
99 
630 
14.9% 
No Stop 
100 
630 
15.06% 
Stop 
101 
640 
14.98% 
No Stop 
102 
640 
15.13% 
Stop 
102 
650 
14.9% 
No Stop 
104 
660 
14.97% 
No Stop 
105 
660 
15.12% 
Stop 
105 
670 
14.89% 
No Stop 
106 
670 
15.03% 
Stop 


Signature Page for Protocol - BO42863 - GAVRETO - v15 - Global/Core - Published
System identifier: RIM-CLIN-460147
Approval Task
Company Signatory
01-Dec-2022 15:26:39 GMT+0000

SAP_001.pdf: 
Official Title: 
NCT Number: 
Document Date: 
A Phase 1/2 Study of the Highly-Selective RET Inhibitor, BLU-667, in 
Patients with Thyroid Cancer, Non−Small Cell Lung Cancer (NSCLC) 
and Other Advanced Solid Tumors
NCT03037385
Statistical Analysis Plan Version 6: 02-November-2022


Pralsetinib—{Genentech, Inc./F. Hoffmann-La Roche Ltd} 
Statistical Analysis Plan BO42863 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: A PHASE 1/2 STUDY OF THE HIGHLY-SELECTIVE RET 
INHIBITOR, BLU-667, IN PATIENTS WITH THYROID CANCER, 
NON-SMALL CELL LUNG CANCER (NSCLC) AND OTHER 
ADVANCED SOLID TUMORS 
STUDY NUMBER: 
BO42863 
STUDY NAME:  
ARROW 
VERSION NUMBER: 
6.0 
ROCHE COMPOUND(S): 
Pralsetinib/RO7499790 
EUDRACT NUMBER: 
2016-004390-41 
IND NUMBER: 
131825 
NCT NUMBER: 
NCT 03037385 
PLAN PREPARED BY: 
 
CONFIDENTIAL
This is {a Genentech, Inc./an F. Hoffmann-La Roche Ltd} document that contains confidential 
information.  Nothing herein is to be disclosed without written consent from {Genentech, Inc./F. 
Hoffmann-La Roche Ltd}. 


 
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STATISTICAL ANALYSIS PLAN APPROVAL 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp above  


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 9 
1.1 
Study Design ............................................................................. 9 
1.2 
Study Objectives ...................................................................... 12 
1.2.1 
Phase 1 Objectives .................................................................. 12 
1.2.1.1 
Primary Objectives ................................................................... 12 
1.2.1.2 
Secondary Objectives .............................................................. 12 
1.2.1.3 
Exploratory Objectives ............................................................. 12 
1.2.2 
Phase 2 Objectives .................................................................. 12 
1.2.2.1 
Primary Objectives ................................................................... 13 
1.2.2.2 
Secondary Objectives .............................................................. 13 
1.2.2.3 
Exploratory Objectives ............................................................. 13 
1.3 
Study Endpoints ....................................................................... 13 
1.3.1 
Phase 1 Endpoints ................................................................... 13 
1.3.1.1 
Primary Endpoints ................................................................... 13 
1.3.1.2 
Secondary Endpoints ............................................................... 14 
1.3.1.3 
Exploratory Endpoints .............................................................. 14 
1.3.2 
Phase 2 Endpoints ................................................................... 14 
1.3.2.1 
Primary Endpoints ................................................................... 14 
1.3.2.2 
Secondary Endpoints ............................................................... 14 
1.3.2.3 
Exploratory Endpoints .............................................................. 15 
1.4 
Sample Size Justification ......................................................... 16 
1.4.1 
Phase 1 (Dose-escalation) ...................................................... 16 
1.4.2 
Phase 2 (Dose-expansion at the MTD/RP2D) ......................... 16 
2. 
POPULATIONS FOR ANALYSIS .................................................. 17 
2.1 
Safety Population ..................................................................... 17 
2.2 
Efficacy Population .................................................................. 17 
2.3 
RET-altered Measurable Disease Population .......................... 18 
2.4 
Response-Evaluable Population .............................................. 18 
2.5 
Sub-Population ........................................................................ 19 
2.5.1 
Central Nervous System Metastases NSCLC Sub-
population ................................................................................ 19 


 
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3. 
GENERAL STATISTICAL CONSIDERATIONS ............................ 19 
3.1 
Randomization, Stratification, and Blinding ............................. 19 
3.2 
Multiplicity Adjustment ............................................................. 19 
3.3 
Data Analysis General Information and Definition ................... 19 
3.3.1 
Study Drug ............................................................................... 19 
3.3.2 
Day 1 and Other Days ............................................................. 19 
3.3.3 
Study Day Derivation ............................................................... 19 
3.3.4 
Duration Derivation .................................................................. 20 
3.3.5 
Baseline Values ....................................................................... 20 
3.3.6 
Last Contact Date(s) ................................................................ 20 
3.4 
Methods for Handling Missing Data ......................................... 20 
3.5 
Visit Window(s) ........................................................................ 21 
3.6 
Pooling Strategies .................................................................... 22 
3.6.1 
Grouping Patients by Age ........................................................ 22 
3.6.2 
Pooling Sites by Geographic Region(s) ................................... 22 
3.6.3 
Grouping Patients by Race ...................................................... 22 
3.6.4 
Combining Disease Types and RET alteration Status ............. 22 
3.6.5 
Dose Levels ............................................................................. 24 
3.6.5.1 
Grouped Dose Levels I ............................................................ 24 
3.6.5.2 
Grouped Dose Level II ............................................................. 24 
3.6.6 
Grouping Patients by baseline Weight ..................................... 25 
4. 
STATISTICAL ANALYSIS ............................................................. 25 
4.1 
Study Patients .......................................................................... 26 
4.1.1 
Analysis Population ................................................................. 26 
4.1.2 
Patient Disposition ................................................................... 27 
4.1.3 
Protocol Deviations .................................................................. 28 
4.2 
Demographics and Baseline Disease Characteristics ............. 28 
4.2.1 
Demographics .......................................................................... 28 
4.2.2 
Baseline Disease Characteristics ............................................ 29 
4.3 
Medical History ........................................................................ 31 
4.4 
Prior and Concomitant Medications ......................................... 31 
4.4.1 
Prior and Concomitant Medications ......................................... 31 


 
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4.4.2 
Prior Antineoplastic Therapy .................................................... 32 
4.5 
Study Treatments and Extent of Exposure .............................. 33 
4.5.1 
Treatment Duration and Exposure ........................................... 33 
4.5.2 
Cumulative Dose ..................................................................... 34 
4.5.3 
Average Daily Dose ................................................................. 34 
4.5.4 
Dose Intensity .......................................................................... 34 
4.5.5 
Relative Dose Intensity ............................................................ 34 
4.5.6 
Dose Modification .................................................................... 34 
4.6 
Efficacy Analysis ...................................................................... 35 
4.6.1 
Primary Efficacy Endpoint ........................................................ 36 
4.6.1.1 
RET-fusion NSCLC .................................................................. 36 
4.6.1.2 
RET-mutation MTC .................................................................. 38 
4.6.1.3 
RET-fusion Thyroid Cancer ..................................................... 40 
4.6.1.4 
RET-mutation other than MTC ................................................. 40 
4.6.1.5 
RET-fusion solid tumors other than NSCLC and thyroid 
patients .................................................................................... 40 
4.6.1.6 
Other patients .......................................................................... 40 
4.6.2 
Secondary Efficacy Endpoints ................................................. 41 
4.6.2.1 
Progression Free Survival ....................................................... 41 
4.6.2.2 
Duration of Response .............................................................. 42 
4.6.2.3 
Clinical Benefit Rate ................................................................ 44 
4.6.2.4 
Disease Control Rate ............................................................... 44 
4.6.2.5 
Overall Survival ........................................................................ 44 
4.6.2.6 
CNS Metastases Activity ......................................................... 45 
4.6.3 
Analysis of Exploratory Efficacy Endpoints .............................. 46 
4.6.3.1 
EORTC QLQ-C30 .................................................................... 46 
4.6.3.2 
Disease-related symptom, bowel movement history ................ 47 
4.6.3.3 
CNS Metastases Activity for Other Tumor Types other than 
NSCLC .................................................................................... 47 
4.7 
Safety Analysis ........................................................................ 47 
4.7.1 
Adverse Events ........................................................................ 47 
4.7.1.1 
Adjacent Adverse Events ......................................................... 47 
4.7.2 
Adverse Event Special Interest ................................................ 57 


 
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4.7.2.1 
Time to Onset .......................................................................... 57 
4.7.2.2 
Time to Resolution ................................................................... 57 
4.7.3 
Grouped Adverse Events ......................................................... 61 
4.7.4 
Serious Adverse Events and Deaths ....................................... 61 
4.7.5 
Clinical Laboratory Evaluations ................................................ 61 
4.7.6 
Vital Signs ................................................................................ 62 
4.7.7 
Electrocardiograms .................................................................. 63 
4.7.8 
Electrocardiogram Holter Monitor ............................................ 63 
4.7.9 
ECOG Performance Status...................................................... 63 
4.7.10 
Other Safety Parameters ......................................................... 63 
4.8 
Pharmacokinetic and Pharmacodynamic Analysis .................. 63 
4.8.1 
Pharmacokinetic Analysis ........................................................ 63 
4.8.2 
Calcitonin and Carcinoembryonic Antigen 
Pharmacodynamics ................................................................. 63 
5. 
INTERIM ANALYSIS ..................................................................... 64 
6. 
CHANGES FROM THE PLANNED ANALYSIS ............................ 64 
6.1 
Changes from the planned analyses in protocol to SAP 
version 1.0 ............................................................................... 64 
6.2 
Changes from SAP version 1.0 to SAP version 2.0 ................. 65 
6.3 
Changes from SAP version 2.0 to SAP version 3.0 ................. 65 
6.4 
Changes from SAP version 3.0 to SAP version 4.0 ................. 66 
6.5 
Changes from SAP version 4.0 to SAP version 5.0 ................. 67 
6.6 
Changes from SAP version 5.0 to SAP version 6.0 ................. 67 
7. 
APPENDICES ............................................................................... 68 
7.1 
Data Imputation Guidelines...................................................... 68 
7.1.1 
Adverse Event Date Imputation ............................................... 69 
7.1.2 
Concomitant Medication Date Imputation ................................ 70 
7.1.3 
Prior Therapies Date Imputation .............................................. 70 
7.1.4 
Death Date Imputation ............................................................. 70 
7.1.5 
New Anticancer Therapy Date Imputation ............................... 70 
7.2 
Derivation of Prior Line of Systemic Therapy ........................... 71 
7.3 
Derivation of RET gene status for MTC patients ...................... 71 


 
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7.4 
Table, Listing, and Figure Format ............................................ 72 
7.5 
Conventions ............................................................................. 72 
8. 
SOFTWARE .................................................................................. 73 
9. 
TABLES, LISTINGS, AND GRAPHS (TLGS) SHELLS AND 
PROGRAMMING SPECIFICATIONS ........................................... 73 
10. 
REFERENCES.............................................................................. 73 
 
 
LIST OF TABLES 
Table 1 
Visit Windows .............................................................................. 22 
Table 2 
Efficacy Endpoints and Analysis Population ............................... 35 
Table 3 
Summary of ORR, BOR, CBR, DCR analysis table(s) for 
RET-fusion NSCLC patients ....................................................... 37 
Table 4 
Summary of ORR, BOR, CBR, DCR analysis table(s) for 
RET-fusion NSCLC patients by prior line of therapy ................... 38 
Table 5 
Summary of ORR, BOR, CBR, and DCR analyses for RET-
mutation MTC Patients ............................................................... 38 
Table 6 
Summary of ORR, BOR, CBR, DCR analysis table(s) for 
RET-mutation MTC patients by prior line of therapy ................... 39 
Table 7 
Summary of ORR, BOR, CBR, and DCR analyses for RET-
fusion thyroid patients ................................................................. 40 
Table 8 
Duration of Response and Progression Free Survival 
Censoring Rules ......................................................................... 41 
Table 9 
Summary of PFS analyses.......................................................... 42 
Table 10 
Summary of DOR analyses......................................................... 43 
Table 11 
Scoring the EORTC QLQ-C30 Version 3.0 ................................. 46 
Table 12 
Summary of Adverse Event analyses ......................................... 51 
Table 13 
Summary of AESI analyses ........................................................ 59 
 
 
LIST OF FIGURES 
Figure 1 
Study Schematic ......................................................................... 11 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BGPL 
Biometrics Global Process Library 
BMI 
body mass index 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
HR 
hazard ratio 
IA 
interim analysis 
ICH 
International Council on Harmonization 
iDMC 
independent Data Monitoring Committee 
IMC 
Internal Monitoring Committee 
IRF 
Independent Review Facility 
ITT 
intent to treat 
IxRx 
interactive voice/web-based response system 
LLoQ 
lower limit of quantification 
MDD 
minimally detectable difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMPA 
National Medical Products Administration 
OS 
overall survival 
PFS 
progression-free survival 
PRO 
patient-reported outcomes 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SMART 
sequential multiple assignment randomized study 
SMQs 
standardized MedDRA queries 
 
 


 
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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analysis 
and data reporting for protocol BO42863 (BLU-667-1101/ARROW, hereafter referred to 
as BO42863) “A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in 
Patients with Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other 
Advanced Solid Tumors” for the completion of the Clinical Study Report (CSR) to 
support new drug application (NDA) filing of pralsetinib (BLU-667) for 1) Rearranged 
during transfection (RET)-fusion positive NSCLC patients, 2) RET-mutation positive 
medullary thyroid cancer (MTC) patients and RET-fusion positive thyroid cancer 
patients, 3) RET-fusion other solid tumor, and other specific types, respectively. Herein, 
RET-fusion NSCLC refers to RET-fusion positive NSCLC patients, RET-mutation MTC 
patients refers to RET-mutation positive MTC, and RET-fusion thyroid cancer patients 
refers to RET-fusion positive thyroid cancer patients, RET-fusion other solid tumors refer 
to RET-fusion other solid tumors, respectively. 
This SAP is based on global Protocol Amendment 14 (PA14) (Dated, 28 March 2022).  
Any additional post-hoc analysis performed in submission documents but not described 
in this version of SAP will be clearly documented in the corresponding documents for 1) 
RET-fusion NSCLC NDA, 2) RET-mutation MTC and RET-fusion thyroid cancer, 3) RET-
fusion other solid tumors, and other specific types, respectively. 
Pharmacokinetic (PK) analysis, including PK profile of pralsetinib and correlated drug 
exposure, and analyses of patients who undergo continuous Holter monitoring are not 
within the scope of this SAP and will be addressed in separate document or report. 
Therefore, the PK Population and electrocardiogram (ECG) Population specified in the 
protocol will not be included in this SAP.  
The planned analyses related to the Dose-Determining Population, which have been 
described in SAP Version 2.0 used for NDA filing of pralsetinib for RET-fusion positive 
NSCLC patients, will not be included in this version. Similarly, the planned analyses 
related to the dose escalation patients (Phase 1 patients) of Safety Population, which 
have been described in SAP Version 2.0, will not be repeated in this version unless 
modifications are needed. 
The planned analyses related to the mitogen-activated protein kinases pathway 
expression signature, which have been also described in SAP Version 2.0, will not be 
included in this version. 
1.1 
STUDY DESIGN 
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the 
safety, tolerability, PK, pharmacodynamics, and preliminary antineoplastic activity of 
pralsetinib, a potent and selective RET inhibitor, administered orally in patients with 


 
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medullary thyroid cancer (MTC), RET-altered NSCLC, and other RET-altered solid 
tumors. 
The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part 
(Phase 2) (Figure 1 ). Both parts will enroll patients with RET-altered advanced non-
resectable NSCLC, advanced non-resectable thyroid cancer and other advanced non-
resectable solid tumors that have experienced progression following standard systemic 
therapy; have not adequately responded to or are intolerant to standard systemic 
therapy; for whom the Investigator has determined that the treatment with standard 
therapy is not appropriate; or for whom there is no acceptable standard therapy for their 
disease. Additionally, the Phase 2 dose expansion part of the study allows for treatment 
naïve patients with RET-fusion positive metastatic NSCLC and advanced MTC to be 
enrolled and treated. 
The dose-escalation portion of the study (Phase 1) enrollment was completed on 
3 April 2018. It employed the Bayesian optimal interval (BOIN) design to find the 
maximum tolerated dose (MTD) of pralsetinib. Dose escalation continued to enroll in 
cohorts of 3-6 (1-3 for the first 3 dose levels) patients until 12 patients were treated and 
evaluable for dose-limiting toxicity (DLT) at one dose level, at which time the MTD or 
recommended Phase 2 dose (RP2D) could be determined. The total number of patients 
to be enrolled during the dose escalation part of the study could vary depending on the 
toxicity profile of pralsetinib and the number of dose levels tested prior to reaching the 
MTD. 
All patients treated at doses > 120 mg per day were required to have MTC, or a RET-
altered solid tumor per local assessment of tumor tissue and/or blood. Additionally, these 
patients could be enrolled into an enrichment cohort, if it previously included less than 12 
patients evaluable for dose-limiting toxicity (DLT), was reviewed at a dose-escalation 
meeting, and did not exceed the MTD. Data from these patients allows for further 
assessment of safety, PK, and pharmacodynamics. 
In Phase 2, patients will enroll into 1 of 9 groups based on their tumor type and prior 
therapy status (if applicable). 
 
