Clinical trial NCT04462471
Conditions: Thyroid Carcinoma Thyroid Cancer Thyroid Cancer, Follicular Thyroid Cancer (Follicular Cell) Thyroid Cancer, Papillary BRAF V600E Mutation Positive
Keywords: thyroid carcinoma of follicular origin thyroid cancer thyroid cancer, follicular thyroid cancer, papillary thyroid cancer, poorly differentiated BRAF V600 RAIR disease Memorial Sloan Kettering Cancer Center 20-053
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2020-06-26; Completion date: 2023-09-29
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to develop a new drug treatment to reverse tumor resistance to radioiodine in BRAF mutant tumors so that radioiodine can be given to shrink tumors. This study is also being done to find out the highest doses of copanlisib and vemurafenib that, when given in combination, do not cause serious side effects, and whether the study treatment will make radioiodine therapy work better in patients with BRAF-mutant thyroid cancers.

Detailed description:

Arms: arm 1: Eligible participants will have a diagnosis of BRAF mutant RAIR thyroid cancer
Interventions: intervention 1: I-124 PET/CT lesion dosimetry intervention 2: Vemurafenib intervention 3: Copanlisib
Intervention descriptions: intervention 1: I-124 PET/CT scans will be performed during this process to quantify baseline RAI avidity in index metastatic lesion(s) intervention 2: Dose level 1 \& 2: 960 mg PO bid Dose level -1: 720 mg PO bid Dose level -2: 480 mg PO bid intervention 3: Dose level 2: 60 mg IV weekly Dose level 1, -1, -2: 45 mg IV weekly

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
 
MSK PROTOCOL COVER SHEET 
A Phase lb Trial of Vemurafenib Plus Copanlisib to Enhance Radioiodine 
Avidity in Radioiodine-RefractoryThyroid Cancers 
Alan Ho, MD, PhD/ Medicine/Head & Neck Oncology 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 5 
3.0 
BACKGROUND AND RATIONALE..................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 10 
4.1 
Design ................................................................................................................................ 10 
4.2 
Intervention......................................................................................................................... 10 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 11 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY........................................................................... 12 
6.1 
Subject Inclusion Criteria .................................................................................................... 12 
6.2 
Subject Exclusion Criteria ................................................................................................... 14 
7.0 
RECRUITMENT PLAN ...................................................................................................... 16 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 17 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................... 27 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................ 30 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 39 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 44 
14.0 BIOSTATISTICS ................................................................................................................ 44 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES47 
15.1 Research Participant Registration ....................................................................................... 47 
15.2 Randomization ................................................................................................................... 48 
16.0 DAT A MANAGEMENT ISSUES ........................................................................................ 48 
16.1 Quality Assurance .............................................................................................................. 48 
16.2 Data and Safety Monitoring ................................................................................................ 48 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................................ 49 
17.1 Privacy ............................................................................................................................... 50 
17.2 Serious Adverse Event (SAE) Reporting............................................................................. 50 
17.2.1 
Other Adverse Events Reporting ................................................................................. 51 
Adverse events of special safety interest. ............................................................................. 51 
Pregnancies ............................................................................................................................. 51 
18.0 INFORMED CONSENT PROCEDURES ........................................................................... 52 
19.0 REFERENCES .................................................................................................................. 53 
20.0 APPENDICES ................................................................................................................... 55 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Appendix A: 1-124 Normal Organ Radiation Dosimetry .................................................................. 56 
Appendix B: 1-124 PET/CT-based Lesional Dosimetry Image Acquisition, Analysis, and 
Interpretation ................................................................................................................................. 57 
Appendix C: The Low-Iodine Diet. ................................................................................................. 60 
Appendix D: Glycemic Index Foods ............................................................................................... 65 
Appendix E: Permeability Glycoprotein (Pg-p) Substrates, Breast Cancer Resistance Protein 
(BCRP) Substrates, and Multidrug and Toxin Extrusion Protein 2 (MATE2K) Substrates ............. 65 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Incurable BRAF V600 
mutant RAIR OTC 
Pretreatment Thyrogen-stimulated 1-124 
PET/CT lesional dosimetry 
Treat with vemurafenib for 1 week then add 
copanlisib according to dose escalation 
Discontinue study drugs and 
conduct final tumor assessment 
Continue study drugs and 
perform tumor assessment 
Thyrogen-stimulated RAI administration 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
• 
◄........................... 
 
 
 
 
• 
◄........................... 
Research biopsy #2* 
On-treatment Thyrogen-stimulated 1-124 
PET/CT lesional dosimetry 
Insufficient 1-124 response 
Sufficient 1-124 response 
 
 
 
 
 
When the MTD is reached, 4 
additional patients will be enrolled at 
the MTD in an expansion cohort. 
Target enrollment: 6-32 patients 
 
This is a single-cohort phase lb study, with a 3+3 dose-escalation design, to establish the maximum 
tolerated dose (MTD) of combined MAPK and PI3K pathway inhibition with vemurafenib (BRAF 
inhibitor) and copanlisib (pan-Pl3K inhibitor) in patients with advanced radioiodine-refractory (RAIR) 
BRAFV600 mutant thyroid carcinoma. Once the MTD for the combination is established, 4 
additional patients will be enrolled in an expansion cohort at the identified MTD (to ensure that a 
total of 10 patients are treated at the MTD). 
The goal of this study is to determine a safe dosage of vemurafenib plus copanlisib that effectively 
redifferentiates RAIR tumors such that they become susceptible to radioiodine (RAI) therapy and 
Disease monitoring: 
1 month: Thyroglobulin 
3-4 months: Tumor imaging plus thyroglobulin 
6 months: Tumor imaging plus thyroglobulin 
Research biopsy #1* 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
enhances retention. Following pretreatment 1-124 PET/CT assessment, vemurafenib alone will be 
given for about 1 week followed by the combination of vemurafenib plus copanlisib. During this 
period, patients will be assessed with 1-124 PET/CT to establish whether they meet the dosimetry 
requirements to warrant treatment with RAI (1-131). Patients who meet the dosimetry requirements 
will be treated with 1-131. Those who do not will have study drug discontinued and removed from 
study. 
The primary objective of this study is to establish the MTD for vemurafenib plus copanlisib. 
Secondary objectives include assessing the proportion of patients who meet the criteria for 1-131 
therapy, evaluating the effect of vemurafenib plus copanlisib on RAI uptake and retention on serial 1- 
124 PET/CT scans, and determining the overall response rate (ORR; per RECIST v1.1 [response 
evaluation criteria in solid tumors version 1.1]) and progression-free survival (PFS) at 6 months after 
combination vemurafenib plus copanlisib and 1-131 therapy. 
Pre- and on-treatment biopsies will be performed to assess changes in tumoral gene expression; 
these findings will be correlated with changes observed in RAI uptake quantified on 1-124 PET 
scans. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objective: 
 
• To identify the MTD of vemurafenib plus copanlisib for patients with BRAF mutant RAIR thyroid 
cancer. 
 
Secondary objectives: 
 
• To determine the proportion of patients with BRAF mutant RAIR thyroid cancer treated with 
vemurafenib and copanlisib at the MTD who meet the criteria for 1-131 treatment as determined by 
1-124 PET/CT lesional dosimetry. 
 
• To determine the proportion of patients with BRAFmutant RAIR thyroid cancer treated with 
vemurafenib and copanlisib (all dose levels) who meet the criteria for 1-131 treatment as 
determined by 1-124 PET/CT lesional dosimetry. 
 
• To quantify the effect of vemurafenib and copanlisib on RAI uptake and retention using serial 1-124 
PET/CT scans. 
 
• To evaluate whether the combination of vemurafenib and copanlisib enhances 1-131 activity, by 
determining the ORR (per RECIST v1.1) at 6 months after treatment with vemurafenib plus 
copanlis ib and 1-131. 
 
• To evaluate whether the combination of vemurafenib and copanlisib enhances 1-131 activity, by 
determining progression-free survival (PFS) at 6 months (per RECIST v1.1) after treatment with 
vemurafenib plus copanlisib and 1-131. 
 
Exploratory objectives: 
 
• To evaluate tumoral gene expression changes associated with vemurafenib plus copanlisib in 
serial research biopsy specimens. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• To examine genomic alterations in tumors from patients in whom vemurafenib plus copanlisib does 
and does not enhance RAI uptake and retention, by use of research biopsy specimens or archival 
tissue. 
 
• To evaluate time to next thyroid cancer treatment, tumor changes after study therapy, serum 
thyroglobulin changes and survival. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
RAIR differentiated thyroid cancers (DTCs) 
The majority of thyroid cancers are differentiated carcinomas of follicular origin, with papillary thyroid 
cancer {PTC) the most common, followed by follicular thyroid cancer. rvletastatic disease represents 
the most frequent cause of thyroid cancer-related death,1 and RAI (1-131) remains a mainstay of 
therapy. RAI is selectively concentrated in thyroid tumors, making it an effective therapy, with 
manageable side effects. However, many patients with metastatic tumors do not have, or lose, the 
ability to trap iodine; this is designated as RAIR disease. RAIR metastatic DTCs are incurable, with a 
10-year overall survival of only 10%.1 
Standard therapy for RAIR DTCs includes the multitargeted tyrosine kinase inhibitors {TKls) lenvatinib 
and sorafenib.2•3 SELECT, a randomized phase Ill trial evaluating lenvatinib (Eisai) compared with 
placebo, met its primary PFS endpoint (median PFS, 18.3 months [lenvatinib] versus 3.6 months 
[placebo]; hazard ratio, 0.23 [95% Cl, 0.14-0.31]; p<0.0001), leading to FDA approval.2 Unfortunately, 
toxicity remains a significant issue, with a 76% rate of grade 3 treatment-related toxicity in the 
lenvatinib group, compared with 9.9% in the placebo group. Treatment that can restore the capacity 
of RAIR tumors to trap and respond to a single administration of 1-131 ("redifferentiation") without the 
need for maintenance drug therapy could replace or defer the need for TKls. Last, a survival benefit 
of TKls in patients with RAIR thyroid cancer has yet to be demonstrated. 
3.2 Inhibition of aberrant mitogen-activated protein kinase (MAPK) signaling partially 
redifferentiates RAIR thyroid cancers and restores RAI avidity 
Approximately 70% of PTCs possess mutually exclusive oncogenic mutations in the rv1APK pathway,4 
the most common of which is BRAFv600E, which has been shown to be a factor of poor prognosis.5 
Constitutive rv1APK pathway activation promotes RAI refractoriness by suppressing the expression of 
genes that mediate iodide uptake and thyroid hormone biosynthesis, such as the Na+n- symporter, 
thyroid peroxidase, and thyroglobulin.6,7 Using genetically engineered mouse models of BRAFmutant 
thyroid cancer, we previously demonstrated that f'v1APK pathway inhibition restores the expression of 
these genes to enhance tumor RAI avidity.6,7 
We subsequently translated this concept to the clinic, demonstrating in a proof-of-concept study that 
the allosteric MEK 1/2 inhibitor selumetinib (AstraZeneca) can restore RAI avidity and efficacy in 
patients with RAIR disease (Figure 1).8 A critical feature of this study was the use of 1-124 PET/CT 
scans to precisely quantify drug-induced changes in iodine incorporation within specific lesions 
("lesional dosimetry").19•20 This technique provides a substantial advantage over traditional whole-body 
radioactive iodine scintigraphy, which does not provide correlative anatomic localization for iodine 
uptake, is less sensitive for detecting iodine-avid metastases,21 and is only loosely quantitative 
(visually similar lesions can represent as much as a 3-log range of radiation dosages). Using 1-124 
PET, we can transform the 1-124 quantification into the predicted 1-131 radiation dosage delivered 
within every individual tumor within a patient's body. Each of the 20 evaluable patients in the study 
had RAIR disease, defined as having one of the following criteria: (1) non-RAl-avid lesion/s on 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Figure 1. Se/umetinib restores iodine incorporation in RAIR thyroid cancers. A) Sum maryof the 1-124 PET/CT data. B)
Fused 1-124 PET/CT images showing new/increased iodine incorporation after selumetinib (NRAS mutant patient). C)
Fused and 3-D rendering of a skull metastasis showing new/increased iodine incorporation (another NRAS mutant 
patient). D) Waterfall plot of the maxim um change in target lesions(%) (relative to a prestudy scan) for the 8 patients 
who received 1-131. 
Figure 1. Selumetinib restores iodine incorporation in RAIR thyroid cancers. A) Sum maryof the 1-124 PET/CT data. B)
Fused 1-124 PET/CT images showing new/increased iodine incorporation after selumetinib (NRAS mutant patient). C)
Fused and 3-D rendering of a skull metastasis showing new/increased iodine incorporation (another NRAS mutant 
patient). D) Waterfall plot of the maxim um change in targetlesions (%) (relative to a prestudy scan) for the 8 patients 
who received 1-131. 
diagnostic whole-body radioactive iodine scintigraphy, (2) RAl-avid lesion/s that did not respond to 
RAI therapy, or (3) fluorodeoxyglucose (FDG)-avid lesion/s on PET scan. Eligible patients with RAIR 
disease underwent 1-124 PET/CT scans after stimulation with recombinant thyroid-stimulating 
hormone (TSH), before and after receiving a 4-week course of selumetinib (75 mg BID twice a day). 
If the second 1-124 PET scan predicted that a lesional RAI dose of 2,000 cGy could be achieved, 1- 
131 was administered while patients continued to receive selumetinib. Of the 20 evaluable patients, 
12 (60%) had new or increased 1-124 incorporation after selumetinib (Figure 1A-C). For 8 patients 
(40%), the second 1-124 PET scan predicted that the lesional absorbed radiation dose would exceed 
2,000 cGy; these patients continued to receive selumetinib and went on to receive therapeutic RAI. 
Reduction in tumor size, by RECIST, was achieved in all patients, with 5 confirmed partial responses; 
3 patients had stable disease (Figure 1D). Substantial decreases in serum thyroglobulin (Tg) following 
RAI therapy were achieved in all 8 patients. These results were reported in the New England Journal 
of Medicine. 18 
However, in the selumetinib study, only 1 of 9 patients with BRAFv600E responded to MEK 1/2 inhibitor 
treatment.8 We hypothesized that to improve outcomes in the BRAFmutant group would require more- 
potent inhibition of MAPK signaling than what could be achieved with MEK inhibition alone. 
Vemurafenib is an ATP-competitive BRAF inhibitor that abrogates monomeric BRAFv6ooE signaling 
and paradoxically activates BRAF wild-type dimers in normal cells,22 resulting in a wide therapeutic 
 
 
window that facilitates robust MAPK inhibition in the tumor cells. We subsequently studied 
vemurafenib in a 10-patient pilot study of BRAF mutant RAIR OTC. Six of the 10 patients had 
increased iodine avidity, as quantified on 1-124 PET/CT-4 of whom met the criteria for treatment with 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Figure 2. MAPK and Pl 3K pathway inhibition enhances RA/ retention and redifferentiates thyroid tumors to form 
follicular structures in a TPO-Cre/LSL-BRAFv600E mouse model. A) After 1 week of therapy with the indicated 
drug, effective tum oral half-life of RAI is calculated on serial measurements made with 1-124 microPETscans. 
8) Histologyof normal thyroid (WT) and vehicle or drug-treated tumors examined after 5 days of treatment. Veh, 
vehicle; CK/, I CH5126766 BRAF/MEK inhibitor; GOG, GDC-0941 (pan class I Pl3K inhibitor). 
1-131.9 At 6 months, 2 of these patients had partial responses and 2 had stable disease. Transcriptional 
analysis of sequential biopsy specimens from 3 patients showed that successful inhibition of the 1\/lAPK 
pathway with vemurafenib led to induction of thyroid-specific gene expression, which we predicted 
would mediate RAI uptake.10 These exciting results, derived from patient samples, validated the 
biologic principles first demonstrated in our mouse models. 
3.3 Preclinical data supporting the use of combined MAPK and Pl3K pathway inhibition 
to enhance RAI uptake and retention 
The effectiveness of 1-131 is governed by the degree to which thyroid tumors can absorb (uptake) and 
retain (retention) RAI. In our BRAFmutant mouse models, we observed that, although 1\/lAPK inhibition 
enhanced RAI uptake, deficient iodide retention was not changed. Exposure to BRAF inhibition led to 
increased AKT phosphorylation, suggesting that activated Pl3K signaling contributes to the 
suppression of genes involved in iodide retention. Using our BRAF mutant thyroid cancer mouse 
model, we investigated the effect of the pan class I PI3K inhibitor GDC-0941 (Genentech) in 
combination with the BRAF/MEK inhibitor CH5126766 (Chugai) on iodide uptake and retention. After 
8 days of therapy, both iodide uptake and retention were enhanced with combination therapy, with 
retention enhanced to levels approximating what is observed in normal thyroid glands (Figure 2A). 
On histopathologic examination, the combination resulted in a significant reorganization of tumor 
cytologic architecture, including the creation of large colloid-filled follicles. These are thyroid hormone- 
producing mechanical subunits in normal thyroid glands that take up elemental iodide and catalyze its 
covalent bonding to the protein thyroglobulin (a process known as "iodine organification") (Figure 2B). 
The physiologic and histopathologic changes observed in this thyroid cancer mouse model correlated 
with dramatic restoration of expression of dual oxidase 1 and 2 (DUOX1, DUOX2), thyroid-specific 
genes that catalyze a critical step in iodine organification and that are key mediators of iodine retention. 
In animals treated with 1-131 concurrently with combination targeted drug therapy, higher levels of 
 
RAl-bound thyroglobulin, which is a surrogate marker for greater RAI retention, were observed within 
the tumors. Taken together, these results strongly suggest that adding pan-Pl3K inhibition to 1\/lAPK 
pathway targeting restores both RAI uptake and retention by promoting the creation of normal thyroid 
follicles that facilitate iodine organification within the tumor, translating to a greater concentration and 
residence time of the 1-131 radiation dose to the tumor, which would be predicted to result in greater 
antitumor efficacy. 
3.4 
BRAF inhibition in DTC 
 
BRAFv600E mutant thyroid cancers are associated with a more aggressive course and increased 
cancer-related mortality, compared with non-BRAF mutant PTCs.11•12 Targeting BRAF in these 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
patients has been shown to have clinically meaningful activity. In a phase II study of vemurafenib in 
patients with BRAFV600E mutant PTC, the response rate was 39% in the untreated cohort and 
27% in the cohort previously exposed to multitargeted VEGF TKls.13 
Whereas the addition of MEK inhibition has been shown to improve outcomes in other cancers, such 
as BRAFmutant melanoma14•15 and anaplastic thyroid carcinoma,16the same has not yet been 
demonstrated for BRAF mutant PTC. In a randomized phase II trial of dabrafenib versus dabrafenib 
plus trametinib in patients with BRAF mutant PTC, objective response rates were largely similar 
(45% with dabrafenib, 38% with dabrafenib plus trametinib).17 In addition, median PFS was not 
statistically different (11.4 months for dabrafenib versus 15.1 months for dabrafenib plus trametinib), 
nor was median duration of response (15.7 months for dabrafenib versus 13.3 months for dabrafenib 
plus trametinib).17 
Given the lack of compelling clinical data supporting enhanced efficacy of combined BRAF/MEK 
inhibition and the potential for increased toxicity when drugs inhibiting both pathways are 
administered, the present study is limited to targeting BRAF alone with vemurafenib plus copanlisib. 
Furthermore, the data from our 10-person pilot study of vemurafenib for redifferentiation of BRAF 
mutant RAIR thyroid cancer will serve as a useful comparator to evaluate the contribution of 
copanlisib for this purpose. 
 
