MATCH Treatment Subprotocol T: GDC-0449 (Vismodegib) in Patients With Tumors (Except Basal Cell Skin Carcinoma) With Smoothened (SMO) or Patched 1 (PTCH1) Mutations
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphatic System Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

i 
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900 
f: 617. 589.0914
ecog-acrin.org
August 19, 2020
 MS RAC
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 
Bethesda, MD   20892
Dear Ms. 
:
Enclosed is Addendum #25 to EAY131-T, GDC-0449 (vismodegib) in Patients with Tumors 
(except basal cell skin carcinoma) with Smoothened (SMO) or Patched 1 (PTCH1) Mutation
This addendum is in response to Dr. 
 Amendment Request for updates to specific 
protocol language for GDC-0449 (vismodegib) dated June 5, 2020.
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements:
This addendum has been reviewed and approved by the Central IRB, which is the sole 
IRB of record for this study. Local IRB review and approval is unnecessary.
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum.
The following revisions to EAY131-T protocol have been made in this addendum:
Section
Change 
1.
Cover Page
Updated version date and addendum number.
2.
Appendix III
Updated patient drug information template format.
The following revisions to EAY131-T Informed Consent Document have been made in this 
addendum:
Section
Change 
1.
Page 1
Updated version date.
If you have any questions regarding this addendum, please contact 
or 
857-504-2900.
We request review and approval of this addendum to EAY131-T so ECOG-ACRIN may activate 
it promptly.  
Thank you.
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ii 
Sincerely, 
 
 
 
 
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EAY131-T 
1 
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol T: GDC-0449 
(vismodegib) in Patients with Tumors (except basal cell 
skin carcinoma) with Smoothened (SMO) or Patched 1 
(PTCH1) Mutations
GDC-0449 (VISMODEGIB) TREATMENT ARM 
CHAIR:
, MD
GDC-0449 (VISMODEGIB) TREATMENT ARM 
CO-CHAIR:
, MD
GDC-0449 (VISMODEGIB) TRANSLATIONAL 
CHAIR:
, MD
Version Date: August 19, 2020
NOTE: This subprotocol (EAY131-T) should be 
used in conjunction with the MATCH 
Master Protocol (EAY131)  
NOTE: As of 11/17, all protocol changes will be 
noted by addendum number. Please 
reference the activation memo for the 
addendum activation date.
SUBPROTOCOL ACTIVATION DATE
February 25, 2016 (Incorporated in Addendum #2)
Addendum #3 – 5/16
Addendum #5 – 12/16
Addendum #7 – 3/17
Addendum #10 – 5/17
Addendum #13
Addendum #21
Addendum #25
Agent
IND#
NSC#
Supply 
GDC-0449 (vismodegib)
IND Sponsor: DCTD, NCI IND#: 
747691
NCI Supplied
T
Rev. Add13
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ECOG-ACRIN
EAY131-T 
Cancer Research Group
Version Date: August 19, 2020
2 
Table of Contents
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i
MATCH Treatment Subprotocol T: GDC-0449 (vismodegib) in Patients with Tumors 
(except basal cell skin carcinoma) with Smoothened (SMO) or Patched 1 
(PTCH1) Mutations.............................................................................................. 1
Table of Contents ...................................................................................................... 2
Schema ...................................................................................................................... 4
1.
Introduction ........................................................................................................ 5
1.1
Patched-1 (PTCH1) and Smoothened (SMO) genes and pathway............ 5
1.2
GDC-0449 (vismodegib) ............................................................................ 7
1.3
Proposed mechanisms of resistance to SMO inhibitors ........................... 9
1.4
Scientific Rationale to study GDC-0449 (vismodegib) in SMO and PTCH 
mutant tumors........................................................................................10
2.
Selection of Patients .........................................................................................12
2.1
Eligibility Criteria .....................................................................................12
3.
GDC-0449 (vismodegib) Treatment Plan ..........................................................14
3.1
Administration Schedule.........................................................................14
3.2
Adverse Event Reporting Requirements.................................................14
3.3
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
GDC-0449 (Vismodegib, NSC 747691) ....................................................17
3.4
Dose Modifications .................................................................................20
3.5
Supportive Care.......................................................................................22
3.6
Duration of Agent-specific treatment.....................................................22
3.7
Duration of Follow-Up.............................................................................23
4.
Study Parameters..............................................................................................24
4.1
Therapeutic Parameters for GDC-0449 (vismodegib) Treatment...........24
5.
Drug Formulation and Procurement................................................................. 26
5.1
GDC-0449 (NSC 747691) .........................................................................27
6.