Group 1: NSCLC with a RET fusion previously treated with a platinum-based 
chemotherapy (N ~80). 
 
Group 2: NSCLC with a RET fusion not previously treated with a platinum-based 
chemotherapy, including those who have not had any systemic therapy. Prior 
platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if the 
last dose of platinum was 4 months or more before the first dose of study drug 
(N~200, including approximately 30 patients with prior systemic therapy). 
 
Group 3: MTC previously treated with cabozantinib and/or vandetanib (N ~65). 
 
Group 4: MTC not previously treated with cabozantinib or vandetanib (N ~40). 


 
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 
Group 5: Other solid tumors with a RET fusion not eligible for any of the other 
groups (N ~100). Patients should have previously received standard of care (SOC) 
appropriate for their tumor type, unless there is no accepted standard therapy for 
the tumor type or the Investigator has determined that treatment with standard 
therapy is not appropriate. As the intent of this cohort is to enroll a variety of RET-
fusion tumor types, Blueprint will notify sites if/when sufficient data are available, 
and accrual should cease for a particular tumor type. 
 
Group 6: Any solid tumors with a RET alteration (fusion or mutation) previously 
treated with a selective RET tyrosine kinase inhibitor (TKI) (N ~20). 
 
Group 7: Other solid tumors with a RET mutation previously treated with SOC 
appropriate for the disease type (N ~20). 
 
Group 8: NSCLC with a RET fusion previously treated with a platinum-based 
chemotherapy (China only; N ~30). 
 
Group 9: MTC not previously treated with systemic therapy (except prior cytotoxic 
chemotherapy is allowed) for advanced or metastatic disease extension cohort 
(China only; N ~30). 
 
Figure 1 Study Schematic 
 
 


 
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Abbreviations: BOIN = Bayesian optimal interval; MTC = medullary thyroid cancer; NSCLC = non-
small cell lung cancer; RET = rearranged during transfection; TKI = tyrosine kinase inhibitor; PO, 
orally; QD, once daily; BID, twice daily. 
Determination of RET status, as required for enrollment of all patients except those with 
MTC, is based on local assessment, or central assessment if local testing is not 
available. All patients enrolled in Phase 2 (all 9 groups) must submit tumor tissue 
(archived or new) for retrospective assessment of RET status and other pathway 
biomarkers. Patients enrolled into Group 6 (previous treatment with a selective RET-
inhibitor) are required to have a new tumor biopsy prior to enrollment.   
1.2 
STUDY OBJECTIVES 
1.2.1 
Phase 1 Objectives 
1.2.1.1 
Primary Objectives 
 
To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose 
(RP2D) of pralsetinib. 
 
To determine the safety and tolerability of pralsetinib. 
1.2.1.2 
Secondary Objectives 
 
To determine the ORR by RECIST v1.1 (or Response Assessment in Neuro-
Oncology [RANO], if appropriate for tumor type) for all patients treated with BLU-667 
according to their disease type, and/or RET-altered status if applicable, and/or prior 
treatment status, if appropriate. Patients initially treated with MTD/RP2D will be 
pooled with Phase 2 patients. 
 
To assess Baseline RET gene status in plasma and/or tumor tissue and correlate 
with measures of antineoplastic activity including, but not limited to overall response 
rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and duration of 
response (DOR). 
 
To characterize the PK profile of pralsetinib and correlate drug exposure with safety 
assessments. 
 
To characterize the pharmacodynamics of pralsetinib, including, but not limited to, 
changes in blood calcitonin and carcinoembryonic antigen (CEA) in MTC patients 
only, and changes in turmor dual specificity phosphatase (DUSP6) and sprout 
receptor tyrosine kinase (RTK) signaling antagonist 4 (SPRY4) levels in all patients. 
1.2.1.3 
Exploratory Objectives 
To identify potential new blood and tumor tissue biomarkers (eg, deoxyribonucleic acid 
[DNA], ribonucleic acid [RNA], and/or protein markers) of pharmacodynamic activity, 
antineoplastic activity, and/or toxicity. 
1.2.2 
Phase 2 Objectives 
Phase 1 patients treated at the MTD/RP2D will be pooled with Phase 2 patients for 
Phase 2 objectives.  


 
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1.2.2.1 
Primary Objectives 
To determine the ORR by RECIST v1.1 (or RANO, if appropriate for tumor type) by 
disease type, and/or RET-altered status (including patients treated at MTD/RP2D in 
Phase 1), and/or prior treatment status specified in enrollment group definition, if 
appropriate. 
To further define the safety and tolerability of pralsetinib. 
1.2.2.2 
Secondary Objectives 
 
To assess additional measures of clinical benefit including DOR, CBR, DCR, 
progression-free survival (PFS), and overall survival (OS) in all patients by disease 
type and/or RET-altered status, and/or prior treatment status explained in enrollment 
group definition, if appropriate. Patients treated at MTD/RP2D in Phase 1 will be 
pooled with Phase 2 patients for this analysis. 
 
To assess baseline RET gene status (ie, gene fusion partner or primary mutation 
and, for MTC, whether hereditary or sporadic) in plasma and/or tumor tissue and 
correlate with measures of antineoplastic activity including, but not limited to ORR, 
CBR, DOR, and DCR in all patients, including patients treated at MTD/RP2D in 
Phase 1, by disease type, and/or RET-altered status if applicable, and/or prior 
specified treatment status if appropriate. 
 
To characterize the pharmacokinetic (PK) profile of pralsetinib and correlate drug 
exposure with safety assessments, including changes in ECG intervals, and 
efficacy. 
 
To characterize the pharmacodynamics of pralsetinib, including, but not limited to, 
changes in blood calcitonin and carcinoembryonic antigen (CEA) in MTC patients 
only. 
 
To assess brain activity in patients with NSCLC. 
1.2.2.3 
Exploratory Objectives 
 
To identify potential new blood and tumor tissue biomarkers (eg, DNA, RNA, and/or 
protein markers) of pharmacodynamic activity, antineoplastic activity, and/or toxicity. 
 
To assess changes in quality of life (QoL) questionnaire. 
 
To explore disease-related symptoms, as measured by bowel movement history 
(MTC patients only). 
 
To explore clinical benefit including ORR, CBR, DCR, PFS for patients previously 
treated with a selective RET tyrosine kinase inhibitor. 
 
To assess brain activity in patients with tumor types other than NSCLC.   
1.3 
STUDY ENDPOINTS 
1.3.1 
Phase 1 Endpoints 
1.3.1.1 
Primary Endpoints 
 
MTD and RP2D of pralsetinib. 


 
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 
Overall safety profile of pralsetinib, as assessed by the type, frequency, severity, 
timing, and relationship to study drug of any adverse events, serious adverse 
events, changes in vital signs, ECGs, and safety laboratory tests. 
1.3.1.2 
Secondary Endpoints 
 
ORR for all pralsetinib treated patients according to patients’ disease type and/or 
RET-altered status if applicable, and/or prior treatment status if appropriate. Patients 
initially treated with MTD/RP2D in Phase 1 will be pooled with Phase 2 patients 
accordingly. 
 
RET gene status and correlation between RET gene status and ORR, CBR, DOR, 
and DCR, and other measures of antineoplastic activity (in plasma and/or tissue) in 
all patients according to their disease type and/or RET-altered status, if applicable, 
and/or prior treatment status, if appropriate. 
 
PK parameters of pralsetinib: Pharmacokinetic parameters of interest will include, as 
appropriate, maximum plasma drug concentration (Cmax), time to maximum plasma 
drug concentration (Tmax), time of last quantifiable plasma drug concentration 
(Tlast), area under the plasma concentration versus time curve from time 0 to 24 
hours postdose (AUC0-24), plasma drug concentration at 24 hours postdose (C24); 
apparent volume of distribution (Vz/F), terminal elimination half-life (t½), apparent 
oral clearance (CL/F), and accumulation ratio (R). 
 
Pharmacodynamic parameters of pralsetinib: changes in tumor/blood including, but 
not limited to, changes in blood calcitonin and carcinoembryonic antigen (CEA) 
(MTC patients); and changes in tumor biomarker levels (DUSP6 and SPRY4) levels 
(all patients). 
1.3.1.3 
Exploratory Endpoints 
 
Levels of exploratory blood and tumor markers (DNA, RNA and protein) as 
compared to antineoplastic activity, and/or toxicity. 
1.3.2 
Phase 2 Endpoints 
Phase 1 patients treated at MTD/RP2D will be pooled with Phase 2 patients for Phase 2 
endpoints accordingly. 
1.3.2.1 
Primary Endpoints 
 
ORR by patients’ disease type, and/or RET-altered status if applicable, and/or prior 
treatment status if appropriate. 
 
Overall safety profile of pralsetinib, as assessed by the type, frequency, severity, 
timing, and relationship to study drug of any AEs, SAEs, changes in vital signs, 
ECGs, and safety laboratory tests. 
1.3.2.2 
Secondary Endpoints 
 
DOR, CBR, DCR, PFS, and OS in all patients by disease type and/or RET-altered 
status, if applicable, and/or prior treatment status, if appropriate. 


 
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 
RET gene status (ie, gene fusion partner or primary mutation and, for MTC, whether 
hereditary or sporadic) and correlation between RET gene status and ORR, CBR, 
DOR, DCR, and other measures of antineoplastic activity (in plasma and/or tissue) 
in all patients according to their disease type and/or RET-altered status, if 
applicable, and/or prior treatment status, if appropriate. 
 
PK parameters of pralsetinib: Pharmacokinetic parameters of interest will include, as 
appropriate, maximum plasma drug concentration (Cmax), time to maximum plasma 
drug concentration (Tmax), time of last quantifiable plasma drug concentration 
(Tlast), area under the plasma concentration versus time curve from time 0 to 24 
hours postdose (AUC0-24), plasma drug concentration at 24 hours postdose (C24); 
apparent volume of distribution (Vz/F), terminal elimination half-life (t½), apparent 
oral clearance (CL/F), and accumulation ratio (R). 
 
ECG Assessment: In Phase 2, the effects of pralsetinib on ECG parameters will be 
evaluated for approximately 20 patients using 12-lead ECGs extracted from 
continuous recordings (12-lead Holter) on C1D1 and C1D15. Individual ECGs will 
be extracted in replicate from the 12-lead Holter recordings at specified time points 
and will be evaluated by a central laboratory. QT intervals will be measured from 
lead II and will be corrected for heart rate (QTc) using Fridericia’s correction factors 
(QTcF). The primary QTc parameter will be QTcF. Secondary parameters (heart 
rate, PR, and QRS, and T-wave morphology) will also be evaluated. Potential 
effects of pralsetinib will be evaluated as change from predose baseline heart rate, 
PR, QRS, and QTcF by postdose time point. For the purpose of QT assessment, 
exposure-response analysis will be performed on the relationship between 
pralsetinib systemic levels and change in QTcF. 
 
Pharmacodynamic parameters of pralsetinib: changes in tumor/blood including, but 
not limited to, changes in blood calcitonin and CEA and biochemical response rate 
(MTC patients only). 
 
Intracranial response rate among patients with NSCLC who have measurable 
(target by RECIST v1.1) lesions in the brain, and time to intracranial progression 
among all patients with NSCLC. 
1.3.2.3 
Exploratory Endpoints 
 
Changes in patient-reported outcomes as assessed by the European Organization 
for Research and Treatment of Cancer Core QoL Questionnaire (EORTC QLQ-C30) 
instruments. 
 
Changes in disease-related symptoms as reported by bowel movement history for 
MTC patients. 
 
ORR, CBR, DCR, PFS for patients previously treated with a selective RET tyrosine 
kinase inhibitor. 
 
Intracranial response rate among patients with tumor types other than NSCLC who 
have measurable (target by RECIST v1.1) lesions in the brain, and time to 
intracranial progression among all patients with tumor types other than NSCLC. 


 
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1.4 
SAMPLE SIZE JUSTIFICATION 
1.4.1 
Phase 1 (Dose-escalation) 
The dose escalation part of the study (Phase 1) employs the local BOIN design (Liu and 
Yuan, 2015) to find the MTD. The BOIN design is implemented in a simple way similar to 
the traditional 3+3 design but is more flexible and possesses superior operating 
characteristics that are comparable to those of the more complex model-based designs, 
such as the continual reassessment method (CRM).   
The target toxicity rate for the MTD is 30%. Alternatives under which decision errors are 
minimized are: 18% (subtherapeutic) and 42% (overly toxic). To avoid assigning too 
many patients to the overly toxic doses, a dose level will be eliminated (and any planned 
doses that are higher) when the posterior probability is greater than 95% that the toxicity 
rate of a dose level is >30%, given the number of patients (≥ 3) and DLTs observed at 
the dose level. Dose escalation will continue to enroll and treat patients in cohorts of size 
3-6 (1-3 for the first 3 dose levels) until 12 patients are treated and evaluable for DLT at 
one dose level. The total number of patients to be enrolled during the dose escalation 
part of the study will vary depending on the underlining dose-toxicity curve and the 
number of dose levels tested prior to reaching MTD and is estimated to be 
approximately 20 to 50 patients. 
1.4.2 
Phase 2 (Dose-expansion at the MTD/RP2D) 
 
Group 1:  The sample size of approximately 80 RET-fusion NSCLC patients who 
previously received treatment with a platinum-based chemotherapy will provide > 
95% power at the 2-sided significance level of 0.05 for testing the assumption of the 
null hypothesis ORR=0.23 versus the alternative ORR=0.5. 
 
Group 2:  The sample size of approximately 170 treatment naïve (1st line) RET-
fusion NSCLC patients will provide >90% power at the 2-sided significance level of 
0.05 for testing the assumption of the null hypothesis ORR=0.48 versus the 
alternative ORR=0.61.  
 
Group 3: The sample size of approximately 65 MTC patients previously treated with 
cabozantinib and/or vandetanib will provide > 90% power at the 2-sided significance 
level of 0.05 for testing the assumption of the null hypothesis ORR=0.2 versus the 
alternative ORR=0.4. 
 
Group 4: The sample size of approximately 40 MTC patients not previously treated 
with cabozantinib or vandetanib will be enrolled for exploratory analysis. 


 
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 
Group 5: The sample size of approximately 100 patients who have solid tumors with 
a RET fusion previously treated with SOC, have previously received SOC 
appropriate for their tumor type (unless there is no accepted standard therapy for 
the tumor type or the Investigator has determined that treatment with standard 
therapy is not appropriate), and must not eligible for any of the other groups. This 
sample size will provide >90% power at the 2-sided significance level of 0.05 for 
testing the assumption of the null hypothesis ORR=0.1 versus the alternative 
ORR=0.3. 
 
Group 6: The sample size of approximately 20 patients who have RET-fusion solid 
tumors that failed prior selective-RET inhibitor will be enrolled for exploratory 
analysis. 
 
Group 7: The sample size of approximately 20 patients who have solid tumors with 
an activating RET mutation previously treated with SOC will be enrolled for 
exploratory analysis. 
 
Group 8: The sample size of approximately 30 RET-fusion NSCLC patients that 
have failed treatment with prior platinum-based chemotherapy will be enrolled by 
assuming the observed ORR from 27% to 50% based on the preliminary data. 
 
Group 9: The sample size of approximately 30 MTC patients that were not 
previously treated with systemic therapy (except prior cytotoxic chemotherapy is 
allowed) for the advanced or metastatic disease will be enrolled by assuming the 
observed ORR from 27% to 50% based on the preliminary data. 
2. 
POPULATIONS FOR ANALYSIS 
2.1 
SAFETY POPULATION 
The Safety Population includes all patients who have received at least 1 dose of study 
drug regardless of starting dose levels. The Safety Population will be the primary 
population for safety analysis unless otherwise specified. Patients will be analyzed 
based on the initial dose prescribed on Day 1, regardless of phases. 
Patients will be further categorized into different subgroups as described in Section 
3.6.4.  
Prior selective RET-inhibitor treated patients will be explored separately and will not be 
included in any defined safety subgroups but will be included in overall Safety 
Population.  
2.2 
EFFICACY POPULATION 
The Efficacy Population includes all patients in the Safety Population who are dosed on 
or prior to a certain enrollment date, which will be defined in CSR or submission 
documents.  The Efficacy Population will be the primary population for analysis of 
efficacy endpoints (except for ORR, best overall response [BOR], CBR, DCR, and DOR) 
unless otherwise specified. Patients will be analyzed based on the initial dose prescribed 
on Day 1, regardless of phases. 