3.5 
Clinical experience with combined MAPK and Pl3K inhibition 
 
Previous studies attempting to combine MAPK and Pl3K pathway inhibitors reported variable 
tolerability, including 2 trials that failed to identify an MTD with a continuous dosing schedule (MEK 
inhibitor trametinib plus AKT inhibitor afuresertib24 and vemurafenib plus pan-Pl3K inhibitor 
BKM12025) and 1 that successfully established an MTD but still identified issues with long-term 
tolerability (trametinib plus pan-Pl3K inhibitor buparlisib26). A phase I trial combining vemurafenib 
with the pan-Pl3K inhibitor PX-866 successfully identified an MTD for the combination (vemurafenib 
720 mg BID plus PX-866 8 mg daily).27 The most common all-grade treatment-related adverse 
events observed included gastrointestinal toxicities (nausea, diarrhea, vomiting), arthralgia, fatigue, 
and skin adverse events (rash and photosensitivity). Evaluation of 4 dose levels identified 2 dose- 
limiting toxicities (DLTs): grade 3 rash and grade 3 pancreatitis. Other grade .::3 treatment-related 
adverse-events included lipase elevation and liver function test abnormalities (AST/ALT elevation). 
The additional advantage of developing a MAPK plus Pl3K pathway inhibitor combination for tumor 
redifferentiation is that only a limited, discrete period of drug therapy would need to be applied (~16 
days without dose interruptions), increasing the likelihood of identifying therapeutic doses that are 
effective and tolerable. 
 
Vemurafenib is FDA approved for the treatment of unresectable or metastatic melanoma with BRAF 
V600E mutation and for Erdheim-Chester disease with BRAFV600 mutation. Vemurafenib is also 
National Comprehensive Cancer Network (NCCN) Compendium-approved for BRAF-positive OTC. 
Copanlisib is FDA approved for the treatment of patients with relapsed follicular lymphoma who have 
had at least 2 prior systemic therapies. 
 
We will likely be able to establish a safe and effective dose/schedule for combination vemurafenib 
and copanlisib administered for only slightly more than 2 weeks in total (~16 days). We hypothesize 
that vemurafenib (BRAF inhibitor) plus copan/isib (P/3K inhibitor) can be safely administered to 
restore RA/ uptake and retention, thus vvarranting therapy Vvith 1-131, in patients Vvith RAIR thyroid 
cancer. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a phase lb trial that will follow a 3+3 dose-escalation design, as detailed in Section 9.2. The 
primary objective of this study is to determine the MTD of vemurafenib plus copanlisib. When the 
MTD is reached, 4 additional patients will be enrolled at the MTD. Patients for whom vemurafenib 
plus copanlisib enhances RAI avidity (as measured on serial 1-124 PET/CT scans) beyond the 
lesional dosimetry threshold specified in the protocol will receive Thyrogen-stimulated 1-131 therapy. 
Secondary objectives include determining the proportion of patients in whom the combination of 
vemurafenib plus copanlisib increases tumoral iodine incorporation (calculated for patients treated at 
the MTD and all dose levels). Tumor uptake and retention of iodine will be evaluated. For patients 
treated with 1-131, the efficacy of the therapy will be evaluated by assessing the ORR (by RECIST 
v1.1) and the proportion of patients alive and without disease progression at 6 months after 
treatment with vemurafenib plus copanlisib and 1-131. 
As an exploratory objective, we will perform sequential pre- and on-treatment biopsies to analyze the 
changes in tumoral gene expression induced by vemurafenib plus copanlisib, as well as the putative 
associations of genetic alterations in the tumor that may portend successful redifferentiation with the 
experimental combination. We will also collect data about time for patients to initiate new thyroid 
cancer treatment and radiographic progression after study treatment. 
4.2 
Intervention 
Eligible patients with BRAF mutant RAIR thyroid cancer will undergo recombinant human TSH 
(Thyrogen; Genzyme Corporation, Cambridge, MA)-stimulated 1-124 PET/CT lesion dosimetry (total 
of 4 1-124 PET/CT scans will be performed during this process) to quantify baseline RAI avidity in 
index metastatic lesion(s). 
Patients will then receive vemurafenib alone for approximately 7 days, followed by the addition of 
copanlisib at the designated dose levels (see Table 9-1). A second on-treatment Thyrogen- 
stimulated 1-124 PET/CT lesional dosimetry analysis will be performed to assess for changes in 1- 
124 uptake and retention. If lesional dosimetry with the second 1-124 PET/CT scan (at ~48 h {~2 
days) after delivery of 1-124) reveals that a dose of .::2000 cGy can be delivered to at least 1 tumor 
with :s;300 mCi of 1-131, then the Principal Investigator (Pl) and treating physician(s) will decide 
whether 1-131 therapy should proceed for that patient. For eligible patients, therapeutic 1-131 will be 
administered concurrently with vemurafenib and copanlisib. The study medication will then be 
discontinued, and tumor assessments will be conducted by serial radiologic scan(s) and serum 
thyroglobulin tests (scans will be performed at baseline, before 1-131, 3-4 months after 1-131, and 6 
months after 1-131). For patients whose tumors do not demonstrate sufficient iodine incorporation, 
the study medication will be discontinued, a final imaging assessment will be performed, and the 
patient will be removed from the study. Without dose interruption, this schedule would involve 
treating patients with vemurafenib for approximately 20 days; copanlisib will be administered once a 
week, for a total of 2 doses. 
If there is evidence of disease progression before completing treatment with vemurafenib and 
copanlisib, study treatment with these drugs and 1-131 will be allowed to continue if the treating 
physician deems that such a decision is clinically justifiable. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Therapeutic agent copanlisib 
 
The Pl3K/AKT/mammalian target of the rapamycin (mTOR) pathway is one of the most prominent 
pathways that promote cellular survival and is constitutively activated in many types of cancers.21 
Class I Pl3K is downstream of most cancer-associated tyrosine kinase growth factor receptors (such 
as epidermal growth factor receptor/human epidermal growth factor receptor, insulin-like growth 
factor 1 receptor, platelet-derived growth factor receptor, vascular endothelial growth factor, and c- 
KIT or mesenchymal epithelial transition factor). 
Four of these Pl3K isoforms (Pl3Ka, Pl3Kf3, Pl3Ky, and Pl3Ko) are categorized as class I enzymes 
because they can use phosphatidylinositol-4,5-bisphosphate (Pl-4,5-P2) as a substrate to generate 
phosphatidylinositol-3,4,5-trisphosphate (PIP3). Elevated PIP3 in cellular membranes drives several 
hallmarks of the cancer phenotype: cell proliferation, survival, metabolic reprogramming, and 
migration. PI3Ka and f3 are ubiquitous; PI3Ky and o are expressed mostly in hematopoietic tissues. 
As expected from its pharmacological properties, copanlisib, a small molecule pan-class 1 Pl3K 
inhibitor with predominant activity against Pl3Ka and Pl3Ko isoforms, demonstrated antitumor 
activity in preclinical models, characterized by activating genetic aberrations of the Pl3K pathway. 
Copanlisib exhibits a potent kinase inhibitory effect on all 4 isoforms, with biochemical ICso (the half 
maximal inhibitor concentration) values of 0.5 nM, 0.7 nM, 3.7 nM, and 6.4 nM for Pl3Ka, Pl3Ko, 
Pl3Kf3, and Pl3Ky, respectively. Copanlisib also potently regulates nuclear localization of the 
forkhead family members, resulting in the induction of transcriptional programs that lead to rapid cell 
death by apoptosis. For additional background information, please refer to the Investigator's 
Brochure. 
Copanlisib is supplied as a lyophilized preparation in a 6-ml injection vial. The total amount of 
copanlisib (BAY 80-6946) per vial is 60 mg. The solution for intravenous (IV) infusion is obtained 
after reconstitution of the lyophilisate with 0.9% sodium chloride solution. 
Please refer to the Pharmacy Instructions for detailed instructions for the reconstitution of the 
lyophilisate and for further dilution of the reconstituted solution. 
Copanlisib is administered in a normal saline solution IV during the course of 1 h. No IV glucose 
preparations should be administered on the days of infusion. 
For continuous use (as in follicular lymphoma), dosing is weekly for the first 3 weeks of a 28-day 
cycle (on days 1, 8, and 15), followed by a 1-week break (i.e., no infusion on day 22). 
Copanlisib will be supplied by Bayer (Bayer AG; Leverkusen, Germany). 
5.2 
Therapeutic agent vemurafenib 
Vemurafenib is a low-molecular-weight orally available inhibitor of the activated form of the BRAF 
serine-threonine kinase enzyme, which is commonly found in thyroid cancer. Vemurafenib 
selectively inhibits oncogenic BRAF kinase. The rationale for identifying such a compound was first 
provided in 2002, when the high prevalence of activating mutations in the BRAF gene was identified 
in a variety of cancers. The high level of selectivity of vemurafenib has been demonstrated in 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
biochemical, cell-based, and in vivo assays. The dose of vemurafenib, 960 mg BID, was identified in 
the phase I dose-finding study PLX 06-02 and is established as the recommended dosage for phase 
II and Ill trials. Commercial supply of vemurafenib will be used for this trial. 
5.3 
Diagnostic agentthyrotropin a (Thyrogen; Genzyme) 
Patients will undergo 1-124 PET/CT scanning after 2 consecutive daily injections of thyrotropin a 
(Thyrogen; Genzyme, Cambridge, rv1A, USA) at 0.9 mg intramuscularly, as previously described.37 
Thyrogen contains a highly purified recombinant form of human TSH and is FDA approved for 
thyroid dosimetry. 
5.4 
Therapeutic agent 1-131 (RAI) 
 
Oral 1-131 (RAI) will be used for treatment of patients whose second lesional dosimetry 1-124 
PET/CT scan reveals iodine incorporation that satisfies the threshold for RAI (1-131) treatment. 1-131 
has a half-life of 8 days and a relatively high principal photon energy of 364 keV, characterized by 
beta particle emissions. It is administered orally in the form of capsules or liquid. Pregnancy is the 
only contraindication to 1-131 treatment. A serum beta-HCG pregnancy test must be performed up to 
2 days before the administration of 1-131 (for woman of child-bearing potential). Commercial supply 
of 1-131 will be used for this trial. 
5.5 
Diagnostic agent 1-124 PET tracer 
Clinical-grade 1-124 was first produced at 1\/lemorial Sloan Kettering Cancer Center (MSK) in the 
1950s. It has been produced in MSK cyclotrons by bombarding tellurium targets. It is purified using 
novel radiochemical techniques. For this study, clinical-grade 1-124 will be provided by outside 
suppliers (e.g. Sofie Biosciences [Dulles, VA, USA; formerly known as IBA 1\/blecular North America 
and Zevacor Pharma]; 3D Imaging [Little Rock, AR, USA]) who meet MSK's minimum specifications 
as stated in the MSK-held investigational new drug (IND; IND# 71343). 1-124 will be given orally as a 
capsule or liquid. The normal organ dosimetry of 1-124 is provided in Appendix A 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
• 
 Histologically or cytologically confirmed thyroid carcinoma of follicular origin (including 
papillary, follicular, and poorly differentiated subtypes and their respective variants). 
 
• 
 A tumor sample (primary, recurrent, or metastatic tumors) possessing a BRAFV600 
mutation, as confirmed in a CUA-certified laboratory or using an FDA-approved 
assay. 
 
• 
1\/leasurable disease by RECIST v1.1 (tumors in previously irradiated fields may be 
considered measurable if there is evidence of tumor progression after radiation 
treatment) 
 
• 
RAIR disease, as defined by any one of the following: 
o A metastatic lesion that is not RAl-avid on a diagnostic radioiodine scan 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
o 
 An RAl-avid lesion that remained stable in size or progressed despite RAI 
treatment before entry in this study (there are no size limitations for the index 
lesion used to satisfy this entry criterion) 
o The presence of at least 1 FOG-avid lesion 
 
• 
No receipt of treatment for thyroid cancer, defined as: 
o 
No 1-131 therapy <6 months before initiation of the protocol (time of initiation 
of the protocol is defined as the first day of drug therapy with vemurafenib and 
copanlisib); diagnostic activities of 1-131 (0-10m Ci) are allowed within 6 
months of initiating the protocol 
o 
No external beam radiation therapy <4 weeks before initiation of the protocol 
o No chemotherapy or targeted therapy including TKls <4 weeks (or <5 half- 
lives of the drug) before the initiation of this protocol 
 
• 
Age 18 years 
 
• 
ECOG performance status S2 or Karnofsky Performance Score (KPS) 70% 
 
• 
 Tissue from the primary tumor or metastases available for correlative studies. Either a 
paraffin block or at least 20 unstained slides are acceptable (30 unstained slides is 
ideal); if <20 unstained slides are available, and a paraffin block is not available, the 
patient may be able to participate at the discretion of the investigator 
 
• 
 Able to swallow and retain an orally administered pill without any clinically significant 
gastrointestinal abnormalities that may alter absorption, such as malabsorption 
syndrome or major resection of the stomach or bowels 
 
• 
 Agree to undergo 2 research biopsies of (a) malignant lesion(s). Tumor tissue 
obtained before study consent or treatment can also be submitted in lieu of 
performance of the first pretreatment biopsy if the Principal Investigator deems it to be 
of sufficient quantity/quality/timeliness (tumor tissue obtained more than 3 years from 
time of study consent would not be eligible). Patients may be exempt from biopsy if 
(1) the investigator or person performing the biopsy judges that no tumor is 
accessible for biopsy, (2) the investigator or person performing the biopsy feels that 
the biopsy poses too great of a risk to the patient, or (3) the patient's platelet count is 
<100,000/mcl or the patient cannot be safely removed from anticoagulation therapy 
(if the anticoagulation therapy needs to be temporarily held for the biopsy procedure). 
If the investigator deems a second research biopsy to be high risk, the patient may be 
exempt from the second biopsy. 
 
• 
Screening laboratory values meeting the following criteria: 
• 
WBC 2000/µL 
• 
Neutrophils 1500/µL 
■ 
Platelets 100 x 103/µL 
• 
Hemoglobin >9.0 g/dl 
• 
Lipase s1.5 x ULN 
• 
AST/ALT ::,;3 x ULN 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• 
 Total bilirubin 1.5 x ULN (except subjects with Gilbert syndrome, who 
can have total bilirubin <3.0 mg/dl) 
• 
Serum creatinine 1.5 x ULN or creatinine clearance (CrCI) 
.:::40 mUmin (if using the Cockcroft-Gault formula below): 
 
Female CrCI = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dl 
 
Male CrCI = (140 - age in years) x weight in kg x 1.00 
72 x serum creatinine in mg/dl 
 
6.2 
Subject Exclusion Criteria 
 
• 
Untreated metastatic brain or leptomeningeal tumors (metastatic brain or leptomeningeal 
tumors treated with radiation and/or surgery are allowed) 
 
• 
 Prior malignancy if diagnosed and treated within 2 years of trial drug initiation (with the 
exception of nonmelanoma skin cancers or Stage I cancers treated with curative intent). 
Patients may be included if they have completed therapy for a prior malignancy >2 years 
before drug initiation and currently have no evidence of disease 
 
• 
Inability to follow a low-iodine diet or requiring a medication with a high content of iodide 
(amiodarone) 
 
• 
Current congestive heart failure class >2, as defined by the New York Heart Association 
functional classification system 
 
• 
Myocardial infarction <6 months before the initiation of protocol 
 
• 
 Unstable angina (angina symptoms at rest) or new-onset angina (begun within the last 3 
months) 
 
• 
Uncontrolled hypertension (blood pressure >150/90, despite optimal medical management) 
 
• 
Uncontrolled type I or II diabetes mellitus, as judged by the investigator, or Hgb A1C of >8.5 
 
• 
 Arterial or venous thrombotic event or embolic event, such as a cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism, within 
3 months before the start of study medication 
 
• 
Nonhealing wound, ulcer, or bone fracture (tumor-related nonhealing wounds are allowed) 
 
• 
Active, clinically serious infections CTCAE v5.0 grade >2 
 
• 
History of concurrent condition of interstitial lung disease and/or severely impaired lung 
function 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• 
Known history of HIV infection (all patients must be screened for HIV up to 28 days before 
start of study) 
 
• 
Seizure disorder requiring medication 
 
• 
Therapy with a prohibited concomitant medication (Section 9.5) that cannot be temporarily 
held (at least 2 weeks before initiation of vemurafenib plus copanlisib until 1 week after the 
last dose) or replaced with a nonprohibited concomitant medication 
 
• 
 Systemic corticosteroid therapy at a daily dose >15 mg prednisone or equivalent (previous 
corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days before 
study registration) 
 
• 
Cytomegalovirus (Cf\/1\/) PCR-positive at baseline 
 
• 
Evidence or history of a bleeding diathesis or any hemorrhage or bleeding CTCAE v5.0 
grade 3 within 4 weeks before the start of study protocol 
 
• 
 HBV or HCV infection. All patients must be screened for HBV and HCV up to 28 days before 
the start of study medication using the routine hepatitis virus laboratorial panel. Patients 
positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA (these patients 
should receive prophylactic HBV antiviral therapy). Patients positive for anti-HCV antibody 
will be eligible if they are negative for HCV-RNA 
 
• 
Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the 
formulation 
 
• 
 Substance abuse or medical, psychological, or social conditions that may interfere with the 
patient's participation in the study or evaluation of the study results 
 
• 
Patients who are pregnant 
 
• 
 Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during dosing and 
for 6 months after the last administration of study treatment. Highly effective contraception 
methods include: 
 
• 
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of 
contraception 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking 
study treatment. In cases of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone-level assessment 
(FSH level in the postmenopausal range) is this acceptable 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• 
 Male sterilization (at least 6 months before screening). The vasectomized male 
partner should be the sole partner for that patient 
• 
Use of oral, injected, or implanted hormonal methods of contraception or 
placement of an intrauterine device or intrauterine system or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%)-for 
example, hormone vaginal ring or transdermal hormone contraception. Note: In 
cases of use of oral contraception, women should have been stable, on the same 
pill for a minimum of 3 months before taking study treatment 
• 
 Women are considered postmenopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy), total 
hysterectomy, or tubal ligation at least 6 weeks ago. In cases of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by 
follow-up hormone-level assessment is she considered not of child-bearing 
potential. 
 