Translational Studies.........................................................................................29
7. References ........................................................................................................29
Appendix I  Patient Pill Calendar .............................................................................31
Appendix II  Actionable Mutations for Sub-Protocol EAY131-T ..............................33
Appendix III  PATIENT CLINICAL TRIAL WALLET CARD.............................................34
Rev. 12/16
Rev. 3/17
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Version Date: August 19, 2020 
4 
Schema 
 
Long-Term Follow-Up
GDC-0449 (vismodegib) 150 mg po daily
Until Progression or unacceptable toxicity 
Cycle = 28  days
Accrual Goal: 35
 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: August 19, 2020 
5 
1. Introduction 
1.1 
Patched-1 (PTCH1) and Smoothened (SMO) genes and pathway 
The Sonic hedgehog pathway is controlled at the cell surface by two 
transmembrane proteins, the tumor suppressor Patched-1 (PTCH1) in addition to 
the above discussed oncoprotein Smoothened (Smo). In the absence of the 
ligand Shh, Ptch maintains Smo in an inactive state. In the presence of Shh 
ligands (Sonic, Indian or Desert SHh), inhibition of Smo by PTCH1 is relieved 
and signaling is transduced, leading to activation and nuclear translocation of Gli 
1, 2 and 3 transcription factors1. The involvement of Gli1 activation in familial 
tumors came from the discovery that PTCH1 on chromosome 9q22.3, which 
inhibits Gli activation, is mutated in basal-cell nevus syndrome (Gorlin’s 
syndrome) – an autosomal dominant disorder where patients inherit a germline 
mutation in a PTCH1 that causes hereditary predisposition to basal-cell 
carcinomas, medulloblastomas and other tumor types.2,3 Inactivation of PTCH1 
results in constitutive activation of Smo and overexpression of full-length 
activated Gli1, underscoring the potential of this pathway as a therapeutic target. 
Inactivating, acquired PTCH1 mutations have been found in patients with 
sporadic basal cell carcinoma in approximately one third of cases, in patients 
with  basal cell carcinomas related to xeroderma pigmentosum and in some 
sporadic of cases of medulloblastoma.4,5 
Smoothened (SMO) is a 7 membrane spanning receptor involved in the 
hedgehog signaling pathway.6 The SMO gene maps to the 7q31-q32 region. In 
the absence of Patched (PTCH) inhibition, SMO will accumulate, interact with 
Suppressor of fused (SUFU), and activate Gli family transcription factors with 
nuclear translocation. The Gli proteins have several functions, Gli1 and 2 are 
strong activators of transcription, whereas Gli3 is primarily inhibitory. Once the 
hedgehog pathway is activated, Gli3 is released from SUFU and undergoes 
proteasome inhibition, while Gli1 and 2 are translocated preferentially to the 
nucleus for transactivation activity.6   
SMO has been identified as an oncogene; activating mutations in sporadic and 
germline basal cell carcinomas6 and medulloblastomas7 have been reported 
(Table 1). A hot spot for mutation has been identified at codon 535; codon 535 
exon 9 changes tryptophan to leucine and codon 562 exon 10 changes arginine 
to glutamine.6,8 Oral SMO inhibitors, such as GDC-0449 (vismodegib), have 
documented successful anti-tumor activity in basal cell carcinomas (BCC) with 
hedgehog pathway mutations (SMO, PTCH1).9,10  The use of SMO inhibitors in 
medulloblastoma is more complex, and reports are indicating variable sensitivity 
depending on the mutation.7 
Of importance to note, certain SMO mutations (codon D473H Asp to His) have 
been reported to confer disease resistance to GDC-0449 (vismodegib) (Erivedge, 
Genentech, San Francisco, CA), an oral SMO inhibitor.11 This mutation was not 
believed to be an activating oncogenic mutation, but one that was relevant in the 
absence of PTCH1 inhibition. It is believed that D473H prevents GDC-0449 
(vismodegib) binding to mutant SMO. Asp-473 lies along the SMO extracellular 
lip of the cavity for the G-protein coupled receptor, along the c-terminal end of the 
6th transmembrane segment. Also, SMO mutations in gastric cancer have been 
reported, but are not considered to be oncogenic drivers.12   
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6 
1.1.1 
SMO mutations in NSCLC    
Although SMO mutations have been identified in basal cell carcinoma, 
medulloblastoma, and gastric cancers, they have only recently been 
reported in non-small cell lung cancer (NSCLC).13 At M.D. Anderson 
Cancer Center (MDACC), 2 datasets were interrogated for SMO 
mutations and hedgehog pathway dysregulation in NSCLC, the 
MDACC Molecular Diagnostic Lab (MDL) and The Cancer Genome 
Atlas (TCGA) databases for lung adenocarcinoma (n=230) and 
squamous cell carcinoma (n=178). Mutations were determined by 
whole exome sequencing and copy number was assessed by GISTIC 
2.0 (scores of 2 considered high level amplification). Mutations in 
hotspot regions of 46 cancer related genes including SMO was 
performed as part of clinical diagnostic evaluation (Ion AmpliSeq 
Cancer Panel; Life Technologies, CA). At MDACC, approximately 243 
sequential patients were evaluated and 3 had SMO mutations, for an 
incidence of 1.2%.14 This project is still ongoing.   
In TCGA lung adenocarcinoma studies, alterations in SMO (mutation, 
amplification, or mRNA overexpression) were observed in 12.2% of 
tumors. The incidence of SMO mutations was 2.6% and SMO gene 
amplifications 5%. SMO mutations and amplifications strongly 
correlated with sonic hedgehog gene dysregulation (p<0.0001). In the 
TCGA squamous cell lung cancer study, SMO was altered in 10.1% of 
tumors, primarily via mRNA upregulation. Only 1 SMO missense 
mutation was identified in the Lung SCC cohort (D209Y).  