 
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Similarly, patients will be further categorized into different subgroups in Section 3.6.4.  
Prior selective RET-inhibitor treated patients will be explored separately and will not be 
included in any defined efficacy subgroups but will be included in overall Efficacy 
Population. 
2.3 
RET-ALTERED MEASURABLE DISEASE POPULATION 
The RET-altered Measurable Disease (RAMD) Population includes Efficacy Population 
patients who have measurable (target) disease per RECIST v1.1 (or RANO, if 
appropriate for tumor type) at baseline according to blinded independent central review 
(BICR) and sufficient evidence of a RET alteration. The RET altered Measurable 
Disease Population will be the primary population for analysis of ORR, BOR, CBR, DCR, 
and DOR.  
Similarly, patients will be further categorized into different subgroups in Section 3.6.4.  
Prior selective RET-inhibitor treated patients will be explored separately and will not be 
included in any defined efficacy subgroups.  
2.4 
RESPONSE-EVALUABLE POPULATION 
Response-Evaluable (RE) Population includes Efficacy Population patients who have 
measurable (Target) disease per RECIST v1.1 (or RANO, if appropriate for disease 
type) at baseline and at least one evaluable post-baseline disease response assessment 
(based on BICR data) and have experienced no major protocol violation. The RE 
Population will be used as a sensitivity analysis for ORR, DOR, CBR, and DCR. 
The following criteria will lead to exclusion from the RE Population: 
 
Patient has another known primary driver alteration other than RET identified by 
central circulating tumor DNA (ctDNA)/tumor tissue assay at baseline. 
o RET-mutation MTC, such as HRAS or KRAS 
o RET-fusion thyroid, such as BRAF, NRAS, or KRAS  
o RET-fusion NSCLC, such as EGFR, ALK, ROS1, or BRAF 
o RET-fusion solid tumor other than NSCLC and thyroid, with any known co-
driver alterations identified for the disease type  
 
Any additional major protocol deviations identified by the medical review of the data 
that could lead to exclusion from the RE Population will be documented and 
reported in the CSR or submission documents. 
The RE Population will be used for primary efficacy endpoint as a sensitivity analysis for 
ORR, BOR, CBR, and DCR specified in Section 4.6.1.  


 
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2.5 
SUB-POPULATION 
2.5.1 
Central Nervous System Metastases NSCLC Sub-population 
Central nervous system (CNS) metastases NSCLC sub-population will include RET-
fusion positive NSCLC patients who have had measurable (target) lesion(s) in 
CNS/brain, including brainstem, cerebellum, frontal lobe, temporary lobe, occipital lobe, 
parietal lobe, frontoparietal, frontotemporal, temporaloccipital, temporalparietal, and 
parietolccipita at baseline according to RECIST v1.1 by BICR data and have not had 
radiotherapy(ies) or radiosurgery(ies) to brain within 2 months before dosed with 
pralsetinib.   
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1 
RANDOMIZATION, STRATIFICATION, AND BLINDING 
This is an open label, single arm study with no randomization or stratification.  
3.2 
MULTIPLICITY ADJUSTMENT 
No multiplicity adjustment is planned in this study. 
3.3 
DATA ANALYSIS GENERAL INFORMATION AND DEFINITION 
Summary statistics for continuous variables will include n (non-missing observations), 
mean, standard deviation (StdDev), minimum, median, and maximum. Summary 
statistics for categorical variables will be presented in terms of frequencies and 
percentages. Time to event data will be summarized and analyzed using Kaplan-Meier 
(KM) method, which the estimated median with 95% confident intervals (CIs) will be 
included. 
3.3.1 
Study Drug 
Study drug or study treatment used in the rest of document refers to pralsetinib. Study 
drug or study treatment and pralsetinib are interchangeable in this document. 
3.3.2 
Day 1 and Other Days 
Date of first dose of pralsetinib (or Cycle 1 Day 1) is defined as the day of the first 
administration of study drug in the study, i.e., after enrollment. First dose refers to first 
dose in study unless specified otherwise. There is no Day 0 in any analysis. 
Date of last dose of pralsetinib is defined as the date of last administration of study drug 
(last dose) in the study. For patients who are still with study drug treatment and last dose 
date is missing, the cutoff date (i.e., database snapshot date) will be used. 
3.3.3 
Study Day Derivation 
Calculations using dates will adhere to the following conventions: 
 
Study day for a date of interest (target date) is calculated as 
 
Study Day = target date – first dose date + 1, if target date is on or after Day 1;  


 
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 
Study Day = target date – first dose date, otherwise. 
Note that negative study days are reflective of observations obtained prior to the first 
dose administration date. First study drug administration dates should always be known. 
There is no Day 0 in any derivation. 
 
Age (in years) at informed consent is calculated using the following formula  
 
Age at informed consent (in years) = (year of consent) - (year of date of birth (DOB)) 
if passed birthday; 
 
Age at informed consent (in years) = (year of consent) - (year of DOB) - 1 if 
otherwise. 
This is equivalent to the following: 
[(year of consent) - (year of DOB)] – [(month of consent) ≤ (month of DOB)] + [(month of 
consent) = (month of DOB) and (day of consent) ≥ (day of DOB)] 
3.3.4 
Duration Derivation 
Unless otherwise specified for a specific variable, duration variables will be derived 
according to the following rules: 
 
Duration (in days) = (end date – start date +1) 
 
Duration (in weeks) = (end date – start date +1)/ 7 
 
Duration (in months) = (end date – start date +1)/ 30.4375 
 
Duration (in years) = (end date – start date +1)/ 365.25. 
Duration variables that are to be expressed in units greater than day will be rounded to 
1 decimal place.  
3.3.5 
Baseline Values 
In general, baseline is defined as the last observation prior to first dose of study drug, 
including pre-dose value or the last available (including unscheduled) value before Day 1 
if Day 1 pre-dose value is unavailable unless otherwise specified. 
3.3.6 
Last Contact Date(s) 
Last contact is the date of last assessment(s), medication, procedure, last follow-up, 
and/or adverse event date, etc., of a patient. 
3.4 
METHODS FOR HANDLING MISSING DATA 
Refer to Section 7.1 for detailed date imputation guidelines. 


 
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3.5 
VISIT WINDOW(S) 
Visits will be windowed. Data are summarized by visit following the visit windows 
reported in Table 1 when appropriate (e.g. laboratory parameters).  
If multiple assessments regardless of scheduled assessment or unscheduled 
assessment occur within a visit window, the assessment closer to the target day will be 
used. In case of ties, i.e. with equal distance to the target day, the value from the day 
before the target day shall be used.  
If there are two assessment records occurred on the same day, the scheduled one 
assessment be used, if available. Otherwise, the earlier assessment will be used. 
 
 


 
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Table 1 
Visit Windows 
Visit 
Start Day 
Target Day 
End Day 
Day 1 (Cycle 1 Day 1) 
1 
1 
1 
Week 1 (Cycle 1 Day 8) 
2 
8 
11 
Week 2 (Cycle 1 Day 15) 
12 
15 
18 
Week 3 (Cycle 1 Day 22) 
19 
22 
25 
Week 4 (Cycle 2 Day 1) 
26 
29 
36 
Week 6 (Cycle 2 Day 15) 
37 
43 
50 
Week 8 (Cycle 3 Day 1) 
51 
57 
71 
Week 12 (Cycle 4 Day 1) 
72 
85 
99 
Week 4*(x-1) (Cycle x Day 1) 
(x-1)*28-12 
(x-1)*28+1 
(x-1)*28+15 
End of Treatment (EOT) 
 
 
 
EOT, assessment at end of treatment visit. Assessment at end of treatment visit will not be windowed in 
other visits. 
 
3.6 
POOLING STRATEGIES  
3.6.1 
Grouping Patients by Age 
Patients will be pooled based on their age at informed consent. 
 
Age < 65 years 
 
Age    65 years 
3.6.2 
Pooling Sites by Geographic Region(s) 
Sites will be pooled based on their geographic location with the following pooling 
method.   
 
 Geographic Region 
o USA 
o Europe 
o Asia 
3.6.3 
Grouping Patients by Race 
Patients will be grouped based on their race with the following pooling method. 
 
Asian, patients’ race is Asian  
 
White, patients’ race is White 
 
Others, patients’ race is not Asian or White 
3.6.4 
Combining Disease Types and RET alteration Status 
RET-fusion or RET-mutation positive is based by either central lab assessment test or 
local lab assessment or both obtained on a sample(s) collected prior to patients’ first 
dose date. The central lab assessment includes analysis of tumor sample tissue through 
next generating sequencing (NGS) method or blood plasma by ctDNA NGS method. 


 
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The disease types and/or RET alteration status will be combined and grouped according 
to the following rules. For both RET-fusion positive and RET-mutation positive patients, 
patients’ RET alteration status will be based on their disease type. The primary RET 
alteration status is RET-fusion for NSCLC patients, RET-mutation for MTC patients, RET 
fusion for all other solid tumors that bear a RET fusion. The primary RET alteration 
status is used to group patients into different subgroups. 
 
RET-fusion, including RET-fusion positive patients.  
 
RET-fusion NSCLC, including RET-fusion positive NSCLC patients, tested positive 
either by central lab assessment, or local lab assessment test or both 
 
RET-fusion NSCLC prior systemic treated patients, including RET-fusion positive 
NSCLC patients previously treated with systemic therapy(ies)  
 
RET-fusion NSCLC prior platinum treated patients, including RET-fusion positive 
NSCLC patients previously treated with platinum-based chemotherapy(ies) 
regardless of neoadjuvant/adjuvant setting. 
 
RET-fusion NSCLC no prior platinum treated patients, including RET-fusion positive 
NSCLC patients not previously treated with platinum-based chemotherapy(ies) 
 
RET-fusion NSCLC non-platinum systemic treated patients, including RET-fusion 
positive NSCLC patients not previously treated with platinum-based 
chemotherapy(ies) but treated with other systemic therapy(ies) 
 
RET-fusion NSCLC no prior systemic treated patients, including RET-fusion positive 
NSCLC patients without any previous systemic treatment.  
 
RET-fusion thyroid, including RET-fusion positive thyroid patients 
 
RET-fusion thyroid prior systemic treated patients, including RET-fusion positive 
thyroid patients previously treated with systemic therapy(ies) 
 
RET-fusion others, including RET-fusion positive patients other than RET-fusion 
NSCLC and RET-fusion thyroid patients  
 
MTC, all MTC patients regardless of RET alteration status 
 
RET-mutation MTC, all RET-mutation positive MTC patients tested positive by 
central/local lab assessment 
 
RET-mutation MTC prior systemic treated patients, including RET-mutation positive 
MTC patients previously treated with systemic therapy(ies) 
 
RET-mutation MTC prior cabozantinib and/or vandetanib treated patients, including 
RET-mutation positive MTC patients previously treated with cabozantinib and/or 
vandetanib therapy(ies) 
 
RET-mutation MTC prior cabozantinib and vandetanib treated patients, including 
RET-mutation positive MTC patients previously treated with both cabozantinib and 
vandetanib 


 
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 
RET-mutation MTC prior no cabozantinib and/or vandetanib treated patients, 
including RET-mutation positive MTC patients not previously treated with either 
cabozantinib or vandetanib  
 
RET-mutation MTC no prior systemic therapy treated patients, including RET-
mutation positive MTC patients not previously treated with systemic therapy(ies) 
 
No/unknown RET-mutation MTC patients, including MTC patients with no or 
unknown RET-mutation status regardless of prior treatment(s) before starting 
pralsetinib treatment 
 
No RET-mutation MTC patients, including RET-mutation negative MTC patients 
 
Unknown RET-mutation MTC patients, including RET-mutation status unknown 
MTC patients 
 
RET-altered Thyroid, including RET-mutation positive MTC patients and RET-fusion 
positive thyroid patients. 
 
RET-mutation others, including all RET-mutation positive disease types other than 
MTC 
 
No/Unknown RET alteration Other solid tumor, including patients with no RET 
alteration or unknown RET alteration status other than MTC 
 
Prior selective RET-inhibitor treated patients, including all patients previously treated 
with selective RET-inhibitor, such as LOXO-292, regardless of disease type(s) and 
RET alteration status. Prior selective RET-inhibitor treated patients are not included 
in any subgroups defined above 
3.6.5 
Dose Levels 
3.6.5.1 
Grouped Dose Levels I 
The starting dose will be grouped for efficacy analysis endpoints, ORR, BOR, CBR, 
DCR, DOR, PFS, OS, etc., Safety, Efficacy Population, RAMD Population, and RE 
Population subgroups, defined in Section 3.6.4, according to the following rules, 
 
400 mg QD 
 
All, including all QD dose levels (30 mg QD – 600 mg QD) and BID dose levels (100 
mg/100 mg BID and 200 mg/100 mg BID) 
3.6.5.2 
Grouped Dose Level II 
For other analysis endpoints based on overall patients, i.e. all Safety Population, the 
starting dose will be grouped for analyses according to the following rules, 
 
  300 mg QD, patients initially treated with 30 mg QD, 60 mg QD, 100 mg QD, 200 
mg QD, and 300 mg QD 
 
400 mg QD, patients initially treated at 400 mg QD 
 
BID, patients initially treated with 100 mg/100 mg BID and 200 mg/100 mg BID of 
pralsetinib 


 
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 
All, including all QD dose levels (30 mg QD – 600 mg QD) and BID dose levels (100 
mg/100 mg BID and 200 mg/100 mg BID). 
3.6.6 
Grouping Patients by baseline Weight 
Patients will be pooled based on their baseline weight as follows: 
 
Weight < 60 kg 
 
Weight   60 kg and    75 kg 
 
Weight > 75 kg 
4. 
STATISTICAL ANALYSIS 
The endpoints will be analyzed by combined disease types and RET alteration status 
and grouped dose levels accordingly.  
The grouped dose level I will be used on efficacy and safety endpoints for prespecified 
subgroups, defined in Section 3.6.4, based on RAMD Population, Efficacy Population, 
Safety Population, and RE Population, respectively. The grouped dose level II will be 
applied for all Safety Population. However, the primary efficacy and safety analyses will 
be conducted mainly for patients started at 400 mg QD of pralsetinib, unless otherwise 
specified. The efficacy and safety analyses for all patients, regardless of dose level, will 
be provided as supportive analyses. 
The efficacy endpoints will be analyzed for prespecified subgroups, defined in Section 
3.6.4, based on RAMD Population and Efficacy Population, respectively. The ORR, 
BOR, CBR, DCR, and DOR will be analyzed primarily based on RAMD Population and 
supportively based on Efficacy Population. Other efficacy endpoints will be analyzed 
primarily based on Efficacy Population. In addition, the efficacy endpoints ORR, BOR, 
CBR, DCR, DOR, intracranial ORR (including intracranial BOR, CBR, DCR, and DOR) 
will be analyzed based on RE Population.  
The safety endpoints will be analyzed for those prespecified subgroups and “All” patients 
based on Safety Population. Other endpoints, including disposition, demographics, 
baseline characteristics, medical history, prior/concomitant medication, protocol 
deviations, treatment exposure and modification, etc., will be analyzed for prespecified 
subgroups, and “All” patients based on Efficacy, RAMD and Safety Population, 
respectively, unless otherwise specified in each section. 
The prior selective RET-inhibitor treated patients will not be included in any subgroups 
but will be included in “All” patients. 


 
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4.1 
STUDY PATIENTS 
4.1.1 
Analysis Population 
A summary of analysis population by starting dose and “All” will be presented for the 
following items. 
 
Safety Population 
 
RET-fusion 
 
RET-fusion NSCLC 
 
RET-fusion NSCLC prior systemic treatment 
 
RET-fusion NSCLC prior platinum treatment 
 
RET-fusion NSCLC no prior platinum treatment 
 
RET-fusion NSCLC prior non-platinum systemic treatment 
 
RET-fusion NSCLC no prior systemic treatment 
 
RET-fusion thyroid 
 
RET-fusion thyroid prior systemic therapy treated patients 
 
RET-fusion others 
 
MTC 
 
RET-mutation MTC 
 
RET-mutation MTC prior systemic therapy treated patients 
 
RET-mutation MTC prior cabozantinib and/or vandetanib treated 
patients 
o RET-mutation MTC prior cabozantinib and 
vandetanib treated patients 
 
RET-mutation MTC prior no cabozantinib and/or vandetanib 
treated patients 
o RET-mutation MTC no prior systemic therapy 
treated patients 
 
No/unknown RET-mutation MTC patients 
 
No RET-mutation MTC patients 
 
Unknown RET-mutation MTC patients 
 
RET-altered thyroid cancer patients 
 
RET-mutation others  
 
No/Unknown RET alteration status solid tumors other than MTC 
 
Prior selective RET-inhibitor treated 
 
All patients at all doses 
 
Efficacy Population 


 
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The layout for Efficacy Population will follow the same format for Safety Population. 
 