• 
 Sexually active men, unless they use a condom during intercourse while on treatment and 
for 6 months after stopping treatment with study drugs (men should not father a child in this 
period). A condom is required to be used by vasectomized men as well during intercourse to 
prevent delivery of the drug via semen. 
 
 
7.0 
RECRUITMENT PLAN 
Potential research subjects will be identified by a member of the patient's treatment team, the 
protocol investigator, or research team. Patient recruitment most likely will occur in the medical 
oncology and endocrinology clinics of the Head and Neck Disease management team. If the 
investigator is a member of the treatment team, s/he will screen their patient's medical records for 
suitable research study participants and discuss the study and their potential for enrolling in the 
research study. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. Investigators will discuss the study and review/sign the 
informed consent documents with the patient. 
During the initial conversation between the investigator/research staff and the patient, the patient may 
be asked to provide certain health information that is necessary to the recruitment and enrollment 
process. The investigator/research staff may also review portions of their medical records in order to 
further assess eligibility. They will use the information provided by the patient and/or medical record 
to confirm that the patient is eligible and to contact the patient regarding study enrollment. If the 
patient turns out to be ineligible for the research study, the research staff will destroy all information 
collected on the patient during the initial conversation and medical records review. 
 
 
8.0 
PRETREATMENT EVALUATION 
To be performed any time before the start of study medication: 
• 
Collection of ~10 ml of blood, preferably in a lavender-top tube (with EDTA) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• 
Research tumor biopsy: The first of 2 research biopsies will be performed any time before 
administration of vemurafenib and copanlisib. Any tumor site is allowed, but metastatic tumors 
are preferred, and every attempt should be made when performing both biopsies to obtain tissue 
from the same tumor. Tumor tissue obtained before study consent or treatment can also be 
submitted in lieu of performance of the first pretreatment biopsy if the Principal Investigator 
deems it to be of sufficient quantity/quality/timeliness. See Section 6.1 for exemption clauses 
regarding biopsy. 
Within 30 days of starting study, the following tests must be done: 
• 
Signed informed consent form 
• 
History and physical examination 
• 
Vital signs (blood pressure, pulse), including weight 
• 
Performance status (ECOG or Karnofsky Performance score) 
• 
Radiologic studies (CT [without iodinated contrast] or MRI scan) for disease assessment 
• 
Record of concomitant medications 
• 
Comprehensive metabolic panel, including albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT (AST), 
SGPT (ALT), and sodium 
• 
Complete blood count 
• 
Thyroid function studies (TSH level, thyroglobulin, thyroglobulin antibody, and free T4) 
• 
BRAF mutation testing of the primary tumor, recurrent tumor, or metastasis if not done previously 
(results obtained any time before study registration can be used for patient enrollment) 
• 
EKG (or ECG) 
• 
Echocardiogram (ECHO) 
• 
Dermatologic exam 
• 
 Request for archival tumor tissue (if tissue is not already available at MSK; receipt of tissue is not 
required for study enrollment or initiation) 
• 
Lipase 
• 
Crvt\/ PCR 
• 
HIV serologies 
• 
HBV serologies 
• 
HGV serologies 
• 
Hgb A1C 
 
To be performed within 7 days of starting study: 
 
• 
Serum beta-HCG (pregnancy test) in women of child-bearing potential 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Schedule of events (for all patients initiating treatment) 
The week and day designations below may be subject to change if disruption in the evaluation or 
treatment schedule occurs. If there is a disruption to the schedule of events (including but not limited 
to a dose hold, inability to schedule appointments or procedures, or failure to comply with a low- 
iodine diet), making up or rescheduling some or all of the study assessments or treatments may be 
considered after discussion with the Principal Investigator (this is not a requirement). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
• As detailed in the calendars included in Section 10, protocol procedures are subdivided into 3 
consecutive study periods: (1) the pretreatment 1-124 PET/CT lesional dosimetry process (the 
days/scheduling during this period are designated as "Daypre-tx [Dpre-tx]"); followed by (2) on- 
treatment procedures during study drug treatment (designated as "Daytx [Dtx]"), which is the MTD 
period; and ending with (3) posttreatment assessments. The protocol procedures listed above will 
be taking place simultaneously with the dose escalation. 
 
• After providing signed informed consent, patients will be required to perform a pretreatment 
biopsy (before starting vemurafenib and copanlisib), unless the patient is exempt as defined in 
Section 6.1. 
 
 
1)  Pretreatment Thyrogen-stimulated 1-124 PET/CT lesional dosimetry {Dore-txl 
 
Thyrogen-stimulated 1-124 PET/CT lesional dosimetry will be performed to establish baseline iodine 
avidity (for details of 1-124 PET/CT acquisition, analysis, and interpretation, please see Appendix 
B). 
o Patients will adhere to a low-iodine diet (Appendix C) beginning preferably 7 days before the 
initiation of the lesional dosimetry process (but minimally 5 days prior). 
o Blood draw(s) for TSH, free T4, thyroglobulin, and thyroglobulin antibody will be collected on Dpre- 
tx 1 (before Thyrogen injection) and Dpre-tx 3. TSH, thyroglobulin, and thyroglobulin antibody will be 
collected on Dpre-tx 5. 
o Thyrogen injections (0.9 mg) will be administered intramuscularly on Dpre-ix 1 and 2. 
o 1-124 (approximately 6 mCi (4-7 mCi)) will be administered orally on Dpre-tx 3. 
o 1-124 PET/CT will be performed on Dpre-ix 4 (~24 h), Dpre-tx 5 (~48 h), Dpre-ix 6 (~72 h), and Dpre-ix 8 
(~120 h) (hour designations are approximations of the interval from the time that the 1-124 is 
orally administered, not specific hours at which the scans must be done). The low iodine diet can 
be discontinued after the last 1-124 PET/CT scan. Note: If no iodine uptake is detected on the 
PET/CT scan done on Dpre-tx 5 (~48 h after delivery of 1-124), the subsequent PET/CT scans 
(e.g., at ~72, and ~120 h after delivery of 1-124) will not be performed. 
o See Table 10-1 for the baseline (pretreatment) 1-124 PET/CT schedule and requirements. 
 
2)  On-treatment procedures (D!l!. ) (see Figure 3 below) 
 
• The initiation of study drugs (Dix 1) will be scheduled to ensure an interval of at least approximately 
4 weeks between the delivery of 1-124 tracer during the pretreatment 1-124 PET/CT and the on- 
treatment 1-124 PET/CT (to ensure sufficient elimination of the first 1-124 tracer during the 
pretreatment Thyrogen-stimulated 1-124 PET/CT lesional dosimetry process). If the first 1-124 
PET/CT lesional dosimetry scan does not demonstrate any significant uptake, starting vemurafenib 
plus copanlisib earlier may be considered. 
• On Dtx 1, patients will initiate vemurafenib at the dose determined by the dose escalation rules in 
Section 9.2. For ease of scheduling, if possible, Dix1 should be scheduled for a fv1onday. 
• On Dtx8 (+/-1 day) and Day 15 (+/-1 day), patients will receive the copanlisib infusions per the 
dose escalation rules in Section 9.2. 
o For guidance about meal times and glucose monitoring, please see the respective Sections 9.3 
and 9.4 and the table of events in Section 10 (below). All patients must be fasting for a 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
minimum of 8 h before the first infusion of copanlisib. For patients with diabetes, consider 
holding insulin and sulfonylureas on the morning of the fast to avoid hypoglycemia. Fasting for 4 
h or more before the second infusion of copanlisib should be considered. 
o Pre-treatment glucose levels must be <160 mg/dl prior to infusions if fasting, or random 
glucose of <200 mg/dl if not fasting. 
o Blood glucose will be measured approximately 1 hour after completion of infusion and 
subsequently if clinically indicated, at the discretion of the investigator. 
o Low glycemic index meals should be eaten for approximately 48 hours after copanlisib infusion. 
For further guidance about mealtimes and glucose monitoring, please see Sections 9.3 and 9.4 
and the table of events in Section 10 below. 
o Please refer to Table 11-13 and consider consultation with an endocrinologist for management 
of hyperglycemia. 
o  Blood pressure will be measured approximately every 5-10 minutes prior to each copanlisib 
dose until 2 consecutive results <150/90 mmHg are recorded. If blood pressure is 150/90 
mmHg, the investigator can consider a medical intervention or can delay infusion of the study 
drug. The patient should rest before blood pressure is recorded. 
o On infusion days, blood pressure will be measured at Oh (pre-dose), approximately 30 min 
(mid-infusion), approximately 60 min (end of infusion), and approximately 1 h after the end of 
infusion. Note: A window of ±15 min is allowed for all blood pressure measurements, except for 
the 0 h (pre-dose) measurement. 
o No dose should be given if blood pressure is 150/90 mmHg. Antihypertensive medication may 
be given to control increased blood pressure. Dosing can proceed on the scheduled day if at 
least 2 consecutive measurements <150/90 mmHg are recorded. In the absence of these 
measurements, dosing must be delayed. 
• 
Patients will initiate a low-iodine diet preferably 7 days before initiation of the lesional dosimetry 
process, but minimally 5 days before initiation of the lesional dosimetry process (Appendix C). 
• 
 Patients will undergo a second biopsy while on therapy, unless the patient is exempt as defined 
in Section 6.1. When performing the second (on-treatment) biopsy, every attempt should be 
made to obtain tissue from the same tumor sampled at baseline (the pretreatment biopsy). Every 
effort will be made to perform the on-treatment biopsy on Dtx15 or Dtx16 before the Thyrogen 
injection. However, the timing of the biopsy may be changed at the discretion of the Principle 
Investigator to account for patient preference and scheduling needs. 
• 
For DtxB to Dtx 15, patients will complete a second (on-treatment) Thyrogen-stimulated 1-124 
PET/CT lesional dosimetry while on therapy, as described above (see Table 10-2 for the on- 
treatment Thyrogen-stimulated 1-124 PET/CT schedule and requirements). In addition to this, the 
second Thyrogen-stimulated 1-124 PET/CT process will incorporate routine analyses for 
determining the maximum tolerated activity (MTA), to guide subsequent 1-131 therapy. This 
analysis reproduces the standard-of-care MTA analysis used routinely with 1-131, and includes: 
o Routine blood samples will be collected (into green-top tubes) on days 1 (pre-Thyrogen), 3, 4, 
5, 6, and 8 for radioiodine pharmacokinetics (enumeration of days here are relative to the day 
of the first Thyrogen injection [given on DtxB]). These blood collections are non-research and 
will be performed in the Nuclear fv1edicine clinic, therefore deviations from the specific 
timepoints or approach to collection will be allowed. 
o Note: Hour designations noted here are approximations of the intervals from the time that the 
1-124 is orally administered, not specific hours at which the blood collections must be done. 
 
• 
Interpretation of the on-treatment 1-124 PET/CTscan(performed on DtxBto Dtx15) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
o If lesional dosimetry with the second 1-124 PET/CT scan (at~ 2 days after delivery of 1-124 
during the on-treatment Thyrogen-stimulated 1-124 PET/CT lesional dosimetry (Dtx 12 scan)) 
reveals that a dose of 2000 cGy can be delivered to at least 1 tumor with ::;300 mCi of I- 
131(the lesional dosimetry threshold), the Principal Investigator and treating physician(s)will 
decide whether 1-131 therapy should proceed. As an alternative to relying on the PET/CT 
performed just 2 days after 1-124, per the Principal Investigator's discretion, the decision to 
proceed with therapeutic 1-131 could also be determined after the biologic half-life has been 
calculated from the full complement of 1-124 PET/CT images collected (completed by Dtx 15 
according to Table 10.2). 
o If deemed appropriate, the patient will receive Thyrogen (0.9 mg) on Dtx 16 and Dtx 17 and 
then will be treated with 1-131 therapy on Dtx 18. (depending on scheduling issues, Thyrogen 
injection could also be given Dtx 15 and Dtx 16, followed by 1-131 therapy on Dtx 17.) 
o  For patients who have sufficient uptake to warrant treatment with 1-131, the low-iodine diet 
must be continued for 2 days after administration of therapeutic 1-131 (1-131 activity 
administered for each patient will be guided by the calculated MTA). Vemurafenib will 
continue for 2 days after the administration of 1-131 therapy. 
o  For patients who did not meet the lesional dosimetry threshold required for treatment with 1- 
131, study drugs and low-iodine diet will be discontinued immediately, and a final tumor 
assessment will be performed. This includes not administering a second dose of copanlisib 
scheduled for Day 15 (+/-1 day) (these patients will have received only 1 dose of copanlisib). 
o If there is evidence of disease progression before completing treatment with vemurafenib and 
copanlisib, study treatment with these drugs and 1-131 will be allowed to continue if the 
treating physician deems that such a decision is clinically justifiable. 
o Note: If no iodine uptake is detected on the second 1-124 PET/CT scan done on Dtx 12 (~2 
days after 1-124), the subsequent 1-124 PET/CT scans (e.g., at ~3 and ~5 days after 1-124) 
and the planned blood sample collections for MTA determination does not have to be 
completed. If the degree of iodine uptake measured on the Dtx 12 (~2 days after 1-124) 1-124 
PET/CT scan is determined to be insufficient for 1-131 therapy, the planned blood sample 
collections for MTA determination may not be completed; however, the subsequent 1-124 
PET/CT scans (e.g., at ~72 and ~120 h after 1-124) may still be performed to evaluate iodine 
retention. 
• If a patient is unable to receive the on-treatment Thyrogen-stimulated 1-124 PET/CT lesional 
dosimetry process for unanticipated reasons (e.g., weather delays, holidays, travel issues, 
personal conflicts, availability of tracer), performance of the 1-124 PET/CT protocol will be 
rescheduled to the following week. To avoid unnecessary drug exposure, vemurafenib and 
copanlisib can be stopped and restarted 3 days before the rescheduled administration of 1-124 
tracer. 
• Note: If feasible, tumor measurements (per RECIST v1.1) will be performed with CT scans (without 
iodinated contrast) and/or MRI scans at separate times from the 1-124 PET/CT scans according to 
the schedule in Section 10.0. 
 
 
Figure 3. On-treatment and posttreatment schedule of events for patients with sufficient uptake 
to warrant treatment with 1-131. 
D16, 
D1 
D8 
D9  D10 D11 D12 D13 
D15  D17 D18 D20 1 month  3-4 months 
I I I  I 
I 
 
6 months 
T 
T  1-124 PET PET PET  PET 
T 1-131 I 
Thyrstudiesand tumorassessments 
Initiate 
v emurafenib 
& 
Copanlisib 
(#1) 
& 
Copanlisib 
(#2) 
Last dose 
vemurafenib 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
 
 
T = Thyrogen injection; PET= 1-124 PET/CT scans; 1-131 = radioiodine (RAI); Thyr studies= thyroglobulin, TSH, free T4, and 
thyroglobulin antibody. 
 
 
9.2 
Dose-escalation rules and definition of DLT 
Dose escalation will proceed within each cohort according to a 3+3 design as outlined in the schema 
below. 
Table 9-1: Dose levels (modified 3+3 design) 
 
 
Dose 
Level 
Vemurafenib 
Dose 
Copanlisib Dose 
2 
960 mg PO bid 
60 mg IV weekly 
1 (start) 
960 mg PO bid 
45 mg IV weekly 
-1 
720 mg PO bid 
45 mg IV weekly 
-2 
480 mg PO bid 
45 mg IV weekly 
 
Dose-escalation/de-escalation rules for the 3+3 design: Three patients viii be evaluated for the 
dose level being tested. If O of the initial 3 patients experience a DLT, the next higher dose level viii 
be tested. If 1 of the initial 3 patients at any dose level experiences a DLT, 3 additional 
patients w/1 be treated at the same dose level. Escalation to the next dose level viii only occur if 
no additional DLTs are observed. If 2 patients experience a DLT, the next lo'v\er dose level viii be 
tested. Please see below the specific plan for possible iterations that may be observed and how 
MTD viii be determined. 
 
• 
If O of the initial 3 patients at dose level 1 experience a DLT, dose level 2 will be studied. 
• 
If 1 of the initial 3 patients at dose level 1 experiences a DLT, 3 additional patients will be treated 
at the same dose level. Escalation to dose level 2 will proceed only if no additional DLTs have 
been observed. 
• 
If 2 patients at dose level 1 experience a DLT, dose level -1 will be studied. 
• 
If 2 patients at dose level -1 experience a DLT, dose level -2 will be studied. 
 