At MDACC thoracic center, 3 patients with metastatic NSCLC were 
identified with SMO mutations by the MDACC MDL 46-gene panel. 
None of the 3 SMO mutations were known activating mutations and 
subsequent analysis has identified additional thoracic patients with 
SMO mutations (Table 2). The initial 3 SMO mutant patients were 
treated with GDC-0449 (vismodegib) with different clinical response 
outcomes. Patient  had a significant reduction in tumor burden with 
close to 6 months duration of benefit. Patient  with the SMO M525L 
mutation did not respond to GDC-0449 (vismodegib) therapy, 
whereas patient  had disease stabilization. Patient  was unable to 
tolerate GDC-0449 (vismodegib) due to nausea and stopped 
treatment after 14 weeks. His disease rapidly recurred after cessation 
of GDC-0449 (vismodegib).    
SMO mutations and pathway alterations occur in NSCLC and may be 
an actionable target with hedgehog inhibitors. There is enough 
evidence that suggests NSCLC SMO mutant patients may benefit 
from GDC-0449 (vismodegib) therapy. However, additional correlative 
analysis is clearly needed. The preliminary clinical results indicate 
differential sensitivity to GDC-0449 (vismodegib), depending on the 
SMO mutation. Also, in the MDACC study, almost all of the patients 
carried concomitant p53 mutations in their tumors (Table 2). There 
have been preclinical reports suggesting that gain of function SMO 
mutations can inhibit p53 accumulation via MDM2 activation and 
ubiquitination.15  In the TCGA data set, 4 of 6 SMO mutated lung 
adenocarcinomas and the one lung SCC SMO mutated patient had 
concomitant p53 mutations. It is plausible that some SMO mutations 
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ECOG-ACRIN 
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Version Date: August 19, 2020 
7 
in NSCLC are not constitutively activating mutations but require 
potentiation with expression of mutant p53 in order to lead to 
oncogenesis. 
1.2 
GDC-0449 (vismodegib) 
Inhibitors of this pathway have entered clinical development in the last several 
years. Cyclopamine, a plant derived steroidal alkaloid that directly binds to and 
inactivates Smo, thereby blocking activation of Gli1-mediated transcription 16,17, 
has been used mostly in laboratory studies. GDC-0449 (vismodegib) is an 
inhibitor of Smo similar to cyclopamine but with more favorable pharmacologic 
properties with respect to potency, selectivity, solubility, pharmacokinetics and 
bioavailability. Treatment of basal cell carcinoma using GDC-0449 (vismodegib) 
has been extraordinarily successful, providing proof of concept that targeting the 
Shh pathway in the appropriate tumor types is highly effective. An open-label, 
multicenter, two-stage phase I trial to evaluate the safety and tolerability of GDC-
0449 (vismodegib) in patients with a variety of solid tumors refractory to standard 
therapy was conducted9,18. Of 68 patients enrolled at 3 centers, 33 had advanced 
basal cell carcinoma; 18 of these patients showed evidence of objective 
response, and 11 showed stable disease. Eight grade 3 adverse events, 
including fatigue, hyponatremia, muscle spasm and atrial fibrillation, were 
deemed possibly related to study drug and no dose-limiting toxic effects were 
observed. The recommended phase II dose was 150 mg per day, as 
pharmacokinetic analyses indicated that doses greater than this did not result in 
higher plasma concentrations of the drug. In this study, skin biopsies and hair 
follicles were analyzed for Gli1 mRNA expression. Down-modulation of Gli 1 
transcription factor was observed in skin punch biopsy samples after treatment in 
all patients, suggesting that this is a valid pharmacodynamic marker 9,18. 
1.2.1 
GDC-0449 (vismodegib) FDA approval in BCC 
Following this phase I study a multicenter, international trial enrolled 
33 patients with metastatic basal cell carcinoma who exhibited 30% 
response rate as well as 63 patients with locally advanced disease not 
amenable to surgery or radiation who exhibited an overall 43% 
response rate anda 21% complete response rate. The median 
response duration was 7.6 months and the median progression-free 
survival was 9.5 months in both groups, and many of the complete 
responses were durable19. An expanded access program enrolled 119 
similar patients; objective responses were seen in 46.4% of patients 
with locally advanced BCC and 30.8% of patients with metastatic 
BCC. Mean follow-up for safety was 6.5 months, with muscle spasms 
(70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) 
as the most common adverse events.20 
1.2.2 
GDC-0449 (vismodegib) is currently under evaluation in ongoing 
studies in patients with solid tumors. To date, no new safety signals 
have been reported.   
1.2.3 
GDC-0449 (vismodegib) benefit in preclinical models, dosing, 
administration 
In vitro cell-based potency assays involving luciferase reporter genes 
under the control the Gli transcription factor promoter demonstrate 
that GDC-0449 (vismodegib) potently inhibits Hh signaling in human 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: August 19, 2020 
8 
and mouse cell lines with an IC50 of 2.8 nM-13 nM (Investigator’s 
Brochure, Version 8, January 2013). GDC-0449 (vismodegib) has 
been tested in a number of different in vivo model systems, including 
murine allograft, cell line xenograft, and patient-derived xenograft 
(PDX) models. In the mutation-driven Ptch+/- medulloblastoma 
allograft model, GDC-0449 (vismodegib) induces tumor regressions; 
in ligand-driven colorectal carcinoma (CRC) cell line xenografts 
(involving a “paracrine” mechanism of Hh pathway activation driven by 
tumor-produced ligand activation of Hh in the surrounding stroma that 
in turn promotes tumor growth), GDC-0449 (vismodegib) instead 
induces tumor growth inhibition25. 