RET-altered Measurable Disease Population 
 
The layout for Efficacy Population will follow the same format for Safety Population. 
 
Response Evaluable Population 
The layout for RE Population will follow the same format for Safety Population. 
4.1.2 
Patient Disposition 
The number and percentage of patients will be summarized. 
 
Safety Population 
 
Efficacy Population 
 
RET-altered Measurable Disease Population 
 
Response Evaluable Population 
 
Discontinued from Treatment 
 
Continuing Treatment 
 
Discontinued from Study 
 
Continuing Study Follow-up 
 
Reasons for treatment discontinuation will be summarized with the following 
categories collected on the case report form (CRF). 
 
Disease Progression 
 
Adverse Event 
 
Treatment Related Adverse Event 
 
Adverse Event Except Disease Progression 
 
Death 
 
Lost to Follow-up 
 
Protocol Deviation 
 
Withdrew Consent 
 
Pregnancy 
 
Investigator’s Decision 
 
Administrative/Other 
 
Sponsor Decision 
 
Reasons for study discontinuation will be summarized with the following categories 
collected on the CRF. 
 
Disease Progression 
 
Adverse Event 
 
Treatment Related Adverse Event 


 
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 
Death 
 
Lost to Follow-up 
 
Protocol Deviation 
 
Withdrew Consent 
 
Pregnancy 
 
Investigator’s Decision 
 
Administrative/Other 
 
Initial of Another Antineoplastic Therapy 
 
Sponsor Decision 
A by-patient listing including each treated patient will be provided.  
4.1.3 
Protocol Deviations 
Deviations from the protocol, as defined in the protocol and protocol deviation plan, will 
be documented, reviewed, and categorized as important or non-important. Important 
protocol deviations will be summarized descriptively. 
Prior to each database snapshot and final database lock, important deviations will be 
further categorized as major or minor based on medical review with major protocol 
deviations potentially leading to exclusion from the RE Population. Major protocol 
deviations will also be summarized descriptively. 
A by-patient listing of patients with protocol deviations in the safety population was 
provided.  
4.2 
DEMOGRAPHICS AND BASELINE DISEASE 
CHARACTERISTICS 
Demographic and baseline disease characteristic data will be summarized. 
4.2.1 
Demographics 
The number and percentage of patients in each of the following categories will be 
presented. 
 
Age group  
< 65 years  
  65 years 
o 
  65 to 74 years 
o 
  75 to 84 years 
o 
  85 years 
 
Sex 


 
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 
Ethnicity 
 
Race 
 
Race group (Asian, White, Others) 
 
Geographic Region 
o USA 
o Europe 
o Asia 
● 
Weight 
o < 60 kg 
o 
  60 kg and    75 kg 
o > 75 kg 
o  
Age (Years), height (cm), weight (kg), body mass index (BMI) (kg/m2), and body surface 
area (BSA) will be summarized descriptively. 
BMI will be calculated as: BMI (kg/m2) = (weight in kg)/ (height in meter)2. 
BSA will be calculated based on Dubois and Dubois formula (Dubois D, Dubois EF, 
1916) as  
BSA (m2) = 0.007184 x (height in cm)0.725 x (weight in kg)0.425. 
Individual demographics data will be listed in a by-patient listing. 
4.2.2 
Baseline Disease Characteristics 
The number and percentage of patients in each of the following categories will be 
presented.  
 
The Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2 if 
any, 3 if any, 4 if any) 
 
Primary tumor site (Lung, Thyroid, or Other) 
 
Metastatic disease status 
o Yes 
o No 
 
Target/Non-Target Lesion Location, Target/non-target lesion location will be based 
on BICR data 
 
History of CNS metastases,  
including patients who had medical history metastases site in CNS/Brain from 
CRF data, and patients whose target or non-target lesion(s) location were in 
CNS/Brain, brainstem, cerebellum, frontal lobe, temporal lobe, parietal lobe, 


 
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occipital lobe, frontoparietal, frontotemporal, temporaloccipital, temporalparietal, 
parietolccipital at baseline according to RECIST v1.1 by BICR data 
 
TNM Stage at initial diagnosis 
 
Current stage at screening visit 
 
Histology type 
o Lung cancer patients 
▪ 
Adenocarcinoma 
▪ 
Squamous 
▪ 
Undifferentiated 
▪ 
Other 
o Thyroid cancer patients 
▪ 
Medullary 
▪ 
Papillary 
▪ 
Follicular 
▪ 
Anaplastic 
▪ 
Other 
o Other 
▪ 
Cancer type specified from database. 
 
Smoking history for NSCLC patients (Never smoked, Former smoker, Current 
smoker, or Unknown) 
 
Prior line of therapy 
The prior line of therapy is defined as the number of eligible systemic 
therapy(ies) before enrollment. The systemic therapies are provided by medical 
review. The derivation of the prior line of therapy is documented in Section 7.2.  
The prior line of therapy will be summarized. In addition, the prior line of therapy 
will also be categorized into 0, 1, 2, 3, 4, 5, and  6 accordingly. 
 
RET gene status (hereditary, or sporadic, or others) for MTC patients. 
 
The derivation of RET gene status for MTC patients is documented in Section 7.3. 
 
Primary RET alteration mutation status; Patient’s status will be classified according 
to the primary driver RET genotype according to the hierarchy order below 
 
RET fusion 
o KIF5B 
o CCDC6 
o NCOA4 
o Other 
o Unknown 


 
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 
RET mutation 
o M918T 
o 
Cysteine rich domain, including patients with single nucleotide variants of 
or short indels that include the following residues: C609, C611, C618, 
C620, C630 and/or C634 of RET 
o V804X, including patients with RET-mutation status V804M and V804L 
o  Other 
o Unknown 
Individual baseline characteristics, including prior PD-1/PD-L1 status, will be listed in by-
patient listings. Patients with both RET-fusion positive and RET-mutation positive will be 
grouped by primary RET alteration status in disease characteristics tables, detailed in 
Section 3.6.4.  
A consolidated listing for RET-fusion and RET-mutation information collected either from 
local testing method, or tumor tissue by NGS or plasma by central circulating tumor DNA 
(ctDNA) testing results obtained on or prior to first dose date will also be provided. 
A listing and summary tabulation providing additional details from local pathology reports 
for the RET mutation molecular testing results for predefined subgroups that include the 
following information: the test method, mutation identified, fusion partner identified, in-
frame fusion (Y/N), presence of concomitant oncogenic driver mutation other than RET 
(Y/N), oncogenic driver identified (if yes) and if tissue is available for re-testing will be 
provided. 
4.3 
MEDICAL HISTORY 
The medical history is coded with the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). All medical history will be summarized by system organ 
class (SOC) and preferred term (PT).  
All medical history data will be presented in a by-patient listing.  
4.4 
PRIOR AND CONCOMITANT MEDICATIONS 
4.4.1 
Prior and Concomitant Medications 
Prior and concomitant medication will be coded with the most current version of the 
World Health Organization Drug (WHODrug) Dictionary. Any therapies that are 
discontinued before the first dose of study treatment (Day 1) will be considered as prior 
medication. Concomitant medications are all medications taken from Day 1 to 30 days 
after the last dose of study drug. Therapies taken before Day 1 with missing end date 
will be considered as concomitant medications. If the last dose date of study drug is not 
available, the cutoff date is used in place of the last dose date.  
The following analyses will be provided.  


 
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 
The number and percentage of patients taking prior medications and/or significant 
non-drug therapies will be summarized by anatomical class (ATC, ATC code level 3) 
and PT,  
 
The number and percentage of patients taking concomitant medications and/or 
significant non-drug therapies will be summarized and listed by ATC and PT  
A patient taking a same medication multiple times is counted only once for the specific 
PT within an ATC. 
Prior and concomitant medications will be listed in a by-patient listing.  
4.4.2 
Prior Antineoplastic Therapy 
Prior antineoplastic therapies are recorded and coded using the most current version of 
the WHO Drug Dictionary. These therapies will be further grouped into systemic 
therapy(ies), MKI, chemotherapy(ies), platinum-based chemotherapy(ies), 
immunotherapy(ies), selective RET-inhibitor, and others by medical review.  
The number and percentage of patients previously treated with each category will be 
summarized. 
 
Prior antineoplastic systemic therapy (Yes, or No) 
o Multikinase inhibitor(s) 
▪ 
Only cabozantinib, patients treated with cabozantinib other than 
vandetanib  
▪ 
Only vandetanib, patients treated with vandetanib other than 
cabozantinib 
▪ 
Both cabozantinib and vandetanib, patients treated with 
cabozantinib and vandetanib 
▪ 
Cabozantinib or vandetanib, patients treated with cabozantinib 
and/or vandetanib 
▪ 
prior lenvatinib and/or sorafenib 
▪ 
Other MKI therapy(ies), patients treated with MKI therapy(ies) 
other than cabozantinib, vandetanib, lenvatinib, and sorafenib 
regardless of the above 4 types of MKI therapies. 
o Chemotherapy 
▪ 
Platinum-based chemotherapy 
▪ 
Other chemotherapy, patients treated with chemotherapy(ies) 
other than platinum-based chemotherapy regardless of prior 
platinum-based chemotherapy treatment 
o Immunotherapies 
▪ 
Programmed cell death protein 1/ programmed death ligand 1 
(PD-1/PD-L1) inhibitors 


 
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▪ 
Other immunotherapies, patients treated with immunotherapy(ies) 
other than PD-1/PD-L inhibitors regardless of prior PD-1/PD-L1 
inhibitors 
o Selective RET-inhibitor 
o Others 
 
Prior radiation therapy (Yes, or No) 
 
Prior cancer related surgeries or procedures (Yes, or No) 
 
The following item will be added for RET-mutation MTC, RET-fusion thyroid within 
prior systemic therapy.  
 
prior radioactive iodine (RAI)  
A by-patient listing of prior radiotherapy and prior cancer related surgery or procedures 
will also be provided.  
4.5 
STUDY TREATMENTS AND EXTENT OF EXPOSURE 
A summary of study drug exposure, including cumulative dose, dose intensity, relative 
dose intensity (RDI), duration of treatment, and the proportion of patients with dose 
modifications will be produced. 
4.5.1 
Treatment Duration and Exposure 
Duration of treatment (days) = (treatment end date– treatment start date + 1).   
Duration of treatment (weeks) = (treatment end date– treatment start date + 1) / 7.  
Duration of treatment (months) = (treatment end date – treatment start date + 
1)/30.4375. 
The treatment start date is the first dose date of study drug, and the treatment end date 
is the last dose date of study drug or data cutoff date if patients are still ongoing with the 
treatment, whichever is earlier.  
Descriptive statistics will be provided for treatment duration in weeks and months. 
Treatment duration will also be classified into the following categories. 
 
< 6 months 
 
  6 months to < 12 months 
 
  1 year to 2 years 
 
  2 years to 3 years 
 
  3 years  


 
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4.5.2 
Cumulative Dose 
Cumulative dose (mg) is defined as sum of all dose taken. The dosage will be counted 
as 0 for days when the study drug is not taken. 
4.5.3 
Average Daily Dose 
Average daily dose (mg) is defined as the cumulative dose divided by the number of 
days dosed. Each patient has an average daily dose.   
4.5.4 
Dose Intensity 
Dose intensity (mg/day) is defined as the cumulative dose divided by the treatment 
duration (in days).   
4.5.5 
Relative Dose Intensity 
RDI (%) is defined as dose intensity / planned dose intensity x100. Planned dose 
intensity is based on initial assigned daily dose. 
RDI will be summarized descriptively as a continuous variable. The RDI will also be 
categorized into <75%, 75% to <90%, 90% to 120%, 120 to 150%, and ≥150% and be 
presented accordingly.  
Cumulative dose, average daily dose, dose intensity, RDI will also be summarized for 
every cycle, i.e., 4 weeks. 
A by-patient listing of study drug including treatment duration, cumulative dose, average 
daily dose, dose intensity, planned initial dose, and RDI will be provided. 
4.5.6 
Dose Modification 
The number and percentage of patients who had dose modification and reasons for 
dose modification will be summarized as follows. The dose modification will also be 
further categorized as 0 (no dose modification), 1 (one dose modification), 2 (two dose 
modifications), and ≥ 3 (at least three dose modifications).  
 
Dose escalated 
 
Dose interrupted 
o Dose interrupted due to adverse event (AE) 
o Dose interrupted due to treatment related AE 
 
Dose discontinued 
o Dose discontinued due to AE 
o Dose discontinued due to treatment related AE 
 
Dose reduced 
o Dose reduced due to AE 


 
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o Dose reduction due to treatment related AE 
 
Dose missed 
o Dose missed due to AE 
o Dose reduced, or dose interrupted, or dose missed due to AE 
Details of dose modifications will also be provided in a by-patient listing. 
4.6 
EFFICACY ANALYSIS 
Endpoints involving response assessment will be primarily based on BICR data. The 
investigator assessment will also be analyzed using the same analysis method as a 
supportive analysis. The tumor response and progression will be assessed by RECIST 
v1.1 criteria (Eisenhauer version 1.1, 2009) (or RANO criteria [Wen Madcdonald et al, 
2000], if appropriate). 
The efficacy analyses for ORR, BOR, CBR, DCR, DOR will be primarily summarized for 
prespecified subgroups, defined in Section 3.6.4, based on RAMD Population and also 
analyzed based on Efficacy Population as supportive analyses, respectively. The 
efficacy analyses for PFS, OS will be summarized for predefined subgroups based on 
Efficacy Population in Section 3.6.4, respectively, unless otherwise specified in the 
corresponding section. The sensitivity analysis of the primary efficacy analyses for ORR, 
BOR, CBR, DCR, DOR will also be conducted based on RE Population and Efficacy 
Population. The intracranial ORR, including BOR, CBR, DCR, DOR, will be analyzed 
based on RAMD, Efficacy, and RE Population.  
The efficacy endpoints per analysis population are summarized in Table 2. 
Table 2 
Efficacy Endpoints and Analysis Population 
 
RET-altered 
Measurable 
Population 
Efficacy Population Response Evaluable 
Population 
ORR, BOR, CBR, DCR, 
DOR 
X 
X 
X 
Intracranial ORR, BOR, 
CBR, DCR, DOR* 
X 
X 
X 
PFS, and intracranial 
PFS* 
 
X 
 
OS 
 
X 
 
EORTC QoL 
 
X 
 
Bowel function movement 
 
X 
 
* RET-fusion NSCLC CNS metatstases sub-population and other solid tumor if applicable. 
The efficacy endpoints ORR, BOR, CBR, DCR and DOR assessed by RECIST v1.1 
criteria will also be analyzed for RAMD Population treated at 400 mg QD (in either 
Phase 1 or 2) by subgroups defined in Section 3.6.4, and “All” patients. Patients whose 


 
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tumor response and progression assessed by RANO criteria will be analyzed and 
summarized separately. 
Waterfall plots for maximum tumor shrinkage from baseline will be provided for 
prespecified subgroups defined in Section 3.6.4 based on RAMD and Efficacy 
Population if baseline and post baseline target lesion measurements are both available 
assessed by RECIST v1.1. criteria and RANO criteria, respectively and separately. 
Forest plots of ORR and 95% CI will be provided for RAMD and Efficacy Population 
correspondingly. 
4.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of ORR is defined as the proportion of patients with a 
confirmed response (complete response [CR] or partial response [PR] for at least two 
assessments with at least 28 days apart and no disease progression [PD] in between) 
before PD and/or other anticancer therapy. ORR and its two-sided 95% CI, which is 
based on the exact binomial distribution (Clopper-Pearson), will be presented.  
Each patient’s best overall response (BOR) will be derived based on RECIST v1.1 (or 
RANO criteria if appropriate). Patients without post-baseline disease assessments will 
be imputed with not evaluable (NE) as their BOR. The BOR will be summarized by count 
and frequency for each category, CR, PR, stable disease (SD), PD, or NE. Patients 
whose tumor response and progression assessed by RECIST v1.1 or RANO criteria will 
be summarized and listed accordingly and separately. 
Waterfall plots will be provided depicting graphically the maximum percentage shrinkage 
from baseline in sum of diameters of target lesions assessed by RECIST v1.1 on or prior 
to first documented disease progression or new subsequent anticancer therapy. 
Waterfall plots will also be provided separately depicting graphically the maximum 
percentage shrinkage from baseline in sum of the product of diameters assessed by 
RANO on or prior to the first documented disease progression or new subsequent 
anticancer therapy if appropriate.  
Forest plots of ORR and 95% CI will be provided for RET altered Measurable Disease 
Population and Efficacy Population correspondingly. 
Individual tumor assessment and BOR will be provided in a by-patient efficacy data 
listing. 
4.6.1.1 
RET-fusion NSCLC 
ORR will be presented for 1) overall, 2) prior systemic treatment, 3) prior platinum 
treatment, 4) prior non-platinum systemic treatment, and 5) no prior systemic treatment 
patients according to grouped dose level I (400 mg QD and All dose levels), respectively 