MTD determinations: 
• 
If only 3 patients have been treated at the dose under consideration as the MTD, an additional 3 
patients will be treated at the same level. The dose will be declared the MTD if :::;;1 DLTwas 
observed among the 6 treated patients. If there is >1 DLT among the 6 treated patients, the next 
lower dose level will be considered the MTD. 
• 
If 2 patients at dose level 2 experience a DLT, and :::;;1 out of 6 patients treated at dose level 1 
experience a DLT, then dose level 1 will be declared the MTD. 
• 
If 2 patients at dose level -2 experience a DLT, the combination will be determined to be 
unsafe, and the trial will end. 
 
Once the MTD for vemurafenib plus copanlisib is established, up to an additional 4 patients will be 
enrolled in the cohort, bringing the total number of patients treated at the MTD to 10. As an added 
precaution for safety, if 2 of the additional 4 patients experience a DLT, further accrual will be halted. On-treatmentschedulewithvemurafenib(POBID)+copanlisib(IVweekly)
 Posttreatmentschedule
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
Definitions of DLTs: 
Toxicities will be evaluated using CTCAE version 5.0 (CTCAE v5.0). Only toxicities that meet DLT 
definitions within the DLT assessment window (from the initiation of copanlisib study treatment to 7 
days after completion of study drug administration) and are attributed to vemurafenib, copanlisib or 
copanlisib plus vemurafenib will be counted as DLTs. Toxicities unrelated to either drug will not be 
considered DLTs. If a patient withdraws from the study prior to the completion of the DLT 
assessment window for reasons other than a DLT, the patient may be replaced and no DLTwill be 
considered to have occurred, unless the Principal Investigator judges that the case should be 
considered a DLT. Dl Ts will otherwise be defined as: 
1.  Any grade 3 adverse event possibly, probably, or definitely related to vemurafenib, copanlisib or 
the combination of copanlisib and vemurafenib. Exceptions to this rule include nausea, vomiting, 
or diarrhea without maximal supportive therapy, 
grade 3 hypertension without optimal medical 
intervention or which is transient (improves without medical intervention), development of new 
nonmelanoma skin cancer, alopecia, asymptomatic lipase and/or amylase elevation, grade 3 
fatigue lasting for -5.7 days, grade 3 decreased lymphocyte count, hyperglycemia, grade 3 rash 
or palmar-plantar erythrodysethesia that improves to 
grade 2 with supportive therapy within 7 
days, grade 3 fever controlled with medication within 7 days and/or other grade 3 
asymptomatic laboratory abnormalities that can be corrected within 7 days. 
2. Any grade 5 adverse events, unless clearly not related to treatment. 
3. Any adverse event that leads to a dose delay of 7 days. 
4. Any adverse event that requires a permanent dose reduction. 
5.  Febrile neutropenia occurring from the time of initiating study drugs up to 4 weeks after 
therapeutic RAI (1-131) will be considered a DLT. 
 
Patients who experience a DLT will be allowed to continue in the study at a lower dose, in 
accordance with the protocol-specified dose modification, following recovery of the toxicity to grade 
-5.1 or the baseline level of severity (see Section 11). 
 
Patients who delay vemurafenib or copanlisib for 3 days as a result of unanticipated scheduling 
issues (e.g., weather, emergencies; not drug-related toxicity) will not be evaluable and be replaced 
for DLT evaluation but may continue on the protocol. All patients receiving at least one dose of 
copanlisib will be evaluable for DLT. 
 
If a patient experiences intolerable or Grade 3 toxicities possibly, probably, or definitely related to 
vemurafenib before the first dose of copanlisib is administered, this will NOT be considered a DLT 
and the patient will be replaced. The patient can be taken off study OR continue on protocol with 
vemurafenib alone with dose reduction per Section 11.0. 
 
 
9.3 
Recommendations on meal timing with copanlisib 
 
Because of its inhibitory effect on PI3Ka, which has been implicated in insulin metabolism, 
copanlisib infusions could be associated with a temporary increase in blood glucose. Consuming a 
meal in close proximity to copanlisib infusion may exacerbate glucose increase. It is recommended 
that the timing and content of caloric intake on infusion days are monitored by the investigators. 
Consultation with an endocrinologist may be necessary. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
The investigator will review the glucose profile during and after copanlisib infusions. Timing and 
content of caloric intake on infusion days will be managed by the investigator. 
 
To minimize glucose increases, the investigator may manage the timing of postinfusion meals on the 
basis of the glucose profile during prior infusion(s). This is in addition to glucose-lowering 
medication. For only the firstcopanlisib infusion, fasting is required (8-h minimum) before the first 
glucose measurement on the date of infusion. A low-glycemic-index meal may be taken 2 h after 
infusion. For all subsequent copanlisib infusions, the decision regarding meal timing can be made by 
the investigator on the basis of glucose-response patterns during prior treatment days. Generally, a 
low-glycemic-index meal may be taken within 4 h before the start of the study drug infusion. 
 
A low-glycemic-index diet (see Appendix D) is recommended for the first 48 h after study drug 
infusion. However, caloric restriction is not intended for the population under study. 
 
Note: Caloric intake and timing recommendations for patients with diabetes who require insulin 
treatment before the infusion at any time point should be managed by the investigator on the basis 
of consultation with the treating physician or diabetes/endocrinologist physician. 
9.4 
Recommendation on glucose monitoring with copanlisib 
Glucose monitoring for the first copanlisib administration 
• 
 Blood glucose will be measured at Oh (predose) and ~1 h after completion of infusion and 
subsequently if clinically indicated, at the discretion of the investigator. Patients should be 
educated on the signs and symptoms of hyperglycemia, such as frequent urination, increased 
thirst, blurred vision, headaches, and difficulty concentrating, and must report these to the 
investigator or their physician immediately. 
 
Glucose monitoring for the second copanlisib infusion 
 
• 
If hyperglycemia is <250 mg/dl after the first copanlisib infusion, at the discretion of the 
investigator, post-infusion glucose monitoring may or may not be performed. Pre-infusion 
glucose testing before copanlisib is required to ensure fasting levels <160 mg/dl or 
random/nonfasting glucose levels <200 mg/dl. 
 
Glucose monitoring at home 
• 
 For all patients who experience persistent glucose >250 mg/dl (13.9 mmol/L) or who receive 
antidiabetic treatment on the day of infusion, fasting glucose should be measured the next day. 
If the glucose reading is <100 mg/dl (5.5 mmol/L; nondiabetic) or <160 mg/dl (8.9 mmol/L; 
diabetic), record the reading and stop further glucose measurements until the next copanlisib 
infusion. If the glucose reading is >100 mg/dl (5.5 mmol/L; nondiabetic) or >160 mg/dl (8.9 
mmol/L; diabetic), inform the study nurse or investigator. If the patient has known diabetes and 
already monitors his/her blood glucose as part of routine diabetes care, the routine 
measurements should not be replaced by the study-specific measurements. In this situation, 
patients should add the study-specific measurements to their routine. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• 
For patients without diabetes who experience persisting glucose >250 mg/dl (13.9 mmol/L) or 
who require treatment to maintain optimal glucose levels, consultation with an endocrinologist is 
encouraged. These patients without diabetes will be trained on how to measure their capillary 
blood glucose levels at home. If applicable, patients will be provided with a glucose meter and 
supplies (e.g., lancets, test strips, and diary) to register measured values and record oral 
glucose-lowering medication and/or insulin administration. 
Please refer to Table 11-13 and consider consultation with an endocrinologist for the management 
of hyperglycemia. 
 
9.5 
Concomitant medications and therapies 
Permitted concomitant therapy: 
• 
Standard therapies for concurrent medical conditions 
• 
 Treatment with nonconventional therapies (for example, herbs or acupuncture) and 
vitamin/mineral supplements is acceptable, provided they do not interfere with the study 
endpoints, in the opinion of the Investigator. St. John's wort is not permitted. 
• 
Bisphosphonates or other bone-modifying agents (e.g., denosumab) 
• 
Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed 
to participate, provided their medication dose and international normalized ratio/partial 
thromboplastin time is stable. Close monitoring is recommended, in accordance with the 
standard of care. If either of these values is above the therapeutic range, the doses should be 
modified and the assessments should be repeated weekly until the value(s) become(s) stable. 
• 
 Antiemetics: prophylactic anti-emetics may be administered in accordance with standard 
practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, 
ondansetron, or an equivalent agent, is allowed as needed. 
• 
 The use of corticosteroids as antiemetics before copanlisib administration will not be allowed 
(given the risk of worsened hyperglycemia). 
• 
Palliative and supportive care for the other disease-related symptoms and for toxicities 
associated with treatment will be offered to all patients in this trial. 
• 
Patients may receive palliative and supportive care for any underlying illness. 
• 
Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. 
• 
Patients taking narrow-therapeutic-index medications should be monitored proactively if these 
medications cannot be avoided. These medications may include quinidine, cyclosporine, and 
digoxin. 
• 
 Therapeutic drugs known to be substrates of P-gp and/or BCRP with narrow therapeutic index 
should be used with caution, and patients should be monitored for any sign of toxicity. 
Furthermore, sensitive substrates of the renal drug transporter MATE2K (e.g., metformin) should 
be used with caution (see Appendix E). Metformin should be interrupted for 48 h after receipt of 
iodinated contrast media. Please see prescribing information for further information. 
• 
 Calcium channel blockers may be used to control preexisting hypertension. Nondihydropyridine 
calcium channel blockers (e.g., verapamil and diltiazem) should be avoided because of a 
potential interaction with CYP3A4. 
• 
 Short-term (up to 7 days) systemic corticosteroids >15 mg prednisone or equivalent will be 
allowed for the management of acute conditions (e.g., treatment of noninfectious pneumonitis 
[NIP]). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Prohibited concomitant therapy: 
The following medications are prohibited during study treatment (see Table 9-2 below). 
This list is not comprehensive and is only meant to be used as a guide. 
• 
Strong inhibitors or inducers of CYP3M/5 
• 
Substrates of CYP3A4/5 with narrow therapeutic index 
• 
Medications that carry a strong risk for QT prolongation 
• 
Herbal medications/preparations (except for vitamins) 
• 
Other investigational and antineoplastic therapies 
• 
Anti-arrhythmic therapy other than beta blockers or digoxin 
• 
 Systemic corticosteroid therapy at a daily dose >15 mg prednisone or equivalent. Previous 
corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days before 
study registration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de- 
escalated to the maximum allowed dose before the screening. Patients may be using topical or 
inhaled corticosteroids. Short-term (up to 7 days) systemic corticosteroids >15 mg prednisolone 
or equivalent will be allowed for the management of acute issues. The use of corticosteroids as 
antiemetics before copanlisib administration will not be allowed. 
• 
Ongoing immunosuppressive therapy 
• 
Concomitant radiotherapy 
• 
Herbal medications, including but not limited to St. John's wort, Kava, ephedra (ma huang), 
ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh, and 
ginseng. Patients should stop using all herbal medications at least 7 days before the first dose of 
study treatment. 
 
Table 9-2: List of prohibited medications during the study 
 
Category 
Drug name 
Strong CYP3A inhibitors 
Voriconazole, boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, eltegravir/ritonavir, 
grapefruitjuice, indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil,nefazodone, 
nelfinavir, posaconazole, ritonavir,saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin 
Moderate CYP3A inhibitors 
Grapefruit, grapefruit hybrids,pum melos,star-fruit, Seville 
oranges (citrus paradisi fruitjuice) 
Strong CYP3A inducers 
Avasimibe, 
carbamazepine,  mitotane, 
phenobarbi1al, 
phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum) 
CYP3A substrates with narrow 
therapeutic index (NTI) 
Alfentanil, apixaban (doses >2.5 mg only), aprepitan 
astemizole, 
cisapride, 
cyclosporine, 
diergotamine, 
dihydroergotamine, ergotam ine, fentanyl, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban, 
simvastatin,sirolimus, tacrolimus, terfenadine, thioridazine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the 
patient is on the study. Anticancer therapy (chemotherapy, 
biologic or radiation therapy, and surgery) other than the 
study treatments must not be given to patients while the 
patient is on the study medication. If such agents are 
required for a patient, the patient mustdiscontinue the study. 
Herbal preparations/medications 
Herbal preparations/medications are prohibited throughout 
the study. These herbal medications include but are not 
limited to St. John's wort, Kava, ephedra (ma huang), ginkgo 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients should stop using these 
herbal medications 7 days before the first dose of study 
medication. 
 
9.6 
Correlative studies 
Ex oratory objective: To evaluate how vemurafenib and copanlisib affect I\AAPK/Pl3K signaling and 
thyroid differentiation in tumors of patients with RAIR disease. Biopsies will be performed at baseline 
and on treatment with vemurafenib plus copanlisib (as in Table 10-2), unless the patient is exempt 
(Section 6.1). Biopsies of any tumor site is allowed, but metastatic tumors are preferred, and every 
attempt should be made when performing both biopsies to obtain tissue from the same tumor. The 
RNA and DNA assays suggested below may be substituted for other techniques or platforms, 
depending on availability. 
 
Transcriptomic and protein-based analyses of serial biopsy specimens: As the amount of frozen 
tissue obtained from biopsies is limited, we will prioritize sensitive array-based technologies to 
quantify gene expression and to sequence cancer genes. We will isolate RNA from pre- and post- 
treatment biopsy specimens for interrogation. RNAseq will be performed to quantify transcripts 
regulated by MAPK (MAPK output},22 the BRAF-RAS score (a 71-gene signature that distinguishes 
BRAFv6ooE from RAS mutant tumors5), and the enhanced Thyroid Differentiation Score (which is a 
gene signature of thyroid-specific differentiation.5 Each of these scores provides an average fold- 
change for all mRNAs in the respective gene sets, compared with the median of all samples. In 
addition, we will measure the effects of vemurafenib plus copanlisib on the transcription of iodine 
organification genes and PI3K transcriptional output. These transcriptomic readouts will then be 
analyzed in the context of change in lesional 1-124 concentration observed with 1-124 PET. The 
transcriptomic data will also be investigated for other exploratory pathways, signatures, and biologic 
parameters. Alternative platforms to RNAseq may also be used if appropriate and available. Other 
protein markers of interest, such as phospho-AKT, may be analyzed by the appropriate assay (e.g., 
immunohistochemistry, Western blot, mass spectrometry, reverse protein phase array). 
 
Genomic Analysis: Baseline genomic analysis will be performed using MSK-IMPACT, a next- 
generation sequencing platform .23 Alternative techniques may be considered or performed (e.g. 
Sequenom analysis, Sanger sequencing, whole-exome) at the time of analyses, if deemed 
appropriate. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
Table 10-1: Screening and baseline (pretreatment) 1-124 PET/CT schedule 
 
Prestudy 
Screening 
Evaluations 
Baseline 1-124 
PET Protocol 
Dµ,..-tx·2 
Baseline 1-124 
PET Protocol 
Dp,e-tx 1 
Baseline 1-124 
PET Protocol 
Dp,e-tx 2 
Baseline 1-124 
PET Protocol 
Dp,e-tx 3 
Baseline 1-124 
PET Protocol 
Dp,e-tx 4, O.,,e-tx 5, 
Di,,e-tx 6, O.,,e-tx 8 
Serum beta- 
HCG 
Confirmation of 
BRAF mutation 
in tumor 
Informed 
consent 
X 
lv'edical history 
X 
Concurrent 
meds 
X 
Rlysical exam 
X 
Vital signs 
X 
Weight 
X 
CBC w/diff, 
platelets 
X 
Comprehensive 
panel 
X 
Lipase 
X 
Hgb A1c 
X 
Cl\/1\/ PCR 
X 
HIV serologies 
X 
HBV serologies 
X" 
HCV serologies 
X' 
EKG (or ECG) 
X 
Echocardiogram 
X 
Dermatologic 
exam 
X 
Archival tissue 
Research blood 
sample 
Research 
biopsy 
x• 
Adherence to 
low -iodine diet1 
X---------------------- 
Thyrogen9 
X 
X 
1-124 
adninistrationh 
X 
1-124 PET/CT"' 
X 
TSH, free T4, 
thyroglobulin, 
thyroglobulin 
antibody 
xn 
X 
X' 
Radiologic 
)(I 
evaluation 
(CT[s] and/or 
MRl[s]) for 
tumor 
measurements 
•serum pregnancy test (for women of child-bearing potential). The prestudy test must be done within 7 days of starting the study. 
bTumor genotyping can be conducted on the primary tumor, recurrent tumor, or a metastasis. Results can be obtained anytime 
before the patient is registered to the study. 
cAvailability of archival tumor tissue needs to be confirmed before study enrollment (if tissue is not already available at MSK, 
physical receipt of tissue is not required for study enrollment or initiation). 
dThe research blood sample can be obtained anytime before the start of the study. 
0Research biopsy can be performed anytime before starting vemurafenib and copanlisib (Section 6.1). 
1Patients should adhere to a low -iodine diet for preferably 7 days before the initiation of the lesional dosimetry, but minimally 5 
days, before the initiation of the lesional dosimetry until its completion. Rease see Appendix C for details of the low -iodine diet. 
9Thyrogen (0.9 mg) will be administered intramuscularly on the 2 consecutive days beforeadninistration of 1-124 6 mCi (4-7 mCi) 
orally for both baseline and on-treatment Thyrogen-stimulated 1-124 PET/CT scans. 
hl-124 6 mCi (4-7 mCi) will be adninistered orally before the pretreatment and on-treatment Thyrogen-stimulated 1-124 PET/CT 
scans. 
;  TSH, thyroglobulin, and thyroglobulin antibody will be drawn on Dp,e-tx 5. 
iNo iodinated IV contrast is pernitted with CT scans. MRI contrast is pernitted. 
kHBV serologies include HBV surface antigen, surface antibody, and core antibody. If patients are positive for the surface antigen 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
I 
 
Green-top tube bloodI 
I 
I 
I 
 
 
 
 
 
 
 