Integrated pharmacodynamic modeling of the concentration-response 
relationship in the Ptch1+/- medulloblastoma allograft and colorectal 
carcinoma (CRC) xenograft models revealed that 50% of the maximal 
anti-tumor effect achieved correlated to approximately 82% pathway 
inhibition (as measured by drug-mediated decrease in Gli1 transcript 
levels)25. The correlation between the suppression of Gli1 transcript 
levels and tumor growth inhibition/regression is characterized by a 
steep Hill slope, implying that a modest change in pathway inhibition 
translates to a disproportionately significant impact upon the 
therapeutic efficacy achieved. This is consistent with the general 
principle that efficacy with molecularly targeted agents directed at 
oncogenic driver pathways requires both potent and durable target 
inhibition that in many cases can only be achieved within a narrow 
pharmacokinetic window26,27. 
1.2.4 
Clinical Pharmacology 
1.2.4.1 
Mechanism of Action 
GDC-0449 (vismodegib) is an inhibitor of the Hedgehog 
pathway. GDC-0449 (vismodegib) binds to and inhibits 
Smoothened, a transmembrane protein involved in 
Hedgehog signal transduction. 
1.2.4.2 
Pharmocokinetics 
Absorption  
GDC-0449 (vismodegib) is a compound with low aqueous 
solubility (BCS Class 2). The single dose absolute 
bioavailability of GDC-0449 (vismodegib) is 31.8%. 
Absorption is saturable as evidenced by the lack of dose 
proportional increase in exposure after a single dose of 
270 mg or 540 mg GDC-0449 (vismodegib). GDC-0449 
(vismodegib) capsule may be taken without regard to 
meals because the systemic exposure of GDC-0449 
(vismodegib) at steady state is not affected by food. 
Distribution  
The volume of distribution of GDC-0449 (vismodegib) 
ranges from 16.4 to 26.6 L. GDC-0449 (vismodegib) 
plasma protein binding in patients is greater than 99%. 
GDC-0449 (vismodegib) binds to both human serum 
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ECOG-ACRIN 
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Version Date: August 19, 2020 
9 
albumin and alpha-1-acid glycoprotein (AAG) and binding 
to AAG is saturable. 
Metabolism  
Greater than 98% of the total circulating drug-related 
components are the parent drug. Metabolic pathways of 
GDC-0449 (vismodegib) in humans include oxidation, 
glucuronidation, and pyridine ring cleavage. The two most 
abundant oxidative metabolites recovered in feces are 
produced in vitro by recombinant CYP2C9 and CYP3A4/5. 
Elimination  
GDC-0449 (vismodegib) and its metabolites are eliminated 
primarily by the hepatic route with 82% of the administered 
dose recovered in the feces and 4.4% recovered in urine. 
The estimated elimination half-life (t1/2) of GDC-0449 
(vismodegib) is 4 days after continuous once-daily dosing 
and 12 days after a single dose.  
Pharmacokinetics in Specific Populations  
Hepatic Impairment: The effect of hepatic impairment on 
the systemic exposure of GDC-0449 (vismodegib) has not 
been studied.  
Renal Impairment: The effect of renal impairment on the 
systemic exposure of GDC-0449 (vismodegib) has not 
been studied.  
Population pharmacokinetic analyses showed that weight 
(range: 41-140 kg), age (range: 26-89 years), creatinine 
clearance (range: 30 to 80 mL/min), and sex do not have a 
clinically meaningful influence on the systemic exposure of 
GDC-0449 (vismodegib). 
1.2.4.3 
Cardiac Electrophysiology 
In a thorough QTc study in 60 healthy subjects, there was 
no effect of therapeutic doses of ERIVEDGE on the QTc 
interval. 
1.3 
Proposed mechanisms of resistance to SMO inhibitors 
Several mechanisms of resistance to GDC-0449 (vismodegib) have been 
proposed and discovered. The most striking example comes from the clinical 
case report of a patient with metastatic, Ptch1 mutant medulloblastoma in whom 
GDC-0449 (vismodegib) produced a remarkable clinical response, only for 
progressive disease to develop 3 months into treatment21. Analysis of a 
progressive tumor revealed the acquisition of the SMO mutation D473H, which in 
vitro studies demonstrated confers drug resistance by disrupting GDC-0449 
(vismodegib) binding to SMO11. A chemical screen of Hh pathway inhibitors 
(HPIs) successfully identified alternate compound antagonists that could inhibit 
this SMO mutation, a proof-of-principle that resistance mediated by such 
alterations can be overcome by distinct hedgehog pathway inhibitors 22. 
Alternatively, SUFU mutations, Gli2 amplification, cyclin D1 amplification, and 
MYCN amplification are all mechanisms of Hh pathway activation downstream of 
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ECOG-ACRIN
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Version Date: August 19, 2020
12
2.