 
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and separately. However, the ORR is mainly conducted for patients started at 400 mg 
QD of the study drug. 
ORR will also be analyzed for 1) – 5) by prior MKI status (yes vs. no), prior 
chemotherapies other than platinum-based therapies status if applicable, and by prior 
PD-1/PD-L1 status (yes vs. no), respectively. In addition, ORR will be analyzed by RET 
genotype, KIF5B, CCDC6, and others; and further analyzed by age group, grouped race, 
geographic region, and sex, respectively. 
The analysis for ORR and DOR will also be summarized for RET-fusion NSCLC 
patients.  
The following ORR analyses will be provided (Table 3). 
Table 3 
Summary of ORR, BOR, CBR, DCR analysis table(s) for RET-
fusion NSCLC patients 
 
Dose group 
RET-fusion NSCLC * 
400 mg QD 
All 
Overall 
X 
X 
Prior Systemic Treatment 
X 
X 
Prior Platinum Treatment 
X 
X 
Prior non-Platinum Systemic Treatment 
X 
X 
No Prior Systemic Treatment 
X 
X 
Prior MKI Treatment Status 
 
 
RET-fusion NSCLC Prior MKI Treatment  
X 
X 
RET-fusion NSCLC No Prior MKI Treatment     
X 
X 
Prior Chemotherapy other than Platinum 
X 
X 
Prior PD-1/PD-L1 Treatment Status 
 
 
RET-fusion NSCLC Prior PD-1/PD-L1 Treatment  
X 
X 
RET-fusion NSCLC No Prior PD-1/PD-L1 Treatment  
X 
X 
RET genotype   
 
 
KIF5B  
X 
X 
CCDC6  
X 
X 
NCOA4 
X 
X 
Others  
X 
X 
Unknown 
X 
X 
Age group (<65,  65) 
X 
X 
Sex (Male, Female) 
X 
X 
Geographic region (USA, Europe, Asia) 
X 
X 
Race (Asian, White, Others) 
X 
X 


 
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Dose group 
RET-fusion NSCLC CNS Metastases Sub-population 
X 
X 
* 1) – 5) is listed for RET-fusion NSCLC for illustration purpose. The same layout will be used for 
all items listed in the table. 
In addition, the ORR will also be analyzed by prior systemic line of therapy for RET-
fusion NSCLC mainly based on RET-altered Measurable Disease Population and 
supportively based on Efficacy Population, respectively, summarized in Table 4.  The 
ORR may be explored by prior line of therapy and prior platinum treatment, and/or prior 
PD-1/PD-L1 status.  
Table 4 
Summary of ORR, BOR, CBR, DCR analysis table(s) for RET-
fusion NSCLC patients by prior line of therapy 
 
Dose group 
RET-fusion NSCLC 
400 mg QD 
All 
Prior line of systemic therapy 
X 
X 
   0 Prior line of systemic therapy 
X 
X 
   1 Prior line of systemic therapy 
X 
X 
   2 Prior line of systemic therapies 
X 
X 
    3 Prior line of systemic therapies 
X 
X 
The forest plot of ORRs by categories documented in Table 3 and Table 4 and their 95% 
CI will be provided.  
Individual tumor assessment and BOR will be also provided in a by-patient efficacy data 
listing. 
4.6.1.2 
RET-mutation MTC 
ORR will be presented for 1) overall, 2) prior systemic treatment, 3) prior cabozantinib 
and/or vandetanib treatment, 4) prior cabozantinib and vandetanib, 5) no prior 
cabozantinib and/or vandetanib treatment, and 6) no prior systemic treatment patients 
according to grouped dose level I (400 mg QD and All dose levels), respectively, for 
RET-mutation MTC subgroup. The ORR will also be analyzed by RET genotype and by 
age group, sex, geographic region, and race group, RET gene status respectively. The 
following ORR analyses will be provided (Table 5). 
Table 5 
Summary of ORR, BOR, CBR, and DCR analyses for RET-
mutation MTC Patients 
 
Dose group 
RET-mutation MTC 1) – 6) **  
400 mg QD 
All 
Overall 
X 
X 
Prior systemic  
 
 


 
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Dose group 
Prior cabozantinib and/or vandetanib 
X 
X 
Prior cabozantinib and vandetanib treated patients 
X 
X 
No prior cabozantinib and/or vandetanib treated patients 
X 
X 
No prior systemic treatment 
X 
X 
   RET-genotype 
 
 
        M918T 
X 
X 
        Cysteine rich domain * 
X 
X 
        V804X+ 
X 
X 
        Others 
X 
X 
  Age group (<65,  65) 
X 
X 
  Sex (Male, Female) 
X 
X 
  Geographic region (USA, Europe, Asia) 
X 
X 
  Race group (Asian, White, Others) 
X 
X 
  RET gene status (hereditary, sporadic, other) 
X 
X 
** 1) – 6) is listed for RET-mutation MTC for illustration purpose.  
* Patients with C609, C611, C618, C620, C630 and/or C634 of RET-mutation genotype. 
+ Patients with V804M and V804L RET-mutation genotype. 
In addition, the ORR will also be analyzed by prior line of therapy for RET-mutation MTC 
subgroup primarily based on RET-altered Measurable Disease Population and 
supportively based on Efficacy Population, respectively, summarized in Table 6.   
Table 6 
Summary of ORR, BOR, CBR, DCR analysis table(s) for RET-
mutation MTC patients by prior line of therapy 
 
Dose group 
RET-mutation MTC 
400 mg QD 
All 
Prior line of systemic therapy 
X 
X 
   0 Prior line of systemic therapy 
X 
X 
   1 Prior line of systemic therapy 
X 
X 
    2 Prior line of systemic therapies 
X 
X 
 
The forest plot of ORRs by categories documented in Table 5 and Table 6 and their 95% 
CI will be provided.  
The ORR may be explored by prior line of therapy and prior cabozantinib and/or 
vandetanib, and/or prior RAI therapy status. 


 
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4.6.1.3 
RET-fusion Thyroid Cancer 
ORR will be presented by 1) overall and 2) prior systemic treatment treated RET-fusion 
thyroid patients. ORR will also be summarized by RET genotype. In addition, the ORR 
will be analyzed by age group, sex, geographic region, and race group if applicable. The 
analyses are summarized in Table 7. 
Table 7 
Summary of ORR, BOR, CBR, and DCR analyses for RET-fusion 
thyroid patients 
 
Dose group 
RET-fusion thyroid 1) – 2) * 
400 mg QD 
All 
Overall  
X 
X 
Prior systemic treatment 
X 
X 
      RET genotype  
 
 
           CCDC6 
X 
X 
           NCOA4 
X 
X 
           Others 
X 
X 
      Age group (<65,  65) 
X 
X 
      Sex (Male, Female) 
X 
X 
      Geographic region (USA, Europe, Asia) 
X 
X 
      Race group (Asian, White, Others) 
X 
X 
* 1) – 2) is listed for RET-fusion thyroid for illustration purpose. 
In addition, the ORR by prior line of therapy may be also explored for RET-fusion thyroid 
subgroup if applicable primarily based on RET-altered Measurable Disease Population 
and supportively based on Efficacy Population, respectively. 
4.6.1.4 
RET-mutation other than MTC 
ORR, BOR, CBR, DCR, and DOR will be presented by grouped dose levels (400 mg QD 
and All) with other RET-alteration status and disease types for RET-mutation other than 
MTC patients.  
4.6.1.5 
RET-fusion solid tumors other than NSCLC and thyroid 
patients 
ORR, BOR, CBR, DCR, and DOR will be presented with other RET alteration status and 
disease types for RET-fusion Others defined in Section 3.6.4.   
4.6.1.6 
Other patients 
The primary efficacy endpoint across RET-altered Measurable Disease Population 
prespecified subgroups, and “All” patients will also be provided. In addition, the primary 
efficacy endpoints with investigator assessment data as a supportive analysis. The prior 
selective RET-inhibitor treated patients will only be included in “All” patients. 


 
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4.6.2 
Secondary Efficacy Endpoints 
4.6.2.1 
Progression Free Survival 
PFS is defined as the time from the first dose of pralsetinib to the date of first 
documented disease progression or death due to any cause, whichever occurs first. 
Patients without disease progression or death at time of data cutoff will be censored at 
their last valid assessment. Complete censoring rules are specified in Table 8.  
PFS will be analyzed using Kaplan-Meier (KM) methods, the estimated median with two-
sided 95% CI and 25th and 75th percentiles will be provided. The confidence interval 
calculation is based on identity (i.e. linear) transformation. PFS at specific time-points 
(e.g. 3-, 6-, 9-, 12-, 18-, 24-, 30-month etc. every 6-month after 12-month) will be 
computed, along with the standard errors using Greenwood’s formula (Klen, 2003). PFS 
will also be displayed with KM plots. 
Table 8 
Duration of Response and Progression Free Survival Censoring 
Rules 
Situation 
Date of Progression or 
Censoring 
FDA Censoring 
Rules 
EMA Censoring 
Rules 
No baseline assessments and 
alive after 2 scheduled 
assessments (at least 128 
days) 
 
Date of first dose of 
treatment 
Censored 
Censored 
 
Progression documented 
between scheduled visits 
Date of radiological 
assessment showing 
progression 
Event 
Event 
 
No progression 
Date of last radiological 
assessment with evidence 
of no progression (or first 
dose date if no assessment) 
Censored 
Censored 
 
New antineoplastic/ non-
protocol treatment started 
prior to progression 
 
Date of last radiological 
assessment with evidence 
of no progression on or 
prior to the start of new 
antineoplastic treatment 
Censored 
 
Event at date of 
disease 
progression/deat
h 
No progression and new 
antineoplastic/ non protocol 
treatment started 
Date of last radiological 
assessment on or prior to 
the start of new 
antineoplastic treatment. 
Censored 
Censored 


 
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Situation 
Date of Progression or 
Censoring 
FDA Censoring 
Rules 
EMA Censoring 
Rules 
Death before the second 
scheduled post-baseline 
assessment if the first 
scheduled post-baseline 
assessment is not PD 
(defined as 128 days after 
first dose) 
 
Date of death 
 
Event 
 
Event 
Death between scheduled 
assessments 
Date of death 
Event 
Event 
Death or progression after 
missing two or more 
consecutively scheduled 
disease assessments (2 more 
missed scheduled 
assessments defined by at 
least x1 days) 
Date of last radiological 
assessment with evidence 
of no progression prior to 
death/progression 
 
 
Censored 
 
Event at date of 
disease 
progression/deat
h 
1 x= 128 days before EOT visit; x=197 days if the death or progression date is after EOT. 
EMA, European Medicine Agency; FDA, Food and Drug Administration (US). 
The following PFS analyses (Table 9) will be conducted based on BICR data and 
investigator assessment, and different censoring rules specified (Table 8). 
Table 9 
Summary of PFS analyses 
 
Dose group 
 
400 mg QD 
All 
RET-fusion NSCLC 1) – 5)* 
X 
X 
RET-fusion NSCLC CNS Metastases Sub-population 
X 
X 
RET-fusion thyroid 1) -2) * 
X 
X 
RET-fusion solid tumor other than NSCLC and thyroid 
X 
 
RET-mutation MTC 1) – 6) + 
X 
X 
* 1) – 5) and 1) -2) are defined in Section 3.6.4 and Table 3.  
+ 1) – 6) are defined in Section 3.6.4 and Table 5. 
4.6.2.2 
Duration of Response 
Duration of response (DOR) will be analyzed for patients with confirmed CR or PR. DOR 
is defined as the time from first documented response (CR/PR) to the date of first 
documented disease progression or death due to any cause, whichever occurs first. 
Patients without confirmed CR or PR will be excluded from this analysis. Patients who 
are still in response at time of data cutoff will be censored at their last valid assessment. 
The DOR analysis will be conducted based on BICR data and different censoring rules 
specified in (Table 8).  


 
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Duration of response will be analyzed using KM methods and will include the estimated 
median with two-sided 95% CI and 25th and 75th percentiles. DOR at specific time-
points (e.g. 3-, 6-, 9-, 12-, 18-, 24-, 30-month etc.) will be computed, along with the 
standard errors using Greenwood’s formula (Klen, 2003). Additionally, the proportion of 
patients with DOR of at least 3, 6, 9, 12, 18, 24, and 30 months will be summarized 
regardless of censoring status. 
The following DOR analyses (Table 10) will be conducted based on BICR data. The 
DOR analysis will also be produced based on investigator assessment as a supportive 
analysis for RET-mutation MTC, RET-thyroid, and DOR across RET alteration status 
and disease types. 
Table 10 Summary of DOR analyses  
 
Dose group 
 
400 mg QD 
All 
RET-fusion NSCLC 1) – 5)* 
X 
X 
  Age group (<65,  65) 
X 
X 
  Sex (Male, Female) 
X 
X 
  Geographic region (USA, Europe, Asia) 
X 
X 
  Race (Asian, White, Others) 
X 
X 
  RET-fusion genotype 
 
 
     KIF5B 
X 
X 
     CCDC6 
X 
X 
     Others 
X 
X 
RET-fusion NSCLC 1) – 5)* 
X 
X 
  Age group (<65,  65) 
X 
X 
  Sex (Male, Female) 
X 
X 
  Geographic region (USA, Europe, Asia) 
X 
X 
  Race (Asian, White, Others) 
X 
X 
RET-fusion NSCLC CNS Metastases Sub-population 
X 
X 
RET-fusion solid tumor other than NSCLC and thyroid  
X 
X 
RET-fusion NSCLC by prior line of systemic therapy (0, 1, 
2,  3) 
X 
X 
RET-fusion thyroid 1) – 2) * 
X 
X 
  RET genotype  
 
 
       CCDC6 
X 
X 
       NCOA4 
X 
X 
       Others 
X 
X 
RET-fusion thyroid if applicable 
 
 


 
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Dose group 
  Age group (<65,  65) 
X 
X 
  Sex (Male, Female) 
X 
X 
  Geographic region (USA, Europe, Asia) 
X 
X 
  Race group (Asian, White, Others) 
X 
X 
RET-mutation MTC 1) – 6) + 
X 
X 
  RET-genotype 
 
 
        M918T 
X 
X 
        Cysteine rich domain ** 
X 
X 
        V804X++ 
X 
X 
        Others 
X 
X 
  RET gene status 
X 
X 
RET-mutation MTC by prior line of systemic therapy (0, 1,  2) 
X 
X 
* 1) – 2) are defined in Section 3.6.4 and Table 3. 
+ 1) – 6) are defined in Section 3.6.4 and Table 5. 
** Patients with C609, C611, C618, C620, C630 and/or C634 of RET-mutation genotype. 
++ Patients with V804M and V804L RET-mutation genotype. 
DOR will be analyzed for the above patient groups if there are confirmed responses in 
the specified groups. Duration of response will also be displayed with KM plots. 
DOR across prespecified subgroups and “All” patients will also be provided with 
investigator assessment data as a supportive analysis, separately.  
4.6.2.3 
Clinical Benefit Rate 
CBR is defined as the rate of CR or PR, or stable disease which stable disease has 
been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first 
dose date. CBR will be analyzed and summarized using the same methods as ORR 
defined in Section 4.6.1. 
4.6.2.4 
Disease Control Rate 
DCR is defined as the proportion of patients with a confirmed CR/PR, or SD, per 
RECIST v1.1 (or RANO if appropriate). DCR will be analyzed and summarized using the 
same methods as ORR defined in Section 4.6.1. 
4.6.2.5 
Overall Survival 
OS is defined as the time from the first dose of pralsetinib to the date of death due to any 
causes. Patients who are still alive or lost to follow-up will be censored at the last known 
alive date. Last date known alive is defined as the last non-imputed date of any patient 
record prior to or on the data cutoff date in the clinical database. It can be the last visit 
date or last contact date that the patient is known to be alive. 