Table 10-2: On-treatment schedule 
 
Dix 1 Dix 5 
Dix 6 Dix 8 
Dix 9 
Dix 10 Dix 11 
Dix 12 
Dix 13 
Dix 15 
Dix 16 
Dix 17 Dix 18 
Vemurafenib 
xa 
xo -------------------------------------------------- xo 
Copanlisibc 
X 
X 
Fasting and 
adherence to low- 
glycerric diet 
Glucose monitoring 
X' 
X' 
Adherenceto low- 
iodine diet 
Thyrogenn 
1-124 adrrinistration' 
l-124PET/C 
I collectionp.q 
Radioiodine 
treatment (1-131) 
I Serum beta-HCG 
I 
A1ysic  exam' 
Vital signs (see blocxJ 
pressure monitoring 
parametersm) 
xg  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xn 
 
xo 
xo 
X 
X 
X 
xm 
xm 
X 
Weight 
X 
I Performance status 
X  I 
I CBC w /diff,  at els 
X 
X  I 
Comprehensive 
panel 
X 
X 
I Lipase 
X 
X  I 
X 
X 
X 
X 
I 
X 
I 
X 
I 
X 
I 
I Concurrent meds 
Adverse event and 
DLT monitoring 
TSH, free T4, 
thyroglobulin, 
thyroglobulin 
antibody 
Radi ogic evaluation 
(CT(s] and/or MRl[s]) 
for tumor 
measurements' 
I 
I 
I 
I  x  I 
xi------------------------- 
 
X 
I 
I 
I 
x 
I 
I 
I 
- ---------------------------------------------------- --·>< 
 
X 
 
 
 
X' 
Research biopsy 
XK 
avernurafenib will be initiated on day 1 at the dose ev  being studied. 
bFor patients for w homthe second 1-124 scan does not establish criteria for adrrinistration of 1-131 treatment, vemurafenib will be 
discontinued (last dose on day 12-15). For patients who have lesional dosimetry on the second 1-124 scan tow arrant treatment with 1-131, 
vernurafenib will continue until about 2 days after adrrinistration of 1-131 (last dose, day 20). 
0Copanlisib can be given on the indicated day within aw indow of ±1 day. Only patients who will receive 1-131 will be given the second 
copanlisib dose. 
dFasting is required for at least 8 h before the first infusion of copanlisib. A low -glycemic meal can be consumed 2 h after the first infusim of 
copanlisib. A low -glycemic diet is recommended for 48 h after the copanlisib infusion. 
"Fasting for 4 h or more before the second and third infusions of copanlisib should be considered. The decision regarding meal timing after 
infusion can be made by the investigator on the basis of glucose response patterns during prior treatment days. A low -glycemic diet is 
recommended for 48 h after the infusion of copanlisib (see Sections 9.3 and 9.4). 
1See Sections 9.3 and 9.4. 
9Patients should adhere to a low -iodine diet for preferably 7 days prior to the initiation of lesional dosimetry, but minimally 5 days before the 
initiation of the lesional dosimetry (see Section 9.1). Rease see Appendix C for details of the low -iodine diet. 
hThyrogen (0.9 mg) will be administered intramuscularly on the 2 consecutive days beforeadrrinistration of 1-124 (5-7 mCi). For patients 
or core antibody, they will require further testing with HBV DNA PCR. 
1HCV antibody is required. If positive, HCV RNA PCR will be required. 
mlf no iodine uptake is detected on the PET/CT scans done on Dp,.-1x 5 (-48 h after 1-124 administration), the subsequent 
PET/CT scans (e.g., at -72 and -120 hours) will not be performed. 
nBlood draw (s) for TSH, free T4, thyroglobulin, and thyroglobulin antibody (thyroid studies) will be collected before Thyrogen 
injection on Di,,e-tx 1. 
I 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
with lesional dosimetry on the second 1-124 scan tow arrant treatment with 1-131, Thyrogen will be given on the 2 consecutive calendar 
days and 1-131 treatment will be given on the day after the second Thyrogen injection. (Depending on scheduling concerns, Thyrogen coL.tl 
also be given Days 15 and 16, with 1-131 admnistration on Day 17). 
;1-124 6 rrCi (4-7 rrCi) will be administered orally before on-treatment 1-124 PET/CT scans. 
iTSH, thyroglobulin, and thyroglobulin antibody will be evaluated on Dix12. 
n-treatment biopsy to be performed while on study treatment, unless exempt according to Section 6.1. Every effort will be made to do 
the biopsy on Dix 15 or 16 prior to Thyrogen injection. How ever, the timng of the biopsy may be changed at the discretion of the A-inciple 
Investigator to account for patient preference and scheduling needs. 
1The screening period for DLTs will be from the initiation of study treatment to 7 days after completion of study drug admnistration. The 
continuous nature of this monitoring does not imply the need for daily communication with the patient; the reporting of adverse events or 
DLTs that are brought to the attention of the study team will be captured. 
mBlood pressure will be measured approximately every 5-10 mn before each copanlisib dose, until 2 consecutive results <150/90 mmHg 
are recorded (no more than 4 measurements). If blood pressure is 150/90 mmHg, the investigator can consider medical intervention or 
delay the infusion of the study drug. The patient should rest before blood pressure is recorded. On infusion days, blood pressure will be 
measured at O h, 30 mn (midinfusion), 60 mn (end of infusion), and 1 h (all approximate time points) after the end of the infusion. Of note, 
aw indo,v of ±15 mn is allowed for all blood pressure measurements, except for the 0-h (pre-dose)measurement. 
0lf patients meet the lesional dosimetry requirements tow arrant treatment with radioiodine (l-131), they will receive this treatment on Dix 18, 
with a total activity guided by the MTA determination performed. (depending on scheduling concerns, Thyrogen and 1-131 admnistration 
could also be performed a day earlier (l-131 admnistered on D17). 
°For women of child-bearing potential, a serum beta-HCG test must be performed up to 2 days before the administration of 1-124 or 1-131. 
Pfor RAI MTA determnation performed with the second 1-124 PET dosimetry process: 
- Routine blood draws into green-top tubes on days 1 (pre-Thyrogen), 3, 4, 5, 6, and 8 for radioiodine pharmacokinetics will be 
collected (enumeration of days here are relative to the day of the first Thyrogen injection). 
- Note:Hour designations above are only approximations of the intervals for assay collection and are not specific hours for which these 
tasks must be done. 
q If no iodine uptake is detected on the PET/CT scans done on Dix 12 (~48 h after 1-124 administration), the subsequent PET/CT scans 
(e.g. at -72 and -120 h after 1-124) and the blood sample collections for MTA determination will not be completed. If the degree of iodine 
uptake is determned to be insufficient for 1-131 therapy, as measured on the Dix 12 (-48 h after 1-124 administration) 1-124 PET/CT scan, 
the blood sample collections for MTA determnation will not be completed; how ever, the subsequent 1-124 PET/CT scans may still be 
performed to evaluate iodine retention. 
'If feasible (not mandatory), tumor measurements (per RECIST v1.1) will be performed with CT scans (without iodinated contrast) and/or 
MRI scans wnle on study therapy and prior to 1-131 admnistration. 
5This draw is to be done prior to Thyrogen administration. 
TPhysical exam can be done up to 3 days before each copanlisib dose. The last physical exam can be performed any day during the 
designated week (week of Day 15). 
 
 
Table 10-3: Post-treatment follow-up schedule 
 
 
Thyroglobulin, TSH, free T4, 
thyroglobulin antibody 
CBC w /diff, platelets 
Comprehensive pan 
Lipase 
Radi ogic evaluation 
(CT[s] and/or MRl[sl) for tumor 
measurementsb 
Collect data on tumor changes 
in radiologic scans, serum 
thyroglobulin/TSH, initiation of 
X 
new thyroid cancertreatments 
and survival 
•Relative to the on-treatment calendar; for patients in w homthe second 1-124 scan does not meet the criteria for admnistration 
of 1-131 treatment, a post-therapy scan can be obtained up to -1 week after discontinuation of vemurafenib and copanlisib. 
bl\Jo iodinated IV contrast is permtted with CT scans. MRI contrast is permtted. 
cThe observation period encompasses up to 1 year after study drug is discontinued for all patients. Data regarding radiographic 
disease progression, thyroglobulin/TSHserum values, survival and initiation of new treatments will be collected. Evaluating 
radiographic disease progression will be performed on both protocol-mandated scans and scans performed as per standard of 
care after protocol-mandated scans have been completed. If progression of disease and initiation of drug therapy, or death, 
occurs then the observation phase may be discontinued. 
Poststudy 
Poststudy 
Poststudy 
Poststudy 
Poststudy 
Poststudy 
Observation Phasec 
(No RAI) 
(Yes RAI) 
(Yes RAI) 
(Yes RAI) 
(Yes RAI) 
(Yes RAI) 
(all patients) 
Day 15 (+1 
7 days (±2 
14 days(± 
1 month{± 
3-4 
6 months 
Up to 1 year after 
week)3 
days) s/p 
2 days) 
1 week) 
months 
{± 2 weeks) 
study drug 
RAI 
s/p RAI 
s/p RAI 
s/p RAI 
s/p RAI 
discontinuation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 
Clinical Toxicity Data forVemurafenib 
Vemurafenib is FDA approved for the treatment of unresectable or metastatic melanoma with BRAF 
V600E mutation and for Erdheim-Chester disease with BRAF V600 mutation. Vemurafenib is also 
NCCN compendium-approved for BRAF-positive OTC. Because clinical studies are conducted 
under widely varying conditions, adverse-reaction rates observed in the clinical studies of a drug 
cannot be directly compared to rates in the clinical studies of another drug and may not predict the 
rates observed in a broader patient population in clinical practice. This section describes adverse 
drug reactions identified from analyses of 2 trials: trial 118 and trial 2.19 Trial 1 randomized (1:1) 675 
treatment-naive patients with unresectable or metastatic melanoma to receive either vemurafenib 
(960 mg PO BID) or dacarbazine (1000 mg/m2 IV every 3 weeks). In trial 2, 132 patients with 
metastatic melanoma and failure of at least 1 prior systemic therapy received treatment with 
vemurafenib (960 mg PO BID). 
Table 11-1 presents the adverse reactions reported in at least 10% of patients treated with 
vemurafenib. The most common adverse reactions of any grade ( 30% in either study) in 
vemurafenib-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, 
nausea, pruritus, and skin papilloma. The most common ( 5%) grade 3 adverse reactions were 
cutaneous squamous cell carcinoma (SCC) and rash. The incidence of grade 4 adverse reactions 
was :54% in both studies. In trial 1, the incidence of adverse events resulting in permanent 
discontinuation of study medication was 7% for the vemurafenib arm and 4% for the dacarbazine 
arm. In trial 2, the incidence of adverse events resulting in permanent discontinuation of study 
medication was 3%. In trial 1, the median duration of study treatment was 4.2 months for 
vemurafenib and 0.8 months for dacarbazine; in trial 2, the median duration of study treatment was 
5.7 months. 
 
 
Table 11-1: Adverse reactions reported in 10% of patient treated with vemurafenib 
Adverse Drug Reactions (Reported 
using MedDRAand graded by CTCAE 
v.5.0) 
Trial 1: Treatment-Naive Patients 
Trial 2: Patients with 
Failure of At Least One 
Prior Systemic Therapy 
Vemurafen
I
ib (n=336) 
Dacarbazine (n=287) 
Vemurafenib (n=132) 
All Grades 
(%) 
Grade 3a 
(%) 
All Grades 
Grade 3 
(%) 
I (%) 
All Grades 
Grade 3a 
(%) 
I (%) 
Skin and subcutaneous tissue 
disorders 
Rash 
37 
8 
2 
0 
52 
7 
Photosensitivity reaction 
33 
3 
4 
0 
49 
3 
Alopecia 
45 
<1 
2 
0 
36 
0 
Pruritus 
23 
1 
1 
0 
30 
2 
Hyperkeratosis 
24 
1 
<1 
0 
28 
0 
Rash maculo-papular 
9 
2 
<1 
0 
21 
6 
Actinic keratosis 
8 
0 
3 
0 
17 
0 
Dry skin 
19 
0 
1 
0 
16 
0 
Rash papular 
5 
<1 
0 
0 
13 
0 
Erythema 
14 
0 
2 
0 
8 
0 
Musculoskeletal and connective 
tissue disorders 
Mhralgia 
53 
4 
3 
<1 
67 
8 
Myalgia 
13 
<1 
1 
0 
24 
<1 
Pain in extremity 
18 
<1 
6 
2 
9 
0 
Musculoskeletal pain 
8 
0 
4 
<1 
11 
0 
Back pain 
8 
<1 
5 
<1 
11 
<1 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
General disorders and 
administration site conditions 
Fatigue 
Edema (peripheral) 
Pyrexia 
Asthenia 
38 
17 
19 
11 
2 
<1 
<1 
<1 
33 
5 
9 
9 
2 
0 
<1 
<1 
54 
23 
17 
2 
4 
0 
2 
0 
Gastrointestinal disorders 
Nausea 
Diarrhea 
Vomiting 
Constipation 
35 
28 
18 
12 
2 
<1 
1 
<1 
43 
13 
26 
24 
2 
<1 
1 
0 
37 
29 
26 
16 
2 
<1 
2 
0 
Nervous system disorders 
Headache 
Dysgeusia 
23 
14 
<1 
0 
10 
3 
0 
0 
27 
11 
0 
0 
Neoplasms benign, malignant, and 
unspecified (includes cysts and 
polyps) 
Skin papilloma 
Cutaneous SCCb 
Seborrheic keratos is 
21 
24 
10 
<1 
22 
<1 
0 
<1 
1 
0 
<1 
0 
30 
24 
14 
0 
24 
0 
Investigations 
GGT increased 
5 
<1 
0 
15 
6 
Metabolism and nutrition disorders 
Decreased appetite 
18 
0 
8 
<1 
21 
0 
Respiratory, thoracic, and 
mediastinal disorders 
Cough 
8 
0 
7 
0 
12 
0 
Injury, poising, and procedural 
complications 
Sunburn 
10 
0 
0 
0 
14 
0 
• Grade 4 adverse reactions lirrited to ganma-glutamyl transferase increases (<1% in trial 1 and 4% in trial 2). 
blncludes both sec of the skin and keratoacanthorra;cases of cutaneous sec were required to be reported as grade 3, per the protocol. 
 
 
Clinically relevant adverse reactions reported in <10% of patients treated with vemurafenib in the 
phase II and phase Ill studies include: 
• 
 Skin and subcutaneous tissue disorders: Palmar-plantar erythrodysesthesia syndrome, 
keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic 
epidermal necrolysis 
• 
Musculoskeletal and connective tissue disorders: Arthritis 
• 
Nervous system disorders: Neuropathy peripheral, Vllth nerve paralysis 
• 
 Neoplasms benign, malignant, and unspecified (includes cysts and polyps): Basal cell 
carcinoma, oropharyngeal squamous cell carcinoma 
• 
Infections and infestations: Folliculitis 
• 
Eye disorders: Retinal vein occlusion 
• 
Vascular disorders: Vasculitis 
• 
Cardiac disorders: Atrial fibrillation 
Postmarketing experience: The following adverse reactions have been identified during postapproval 
use of vemurafenib (Zelboraf). Because these reactions are reported voluntarily from a population of 
uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 
relationship to drug exposure. 
• 
Neoplasms benign, malignant, and unspecified (including cysts and polyps): Progression of 
preexisting chronic myelomonocytic leukemia with NRAS mutation 
• 
Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic 
symptoms (DRESS syndrome) 
• 
Blood and lymphatic systems disorder: Neutropenia 
• 
Injury, poisoning, and procedural complications: Radiation sensitization and recall 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• 
Gastrointestinal disorders: Pancreatitis 
• 
Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis 
• 
Musculoskeletal and connective tissue disorders: Dupuytren's contracture and plantar fascial 
fibromatosis 
 
Table 11-2: Change in baseline to grade 3 or 4 liver abnormalities 
Parameter 
Change from Baseline to Grade 3 or 4 Liver Abnormalities 
Vemurafenib (%) 
Dacarbazine (%) 
GGT 
11.5 
8.6 
AST 
0.9 
0.4 
ALP 
2.8 
1.9 
Alkaline phosphate8 
2.9 
0.4 
Bilirubin8 
1.9 
0 
•For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 
 
 
 
11.2 
Clinical toxicity data for copanlisib 
 
Copanlisib is FDA approved for the treatment of patients with relapsed follicular lymphoma who have 
had at least 2 prior systemic therapies. This approval was based on a large phase II study of 
copanlisib in 142 patients with relapsed/refractory indolent lymphoma who had received 2 or more 
prior therapies. The objective response rate was 59% (84/142 patients), with a median duration of 
response of 22.6 months.20 The overall safety profile of copanlisib is based on data from 317 
subjects treated in clinical studies. In clinical studies, the most commonly reported suspected 
adverse reactions in patients with non-Hodgkin's lymphoma (indolent and aggressive) and solid 
tumors treated with copanlisib monotherapy included pneumonitis, lower respiratory tract infections 
(including pneumonia), and febrile neutropenia; the most common adverse reactions ( 20%) were 
hyperglycemia, decreased general strength and energy (including fatigue and asthenia), 
hypertension, diarrhea, nausea, leukopenia, and neutropenia. 
Table 11-3: Adverse drug reactions in patients treated with copanlisib monotherapy reported in 
multiple clinical trials 
I
System Organ Class 
I
Very Common ( 1/10) 
Common ( 1/100to <1/10) 
Uncommon ( 1/1000 to 
I <1/100) 
Blood and lymphatic 
system disorders 
Leukopenia, 
neutropenia,8 
throm bocytopenia 
Lym phopenia, febrile 
neutropenia,8 eosinophilia 
Gastrointestinal disorders 
Diarrhea, nausea, 
stomatitis (including 
oropharyngeal erosion 
and ulcer and oral pain) 
Dysgeusia, dry mouth, dysphagia 
Pancreatitis 
General disorders and 
administration site 
conditions 
Decreased general 
strength and energy 
(including fatigue and 
asthenia) 
Mucosal inflammation, injection 
site reactions 
Immune system disorders 
Hypersensitivityreactions 
(including allergic edema and 
angioedema, vasodilatation and 
flushing, and infusion-related 
reaction) 
Infections and 
infestations 
Lower respiratorytract 
infectionb (including terms 
pneumonia,b pneumonia 
bacterial, pneumonia 
pneumococcal, 
pneumonia fungal, 
pneumonia viral, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
Pneumocystisjirovecii 
pneumonia, 
bronchopulmonary 
aspergillosis, and lung 
infectionb) 
Investigations 
Increase in lipase, increase in 
amylase 
Metabolism and nutrition 
disorders 
Hyperglycemiaa 
Hyperlipidem ia, hyperinsulinemia, 
polydipsia 
Nervous system 
disorders 
Paresthesia and dysesthesia 
Respiratory, thoracic, and 
mediastinal Disorders 
Pneumonitis (including interstitial 
lung disease and noninfectious 
pneumonitis) 
Skin and subcutaneous 
tissue disorders 
Rash (including exfoliati-..e 
skin reactions) 
Alopecia 
Vascular disorders 
Hypertension (including 
secondary hypertension) 
8life-threateningcases have been reported. 
bFatal cases have been reported. 
 