Selection of Patients
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, in order for a patient to be considered eligible for this 
study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. ____________________________
Patient’s Initials (L, F, M) _______________________
Physician Signature and Date ___________________
NOTE:
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu).
NOTE:
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.
NOTE:
All patients must have signed the relevant treatment consent form
2.1
Eligibility Criteria
2.1.1
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7).
2.1.2
Patients must have activating mutations of Smoothened (SMO) or 
deleterious Patched 1 (PTCH1) as determined via the MATCH Master 
Protocol and described in Appendix II. See Appendix II for information 
on the Smoothened (SMO) or Patched 1 (PTCH1) mutations and 
corresponding Levels of Evidence.
2.1.3
Patient must not have basal cell carcinoma.
2.1.4
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have NONE of the following 
cardiac criteria:
x
No clinically unstable abnormalities in rhythm, conduction or 
morphology of resting ECG e.g. complete left bundle branch 
block, third degree heart block.
x
No factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as congenital long QT syndrome, family 
history of long QT syndrome or unexplained sudden death under 
40 years of age
_____
_____
_____
_____
Rev. Add13
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Date of ECG:  _______________
2.1.5
Patients with known left ventricular dysfunction must have ECHO or 
nuclear study (MUGA or First Pass) within 4 weeks prior to 
registration to treatment and must not have left ventricular ejection 
fraction (LVEF) < institutional lower limit of normal (LLN). If the LLN is 
not defined at a site, the LVEF must be > 50% for the patient to be 
eligible.
2.1.6
Patients must not have known hypersensitivity to GDC-0449 
(vismodegib) or compounds of similar chemical or biologic 
composition.
Date of ECHO/Nuclear Study:  _______________
2.1.7
Patient must not have had any of the prior therapies: GDC-0449 
(vismodegib)
2.1.8
Women of childbearing potential and men who are sexually active 
must agree to use adequate contraception defined as appropriate 
double barrier method of birth control (such as female use of a 
diaphragm, intrauterine device (IUD), sponge and spermicide, in 
addition to the male use of a condom or involve female use of 
prescribed "birth control pills" or a prescribed birth control implant). 
Both double barrier contraception and birth control pills or implants 
must be used for at least one week prior to the start of the study and 
continue for 24 months after completion of study for women, and 3 
months after completion of study for men.
Physician Signature
Date
OPTIONAL:
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation.
_____
_____
_____
Rev. 5/16
Rev. Add13 
_____
Rev. 5/16
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14
3.
GDC-0449 (vismodegib) Treatment Plan
3.1 
Administration Schedule
GDC-0449 (vismodegib) will be administered as a flat dose and will not be based 
on ideal or actual body weight. GDC-0449 (vismodegib) will be administered as 
150 mg po daily dose on a continual daily schedule.  
One cycle of treatment will be 28 days. Tumor measurements will be conducted 
every other cycle or 8 weeks.
Patients will continue GDC-0449 (vismodegib) 150 mg po daily until disease 
progression, unacceptable toxicity or withdrawal of consent.
If a patient misses a dose of GDC-0449 (vismodegib), they should not take the 
missed capsule, but resume with the next scheduled dose. GDC-0449 
(vismodegib) may be taken with or without food.
3.2
Adverse Event Reporting Requirements
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol. Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS).  
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met.
3.2.1
Additional instructions, requirements and exceptions for protocol 
EAY131 – Subprotocol T 
Additional Instructions
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis.
EAY131 – Subprotocol T specific expedited reporting 
requirements:
x
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while a female patient is on 
GDC-0449 (Vismodegib), or within 24 months of the female 
patient’s last dose of GDC-0449 (Vismodegib), are considered 
immediately reportable events. A female partner of a male 
patient who becomes pregnant within 3 months of the male’s 
last dose of GDC-0449 (Vismodegib) is also considered a 
reportable event.  The pregnancy, suspected pregnancy, or 
positive/ inconclusive pregnancy test must be reported via 
CTEP-AERS within 24 hours of the Investigator’s knowledge. 
Please refer to Appendix VIII in MATCH Master Protocol for 
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detailed instructions on how to report the occurrence of a 
pregnancy as well as the outcome of all pregnancies. 
NOTE: 
The timeframes and requriements stated here 
for reporting a pregnancy are different on this 
protocol than what is outlined in Appendix VIII 
of the MATCH Master Protocol. Please adhere to 
the timeframes and requirements listed here. 
 
EAY131 – Subprotocol T specific expedited reporting 
exceptions: 
For Subprotocol T, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
x 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event.  