 
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OS will be analyzed and summarized in a same manner as for PFS in Table 9 based on 
Efficacy Population. 
4.6.2.6 
CNS Metastases Activity 
NSCLC patients’ brain tumor lesions will be assessed by RECIST v1.1 (Eisenhauer 
version 1.1, 2009).   
CNS metastases lesion response (CR) is defined as 
 
disappearance of all target CNS/brain lesion(s), including lesions in brain stem 
and/or cerebellum identified at baseline, and, 
 
disappearance of all non-target CNS/brain lesion(s), identified as RECIST 1.1 
nontarget lesions at baseline, and 
 
no identification of new CNS/brain lesion(s). 
 
CNS metastases lesion response (PR) is defined as 
 
at least a 30% decrease in the sum of diameters of any CNS/brain lesion(s), 
identified as RECIST 1.1 target lesions at baseline, and, 
 
if in the absence of 
 
unequivocal progression of any non-target CNS/brain lesion(s) identified as RECIST 
1.1 nontarget lesions at baseline, or 
 
the identification of new CNS/brain lesion(s). 
CNS metastases progression is defined as either 
 
at least 20% increase in the sum of diameters of target CNS/brain lesion(s), taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5mm, or, 
 
unequivocal progression of any CNS/brain lesion(s) identified as RECIST 1.1 
nontarget lesions at baseline, or 
 
the identification of new CNS/brain lesion(s). 
CNS metastases SD is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD for target/non-target CNS/brain lesion(s), taking as 
reference the smallest sum diameters while on study.   
CNS metastases activity analysis of intracranial ORR, BOR, CBR, DCR, and DOR will 
be summarized for RET-fusion CNS metastases sub-population based on RE, RAMD, 
and Efficacy Population. The intracranial PFS will be also summarized CNS metastases 
sub-population based on Efficacy Population. 


 
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4.6.3 
Analysis of Exploratory Efficacy Endpoints 
4.6.3.1 
EORTC QLQ-C30 
EORTC QLQ-C30 are collected for patients enrolled on or after protocol amendment 
(PA) 4.1 during Phase 2, which all patients’ starting dose will be 400 mg QD. The 
EORTC QLQ-C30 (version 3.0) is a 30-item questionnaire used to evaluate quality of 
life, and includes five functional domains (physical (PF), cognitive (CF), role (RF), 
emotional (EF), and social (SF)), three symptom scales (fatigue (FA), nausea and 
vomiting (NV), and pain (PA)), a global health status / QoL scale (QL), and six single 
items (dyspnea (DY), insomnia (SL), appetite loss (AP), constipation (CO), diarrhea (DI), 
and financial difficulties (FI)). Patients in Phase 2 of the study will complete the EORTC 
QLQ-C30 on Day 1 of Cycles 1 to 12.  
All the scales and single-item measures range in score is from 0 to 100. A high score for 
a functional scale represents a high/healthy level of functioning, a high score for the 
global health status represents a high QoL, but a high score for a symptom scale / item 
represents a high level of symptomatology / problems. Scoring method is outlined in 
Table 11 and the following paragraphs. 
Table 11 Scoring the EORTC QLQ-C30 Version 3.0 
 
Scale 
Number 
of items 
Item 
range 
Version 
3.0 Item 
numbers  
Function 
scales 
Global health Status /QoL 
QL 
2 
6 
29, 30 
 
Functional Scales 
Physical functioning 
PF 
5 
3 
1 to 5 
F 
Role functioning 
RF 
2 
3 
6,7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social function 
SF 
2 
3 
26, 27 
F 
Symptom scales/items 
Fatigue 
FA 
3 
3 
10, 12, 18 
 
Nausea and vomiting 
NV 
2 
3 
14,15 
 
Pain 
PA 
2 
3 
9, 19 
 
Dyspnea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
 


 
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Raw score (RS) is calculated as the average of item score when at least half of the items 
are not missing.  
After RS is calculated, a linear transformation to 0-100 will be applied to get the score 
(S) use ranges provided in Table 3. 
For functional scales S = (1- (RS-1)/range) x 100 
For symptom scales / items and global health status S= ((RS-1)/range) x 100 
Summary statistics and change from Baseline to Day 1 of each cycle will be presented 
for all calculated scores for Efficacy Population prespecified subgroups, defined in 
Section 3.6.4.   
A by-patient listing will be provided for EORTC QLQ-C30. 
4.6.3.2 
Disease-related symptom, bowel movement history 
Disease-related symptoms as reported by bowel movement history are collected only for 
MTC patients from D1 every cycle from Cycles 1 through 12, and D1 on odd cycles after 
Cycle 13 during Phase 2, which all patients’ starting dose will be 400 mg QD.  
Summary and change from baseline in bowel movement history over time will be 
analyzed only for RET-mutation MTC subgroup.  
In addition, the frequency of patients who do not have diarrhea over time will be provided 
for RET-mutation MTC subgroup.  
A by-patient listing of bowel movement history will be provided. 
4.6.3.3 
CNS Metastases Activity for Other Tumor Types other than 
NSCLC 
The intracranial ORR, BOR, CBR, DCR, and DOR for other tumor types other and 
NSCLC will be summarized accordingly if applicable.  
4.7 
SAFETY ANALYSIS 
The safety data will be summarized by grouped dose level II for overall Safety 
Population, and by grouped dose level I for prespecified subgroups defined in Section 
3.6.4, unless otherwise specified. The safety analysis is primarily conducted for patients 
started at 400 mg QD of study drug. 
4.7.1 
Adverse Events 
4.7.1.1 
Adjacent Adverse Events 
Adjacent Adverse Events (AEs) coded to the same PT will be linked. Events are 
considered adjacent if, for the same PT, the end date of an episode is the same as, or 1 
day before, the start date of the next episode. Once linked the adjacent AE will be 
reported as one AE as follows: 


 
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 
The start date of the linked AE is the initial onset date (the start date of the first 
episode).  
 
The end date of the linked AE is the end date of the last episode or missing if the 
last episode is ongoing.  
 
The initial severity grade of the linked AE is the severity grade of first AE episode. 
 
The highest severity grade of the linked AE is the highest severity grade of all AE 
episodes (reported severity). 
 
The linked AE will be considered as treatment related if at least one episode is 
treatment related.  
 
The linked AE will be considered as serious if at least one episode is serious.  
 
The linked AE will be considered as leading to treatment discontinuation if at least 
one episode leads to treatment discontinuation (similarly for treatment interruption 
and treatment reduction). 
 
The outcome of the linked AE is the outcome of the last episode. 
 
The AE will be considered as requiring treatment if at least one episode is 
considered as requiring treatment.  
AEs and Serious AEs will be recorded on the CRF from screening visit through 30 days 
after the last dose of study drug. In addition, SAEs that are assessed as related to study 
treatment and which occur > 30 days post-treatment will also be reported. All AEs will be 
coded using the most current version of MedDRA. The severity will be graded per the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) 4.0  
A patient experiencing multiple AEs (after adjacent AEs have been linked) under the 
same PT (SOC) will be counted only once for that PT (SOC) by worst severity. If a 
patient experiences the same (linked) AE more than once with more than one 
relationship to study drug, the worst causal relationship to study drug will be given 
precedence. Any missing severity, causality, or outcome will not be imputed and 
classified as ‘Missing’. Detailed imputation rule for missing AE dates are in Section 7.1. 
AEs will be analyzed in terms of treatment-emergent adverse events (TEAEs) which are 
defined as any (linked) AE that has an onset date during or after administration of the 
first dose of study drug through 30 days after the last dose of study drug or until a 
subsequent new anticancer therapy, any event that is considered study drug-related 
regardless of the start date of the event, or any event that is present at baseline but 
worsens intensity or is subsequently considered study drug-related by the Investigator.  
Adverse Event refers to TEAEs unless otherwise specified throughout this document. 
The following tables will be provided (Table 12). 


 
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1. 
AE Summary (including all subsequent items) 
 
Any AE 
 
Grade 3/4/5 AE 
 
Any treatment-related AE 
 
Grade 3/4/5 treatment-related AE 
 
Any SAE 
 
Grade 3/4/5 SAE 
 
Any treatment-related SAE 
 
Study drug adjustment due to AE 
 Any AE leading to treatment discontinuation 
 Any AE leading to treatment discontinuation due to disease 
progression 
 Any AE leading to treatment discontinuation excluding disease 
progression  
 Any AE leading to treatment interruption 
 Any AE leading to treatment reduction 
 
Study drug adjustment due to treatment-related AE 
 Any treatment related AE leading to treatment discontinuation 
 Any treatment related AE leading to treatment discontinuation due 
to disease progression 
 Any treatment related AE leading to treatment discontinuation 
except disease progression  
 Any treatment related AE leading to treatment interruption 
 Any treatment related AE leading to treatment reduction 
 
Death (Grade 5) due to AE 
 
Death due to AE related to study drug 
 
Patients with treatment related AE by NCI CTCAE grade 
 
Patients with SAE by NCI CTCAE grade 
2. 
AE by PT/ by SOC and PT  
1. Treatment-related AE by PT/by SOC and PT 
3. 
SAE by PT/by SOC and PT 
4. 
SAE related to study drug by PT/by SOC and PT 
5. 
Grade   3 AE by PT/by SOC and PT 
6. 
Grade   3 treatment related AE by PT/by SOC and PT 
7. 
AE by PT/by SOC and PT, and NCI CTCAE Grade 


 
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8. 
Treatment related AE by PT/by SOC and PT, and NCI CTCAE Grade 
9. 
SAE by PT/by SOC and PT, and NCI CTCAE Grade 
10. Treatment related SAE by PT/by SOC and PT, and NCI CTCAE Grade 
11. AE leading to interruption of study drug regardless of causality by PT/ by SOC and 
PT 
12. Treatment related AE leading to interruption of study drug regardless of causality by 
PT/ by SOC and PT 
13. AE leading to reduction of study drug regardless of causality by PT/ by SOC and PT 
14. Treatment related AE leading to reduction of study drug regardless of causality by 
PT/ by SOC and PT 
15. AE leading to permanent discontinuation of study drug regardless of causality by 
PT/ by SOC and PT 
16. Treatment related AE leading to permanent discontinuation of study drug regardless 
of causality by PT/ by SOC and PT 
In addition, AEs, SAEs, treatment related AEs, treatment related SAEs will be analyzed 
by age group, sex, geographic region, weight group and race group, and by PT, 
SOC/PT, or SOC/PT/CTCAE severity grade for prespecified subgroups if applicable, and 
“All” patients based on Safety Population. 
The AEs, related AEs, SAEs, and related SAEs will be further analyzed across RET 
alteration status and disease types, i.e., RET-mutation MTC, RET-mutation others, RET-
fusion thyroid, RET-fusion NSCLC, RET-fusion others, and “All” for Safety Population. 
All AEs will be listed for each treated patient in a by-patient listing. Table 12 summarizes 
tables for AE data analyses.


 
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Table 12 Summary of Adverse Event analyses 
Safety Endpoint 
Main 
By PT 
By SOC and PT 
By PT and 
CTCAE Grade 
BY SOC, PT, and 
CTCAE Grade 
Overall, 
Subgroups [1] 
Overall, 
Subgroups [1] 
Overall, 
Subgroups [1] 
Overall, 
Subgroups [1] 
Overall, 
Subgroups [1] 
Summary Table [4] 
X 
 
 
 
 
AE 
 
X 
X 
X 
X 
SAE 
 
X 
X 
X 
X 
Grade   3 AE 
 
X 
X 
  
  
Related AE 
 
X 
X 
X 
X 
Related SAE 
 
X 
X 
X 
X 
Related Grade   3 AE 
 
X 
X 
  
  
AE Leading to Permanent Study Treatment 
Discontinuation 
 
X 
X 
 
 
Related AE Leading to Permanent Study 
Treatment Discontinuation 
 
X 
X 
 
 
Adverse Events Leading to Dose 
Interruption 
 
X 
X 
 
 
Related Adverse Events Leading to Dose 
Interruption 
 
X 
X 
 
 
Adverse Events Leading to Dose 
Reduction 
 
X 
X 
 
 
Related Adverse Events Leading to Dose 
Reduction 
 
X 
X 
 
 
AE Leading to Death 
 
X 
 
 
 
Related AE Leading to Death 
 
X 
 
 
 


 
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Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; PT = preferred term; SAE = serious adverse 
event; SOC = system organ class.  
[1] Overall, All Safety Population; Subgroups, prespecified subgroups defined in Section 3.6.4 if applicable.  
[2] Overall, All Safety Population; Subgroups patients treated at 400 mg QD. 
[3] RET alteration status and disease type subgroups, RET-mutation MTC, RET-mutation others, RET-fusion thyroid, RET-altered thyroid, RET-
fusion NSCLC, RET-fusion others, and “All”. 
[4] Summary AE will also be analyzed by age group, sex, geographic region, and race group for All Safety Population and RET-mutation MTC 
patients treated at 400 mg QD if applicable. 
 
 


 
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Table 12 Summary of Adverse Event Tables (Cont’d) 
Safety Endpoint 
By PT and Age 
Group (<65 
years, ≥ 65 
Years) 
By SOC, PT and 
Age Group (<65 
years, ≥ 65 
Years) 
By PT and Sex 
(Male, Female) 
By SOC and PT, 
and Sex (Male, 
Female) 
By PT, and 
Geographic 
Region (USA, 
Europe, Asia) 
By SOC and PT, 
and Geographic 
Region (USA, 
Europe, Asia) 
Overall, and 
subgroups [2] 
Overall, and 
subgroup [2] 
Overall, and 
subgroup [2] 
Overall, and 
subgroup [2]  
Overall, and 
subgroup [2]  
Overall, and 
subgroup [2]  
AE 
X 
X 
X 
X 
X 
X 
SAE 
X 
X 
X 
X 
X 
X 
Grade   3 AE 
X 
X 
X 
X 
X 
X 
Related AE 
X 
X 
X 
X 
X 
X 
Related SAE 
X 
X 
X 
X 
X 
X 
Related Grade   3 
AE 
X 
X 
X 
X 
X 
X 
AE/Related AE 
Leading to Permanent 
Study Treatment 
Discontinuation 
 
 
 
 
 
 
AE/Related AE 
Leading to Dose 
Interruption 
 
 
 
 
 
 
AE/Related AE 
Leading to Dose 
Reduction 
 
 
 
 
 
 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; PT = preferred term; SAE = serious adverse 
event; SOC = system organ class.  
[1] Overall, All Safety Population; Subgroups, prespecified subgroups defined in Section 3.6.4 if applicable.  
[2] Overall, All Safety Population; Subgroups patients treated at 400 mg QD. 


 
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[3] RET alteration status and disease type subgroups, RET-mutation MTC, RET-mutation others, RET-fusion thyroid, RET-altered thyroid, RET-
fusion NSCLC, RET-fusion others, and “All”. 
[4] Summary AE will also be analyzed by age group, sex, geographic region, and race group for All Safety Population and RET-mutation MTC 
patients treated at 400 mg QD if applicable. 
 
 


 
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Table 12 Summary of Adverse Event Tables (Cont’d) 
Safety Endpoint 
By PT and Race 
Group (Asian, 
White, Others) 
By SOC and PT, 
and Race 
Group (Asian, 
White, Others) 
By PT and Weight 
Group (<60 
kg,  60 kg 
and   75kg, >75kg) 
By SOC and PT, 
and Weight Group 
(<60 kg,  60 kg 
and   75kg, >75kg) 
By PT and RET 
alteration 
status and 
disease types [3] 
By SOC, PT, and 
RET alteration 
status and 
disease types [3] 
Overall, and 
subgroup [2]  
Overall, and 
subgroup [2]  
Overall, and 
subgroup [2]  
Overall, and 
subgroup [2]  
Overall 
Overall 
AE 
X 
X 
X 
X 
X 
X 
SAE 
X 
X 
X 
X 
X 
X 
Grade   3 AE 
X 
X 
X 
X 
 
 
Related AE 
X 
X 
X 
X 
X 
X 
Related SAE 
X 
X 
X 
X 
X 
X 
Related Grade   3 AE 
X 
X 
X 
X 
 
 
AE/Related AE 
Leading to Permanent 
Study Treatment 
Discontinuation 
 
 
 
 
 
 
AE/Related AE 
Leading to Dose 
Interruption 
 
 
 
 
 
 
AE/Related AE 
Leading to Dose 
Reduction 
 
 
 
 
 
 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; PT = preferred term; SAE = serious adverse 
event; SOC = system organ class.  
[1] Overall, All Safety Population; Subgroups, prespecified subgroups defined in Section 3.6.4 if applicable.  
[2] Overall, All Safety Population; Subgroups patients treated at 400 mg QD. 
[3] RET alteration status and disease type subgroups, RET-mutation MTC, RET-mutation others, RET-fusion thyroid, RET-altered thyroid, RET-
fusion NSCLC, RET-fusion others, and “All”. 