Table 11-4: Treatment-emergent laboratory test abnormalities ( 10%) in patients with non- 
Hodgkin's lymphoma and solid tumors from open-label phase I and phase II monotherapy studies 
Laboratory Parameter 
(Copanlisib Monotherapy 
n=317) 
All Grades3 (%) 
Grade 3a (%) 
Grade 4a (%) 
Blood and lymphatic system 
Hgb decreased 
Lymphocyte countdecreased 
Platelet count decreased 
Neutrophil count decreased 
84 
75 
56 
53 
8 
28 
6 
11 
0 
5 
3 
13 
Metabolism and nutrition 
Elevated blood glucose 
Hypophosphatemia 
96 
40 
38 
13 
3 
0 
Investigations 
Serum amylase increased 
Serum lipase increased 
21 
18 
2 
5 
8CTCAE V 5.03. 
 
Special warnings with copanlisib monotherapy: 
 
• 
 Infections: Serious infections (including fatal infections) occurred in 19% of 317 subjects 
treated with copanlisib monotherapy. The most common infections were pneumonia, lung 
infection, and lower respiratory tract infection. Pneumocystis jirovecii pneumonia occurred in 
0.6% of 317 subjects treated with copanlisib monotherapy. Before initiating treatment with 
copanlisib, consider Pneumocystisjiroveciipneumonia prophylaxis for populations at risk. 
 
• 
Noninfectious pneumonitis (NIP): NIP (all events grade S3) occurred in 5.0% of 317 subjects 
treated with copanlisib monotherapy. 
 
• 
 Neutropenia/febrile neutropenia: Grade 4 neutropenia (febrile and nonfebrile) occurred in 
9.1% of 317 subjects treated with copanlisib monotherapy. Serious febrile neutropenia 
occurred in 1.9%. 
 
• 
 Transient hypertension: Serious hypertension (all events grade 3) occurred in 0.9% of 317 
subjects treated with copanlisib monotherapy. Treatment with copanlisib may result in 
transient hypertension. The mean systolic blood pressure and diastolic blood pressure 
increased after dosing on cycle 1, day 1 and started to decrease approximately 2 h 
postinfusion. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 DoseLevel
 0
 -1
 
Copanlisib Dose/Schedule 
60 mg IV weekly 
45 mg IV weekly 
• 
 Transient hyperglycemia: Serious grade 4 hyperglycemia (>500 mg/dl) occurred in 0.9% of 
317 subjects treated with copanlisib monotherapy. Treatment with copanlisib may result in 
transient hyperglycemia. Blood glucose levels typically peaked 5 to 8 h postinfusion and 
subsequently declined to baseline levels. Optimal blood glucose control should be achieved 
before starting each copanlisib infusion. Of the 20 subjects with diabetes mellitus treated in 
CHRONOS-1, 7 developed grade 4 hyperglycemia and 2 discontinued treatment. 
 
• 
Embryofetal toxicity: On the basis of its mechanism of action and findings in a rat embryofetal 
development study, copanlisib may cause embryofetal harm. 
 
 
General guidelines for dose modification and toxicity management 
The recommendations for the management of adverse events in this section are to serve as general 
guidelines; dose reductions or delays for any event of any CTCAE grade may always be considered 
for safety reasons, at the discretion of the treating investigator. 
 
Patients who require discontinuation of either drug may continue to receive the remaining drug 
(vemurafenib or copanlisib). 
 
 
Table 11-5: Dose leveIs for dose modification of vemurafenib-related adverse events 
 
Dose Level 
Vemurafenib Dose/Schedule 
0 
960 mg PO BID 
-1 
720 mg PO BID 
-2 
480 mg PO BID 
 
Table 11-6: General criteria for dose modification for ve murafe nib-re lated adverse events 
 
Related Adverse Events 
Intervention 
Grade 1 
Continue at the same dose level 
Grade 2 
Continue at the same dose level 
Grade 3 nonhematologictreatment-related toxicity" 
Interrupt dosing until resolution to grade 1 and then 
restart at 1 dose level lower 
Grade 4 nonhem atologic treatment-related toxicity or 
grade 4 hematologic toxicity' 
On the basis of investigator judgment, discontinue study 
treatment or interrupttreatment until resolution to grade 1 
and then restart at dose level-2 (480 mg PO BID) 
3For manageable grade 3 nonhematologic toxicities (e.g., cutaneous SCC) or those that can be 
controlled with medications, treatment may continue at the same dose level without interruption, at 
the discretion of the investigator. 
bPatients who develop grade ::;4 lymphopenia or grade ::;4 asymptomatic biochemical laboratory 
abnormality may continue study treatment at the same dose level without interruption, on the basis 
of the investigator's judgment. 
 
Table 11-7: Dose levels for necessarydose modification of copanlisib-related adverse events 
 
 
Table 11-8: Dose modification for copanlisib-related nonhematological toxicity (except 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 IToxicitya
 I
 
Occurrence IGrade
 Jb
 
I Grade 1-2 
I 1st appearance 
I Any appearance 
I No change 
!For current course of therapy I For next course of therapy 
I No change I
 I
 
I 2nd appearance 
I Delay until grade ::;2 
I No change 
I Grade 4 
I 3rd appearance 
I Any appearance 
I Permanently discontinue 
I Delay until grade :s:;2
 
I Permanently discontinue I
 
I Decrease by 1 dose levelc 
!Toxicity requiring delay for >21 days 
I Permanently discontinue I
 I
 
glucose increases, dermatologic toxicity, noninfectious pneumonitis, and blood pressure 
increases) 
 
 
 
 
 
 
 
 
 
 
 
 
 
•Toxicities according to CTCAE version 5.0. 
bDespite rnaxirrum supportive therapy. 
0Not applicable for 45-mg dose level. 
 
 
 
Table 11-9: Dose modification for copanlisib-related hematologic toxicity 
 
Hematological toxicity (any of the following) 
Study treatment action (for any toxicity) 
• CTCAE grade 3 thrombocytopenia (platelet<50,000/mm3) 
• Febrile neutropenia 
• CTCAE grade 3 neutropenia (ANC <1000/mm3) 
• INR or PTT CTCAE grade 3 with bleedinga 
• CTCAE grade 3 anemia (Hb <8 g/dl) 
Delay infusion until Hgb 8, platelets 75, and ANC 
1500/m m3withoutfever.0 Patient can be treated at 1 
dose level lower, at the investigator's discretion.bIf more 
dose reductions are required than are allowed per the 
protocol, discontinue copanlisib permanently. 
ANC = absolute neutrophil count;Hb = hemoglobin;INR = international normalized ratio; PTT= partial thromboplastin 
time. 
8INR and PTT should have returned to s;1.5 and s;1.5 x ULN, respectively, with no signs of bleeding. 
bMer full recovery from toxicity and in the absence of any criteria for further dose reduction or study drug discontinuation, 
re-escalation to dose level -1 or 1 is allowed, at the investigator's discretion. 
0Treatmentwith transfusion or growth factors is allowed, atthe investigator's discretion. 
 
Table 11-10: Dose modification for copanlisib-related dermatologic toxicity 
Toxicity" 
Occurrence 
For current course of therapy 
For next course of therapy 
Grade 1 
Any appearance 
No change 
No change 
 
1st appearance 
Interruption until grade s;1 
No change 
2nd appearance 
Interruption until grade s;1 
Decrease by one dose level0 
3rd appearance 
Permanent discontinuation 
Grade 3b 
1st appearance 
Interruption until grade s;1 
Decrease by one dose level0 
2nd appearance 
Permanentdiscontinuation 
Grade 4 
pt appearance 
Permanent discontinuation 
aToxicities according to CTCAE version 5.0. 
bDespite maximum supportive therapy. 
0Not applicable for 45-mg dose level. 
The lowest dose level is 45 mg; if a patient is already at the 45-mg dose level and meets criteria for a further decrease of 
dose, the study drug will be discontinued permanently. 
 
Recommendations for Non-infectious Pneurnonitis (NIP) 
In the event of suspected NIP of any grade, copanlisib must be interrupted and diagnostic 
examination of the patient experiencing pulmonary symptoms conducted. If NIP is the final 
diagnosis, copanlisib must be permanently discontinued if CTC grade 3. For CTC grade 2, the 
patient should be treated until resolution or improvement to CTC grade 1; the next lower dose level 
of copanlisib should then be given. Pneumonitis is to be reported as such only in the event of NIP. If 
NIP related to copanlisib is confirmed, the treating investigator should administer systemic steroids. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
The investigator is requested to differentiate between NIP and infectious pneumonitis (viral, 
bacterial, fungal), aspiration pneumonitis, or other pneumonitis clearly not due to a potential 
hypersensitivity reaction to the copanlisib infusion; the investigator must provide the basis for their 
assessment of infectious or other diagnosis, as appropriate. The investigator is requested to use the 
most-specific clinical terms to describe the condition in their report, not simply "pneumonitis." 
Table 11-11: Dose adjustment in cases of NIP 
 
Suspected or confirmed NIP per 
CTCAE 
Action Taken 
Retreatment dose 
after recovery 
Grade 1 
I 
No change 
Grade 2 
Dose interruption until recovery to 
grade ::;1 
Decrease dose to the next lowest 
dose levela 
Grade 2 second re-occurrence 
Perm anent discontinuation 
NA 
Grade 3 
Perm anent discontinuation 
NA 
Grade 4 
Perm anent discontinuation 
NA 
NA= Not applicable. 
aNot applicable for45-mg dose level. No re-escalation is allowed after the dose reduction. 
The lowest dose level is 45 mg; if the patient is already at the 45-mg dose level and cannottolerate treatment, the study 
treatmentwill be discontinued permanently. 
 
Recommendations for arterial hypertension 
Blood pressure will be measured every 5-10 min before each copanlisib dose (no more than 4 
measurements) until 2 consecutive results <150/90 mmHg are recorded. If blood pressure is 150/90 
mmHg, the investigator can consider a medical intervention or delay infusion of the study drug. The 
patient should rest for 5-10 min before blood pressure is recorded. 
On infusion days, blood pressure will be measured at Oh (predose), 30 min (midinfusion), 60 min (end 
of infusion), and 1 h after the end of infusion 
Note: A window of ±10 min is allowed for all blood pressure measurements, except for the 0-h 
(predose) measurement. 
 
No dose should be given if blood pressure is 150/90 mmHg. Antihypertensive medication may be 
given to control increased blood pressure. Dosing can proceed on the scheduled day if at least 2 
consecutive measurements <150/90 mmHg are recorded. Otherwise, dosing must be delayed. 
 
If drug-related arterial hypertension (postdose blood pressure of CTCAE grade 3 or 160/100 mmHg) 
is not manageable with optimal antihypertensive treatment, the dose for the subsequent copanlisib 
administrations should be at the next lowest dose level. Patients with a postdose blood pressure that 
may have life-threatening consequences (e.g., malignant arterial hypertension, transient or permanent 
neurologic deficit, hypertensive crisis) must permanently discontinue the study drug. 
 
It is important that patients with preexisting arterial hypertension adhere to their regular medication 
schedule and take their usual doses on the days of study drug infusion. 
 
The management of acute blood pressure increases following copanlisib will be individualized for each 
patient, but the experience in phase I study has suggested a benefit of dihydropyridine calcium 
channel blockers (i.e., amlodipine, felodipine). Nitrates should also be considered. Verapamil and 
diltiazem (non-dihydropyridine calcium channel blockers and moderate inhibitors of CYP3M) should 
be used with caution, owing to a potential interaction with CYP3M. In general, it is advisable for sites 
to be prepared so that antihypertensive medication is readily available if needed. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
In the event of arterial hypertension 150/90 mmHg during infusion of copanlisib during any cycle, 
antihypertensive treatment is suggested, as indicated in Table 8. In the event of CTCAE grade 3 
arterial hypertension ( 160/100 mmHg) during infusion of copanlisib, the infusion should be 
interrupted and antihypertensive treatment administered, as suggested above. Infusion can be 
resumed when blood pressure has returned to <150/90 mmHg. 
 
Table 11-12: Dose modification for copanlisib-related arterial hypertension 
 
 
Toxicity (CTCAE) 
Study drug action 
Recommendation 
Predose measurements 
Blood pressure 150/90 
mmHg 
No dose should be 
given until recovery to 
<150/90mmHg. 
Blood pressure-lowering medication should be 
considered.Dosing can proceed on the scheduled 
day if 2 consecutive measurements 
<150/90 mmHg are recorded.If blood pressure 
doesn't return to <150/90 mmHg, delaydosing 
until the next visit. 
During infusion: 
CTCAE hypertension of 
grade 3 or 160/100 
mmHg 
Infusion can be 
interrupted or slowed 
down, and 
administration of 
blood pressure-- 
lowering therapy 
should be initiated. 
Infusion maybe resumed when blood pressure 
has returned to <150/90 mmHg, at the 
investigator's discretion, or it can be skipped. 
Subsequentstudydrug administrations maybe 
reduced by 1 dose level, at the investigator's 
discretion.b 
Postdose: 
Drug-related 
CTCAE hypertension of 
Administration of blood pressure-lowering 
therapy should be initiated, in accordance with the 
local standard of care. 
grade 3 or 160/100 
mmHg• 
Additional measurements to be performed as 
clinically indicated until recovery to 
<150/90mmHg. 
Subsequentstudydrug administrations maybe 
reduced by 1 dose level, at the investigator's 
discretion.b 
CTCAE hypertension of 
grade 4 
Permanently 
discontinue study 
drug. 
3Not manageable despite optimal antihypertensive treatment. 
bThe lowest dose level is 30 mg. 
 
Table 11-13 
Management of copanlisib-related infusion-related hyperglycemia 
 
Criteria 
Recommendation 
Suggested Treatment 
A5ymptomaticglucose 
increase :5250 mg/dl (13.9 
mmol/L) 
Does notgenerallyrequire treatment with 
glucose-lowering medication 
Ora hydration 
A5ymptomaticglucose 
increase >250 mg/dl (13.9 
mmol/L) 
• Repeatglucose testing 
• 
If glucose value is decreasing, glucose 
levels may be followed withoutglucose- 
lowering medication treatment if hydration 
status is normal, as clinicallyassessed 
Oral and/or IV hydration as 
appropriate 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
• 
Consultation with endocrinologist can be 
considered 
Symptomatic or persisting 
glucose increase >250 mg/dl 
(13.9 mmol/L) 
• 
Hydration status should be clinically 
assessed 
• 
If clinical assessment is consistent with 
dehydration,fluids should be given as 
clinicallyappropriate (orallyor IV) 
• 
 Laboratorytestconfirming increase should 
be repeated.If the repeated glucose value is 
persistent and/or the patient is symptom atic 
and/or the hydration status indicates the 
need for hydration, glucose-lowering 
medication should be administered 
• 
 Promptinputfrom an endocrinologist should 
be obtained 
• Keep well-hydrated.Rapid/short- 
acting insulin maybe given if 
glucose persisting at>250 mg/dl 
(13.9 mmol/L) and the patient is 
symptomatic 
Rapid/short-acting insulin, 
according to the institution's 
sliding scale coverage of glucose 
persisting at >250 mg/dl (13.9 
mmol/L},is recommended, with 
oral or IV hydration, as clinically 
appropriate 
Asymptomatic glucose 
increase >500 mg/dl 
• 
Will require dose reduction for subsequent 
treatment infusion 
• 
Repeat glucose testing 
• 
If glucose value is decreasing, glucose 
levels may be followed withoutglucose- 
lowering medication treatment, if hydration 
status is normal, as clinicallyassessed 
• 
 Consultation with endocrinologist is 
recommended 
• Keep well-hydrated.Rapid/short- 
acting insulin maybe given if 
glucose persisting at>250 mg/dl 
(13.9 mmol/L) and the patient is 
symptomatic 
• For insulin-naive patients, monitor 
for signs of hypoglycemia 3 h after 
insulin administration due to risk 
for hypoglycemic events 
Persistent glucose >200 
mg/dl(11.1 mmol/L} 
nonfasting or>160 mg/dl 
(8.9 mmol/L)fasting 
postinfusion 
• 
 Oral glucose-lowering medications and 
consultation with endocrinologist can be 
considered 
• The use of 
sulphonylurea/meta inides,insulin 
secretagogues medications to 
manage increased glucose levels 
following drug infusions is not 
recommended 
• Treatmentwith glucose-lowering 
medication is suggested,in 
accordance with the local 
standards of practice 
 
 
 
 
Treatment of copanlisib-related vomiting and diarrhea 
 
The hydration status of the patient should be clinically assessed and fluid replacement (oral or IV) 
given as appropriate. Adequate hydration through appropriate fluid maintenance is essential for the 
treatment of diarrhea or vomiting. Antidiarrhea medications may be introduced if symptoms occur. 
 
The recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 h until 
diarrhea-free for 12 h; a maximum daily dose of 16 mg is not to be exceeded. If clinically indicated, 
diphenoxylate hydrochloride with or without atropine sulfate can be used. The routine use of 
standard antiemetics, including 5-HT3 blockers, is allowed (see permitted concomitant therapy 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
section below). In the event of CTCAE grade 3 diarrhea with maximal pharmacological support, 
administration of the study drug should be delayed. 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
For the purposes of this study, patients should be re-evaluated for response as per the study 
calendars in Section 10.0. Confirmatory scans for assessment of partial and complete responses 
should also be obtained no less than 4 weeks after initial documentation of objective response. 
 
Response and progression will be evaluated using the new international criteria proposed by the 
revised RECIST guidelines (version 1.1)24, with some amendments, as indicated below for this 
protocol. Changes in the largest diameter (unidimensional measurement) of the tumor lesion and the 
shortest diameter, in the case of malignant lymph nodes, are included in RECIST 1.1. 
 