3.2.2 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
x 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
x 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov  
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
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4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
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conditions - Other (general physical health deterioration); Injection site reaction; Non-cardiac 
chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Portal hypertension 
INFECTIONS AND INFESTATIONS - Infection4 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall; Hip fracture 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Blood bilirubin increased; Blood lactate dehydrogenase increased; Cholesterol high; Creatinine 
increased; INR increased; Investigations - Other (brain natriuretic peptide increased); 
Investigations - Other (increased platelet count); Lipase increased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hyperlipidemia; Hypermagnesemia; Hypernatremia; Hypoalbuminemia; 
Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Flank pain; 
Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective 
tissue disorder - Other (muscle tightness/stiffness); Neck pain; Pain in extremity; Trismus 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysesthesia; Intracranial 
hemorrhage; Movements involuntary; Nervous system disorders - Other (amimia); Olfactory 
nerve disorder; Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Seizure; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Hallucinations; 
Insomnia; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal hemorrhage 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Cough; Dyspnea; 
Epistaxis; Hiccups; Hypoxia; Oropharyngeal pain; Pleural effusion; Pneumonitis; Postnasal drip; 
Pulmonary edema; Respiratory, thoracic and mediastinal disorders - Other (COPD); Sneezing; 
Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Eczema; Hair color changes; 
Hyperhidrosis; Nail ridging; Rash acneiform; Rash maculo-papular; Skin and subcutaneous 
tissue disorders - Other (actinic keratosis); Skin and subcutaneous tissue disorders - Other 
(psoriasis); Skin and subcutaneous tissue disorders - Other (skin exfoliation); Skin ulceration; 
Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event; Vasculitis 
NOTE: 
GDC-0449 (Vismodegib) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
 
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3.4 
Dose Modifications  
3.4.1 
Dose Reductions 
Dose reduction of GDC-0449 (vismodegib) is not permitted as there is 
only a 150-mg capsule strength available. Capsules must not be 
opened or crushed. If a patient misses a dose of GDC-0449 
(vismodegib), they should not take the missed capsule, but resume 
with the next scheduled dose. GDC-0449 (vismodegib) may be taken 
with or without food. 
If a treatment interruption occurs, and it is determined that GDC-0449 
(vismodegib) will be re-started, the original dose of 150 mg daily dose 
will be maintained 
GDC-0449 (vismodegib) dose reduction and schedule modifications 
during the study are not recommended due to the pharmacokinetic 
characteristics of the drug (see GDC-0449 (vismodegib) Investigator 
Brochure v8). Briefly, GDC-0449 (vismodegib)’s pharmacokinetic 
profile is a result of high affinity, reversible binding to Alpha-1 acid 
Glycoprotein (AAG) and binding to albumin, in addition to solubility 
limited absorption and slow metabolic elimination properties (Graham 
2011). Initiation of less frequent administration schedules than the 
approved dose and schedule of GDC-0449 (vismodegib) of 150 mg 
orally once daily,( i.e. 150 mg three times weekly or 150 mg once 
weekly dosing), was associated with marked decrease in the 
pharmacologically active unbound fraction. 
Unbound steady-state GDC-0449 (vismodegib) concentrations were 
60% and 85% lower for the TIW and QW dose groups, respectively, 
relative to the QD dose group.  Such decreases may be associated 
with loss of GDC-0449 (vismodegib) activity based on findings from 
nonclinical models. Integrated PK/PD modeling of GDC-0449 
(vismodegib) in xenograft models has revealed a steep relationship 
between pathway modulation (GLI1 inhibition) and anti-tumor effect, 
suggesting that even small reductions in exposure could lead to 
dramatic loss in GDC-0449 (vismodegib) activity (see GDC-0449 
(vismodegib) Investigator Brochure v8) 
3.4.2 
Dose Modifications 
All toxicity grades below are described using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Dose 
modification guidelines below apply only to toxicities judged to be 
related to GDC-0449 (vismodegib). 
All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). 
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Nausea 
Management/Next Dose for GDC-0449 (vismodegib) 
 *UDGH  
No change in dose 
Grade 2 
May continue dosing while managing with anti-emetics.  If occurs despite optimal management, 
KROG XQWLO  *UDGH  5HVXPH DW VDPH GRVH OHYHO 
Grade 3 
Hold* XQWLO  *UDGH  5HVXPH DW VDPH GRVH OHYHO 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of > 2 weeks should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Vomiting 
Management/Next Dose for GDC-0449 (vismodegib) 
 *UDGH  
No change in dose 
Grade 2 
+ROG XQWLO  *UDGH  5HVXPH DW VDPH GRVH OHYHO 
Grade 3 
Hold* until < Grade 2.  Resume at same dose level. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  antiemetics, IV fluid hydration if indicated. 
 
Diarrhea 
Management/Next Dose for GDC-0449 (vismodegib) 
 *UDGH  
No change in dose 
Grade 2 
+ROG XQWLO  *UDGH  5HVXPH DW VDPH GRVH OHYHO 
Grade 3 
Hold* until < Grade 2.  Resume at same dose level. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours 
(maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
For any other non-hematologic grade 3 toxicity that is deemed to be 
related to GDC-0449 (vismodegib), the study drug GDC-0449 
(vismodegib) can be held for up to 2 weeks until the toxicity resolves 
to  grade 1. GDC-0449 (vismodegib) will be restarted at 150 mg daily 
dosing. 
Neutropenia 
Management/Next Dose for GDC-0449 (vismodegib) 
 *UDGH  
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold* until < Grade 2.  Resume at same dose level. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management: Consider growth factor support if neutropenia lasts over 1 week after holding GDC-
0449 (vismodegib). 