 
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[4] Summary AE will also be analyzed by age group, sex, geographic region, weight, and race group for All Safety Population and prespecified 
subgroup patients treated at 400 mg QD if applicable. 


 
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4.7.2 
Adverse Event Special Interest  
The adverse event special interest (AESI) categories will be defined by groups of 
selected and relevant PTs. Seven identified AESI categories are tumour lysis syndrome, 
pneumonia, pneumonitis, hypertension, hepatotoxicity, cases of potential drug-induced 
liver injury and suspected transmission of an infectious agent by a study treatment.  
The number and percentage of patients with AESIs will be summarized by AESI 
category and PT. In addition, the number and percentage of patients with AESIs will be 
summarized by AESI category, PT, and NCI CTCAE. Similar analyses for treatment 
related AESIs will also be provided. Any adjacent AEs are reported as one single AE, 
see Section 4.7.1.1. 
Exploratory time to event analyses for the AESI terms will be provided, respectively. 
Herein, in this section, an event will be used to represent any one of the five AESIs. The 
analyses include the following categories.  
● 
time to onset (for AEs of any grades, for AEs of Grade 3 or worse [Grade 3+]) 
● 
time to resolution (for AEs of any grades, for AEs of Grade 3+)  
The time to event analyses will be using KM analysis method and the estimated median 
with two-sided 95% CI and 25th and 75th percentiles will be provided. The KM will be 
presented over time in weeks for all Safety Population, prespecified subgroups, defined 
in Section 3.6.4, based on Safety Population. In addition, the summary analyses for time 
to events will also be provided. 
4.7.2.1 
Time to Onset 
Time to onset is defined from the treatment start date to the start date of first event (the 
event onset date – study drug start date + 1). Patients without an event will be censored 
at the date of last study drug plus 30 days (or the data cutoff if earlier).  
The time to onset analyses will examine an event at any grade if there is an event, as 
well as an event of Grade 3+, respectively. 
4.7.2.2 
Time to Resolution 
Resolution is defined as complete resolution. Resolution is achieved if the outcome is 
resolved with no sequalae.  
Time to resolution is defined as (date of resolution – date of onset of (linked) event + 1). 
Those events that are not resolved will be censored at the earliest of data cutoff date, 
end of study date, and death date.  
If multiple occurrence of an event with different grades are identified, the one with the 
highest grade will be included. If multiple occurrence of an event with same grade are 
identified, the one with the longest duration (of linked event) will be included. If multiple 


 
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occurrence of an event with same grade and same duration are identified, the first event 
will be taken. 
Here are some examples,  
a patient started a Grade 1 event at Day 3 and continued through Day 5. This patient 
had a Grade 2 at Day 6 through Day 9. This patient had a Grade 3 at Day 10 and 
continued through Day 19. This patient then had a Grade 2 at Day 20. Furthermore, the 
patient had Grade 1 at Day 30 and resolved at Day 40. The time to resolution should be 
Day 40 – Day 3 + 1.  
a patient started a Grade 1 event at Day 3 and continued through Day 5. This patient 
had a Grade 2 at Day 6 through Day 9. This patient had a Grade 3 at Day 10 and 
continued through Day 19. This patient then had a Grade 2 at Day 20. Furthermore, the 
patient had Grade 1 at Day 30 and ongoing till the end of study date, death date, or 
cutoff date. The patient should be censored at the data cutoff date since the event has 
not been resolved. 
The following AE related analyses will be provided for AESIs (Table 13) 
. 


 
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Table 13 Summary of AESI analyses 
Safety Endpoint 
By AESI 
category and 
PT 
By AESI 
category 
and PT 
By AESI 
category, PT, 
and Age 
Group 
By AESI 
category, PT, 
and Sex 
By AESI 
category, PT, 
and 
Geographic 
Region 
By AESI 
category, PT, 
and Race 
group 
By AESI 
category, PT 
and NCI 
CTCAE 
Overall and 
Subgroups [1] 
RET 
alteration 
status and 
Disease 
Type(s) [2] 
Overall 
and subgroup 
[3] 
Overall 
and subgroup 
[3] 
Overall 
and subgroup 
[3] 
Overall 
and subgroup 
[3] 
Overall, and 
subgroup [3] 
AE 
X 
X 
X 
X 
X 
X 
X 
Grade  3 AE 
X 
X 
 
 
 
 
X 
SAE 
X 
X 
X 
X 
X 
X 
X 
Related AE 
X 
X 
X 
X 
X 
X 
X 
Grade  3 Related AE 
X 
X 
 
 
 
 
X 
Related SAE 
X 
X 
X 
X 
X 
X 
X 
AESI leading to dose  
discontinuation, interruption, 
reduction, respectively 
X 
X 
 
 
 
 
X 
Time to Onset 
(All grades, Grade 3+) [4] 
X 
X 
 
 
 
 
 
Time to Resolution 
(All grades, Grade 3+)[4] 
X 
X 
 
 
 
 
 
AE Leading to Death 
X 
 
 
 
 
 
 
Related AE Leading to 
Death 
X 
 
 
 
 
 
 
[1] Overall, All Safety Population; Subgroups, prespecified subgroups defined in Section 3.6.4 if applicable.  


 
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[2] Overall, All Safety Population; prespecified subgroups patients treated at 400 mg QD if applicable. 
[3] RET alteration status and disease type subgroups, RET-mutation MTC, RET-mutation others, RET-fusion thyroid, RET-fusion NSCLC, RET-
fusion others, and “All”. 
[4] Summary AE will also be analyzed by age group, sex, geographic region, and race group for All Safety Population and prespecified subgroup 
patients treated at 400 mg QD if applicable. 


 
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4.7.3 
Grouped Adverse Events 
Adverse events, for the purpose of analysis, a set of comprehensive definitions 
comprising Sponsor-defined, standardized MedDRA queries [SMQ], high-level terms 
[HLTs], and Sponsor-defined AE Grouped Terms [AEGTs] will be used to identify and 
summarize grouped adverse events by medical concept. The medical concepts include 
identified and potential risks, if not already considered AESIs, as well as potential class 
effects and include the following: 
 
Neutropenia 
 
Thrombocytopenia 
 
Anaemia 
 
Haemorrhage  
 
Severe Infection with Grade 3+ 
 
QT Prolongation  
 
Decreased Calcium 
 
Increased Phosphorus 
 
Increased Potassium 
 
Lymphopenia 
 
Transaminase Elevation 
Summary analyses will be presented for grouped adverse events. Time to event analysis 
will be provided for grouped adverse events similar as the ones for AESI terms. Any 
adjacent AEs are reported as one single AE, see Section 4.7.1.1. 
4.7.4 
Serious Adverse Events and Deaths 
All serious adverse events (SAEs) must be reported whether they are considered 
causally related to pralsetinib or protocol procedures. SAEs that are assessed as related 
to pralsetinib will also be reported even if the occurrence is more than 30 days after the 
last dose of study drug. Any adjacent AEs are reported as one single AE, see Section 
4.7.1.1. 
A listing of all AEs for patients who died will be provided specifying the date of death, the 
cause, and the date of last study treatment dose. On treatment death (from first dose 
date to last dose date + 30 days) will be clearly marked. 
4.7.5 
Clinical Laboratory Evaluations 
Clinical laboratory values are graded according to NCI CTCAE version 4.0 for applicable 
parameters except creatinine, which will be graded according to NCI CTCAE version 5.0 
to correct the grading error for this specific laboratory test used in CTCAE version 4.0.  


 
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The summary and changes from baseline will be presented for hematology, serum 
chemistry (including coagulation), thyroid test laboratory values based on overall Safety 
Population, and Safety Population RET-mutation MTC and RET-fusion thyroid, 
respectively.  
Shift tables of laboratory data from baseline to worst grade during treatment will be 
presented for the following parameters.  Patients with baseline and post-baseline 
assessments available will be included in corresponding parameters. The shift table in 
maximum CTCAE grades of worst (high) and worst (low) assessment will be presented 
separately. 
 
Serum chemistry parameters, activated partial thromboplastin time, alanine 
aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), total bilirubin, magnesium, phosphate, potassium, 
prothrombin time and international normalized ratio, sodium, creatinine, and 
corrected calcium (mmol/L), which is calculated as total calcium in mmol/L + 
(0.02×(40 – albumin measured in g/L)).  
 
Hematology parameters, hemoglobin, leukocytes, lymphocytes (absolute), 
neutrophils (absolute), platelets.  
A Hy’s law analysis will be provided. The potential Hy’s law quadrant is defined as ALT 
or AST increases above 3-fold the ULN with concomitant total bilirubin increases above 
2-fold the ULN. 
Urinalysis will be presented in listing only. 
Boxplot of selected laboratory tests (including serum chemistry parameters [ALT, 
albumin, AST, ALP, total bilirubin, phosphate, sodium, calcium, corrected calcium, 
potassium], hematology parameters [hemoglobin, leucocytes, neutrophils (absolute), 
lymphocytes (absolute), platelets], and thyroid-test for thyroid patients [thyroid-
stimulating hormone (TSH)]) values will be presented by visit. 
A by-patient listing will be provided for each laboratory parameter. All results outside 
predefined normal ranges, and CTCAE grade will be flagged in the data listings. 
4.7.6 
Vital Signs 
Results for height, weight, body mass index (BMI), systolic and diastolic blood pressure 
(BP), heart rate, and body temperature will be summarized over time point. Changes 
over time point in BP, pulse rate, and body temperature from baseline will be 
summarized based on Safety Population. Boxplot of vital sign values and change from 
Baseline over time will be presented by visit based on overall Safety Population, and 
prespecified subgroups based on Safety Population, respectively. 
Vital sign assessments will also be provided in a by-patient listing. 


 
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4.7.7 
Electrocardiograms 
Electrocardiogram (ECG) overall interpretation (normal, abnormal not clinically 
significant [NCS], abnormal clinically significant [CS], and not evaluable [NE]) will be 
presented for actual values and changes from baseline (expressed as improvement, no 
change, and deterioration) for overall Safety Population and Safety Population 
subgroups, RET-mutation MTC and RET-fusion thyroid patients. 
All ECG assessments will also be provided in a by-patient listing. 
4.7.8 
Electrocardiogram Holter Monitor 
ECG Holter Monitor data and the correlation between ECG Holter Monitor data and PK 
will be discussed and analyzed in a separate report. 
4.7.9 
ECOG Performance Status 
The frequency counts of patients in each ECOG performance status score over time 
point will be summarized. 
A by-patient listing for all performance status data will also be provided. 
4.7.10 
Other Safety Parameters 
A by-patient data listing for all pregnancy status, physical exam data will be provided.  
4.8 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
4.8.1 
Pharmacokinetic Analysis 
All PK and exposure-response analyses specified in the protocol will be discussed and 
provided in a separate report. 
4.8.2 
Calcitonin and Carcinoembryonic Antigen Pharmacodynamics  
Circulating plasma concentrations of calcitonin and CEA will be collected and analyzed 
for RET-mutation MTC patients across all doses.  
For each patient, the change and percent change from baseline will be calculated at 
each time point with available plasma at baseline and post-baseline at a certain time 
point.  The change from baseline is defined as the difference between post-baseline and 
baseline, i.e. post-baseline – baseline, respectively. The percent change from baseline 
in calcitonin and CEA is defined as 100*(post-baseline – baseline)/baseline.  
The change and percent change from baseline will be summarized over time for RET-
mutation MTC patients by dose level, respectively.  
The Waterfall plots for maximum reduction from baseline, defined as the minimum 
percent change from baseline in calcitonin and CEA, respectively, will be provided for 
Safety Population RET-mutation MTC all patients and RET-mutation MTC patients 
treated at 400 mg QD. 


 
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In addition, patients’ best biochemical response based on calcitonin and CEA will also 
be analyzed (Wells, et al. (2012), respectively. The definition for CR, PR, SD, PD, and 
NE are the following in order.  
 
Complete response is defined as normalization of serum levels (calcitonin and CEA, 
respectively) following treatment confirmed at a minimum of 4 weeks later. The 
normalization of serum levels is defined to have serum values within the normal 
range. Patients having to have normalized serum levels at two visits, which are at 
least 4 weeks apart (28 days), are complete responses.  
 
Partial response is defined as at least 50% decrease from baseline levels 
maintained over a minimum of 4 weeks.  
 
Stable disease is defined as the change from baseline should be within (-50%, 50%) 
and maintained for at least 4 weeks. 
 
Progressive disease is defined as patients whose change from baseline is more 
than 50% increase from baseline maintained for at least 4 weeks. 
 
Not evaluable, other situations that are not included in the above 4 categories. 
Biochemical response rate (BRR) is defined as the proportion of patients with a 
confirmed response (complete response [CR] or partial response [PR] for at least two 
assessments with at least 28 days apart and no disease progression [PD] in between) 
before PD and/or other anticancer therapy according to calcitonin or CEA, respectively. 
BRR and its two-sided 95% CI, which is based on the exact binomial distribution 
(Clopper-Pearson), will be presented by dose level for calcitonin and CEA, respectively. 
Patients with normal serum levels at baseline will not be included in BRR analysis. 
5. 
INTERIM ANALYSIS 
There is no interim analysis for this study. 
6. 
CHANGES FROM THE PLANNED ANALYSIS 
6.1 
CHANGES FROM THE PLANNED ANALYSES IN PROTOCOL 
TO SAP VERSION 1.0 
Here is the list for changes from the planned analyses in protocol.  
 
Efficacy Population is not used in this SAP and analyses since Safety Population is 
applied for overall population and each pre-specified subgroup. The definition for 
efficacy population for each pre-specified subgroup is same as the definition based 
on Safety Population.  
 
NSCLC patients tested with oncomine diagnostic target test (ODxTT) is added as an 
ODxTT sub-population in this SAP. RET-fusion positive NSCLC with measurable 
(target) lesions in CNS/brain patients, including brainstem and cerebellum, and 
without radiotherapy and radiosurgery 2 months before study drug, will be included 
into CNS metastases sub-population.  


 
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 
Patients are grouped based on different grouping rules respectively. For example, 
the grouped starting dose will be based on patients’ starting treatment dose.  
 
CNS metastases activity analysis is added as an exploratory analysis. The 
exploratory analysis on medical history, prior or concomitant medication, and time to 
event for pneumonitis, pneumonia, and hypertension are added, respectively.  
 
TEAE, related TEAE, SAE, and related SAE will be analyzed by 1) prior PD-1/PD-L1 
status for RET-fusion NSCLC patients treated at 400 mg QD, 2) by selected 
subgroups, RET-fusion NSCLC, MTC, others, and all Safety Population treated at 
400 mg QD. 
 
6.2 
CHANGES FROM SAP VERSION 1.0 TO SAP VERSION 2.0 
 
The definition for Efficacy Population is added to the SAP. The Efficacy Population 
is defined as a subset of the Safety Population who were dosed on or before July 
11, 2019. This modification was based on feedback received from FDA to allow 
enough follow-up time from initial response among responders. 
 
CNS metastases activity analysis is using only lesions in CNS/brain. The CNS ORR 
which is based on CNS/brain lesions will be provided. However, the analysis for 
PFS and DOR which are based on CNS/brain lesions are removed. 
 
The analysis of DOR across RET alteration status, and tumor types, i.e. RET-fusion 
NSCLC, RET-fusion PTC, MTC, and others, are added as a supportive analysis. 
 
Three AESI categories, pneumonia AESI, pneumonitis AESI, and tumor lysis 
syndrome AESI are added. The additional analyses for the AESIs are defined.  
 
One grouped term neutropenia, which include neutropenia and neutrophil count 
decreased, is also added. The analyses for grouped neutropenia will follow the 
same analysis method for AESIs. The exploratory time to event analyses for a 
single PT hypertension will also be provided. 
 
The summary analyses of demographics, medical history, prior and concomitant 
medication, prior anticancer therapies, dose modification will be provided for the 
AESIs. 
 
The laboratory parameter creatinine will be graded with NCI CTCAE version 5.0 to 
correct the grading error for this specific laboratory test used in CTCAE version 
version 4.03. 
 
6.3 
CHANGES FROM SAP VERSION 2.0 TO SAP VERSION 3.0 
 
The RET-fusion NSCLC subpopulation and corresponding analyses are removed. 
RET-fusion NSCLC will not split into different categories based on patients’ prior 
therapy(ies). 
 
The dose-determing population, and DLT related analyses are removed. 


 
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 
The prior radioactive iodine (RAI) and prior lenvatinib and/or sorafenib are added as 
two additional categories in prior antineoplastic therapy for RET-fusion thyroid 
patients. 
 