Definitions 
 
Evaluable for DLT: All patients will be evaluable for DLT from the time of their first treatment with 
vemurafenib and copanlisib. 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment 
with vemurafenib. 
 
Evaluable for objective response: Please see Section 14 for guidelines regarding evaluable for 
response. 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
Disease Parameters 
 
rvleasurable disease: rvleasurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as 20 mm by chest x-ray or as 10 mm with 
CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in  millimeters 
(or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions under 
Vlthich such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with 2::10 to <15 mm short axis), are considered non- 
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardia! effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are present 
in the same patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
 
rv1ethods for Evaluation of rv1easurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the study. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged 
but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., 
skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. ALL CTs 
SHOULD BE PERFORMED WITHOUT IODINATED CONTRAST. 
 
MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex 
issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up 
should be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can 
document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT, then the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, 
however, that the PET portion of the CT introduces additional data which may bias an investigator if 
it is not routinely or serially performed. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory 
to differentiate between response or stable disease (an effusion may be a side effect of the 
treatment) and progressive disease. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
FOG-PET: While FOG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FOG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FOG-PET imaging 
can be identified according to the following algorithm: 
 
a. 
Negative FOG-PET at baseline, with a positive FOG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. 
 No FOG-PET at baseline and a positive FOG-PET at follow-up: If the positive FOG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FOG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FOG-PET scan). If the 
positive FOG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
c. 
FOG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FOG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FOG-PET and biopsy resolution/sensitivity. 
 
Note: A 'positive' FOG-PET scan lesion means one which is FOG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
 
Evaluation of Target Lesions: 
 
Com ete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
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 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions: 
 
Com ete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response: 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
.::_4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
.::_4 wks.Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
Documented at least once .::_4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
See RECIST 1.1 manuscriptforfurther details on what is evidence of a new lesion. 
inly for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-targetlesions maybe 
accepted as disease progression. 
::>atients with a global deterioration of health status requiring discontinuation oftreatmentwithoutobjective evidence 
of disease progression atthat time should be reported as" symptomatic deterioration." Every effort should be made 
to documentthe objective progression even after discontinuation of treatment. 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this categorywhen no lesions can be measured is 
not advised 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
NOTE: Patients with clinical and/or radiographic evidence of disease progression (as described 
above) on assessments performed before the 6-month evaluation post-vemurafenib and copanlisib 
plus 1-131 evaluation (i.e. on scans and/or evaluations performed prior to the evaluation scheduled 
for 6 months after therapeutic 1-131is co-administered with vemurafenib/copanlisib) will be allowed to 
continue on study treatment and will be assessed as mandated by the protocol, if deemed clinically 
reasonable by the treating physician. For these patients, the final objective response assessment 
will be based on a comparison between the 6-month post-vemurafenib plus 131I radiologic 
scan(s)/evaluations and the baseline, pretreatment radiologic scans. 
 
PFS 
 
PFS is defined as the duration of time from start of treatment (initiation of vemurafenib) to time of 
progression or death, whichever occurs first. 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
• 
 Disease progression. Hovi.ever, patients with evidence of clinical disease progression or 
radiographic progression (such as on the 1-124 PET/CTs or other scans) before the 6-month 
evaluation following vemurafenib, copanlisib, and 1-131 may continue on the protocol to 
complete all mandated assessments if the treating physician deems it clinically reasonable. If 
there is evidence of disease progression before completing treatment with vemurafenib and 
copanlisib, study treatment with these drugs and 1-131 will be allowed to continue if the treating 
physician deems that such a decision is clinically justifiable. 
 
• 
Initiation of new drug treatment for thyroid cancer. 
 
• 
Death 
 
• 
Decision of patient to withdraw from the study. 
 
• 
Completion of all planned study therapies and assessments. 
 
 
14.0 
BIOSTATISTICS 
The primary objective of this study is to determine the MTD of vemurafenib plus copanlisib in 
patients with advanced BRAF mutant RAIR thyroid cancer. The MTD is defined as the highest dose 
at which no more than 1 of 6 patients treated at that dose experience a DLT. The dose levels of 
vemurafenib plus copanlisib will be tested in a standard 3+3 dose-escalation design, as outlined in 
Section 9.2. 
 
If a patient withdraws from the study prior to the completion of DLT assessment window (from the 
initiation of copanlisib study treatment to 7 days after completion of study drug administration) for 
reasons other than a DLT, the patient may be replaced and no DLTwill be considered to have 
occurred, unless the Principal Investigator judges that the case should be considered a DLT. 
 
Patients who experience a DLT will be allowed to continue in the study at a lower dose, according to 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
the protocol-specified dose modification, following recovery of the toxicity to grade =:;;1 or the baseline 
level of severity. If a patient experiences intolerable or.:::, Grade 3 toxicities related to vemurafenib 
before the first dose of copanlisib is administered, this will NOT be considered a DLT and the patient 
will be replaced. The patient can be taken off study OR continue on protocol with vemurafenib alone 
with dose reduction per Section 11.0. 
 
In addition to the formal DLT evaluation, longer term laboratory monitoring will be conducted up to 6 
months following 1-131 to provide greater insight into the overall safety of the study regimen. 
 
October 2021 amendment: In a prior version of the protocol, only patients who received 2 doses of 
copanlisib or experienced a DLT with just 1 dose of copanlisib would have been considered 
evaluable for DLT. After four patients completed Dose Level 1, we observed two patients receive 1311 
with 2 doses of copanlisib and two receive only 1 dose of copanlisib without the 1311.No DLTs were 
observed and no clear differences in toxicity were noted between 1 vs. 2 doses of copanlisib in 
combination with vemurafenib. All Grade 3 and higher adverse events definitely, probably and 
possibly related to vemurafenib, copanlisib or both for each patient are noted below. 
 
Patient #1 (2 doses of copanlisib) 
Grade 3 maculopapular rash, possibly related to copanlisib and vemurafenib, not a DLT given 
improvement to grade 2 within 7 days. 
 
Patient #2 (1 dose of copanlisib) 
- Grade 3 hypertension, possibly related to copanlisib infusion, occurred same day as copanlisib 
infusion and improved to grade 2 the same day without intervention and did not recur. 
- Grade 3 decreased lymphocyte count, possibly related to vemurafenib (not DLT). 
 
Patient #3 (1 dose of copanlisib): 
Grade 3 maculopapular rash, probably related to copanlisib and possibly related to vemurafenib, not 
a DLT given improvement to grade 2 within 7 days. 
 
Patient #4 (2 doses of copanlisib): 
No Grade 3 or higher adverse events were observed. 
 
Given the safety observed thus far, the protocol will include all patients who have received at least 1 
dose of copanlisib in the DLT evaluation, regardless of whether 1-131 is given. With this rule, the first 
four patients treated at Dose Level 1 will count towards DLT assessment. Since those 4 patients did 
not experience a DLT, the protocol will proceed to evaluating Dose Level 2 according to the rules 
outlined in Section 9.2. With historical redifferentiation rates, we would then anticipate that 6 of the 
10 patients treated at the MTD with the planned expansion will have been treated with 2 doses of 
copanlisib and evaluated for safety. 
 
Secondary objectives: 
 
• To determine the proportion of patients with BRAFmutant RAIR thyroid cancer treated with 
vemurafenib and copanlisib at the MTD who meet the criteria for 1-131 treatment as determined by 
1-124 PET/CT lesional dosimetry. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
• To determine the proportion of patients with BRAFmutant RAIR thyroid cancer treated with 
vemurafenib and copanlisib (all dose levels) who meet the criteria for 1-131 treatment as 
determined by 1-124 PET/CT lesional dosimetry. 
 
• To quantify the effect of vemurafenib and copanlisib on RAI uptake and retention using serial 1-124 
PET/CT scans. 
 
• To evaluate whether the combination of vemurafenib and copanlisib enhances 1-131 activity, by 
determining the ORR (per RECIST v1.1) at 6 months after treatment with vemurafenib plus 
copanlis ib and 1-131. 
 
• To evaluate whether the combination of vemurafenib and copanlisib enhances 1-131 activity, by 
determining progression-free survival (PFS) at 6 months (per RECIST v1.1) after treatment with 
vemurafenib plus copanlisib and 1-131. 
 
We will determine the proportion of patients with BRAF mutant RAIR thyroid cancer in which the 
combination of vemurafenib and copanlisib administered at the MTD increases iodine incorporation 
in thyroid cancer metastases such that a dose of 2000 cGy can be delivered to at least 1 tumor 
with :5300 mCi of 1-131. Once the MTD is identified, up to an additional 4 patients will be enrolled in 
the cohort, to bring the total number of patients treated at the MTD to 10. As an added precaution for 
safety, if 2 of the additional 4 patients experience a DLT, further accrual will be halted; the next dose 
1 level below will be evaluated for DLTin a minimum of 6 patients, and expanded to include 10 total 
if 
1 experience DLT. The proportion of patients treated at all vemurafenib and copanlisib dose 
levels who experienced increased iodine incorporation sufficient to warrant 1-131 treatment will also 
be calculated. The number of patients with sufficiently increased RAI uptake to warrant treatment 
with 1-131 will be analyzed using proportions and corresponding confidence intervals. 
We will also determine the ORR (per RECIST v1.1) and the proportion of patients who are alive 
without disease progression (per RECIST v1.1) at the 6-month time point (this refers to the 
assessments designated to occur ~6 months after 1-131 therapy) for patients who receive 1-131 
therapy. Patients who have completed the second 1-124 PET/CT and received 1-131 therapy, but did 
not complete the 6-month evaluation, will be considered to have had a progression/death event for 
the PFS analysis and will be categorized as nonresponders for the ORR analysis. The ORR will be 
analyzed using proportions and corresponding confidence intervals. 
It is possible that patients will have clinical or RECIST v1.1 radiologic evidence of disease 
progression before the 6-month evaluation for several reasons: (1) vemurafenib and copanlisib, 
without the addition of 1-131, may not have significant clinical efficacy; (2) Thyrogen stimulation can 
transiently increase tumor size, which can be mistaken for disease progression; (3) the therapeutic 
effects of 1-131 can be delayed; and (4) evidence of progression may be present before 
administration of 1-131. Hence, patients with evidence of disease progress ion after 1-131, but prior to 
the 6-month evaluation, may remain on the study to complete the 6-month assessments if the 
treating physician deems that such a decision is clinically justifiable. If there is evidence of disease 
progression before completing treatment with vemurafenib and copanlisib, study treatment with 
these drugs and 1-131 will be allowed to continue if the treating physician deems that such a 
decision is clinically justifiable. The final objective response and disease progression assessments 
at 6 months for these patients will be based on a comparison between the 6-month radiologic 
scan(s) and the baseline, prestudy radiologic scans. However, if in the opinion of the treating 
physician, patients with evidence of progression before the 6-month assessment are unlikely to 
experience benefit by the 6-month time point, the patients will be considered to have had a 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
progression/death event for the PFS analysis, categorized as nonresponders for the ORR analysis, 
and removed from the study. 
Patients who receive additional treatment for thyroid cancer outside of this protocol before the 6- 
month time point (except for TSH suppression, palliative radiation to a nontarget lesion, or therapy to 
prevent pathologic fractures caused by bone metastases [e.g., zoledronic acid and denosumab]) will 
be considered to have had a progression/death event for the PFS analysis and will be categorized 
as nonresponders for the ORR analysis. 
 
To characterize how the combination of vemurafenib plus copanlisib affects RAI uptake and 
retention within select index lesions, we propose to analyze the 4 PET/CT scans obtained in each 
the pretreatment and on-treatment periods. This analysis will directly test our hypothesis that the 
combination of vemurafenib plus copanlisib affects not only RAI uptake but also retention within 
thyroid tumors. These data will be analyzed using descriptive statistics. 
Exploratory Objectives: 
 
We will perform correlative studies on serial research biopsy specimens and archival tumor tissue in 
order to evaluate the effect of vemurafenib on (1) expression and phosphorylation of 1\/lAPK 
signaling pathway proteins; (2) expression and phosphorylation of negative feedback loops 
connected to the 1\/lAPK pathway (such as HER3); (3) quantitative levels of mRNA transcripts for 
1\/lAPK, Pl3K, and Sl\tlAD signaling pathways, as well as thyroid-specific gene products; and (4) the 
presence of other genetic alterations (through the use of MSK-IMPACT, supplemented, if needed, 
by the RNA Targeted Archer Solid Tumorfusion panel). These analyses will be descriptive and 
exploratory, given the limited number of samples examined. Changes in these molecular profiles will 
be correlated directly with the changes in RAI uptake and retention measured on the 1-124 PET/CT 
scans. These data will be analyzed using descriptive statistics. 
Another exploratory objective will be to evaluate time to next thyroid cancer treatment, tumor size 
changes after study therapy, serum thyroglobulin changes and survival. This data will be important 
for gaining more insight into the degree of tumor control that may be achieved with vemurafenib plus 
copanlisib +/- 1-131. To collect this data beyond the protocol-mandated scans and tests, an 
observation period to collect data for up to 1 year after study drug discontinuation will be completed 
for all patients. Data that to be collected will include RECIST measurements of both protocol- 
mandated scans and scans conducted as part of standard of care. Thyroglobulin/TSH serum values 
draw on protocol and as part of standard of care will also be collected. Other data to be collected are 
survival status and initiation of new treatments (radiation, surgery and drug therapy). If RECST 
disease progression and initiation of drug therapy, or death, is observed, the observation phase may 
be discontinued. Data encompassing this observation phase may also be collected/analyzed 
retrospectively. This exploratory analysis will be conducted using descriptive statistics. 
Sample size: 6-32 patients. We plan to accrue about 1-2 patient(s) per month for a total accrual 
time of 1-2 years. 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
 
15.2 
Randomization 
 
Not applicable. 
16.0 
DATA MANAGEMENT ISSUES 
A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities of 
the CRC include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinating the activities of 
the protocol study team. 
The data collected for this study will be entered into a secure database, Medidata Rave. 
Source documentation will be available to support the computerized patient record. 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plan utilized for this study must align with the  MSK DSM 
Plan, where applicable. 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. The plans address the new policies set forth by 
the NCI in the document entitled "Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials." 
 
There are several different mechanisms by which clinical studies are monitored for data, 
safety and quality. At a departmental/Pl level there exists procedures for quality control by 
the research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA 
and two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase Ill 
clinical trials, report to the Deputy Physician-in-Chief, Clinical Research. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. 
 
The MSK DSMB monitors phase Ill trials and the DSMC monitors non-phase Ill trials. The 
DSMB/C have oversight over the following trials: 
 
• 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
• 
External studies where MSK is the data coordinating center 
• 
Low risk studies identified as requiring DSMB/C review 
 
The DSMC will initiate review following the enrollment of the first participanUor by the end of 
the year one if no accruals and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will 
initiate review once the protocol is open to accrual. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Inclusion of Children in Research 
This protocol/project does not include children, because the number of children with this 
disease is limited and because the majority of affected children are already accessed by a 
nationwide pediatric cancer research network. This statement is based on exclusion 4b of the 
NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving 
Human Subjects. 
Risks, Benefits, Toxicities/Side Effects 
Potential risks to human subjects include drug-related toxicities, placement of IV catheters, 
phlebotomy, and possible psychological discomfort from the stresses associated with 
obtaining imaging studies (e.g., CT scan, PET scan). All efforts will be made to avoid any 
complication by completely reviewing patients' symptoms, providing appropriate 
management, and monitoring blood tests. 
If an adverse medical event occurs, the patient will first contact the primary oncologist or the 
Principal Investigator. At nights and on weekends, there is an oncology physician on call at 
all times. Patients may either call or come directly to the urgent care center at Memorial 
Hospital (or to their local emergency room) to be seen. Patients suffering serious adverse 
reactions must be carefully followed and all follow-up information also recorded. 
Alternatives/0ptions 
Participation in this trial is voluntary. Depending on the specific details of the situation, patient 
options without being in a study might include: 
• Other palliative chemotherapy off-study. 
 
• Participation in a different clinical trial. 
 
• Best supportive care. 
 
Financial Costs/Burdens 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
The patient will be responsible for all costs related to treatment and complications of 
treatment. Costs to the patient (third-party insurer) will include hospitalizations, routine blood 
tests and diagnostic studies, office visits, baseline EKG, and doctor fees. Patients will not be 
charged the cost of analysis for the research correlates. Bayer will financially support the 
study, and Copanlisib will be supplied by Bayer. The patient will not be charged for the 
subsequent research analysis of these specimens. Vemurafenib is an NCCN compendium- 
approved medication. Serial 1-124 lesion dosimetry scans will be supported through R01 
CA201250-03. 
17.1 
Privacy 
MSK's Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
 An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant's last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 'Reporting of Serious 
Adverse Events', the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to  saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to  sae@mskcc.org. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
The report should contain the following information: 
 
Fields populated from CRDB: 
 
• 
Subject's initials 
• 
1\/ledical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o 
A explanation of how the AE was handled 
o 
A description of the subject's condition 
o 
Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The Pl's signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
17.2.1 
Other Adverse Events Reporting 
Adverse events of special safety interest 
On the basis of data from clinical studies of copanlisib in patients with lymphoma, as 
soon as there is reasonable suspicion of the following adverse event, the investigator 
should immediately notify Bayer (within 24 h), regardless of whether the event is 
assessed as causally related/not related to the study drug or as serious/nonserious. The 
adverse event of special interest should be entered on an SAE form; if the event is 
assessed as nonserious, the nonserious assessment should be noted in the form. 
• 
Noninfectious pneumonitis (NIP) 
 
 
 
Pregnancies 
The investigator must report all pregnancies occurring in female study patients during 
their participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome if the partner or the male participant chooses 
to disclose that information. 
The investigator should submit such events within the same timelines as for an SAE. 
 