 
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Thrombocytopenia
Management/Next Dose for GDC-0449 (vismodegib)
 *UDGH 
No change in dose
Grade 2
+ROG XQWLO  *UDGH  5HVXPH DW VDPH GRVH OHYHO
Grade 3
Hold* until < Grade 2.  Resume at same dose level.
Grade 4
Off protocol therapy
*Patients requiring a delay of >2 weeks should go off protocol therapy.
3.5
Supportive Care 
The following guidelines should be used for patients enrolling onto EAY131-T:
x
If plasma levels need to be lowered emergently, animal studies have 
suggested that oral administration of activated charcoal may lower drug 
plasma levels more quickly than drug cessation alone.
x
If a patient is suspected to be pregnant, GDC-0449 should be immediately 
discontinued. In addition, a positive urine test must be confirmed by a serum 
pregnancy test. If it is confirmed that the patients is not pregnant, the patient 
may resume dosing with GDC-0449.  
x
If a female patient becomes pregnant during therapy or within 24 months 
after the last dose of GDC-0449, or if the female partner of a male patient 
exposed to the drug becomes pregnant while the male patient is receiving 
GDC-0449 or within 3 months after the last dose of GDC-0449, the 
investigator must be notified in order to facilitate outcome follow-up.
x
Abortion, whether accidental, therapeutic, or spontaneous, should always be 
classified as serious. Any congenital anomaly/birth defect in a child conceived 
during the study or within 24 months after the last dose of GDC-0449 to a 
female patient or to a female partner of a male patient exposed to the agent 
during treatment or within 3 months after the last dose of GDC-0449 should 
be recorded and reported as an SAE.
x
Female patients must not breastfeed a baby while on this study and should 
not breastfeed for 24 months after last dose of study medication.  
x
Female patients must NEVER donate ova while being treated with GDC-
0449.
x
All sexually active male subjects (including those who have undergone 
vasectomy) must utilize a barrier form of contraception during study treatment 
and for 3 months after the last dose as it is not known whether GDC-0449 
that may be present in seminal fluid would cause serious or life-threatening 
birth defects in a fetus born to the female partner of a male subject. Males 
must also not donate sperm during treatment or up to 3 months after the last 
dose.
x
All patients are prohibited from donating blood for 24 months after the last 
dose of GDC-0449.
All supportive measures consistent with optimal patient care will be given 
throughout the study.
3.6
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies:
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x 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
x 
Patient withdraws consent. 
x 
Patient experiences unacceptable toxicity. 
x 
Non-protocol therapies are administered. 
x 
Disease progression 
3.7 
Duration of Follow-Up  
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 
 
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performed before every cycle for women who are capable of becoming pregnant.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test. 
D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. Submit 
at the following time points, as applicable: 
x 
Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead.  On-treatment kits for blood sample collections will be automatically 
shipped to sites upon registration to the treatment step. 
x 
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
x 
At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up (with 
a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH Master 
Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of the 
MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle. 
H. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle. 
I. As clinically indicated. 
J. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications. 
K. Within 8 weeks of treatment assignment. 
 
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5.
Drug Formulation and Procurement
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees.
Availability
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment arm prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information) The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents. The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution.
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status.
NCI Supplied Agent(s) – General Information
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator.
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
Rev. 12/16
Rev. 3/17
Rev. Add13
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5.1
GDC-0449 (NSC 747691)
5.1.1
Other Names 
vismodegib, Erivedge
5.1.2
Classification 
Hedgehog Pathway Antagonist
5.1.3
Mode of Action 
GDC-0449 provides anticancer responses by inhibiting the hedgehog
pathway. GDC-0449 binds to and inhibits SMO, whose only
established function is to transmit the Hedgehog signal. The
Hedgehog signaling pathway controls cell differentiation, growth, and 
proliferation. It is most active during embryogenesis but may also play 
a role in the regulation of adult stem cells involved in the maintenance 
and regeneration of adult tissues.
5.1.4
Storage and Stability 
Storage:
Do note store above 30°C (85ºF). 
Stability: Stability testing is ongoing.
5.1.5
Dose Specifics 
Patients will be initiated at 150 mg po daily dose. 
If a patient misses a dose of GDC-0449 (vismodegib), they should not 
take the missed capsule, but resume with the next scheduled dose. 
GDC-0449 (vismodegib) may be taken with or without food.
The capsules must be swallowed whole.  Do not open or crush the 
capsules.
5.1.6
How Supplied  
GDC-0449 is supplied by Genentech and distributed by the CTEP, 
NCI.  It is available as 150-mg grey and pink size 1 capsules 
containing vismodegib, microcrystalline cellulose PH101, lactose 
monohydrate, sodium lauryl sulfate, povidone K29/32, talc, sodium 
starch glycolate, and magnesium stearate and purified water. The 
capsule shell consists of gelatin, red iron oxide, black iron oxide, and 
titanium dioxide. A compendial-grade black printing ink may be used.  
Each bottle contains 32 capsules.
5.1.7
Route of Administration 
Oral.