The primary analysis population for MTC has been changed from MTC to RET-
mutation MTC. The detailed analyses for RET-mutation MTC has been added for 
primary analysis, secondary analysis endpoints, and safety analysis endpoints. 
 
The primary analysis population for PTC has been changed from RET-fusion PTC to 
RET-fusion thyroid. The detailed analysis for RET-fusion thyroid has been added for 
primary analysis, secondary analysis endpoints and safety analysis endpoints. 
 
One grouped term thrombocytopenia, which include thrombocytopenia and platelet 
count decreased, is added. The analysis for grouped thrombocytopenia will follow 
the same analysis method for AESIs and grouped neutropenia. 
 
The mitogen-activated protein kinases pathway expression signature analysis is 
removed from this version. The detailed analysis was documented in SAP Version 
2.0. 
 
The C634X are combined with other genotypes, such as C609, C611, C618, C620, 
C630 of RET into cysteine rich domain. 
 
The summary analyses of circulating plasma concentrations of calcitonin and CEA 
are added for RET-mutation MTC patients. In addition, the BRR analyses based on 
calcitonin and CEA are also provided, respectively. 
 
The history CNS metastases are added into baseline characteristics analysis. 
 
Grouped anemia are added into grouped AE analysis and time to onset of grouped 
anemia is also added into time to onset analysis. 
 
The analysis for bowel movement function is added. 
 
The description about table/listing/figure formats is removed. 
6.4 
CHANGES FROM SAP VERSION 3.0 TO SAP VERSION 4.0 
 
The objectives/endpoints/sample size section has been updated according to PA 
13. 
 
The actual enrollment cutoff date has been removed. 
 
The primary efficacy endpoint ORR and the secondary efficacy endpoint CBR, DCR, 
and DOR will be analyzed based on RET-altered Measurable Disease Population. 
The ORR and DOR will be conducted based on Efficacy Population as sensitivity 
analysis. Other efficacy endpoints will be based on Efficacy Population. 
 
The RET-fusion NSCLC subpopulation and corresponding analyses are added back 
to have comprehensive analysis plan. 
 
The subgroup, RET-altered thyroid patients, has been added into Section 3.6.4. The 
safety analyses will also be provided for RET-altered thyroid patients.  
 
The primary efficacy endpoints by RET gene status (hereditary, sporadic, others) for 
RET-mutation MTC patients has been added. 


 
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 
The prior line of therapy has been added into baseline characteristics analysis. The 
primary analysis endpoint by the prior line of therapy will be provided. The derivation 
of prior line of therapy is also documented in Appendix. 
 
The RET gene status for MTC has been added into baseline characteristics 
analysis. The primary analysis endpoint by RET gene status for RET-mutation MTC 
will be provided. The derivation of RET gene status is also documented in Appendix. 
 
The definition of RET-fusion NSCLC CNS metastases population has been updated 
to include more details. In addition, the RET-fusion NSCLC CNS metastases activity 
analysis has been moved from Additional Exploratory Analysis to the Secondary 
Efficacy Analysis. The CNS metastases activity for other tumor types other than 
NSCLC has been added into Additional Exploratory Analysis section (Section 4.6.3).  
 
The AESI pneumonia, tumor lysis syndrome has been removed from AESI section. 
The updated AESI hypertension and new AESI hepatotoxicity have been added.  
6.5 
CHANGES FROM SAP VERSION 4.0 TO SAP VERSION 5.0 
 
Number of protocol amendment when EORTC QLQ-C30 was introduced was 
corrected in section 4.6.3.1 
 
Clarification added in section 4.6.2.1 on the censoring rules for the start of a new 
antineoplastic/non protocol treatment for PFS and DOR. 
 
All AE analyses will be done after adjacent AEs have been linked. Section 4.7.1.1 
was updated to provide a more detailed explanation on how linked AEs will be 
reported. 
 
The AESI of Pneumonia and tumour lysis syndrome have been added back. 
 
Time to improvement has been removed from section 4.7.2 
 
Return to Baseline will no longer be consider when analyzing Time to 
Resolution/Return to Baseline, therefore the name of the endpoint was also 
changed to Time to Resolution. 
 
Data imputation guidelines for new anticancer therapy date imputation have been 
added in section 7.1.5. 
6.6 
CHANGES FROM SAP VERSION 5.0 TO SAP VERSION 6.0 
 
All content from version 5 was migrated to the Roche SAP template from the 
Blueprint Medicines SAP template 
 
Blueprint Medicines protocol number has been updated to Roche protocol number 
throughout the SAP. BLU667-1101 to BO42863. 
 
Updated sections to reflect the changes made in BO42863 Protocol, v14 
 
Response Evaluable population in section 2.4 has been updated with a clarification 
of which RET-fusion Others patients should be excluded 
 
Added Section 3.6.6 - “Grouping patients by baseline weight” 


 
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 
The WHODrug version used to code prior and concomitant medication and prior 
antineoplastic therapy was updated from version WHODrug B3, March 2019 to the 
most current version of WHODrug (section 4.4) 
 
The RET-fusion solid tumor other than NSCLC and thyroid population was added to 
the summary of PFS analyses in section 4.6.2.1.  
 
The MedDRA version used to code adverse events was updated from version 19.1 
to the most current version throughout the document 
 
Summaries of AEs leading to death and related AEs leading to death have been 
added to the to the Adverse Event analyses in table 12, see section 4.7.1 
 
In Section 4.7.2, added two additional AESIs,  
 
cases of potential drug-induced liver injury 
 
suspected transmission of an infectious agent by a study treatment 
● 
In Section 4.7.3, added eight additional grouped AEs: 
o Hemorrhage  
o Severe Infection with Grade 3+ 
o QT Prolongation  
o Decreased Calcium 
o Increased Phosphorus 
o Increased Potassium 
o Lymphopenia 
o Transaminase Elevation 
● 
Deleted list of PTs in sections 4.7.2, 4.7.3 and Appendices 
 
Section 4.7.5 has been updated to include a Hy’s law analysis scatter plot 
Additional minor changes have been made throughout to improve clarity and 
consistency 
7. 
APPENDICES 
7.1 
DATA IMPUTATION GUIDELINES 
No imputation will be made for completely missing date unless otherwise specified. 
General imputation rules mentioned below apply to partially missing or impossible dates: 
 
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date 
 
If the start date is not missing, and the imputed stop date is before the start date, 
then the imputed stop date will be equal to the start date 
 
Any imputed dates need to be logical. For example, last dose date should not be 
later than death date. 


 
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When imputation rules in subsequent sections contradicts the general rule, always follow 
the general rule. 
7.1.1 
Adverse Event Date Imputation 
Follow the general rule specified in Section 7.1. 
Incomplete Start Date: 
Missing day, month, and year 
 
No imputation will be made; the corresponding AE will be included. 
Missing day and month 
 
If the year is the same as the year of the first dose date, then impute day and month 
as the day and month of the first dose date 
 
If the year is prior to the year of the first dose date, then impute day and month as 
31 Dec 
 
If the year is after the year of the first dose date, then impute day and month as 01 
Jan. 
Missing day only 
 
If the month and year are the same as those of the first dose date, then impute day 
as the day of the first dose date 
 
If either the year of partial date is before the year of the first dose date, or the years 
are the same, but the month of partial date is before the month of the first dose 
date, then impute day as last day of the month 
 
If either the year of partial date is after the year of the first dose date, or the years 
are the same, but the month of partial date is after the month of the first dose date, 
then impute day as first day of the month. 
Incomplete Stop Date: 
Missing day, month, and year 
 
No imputation will be made. 
Missing day and month 
 
If the year is the same as the year of the last dose date, then impute day and month 
as the day and month of the last dose date 
 
If the year is prior to the year of the last dose date, then impute day and month as 
31 Dec 
 
If the year is after the year of the last dose date, then impute day and month as 01 
Jan. 
Missing day only 
 
If the month and year are the same as those of the last dose date, then impute day 
as the day of the last dose date; 


 
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 
If either the year of partial date is not the same as the year of the last dose date, or 
the years are the same, but the month of partial date is not the same as the month 
of the last dose date, then impute day as last day of the month. 
7.1.2 
Concomitant Medication Date Imputation 
Follow the general rules specified in Section 7.1 and rules in Section 7.1.1. 
7.1.3 
Prior Therapies Date Imputation 
Follow the general rule specified in Section 7.1. 
 
For partial start date as month and year are available, then impute day as ‘01’; e.g., 
impute partial date of ‘DEC2013’ as ‘01DEC2013’. 
 
For partial start date as year only is available, then impute day and month as 
‘01JAN’; e.g., impute partial date of ‘2013’ as ‘01JAN2013’. 
 
For partial end date as month and year are available, then impute day as last day of 
the month; e.g., impute partial date of ‘JUN2013’ as ‘30JUN2013’. 
 
For end date partial as year only is available, then impute day and month as the last 
day of the year; e.g., impute partial date of ‘2013’ as ‘31DEC2013’. 
If the imputed starting date is earlier than initial diagnosis date, it should be set as the 
initial diagnosis date. No overlap between the exposure to prior therapies and study drug 
will be allowed and any overlap of exposure will be queried at data review stage. The 
end date of prior therapies will be imputed to first dose date of study drug – 15 if there is 
overlap due to imputation of partial dates. When there are multiple lines of prior 
therapies, the end date of prior therapies will be imputed to first dose date of the 
subsequent line of therapy -1 if there is overlap due to imputation of partial dates. If the 
end year for one prior therapy is the same as the start year for the next prior therapy, 
impute Jun 30 and Jul 1 of that year for the end and start days if missing months and 
days. 
7.1.4 
Death Date Imputation 
 
If death date is completely missing, will use latest alive date + 1 
 
If both month and day are missing, then use the first date (01 JAN) of the year, or 
latest alive date + 1, whichever is later 
 
If only day is missing, then use the first day of the month, or latest alive date + 1, 
whichever is later. 
7.1.5 
New Anticancer Therapy Date Imputation 
If at least one new anticancer therapy is used but the start date of new anticancer 
therapy is partially missing, the incomplete stop date imputation rule in Section 7.1.1 is 
used. If the start date of new anticancer therapy is completely missing, the next day of 
the last dose date (i.e. last dose date + 1 day) will be used by assuming the new 
anticancer therapy is taken the next day after permanently discontinue pralsetinib. 


 
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7.2 DERIVATION OF PRIOR LINE OF SYSTEMIC THERAPY 
The number of prior systemic therapy regimen, prior therapy agent name, start/end date, 
response outcome, progression/relapse date if available, and reasons for discontinuation 
of an agent will be considered in derivation of prior line of systemic therapy using the 
following steps.  
 
Step 1, The start of the prior line of therapy is defined as the first eligible systemic 
therapy. Systemic therapies are defined based on medical review. 
 
Step 2, Treatment agent(s) documented by the site as part of the same regimen will 
be considered as the same line of therapy. Maintenance therapies will be 
considered as part of the same line of therapy. The maintenance therapies in the 
derivation includes agents having 1) overlapping/adjacent start/stop dates or 2) date 
of progression being the same across agents. 
 
Step 3, Agent(s) with a prior disease progression date documented due to any 
reasons (for example, disease progression, toxicity, etc.), lead to an increase in the 
line of therapy. If multiple disease progression dates are documented, an increase 
of the line of therapy only occurs if dates are not within 7 days of each other. 
7.3 DERIVATION OF RET GENE STATUS FOR MTC PATIENTS 
The RET gene status for MTC patients will be derived according to the following rules in 
hierarchical order. 
 
Step 1, If a patient’ ctDNA plasma sample collected at Cycle 1 Day 1 (C1D1) is 
analyzed and mutation allele fraction in RET gene is available, the patient’ RET 
gene status is assigned based on the rules below accordingly. 
o If any mutation allele fraction in RET gene is   40%, a patient’s 
RET gene status will be “Hereditary”.  
o If any mutation allele fraction in RET gene is < 40%, a patient’s 
RET gene status will be “Sporadic”.  
 
Step 2, Among patients whose RET gene status are not assigned from Step 1, if 
their ctDNA plasma samples collected at C1D1 have been tested and their ctDNA 
tumor samples collected at Screening visit have also been tested and indicated any 
mutation found in the RET gene, the patients’ RET gene status will be assigned to 
“Sporadic”.  
 
Step 3, Among patients whose RET gene status are not assigned from Steps 1-2, if 
patients’ MTC disease types in electronic data capture (EDC) prior cancer history 
thyroid page is not “Unknown”, the MTC disease types will be used as patients’ RET 
gene status, “Hereditary” or “Sporadic”, respectively. 
 
Step 4, Among patients whose RET gene status are “Unknown” in Step 3, if 
patients’ RET-mutation is “Positive” from EDC RET mutation status page, and their 
ctDNA plasma sample data collected at C1D1 is also valid, the patients RET gene 


 
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status is sporadic. Otherwise, the RET gene status is ‘Unknown’. The ctDNA plasma 
sample collected at C1D1 tested with comment of “failure” or “failed” or “sample not 
hold” will not be considered as valid samples.  
7.4 TABLE, LISTING, AND FIGURE FORMAT  
In the top left portion of each table/listing, a table/listing number followed by the title of 
the table/listing will be presented. After the title line, optional sub-title or population 
information can be presented. Horizontal lines will appear before and after the column 
heading of the table/listing. Footnotes will be put under the main body of text at the 
bottom of the page.  
The sponsor name, protocol number, programmer user identification, status of the 
table/listing (i.e. draft or final) and SAS program name will appear bottom left in a string 
and the page number will appear on the bottom right corner of each table/listing. The 
date and time of creation of table/listing will appear bottom left under the sponsor name. 
The source listing number will appear bottom left.  
A landscape layout is for both table and listing presentations for post-text tables. A 
portrait layout is for in text table. 
In a listing, in the case that a patient’s record has been continued to the next page, an 
appropriate identification (e.g. the patient identification number) must be presented at 
the beginning of that page. 
7.5  
CONVENTIONS 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw 
data, the mean and median will be presented to one extra decimal place compared to 
the raw data, and the standard deviation will be displayed to two extra decimal places 
compared to the raw data. Wherever possible data will be decimal aligned. 
Unless otherwise specified frequency tabulations will be presented by number and 
percentage, where the percentage is presented in parenthesis to 1 decimal place 
(XX.X%). 
P-values, if applicable, will be presented to 3 decimal places. If a p-value is less than 
0.05 but is greater than or equal to 0.01, then an asterisk (*) will be added next to this 
value. If a p-value is less than 0.01 but is greater than or equal to 0.001, then two 
asterisks (**) will be added next to this value. Finally, if the p-value is less than 0.001 
then three asterisks (***) will be added next to this value and it will be presented as 
<0.001. If the rounded result is a value of 1.000, it will be displayed as >0.999.  


 
Pralsetinib—{Genentech, Inc./F. Hoffmann-La Roche Ltd} 
Statistical Analysis Plan BO42863 
73 
 
Any date information in the listing will use the date9. format, for example, 07MAY2002. 
In the listing, a unit associated with a variable will be presented only once within 
parentheses either below or next to that variable in the heading portion. If a parameter 
has multiple units, each unit will be displayed only once, as applicable. 
All tables will have their source listing referenced in a footnote. Listings should be sorted 
by analysis group, patient and visit and have the source data received by data 
management referenced in a footnote. All tables and listings will be converted into 
Microsoft Word documents and collated into two complete documents.  
8. 
SOFTWARE 
All summaries and statistical analysis will be generated using SAS version 9.4. 
9. 
TABLES, LISTINGS, AND GRAPHS (TLGS) SHELLS AND 
PROGRAMMING SPECIFICATIONS 
The mock tables, listings and figures and the programming specifications are provided in 
a separate document. 
10. 
REFERENCES 
Dubois D, Dubois EF, 1916, Dubois D, Dubois EF. A formula to estimate the 
approximate surface area if height and weight be known. Arch Intern Med. 1916; 
17:863-871. 
Eisenhauer, E.A., P. Therasse, et al. (2009). New Response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 45(2): 228-247. 
Klein JP, Moeschberger ML. Survival analysis technique for censored and truncated 
data (second edition). Springer-Verlag; 2003. 
Wells, et al. (2012), “Vandetanib in patients with locally advanced or metastatic 
medullary thyroid cancer: a randomized, double-blind phase III trial.” J Clin Oncol 
30(2): 134-141. 
Wen, P. Y., D. R. Macdonald, et al. (2010). "Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group." J 
Clin Oncol 28(11): 1963-1972. 
 


Signature Page for Statistical Analysis Plan - BO42863 - Published
System identifier: RIM-CLIN-456259
Approval Task
Company Signatory
02-Nov-2022 13:15:18 GMT+0000