5.1.8
Incompatibilities 
Clinically significant PK interactions between vismodegib and CYP450 
inhibitors are not expected. GDC-0449 is not a potent inhibitor of 
P450 isoforms 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 No 
clinically significant PK interaction between vismodegib and 
fluconazole (a moderate CYP2C9 inhibitor) or itraconazole (a strong 
CYP3A4 inhibitor) were seen in healthy volunteers (Genentech study 
GP28465). Inducers of CYP3A4 are not predicted to alter vismodegib 
Rev. 12/16
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ECOG-ACRIN
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systemic exposure since similar steady-state plasma vismodegib 
concentrations were observed in patients in clinical studies 
concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, 
modafinil, phenobarbital) and those concomitantly treated with 
CYP3A4 inhibitors (i.e., erythromycin, fluconazole).
Clinically significant PK interactions between vismodegib and P-gp 
inhibitors are not expected. No clinically significant PK interaction 
between vismodegib and itraconazole (a strong P-glycoprotein 
inhibitor) were seen in healthy volunteers (Genentech study 
GD28465).
GDC-0449 inhibited OATP1B1, OATP1B3, and BCRP, but the 
likelihood of GDC-0449 being a clinically relevant inhibitor of 
OATP1B1, OATP1B3, and BCRP is low. It is unlikely that there will be 
an interaction between GDC-0449 and UGT substrates.
Clinically significant PK interactions between vismodegib and pH 
elevating agents are not considered clinically meaningful. Co-
administration of the PPI rabeprazole with GDC-0449 resulted in a 
slight decrease of approximately 14% in GDC-0449 steady state 
exposure compared with administration of GDC-0449 alone. 
Clinically significant PK interactions between vismodegib and CYP450 
substrates are not expected. No clinically significant PK interaction 
between vismodegib and rosiglitazone (a CYP2C8 substrate) or oral 
contraceptives ethinyl estradiol and norethindrone (Genentech study 
SHH4593g). Clinically significant PK interactions between vismodegib 
and BCRP substrates are not expected. In vitro data indicate that 
vismodegib is an inhibitor of the BCRP transporter; however, the in 
vitro concentrations at which inhibition occurred are significantly 
greater than the unbound vismodegib concentrations observed in 
patients.
5.1.9
Side Effects 
See Section 3.3 for side effects.
5.1.10
Nursing/Patient Implications 
The terminal half-life of GDC-0449 is approximately 9-12 days.   
Vismodegib capsules contain lactose monohydrate. Patients with the 
rare hereditary problems of galactose intolerance, primary 
hypolactasia, or glucose-galactose malabsorption should not take this 
medicine.
Reproductive Risks:
x
Women of child bearing potential should continue 
contraceptive measures for 24 months after the last dose of 
GDC-0449.
x
Male patients should maintain adequate contraception 
methods for 3 months
Patients should not donate blood or blood products during the study 
and for 24 months after discontinuation.
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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
1. Ingham PW, McMahon AP: Hedgehog signaling in animal development: paradigms 
and principles. Genes & development 15:3059-87, 2001 
2. Hahn H, Wicking C, Zaphiropoulous PG, et al: Mutations of the human homolog of 
Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841-51, 
1996 
3. Johnson RL, Rothman AL, Xie J, et al: Human homolog of patched, a candidate 
gene for the basal cell nevus syndrome. Science 272:1668-71, 1996 
4. Bodak N, Queille S, Avril MF, et al: High levels of patched gene mutations in basal-
cell carcinomas from patients with xeroderma pigmentosum. Proceedings of the 
National Academy of Sciences of the United States of America 96:5117-22, 1999 
5. Wolter M, Reifenberger J, Sommer C, et al: Mutations in the human homologue of 
the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell 
carcinomas of the skin and primitive neuroectodermal tumors of the central nervous 
system. Cancer research 57:2581-5, 1997 
6. Xie J, Murone M, Luoh SM, et al: Activating Smoothened mutations in sporadic 
basal-cell carcinoma. Nature 391:90-2, 1998 
7. Kool M, Jones DT, Jager N, et al: Genome sequencing of SHH medulloblastoma 
predicts genotype-related response to smoothened inhibition. Cancer Cell 25:393-
405, 2014 
8. Lam CW, Xie J, To KF, et al: A frequent activated smoothened mutation in sporadic 
basal cell carcinomas. Oncogene 18:833-6, 1999 
9. Von Hoff DD, LoRusso PM, Rudin CM, et al: Inhibition of the hedgehog pathway in 
advanced basal-cell carcinoma. N Engl J Med 361:1164-72, 2009 
10. Sekulic A, Migden MR, Oro AE, et al: Efficacy and safety of vismodegib in advanced 
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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of capsules you take 
each day. You should take your scheduled dose of each capsule. Note the times and 
the number of capsules that you take each day. If you develop any side effects, 
please record them and anything you would like to tell the doctor in the space provided. 
Bring any unused capsules and your completed pill calendar to your doctor’s visits. 
GDC-0449 (vismodegib) 
DAY  
Date 
Time capsules 
taken 
Use the space below to make notes about things you would 
like to tell the doctor (including unusual symptoms you 
experience, other medicine you have taken and anything 
else you think would be of interest.) 
Month 
Day 
Year 
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Patient Signature: __________________________________ Date: _____________ 
Use of this document is governed by the terms of use on the first page of this document. 

Use of this document is governed by the terms of use on the first page of this document.