 
SAE Reporting Requirements: 
The SPONSOR is responsible for all of the pharmacovigilance obligations and safety 
reporting pursuant to the applicable laws and regulations in the country/countries where 
the STUDY is performed. 
Additionally, the SPONSOR shall immediately, within 24 hours at the latest, report to 
BAYER by fax and/or e-mail: (973) 709-2185 DrugSafety.GPV.US@bayer.com 
• 
 All Serious Adverse Events occurring after start of administration of BAYER 
product, independent of their causal relationship to the STUDY DRUG 
• 
Any other relevant safety information including but not limited to: 
o 
Reports of drug exposure via mother/ father with and without adverse 
events (exposure during conception, pregnancy, childbirth and 
breastfeeding) including their outcome; 
o 
If linked to a serious adverse event, reports of misuse, abuse, overdose, 
medication error and other uses outside what is foreseen in the protocol, 
drug dependency, occupational exposure suspected transmission of an 
infectious agent, withdrawal syndrome, drug interactions with respect to 
the STUDY DRUG; 
and 
• 
 Any communication concerning safety related information to regulatory 
authorities or ethics committees including but not limited to: 
• 
 Development Safety Update Reports / relevant parts of IND reports for the 
STUDY; 
• 
 Any other safety related reports, issues and queries that are either raised by or 
communicated to regulatory authorities or ethics committees (e.g., reportable 
non-serious cases). 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRS/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant 
metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine 
therapy. J Clin Endocrinol Metab. 2006;91(8):2892-2899. doi:10.1210/jc.2005-2838 
2. 
 Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus Placebo in Radioiodine- 
Refractory Thyroid Cancer. N Engl J Med. 2015;372(7):621-630. 
doi:10.1056/NEJMoa1406470 
3. 
Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally 
advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 
trial. Lancet (London, England). 2014;384(9940):319-328. doi:10.1016/S0140- 
6736(14)60421-9 
4. 
Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. Advances in Brief High 
Prevalence of BRAF Mutations in Thyroid Cancer: Genetic Evidence for Constitutive 
Activation of the RET / PTC-RAS-BRAF Signaling Pathway in Papillary Thyroid Carcinoma 1. 
CANCER Res. 2003;63(7):1454-1457. 
5. 
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary 
thyroid carcinoma. Cell. 2014;159(3):676-690. doi:10.1016/j.cell.2014.09.050 
6. 
Chakravarty D, Santos E, Ryder M, et al. Small-molecule rv1APK inhibitors restore radioiodine 
incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest. 
2011;121(12):4700-4711. doi:10.1172/JCl46382 
7. 
Nagarajah J, Le M, Knauf JA, et al. Sustained ERK inhibition maximizes responses of 
BraN600E thyroid cancers to radioiodine. J Clin Invest. 2016;126(11):4119-4124. 
doi:10.1172/JCl89067 
8. 
 Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-Enhanced Radioiodine Uptake in Advanced 
Thyroid Cancer. N Engl J Med. 2013;368(7):623-632. doi:10.1056/NEJMoa1209288 
9. 
 Dunn L, Sherman EJ, Baxi SS, et al. Enhancing radioiodine (RAI) incorporation into 
BRAFV600E-mutant, RAl-refractory thyroid cancers with the BRAF inhibitor vemurafenib: A 
pilot study. J Clin Oneal. 2016;34(15_suppl):6099. doi:10.1200/JCO.2016.34.15_suppl.6099 
10. 
Dunn LA, Sherman, E.J., Baxi, S.S., Tchekmedyian, V., Grewal, R., Larson, S.M., Pentlow, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
K.S., Haque, S., Tuttle, R.M., Sabra, M.M., Fish, F., Boucai, L., Walters, J., Ghossein, R.A., 
Seshan, V.E., Ni, A., Knauf, J.A., Pfister, D.G., Fagin, J.A., Ho AL. Vemurafenib 
Redifferentiation of BRAF-mutant, RAI-Refractory Thyroid Cancers. J Clin Endocrinol Metab. 
2018;In press. 
11. 
 Xing M, Alzahrani AS, Carson KA, et al. Association Between BRAF V600E Mutation and 
Mortality in Patients With Papillary Thyroid Cancer. JAMA. 2013. doi:10.1001/jama.2013.3190 
12. 
 Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for 
papillary thyroid cancer. J Clin Endocrinol Metab. 2005. doi:10.1210/jc.2005-0987 
13. 
Brose MS, Cabanillas ME, Cohen EEW, et al. Vemurafenib in patients with BRAFV600E- 
positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a 
non-randomised, multicentre, open-label, phase 2 trial. Lancet Oneal. 2016. 
doi:10.1016/S 1470-2045( 16)30166-8 
14. 
 Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with 
Combined Dabrafenib and Trametinib. N Engl J Med. 2015. doi:10.1056/NEJMoa1412690 
15. 
Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF- 
mutated melanoma. N Engl J Med. 2014. doi:10.1056/NEJMoa1408868 
16. 
 Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and Trametinib Treatment in 
Patients With Locally Advanced or Metastatic BRAFV600-Mutant Anaplastic Thyroid Cancer. 
J Clin Oneal. 2017. doi:10.1200/JCO.2017.73.6785 
17. 
 Shah MH, Wei L, Wirth LJ, et al. Results of randomized phase II trial of dabrafenib versus 
dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.JC/in Oneal. 2017. 
doi:10.1200/JCO.2017.35.15_suppl.6022 
18. 
Chapman PB, Hauschild A, Robert C, et al. Improved Survival with Vemurafenib in Melanoma 
with BRAF V600E Mutation. N Engl J Med. 2011;364(26):2507-2516. 
doi:10.1056/NEJMoa1103782 
19. 
Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-Mutant Advanced Melanoma 
Treated with Vemurafenib. N Engl J Med. 2012. doi:10.1056/NEJMoa1112302 
20. 
 Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by Copanlisib 
in relapsed or refractory indolent lymphoma. J Clin Oneal. 2017. 
doi:10.1200/JCO.2017.75.4648 
21. 
Fruman DA, Rommel C. Pl3K and cancer: Lessons, challenges and opportunities. Nat Rev 
Drug Discov. 2014. doi:10.1038/nrd4204 
22. 
 Pratilas CA, Taylor BS, Ye Q, et al. V600EBRAF is associated with disabled feedback 
inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl 
Acad Sci. 2009;106(11 ):4519-4524. doi:10.1073/pnas.0900780106 
23. 
Cheng OT, Mitchell TN, Zehir A, et al. Memorial sloan kettering-integrated mutation profiling of 
actionable cancer targets (MSK-IMPACT): A hybridization capture-based next-generation 
sequencing clinical assay for solid tumor molecular oncology. J Mo/ Diagnostics. 
2015;17(3):251-264. doi:10.1016/j.jmoldx.2014.12.006 
24. 
 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
doi:10.1016/j.ejca.2008.10.026 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
20.0 
APPENDICES 
 
Appendix A:. 1-124 Normal Organ Radiation Dosimetry 
Appendix B: 1-124 PET/CT-based Lesional Dosimetry Image Acquisition, Analysis, and 
Interpretation 
Appendix C: The Low-Iodine Diet 
Appendix D: Glycemic Index Foods 
Appendix E: Permeability Glycoprotein (Pg-p) Substrates, Breast Cancer Resistance Protein 
(BCRP) Substrates, and Multidrug and Toxin Extrusion Protein 2 (MATE2K) Substrates 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
124Uodide Normal.Organ Radiation Dosimetry 
Appendix A: 1-124 Normal Organ Radiation Dosimetry 
 
 
 
 
 
 
 
 
 
 
 
Adrenals 
Brain 
 
 
 
 
 
 
Target Organ 
 
Absorbed Doses 
 
1 'r:'J:Jogide PEJ-CT 1c10 
2 
1?1:fodidePET.CT scans 
0,9
1 
rad1• 
2 0,9
1 
rad 1• 
1t&t,.fOC1ide 1 
6 mCi 1tAt.lO<lide 
6 mCi 1tAt.lO<lide 
rad/mCi 
raiWmCl 
rad 
rad 
0.21 
1.3 
2.2 
4.3 
0.57 
3.4 
4.3 
8..6 
Bone Surfaces 
Breasts- 
Gal Bladder Wal 
HeaJtWa.l 
Kidn 
Large lntestme - lower Wal 
Large lntes&le - Upper Wal 
Lens.oif Eye,i 
Uver 
Lungs 
uselei 
Panc,e,n 
Red Jarrow 
Smatlestine 
Sl:oma Wal 
Testes, 
Thyroid & 
Total Body 1' 
Umary Bladder Wal 
0·.42 
25 
3.4 
·6.8 
0·.23 
u 
2.3 
4;6 
0.26 
116 
2.5 
4.9 
0·.37 
2.2 
3.1 
6.2 
0.20 
1.2 
2.1 
4.2 
O·.:J.7 
2.2 
3.1 
,6.2 
0.29 
1.7 
2,6 
5.3 
0,.41 
2.5 
3.4 
8.7 
0·.36 
2'.2 
3;1 
6.1 
0·.38 
2.2 
3.1 
,6.1 
0Al1 
2'.5 
3.4 
8.7 
0·.32 
1.9 
2.8 
5,6 
0·.42 
2;5 
3.4 
·6.8 
1.0 
1.0 
1.9 
l. 8 
1.7 
1.7 
2,6 
5.2 
0.24 
1.4 
2.3 
.7 
MIA 
H/A 
H/A 
NIA 
0.41 
2.5 
3.4 
,8.7 
 
 
1 
 Hays r·1et al. tJIRD Dose est.mate:Report No 5. J NuClea16 857-660, 1975. 
As.91.unes.25% 2'4..n lllyrod uplake. 
2 
Wu et al Eur.JNua ed t ol maging,31:38-43, 2004. 
3 
Lens.cf-Eye allSo dose equaled wll'I lhe lll!Sde absorbed dpse 
4 
Ill post-Hlyroidectcmyand post-all&atieln thyroid cancer p
0atients lhere is. NO 
functional lhyol'd lo n-adiate. For Ule --0% 'thyroid· uplake tor sudl palienls, lhe normal-organ 
doses. are 11.ety LOMR man mose presented. 
6 
Total-Bady allSo dose equaled wll'l lhe ' uscie absorbed dose 
2-ttr VOiOiqq Mlet"lal 0·.37
 
2.2 
3.1 
6.2 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Appendix B: 1-124 PET /CT-based Lesional Dosimetry Image Acquisition, 
Analysis, and Interpretation 
 
The 1-124 PET/CT scan will be performed on a PET/CT scanner 2 days after administration of 5-7 
mCi of 1-124, the time at which maximal uptake of iodide by thyroid tumors generally occurs. The 
index lesion (i.e., metastatic thyroid tumor) will be identified by radiology coinvestigators. The index 
lesion volume (in milliliters), V1esion, will be estimated by the CT study performed for attenuation 
correction and anatomic registration as part of the 1-124 PET/CT scan on the PET/CT scanner. This 
"low-dose" attenuation-correction CT scan will be performed without contrast or (respiratory) gating 
and with acquisition and processing parameters routinely used for such scans at the participating 
sites. Once reconstructed, and using the commercial image-processing software provided on the 
PET/CT scanner's computer or a compatible networked workstation, regions of interest (ROls) 
circumscribing the index lesion on all contiguous CT slices on which the lesion appears will be 
drawn, yielding V1esion. Only lesions on the first 1-124 PET/CT scan that are ::_5 mm in length in 
the maximal diameter will be used as an index lesion for this analysis. 
Using the PET acquisition and processing parameters routinely used for PET/CT scans, the 
reconstructed PET images will be parameterized, as usual, in terms of standard uptake value (SUV) 
(= µCi measured by PET/g of tissue/ µCi administered/g of total body mass). Using the commercial 
image-processing software provided on the PET/CT scanner's computer or a compatible 
workstation, ROls circumscribing the index lesion on all contiguous PET slices on which the lesion 
 
appears will be drawn, yielding the index lesion mean SUV, SUV lesion; alternatively, the lesion ROls 
drawn on the CT scan (see above) may be superimposed on the registered PET images to yield 
 
SUV1esion. From the definition of the SUV (above), the mean PET-derived 1-124 concentration (in 
µCi/ml) in the index lesion not corrected for partial-volume-averaging, ( [1241A] lesion)RC-uncorrected, will 
be calculated from SUV lesion: 
 
( [124 1A] lesion)RC-uncorrected 
-- 
AA 
= 
SUV1esion Mm 
(1) 
 
where AA is the 1-124 administered activity (in µCi) and Mrs is the patient total body mass (in µCi). 
 
Note that the SUVs provided by the PET scanner are not automatically corrected for partial-volume 
averaging. Using the CT-derived lesion volume, V1esion, and the volume (V)--dependent recovery 
coefficient (i.e., PET-derived activity concentration [in µCi/ml]/actual activity concentration [in 
µCi/ml]), RC(V), previously measured for the PET/CT scanner, the PET-derived mean 1-124 
concentration (in µCi/ml) in the index lesion not corrected for partial-volume averaging, ([1241A] 
1esion)Rc-uncorrected, will be corrected to yield the actual mean 1-124 concentration in the index lesion, 
 
([124 I A]lesion)RC-corrected: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
 
([1 
 
241 A]iesion)RC-corrected 
 
 
= 
([1241 A]lesion)RC-uncorrected 
RC(V1esion) 
(2) 
 
The mean 1-124 activity concentration in the index lesion per 1-124 administered activity (in 
µCi/ml/mCi), ( [1241 A_ier mci] lesion)Rc-corrected, will then be calculated: 
 
 
( [124 I A_ier mCi] lesion)RC-corrected 
= 
([1241 A]lesion)RC-corrected 
 
AA/1000 
(3) 
( [1241 A_ier mCi] lesion)RC-corrected can be converted to the mean 1-131 activity concentration in the index 
lesion per 1-131 administered activity (in µCi/mUmCi), ( [131I A_iermCi] lesion)RC-corrected, 1-131 (and not 1- 
124) being used for therapy: 
 
 
( [131 I A_ier mCi] lesion)RC-corrected = 
( [124 I A_ier mCi] lesion)RC-corrected eP.-I124- "-l131)timaging 
(4) 
 
where 11,1124 and 11,1131 are the physical decay constants of 1-124 (0.00693/h) and 1-131 (0.00359/h), 
respectively, and !imaging is the  time after administration of PET/CT imaging (in hours). 
On the basis of prior clinical experience, the biological half-life, Tb, of iodine in metastatic thyroid 
cancer lesions is typically 2 d (48 h) to 4 d (96 h), which will be the assumed range of biologic half- 
life used in these calculations. For 1-131, with a physical half-life TP of 8.04 d = 193 h, the effective 
half-life, Te, of 1-131 in the index lesion is therefore (if assuming 48 h biologic half-life): 
 
Te = 
 
 
= 
 Tb Tp  
Tb+ Tp 
(5a) 
 
48 h • 193 h  
48 h + 193 h 
(5b) 
 
= 38.4 h 
(5c) 
 
Assuming, as usual, that the uptake of radioiodine in the index lesion (i.e., the 24- to 48-h uptake 
value) will be instantaneous and that 1-131 lesion irradiation will be due exclusively to complete local 
 
absorption of 1-131 beta rays, the mean lesion absorbed dose (in rad/mCi 1-131), [1311Opermci] lesion, 
will be: 
 
[131I Oper mCi] lesion = 
1.44 Te ( [131I A_ier mCi] lesion)RC-corrected np 
(6a) 
 
 
= 
1.44 • 38.4 h ( [1311A_ier mCi] lesion}RC-corrected 
 
0.405 g-rad/µCi-h 
 
 
= 
22.4 ( [131I A_ier mCi] lesion)RC-corrected 
(6b) 
 
 
(6c) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
where L'.1np = 0.405 g-rad/µCi-h is the equilibrium dose constant for nonpenetrating radiations (i.e., 
beta rays) for 1-131. 
Finally, the 1-131 administered activity (in mCi) required to deliver the stipulated mean absorbed 
dose of 2,000 rad to the index lesion, 1311Mooo rad lesion, will be: 
131 I AA2000 rad lesion  = 
2,000 rad/[131I Oper mci]lesion 
(7) 
 
 
 
If the projected 1311Mooo rad lesion is reasonable ( 300 mCi) (assuming a 48h to 96 h iodine biologic 
half-life), the Principal Investigator and the Co-lnvestigator(s) will decide whether 1-131 therapy 
should proceed. 
While the foregoing analysis will be performed on data from the second 1-124 PET/CT scan 
performed at ~48 hours after 1-124 with the noted assumptions about the biologic half-life of iodine, 
per the Principal Investigator's discretion, the decision to proceed with therapeutic 1-131 could also 
be determined after the biologic half-life has been calculated from the full complement of 1-124 
PET/CT images collected (completed by D1x15 according to Table 10.2). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Appendix C: The Low-Iodine Diet 
 
What is iodine? 
Iodine is a mineral. It plays an important role in several processes thattake place in the body. One is 
the production of a hormone called thyroxine, which occurs in the thyroid gland. 
 
Where is iodine found? 
The amount of iodine found in food varies. Much of the iodine we get comes from iodized salt and 
breads. Adults need 150 micrograms of iodine a day. This booklet describes a low-iodine diet. This 
is a diet with less than 50 micrograms of iodine per day. 
 
Why is a low-iodine diet necessary? 
The iodine in your diet can block the uptake of radioactive iodine by the thyroid gland. Your doctor 
could put you on a low-iodine diet 1 or 2 weeks before you get the radioactive iodine. Stay on this 
diet until your test or treatment is complete. Your doctor will tell you when to begin and when to stop 
this diet. If you have any questions, speak with your doctor. You may also see a dietitian if 
necessary. If you have any questions about your diet, call (212) 639-7312 to speak to a dietitian. 
 
What should you avoid? 
 
Read all food labels to check for iodine content. Do NOT eat or use: 
• Iodized salt 
• Sea salt in any form 
• Onion salt 
• Celery salt 
• Garlic salt 
• Seasoned salt 
• Kelp (seaweed) 
• Any food that has: 
o 
lodates 
o 
Iodides 
o 
Algin 
o 
Alginates 
o 
Carrageen 
o 
Agar 
• Commercial breads and bakery products, because they often contain iodate. 
• Milk (except for 1 ounce a day), eggs, and seafood 
• Vitamins and food supplements, if they have iodine. If you have any doubt, do not take them 
• Food, pills, or capsules with food dyes or that are orange, red, or brown in color. Examples include 
red or pink cereals or candies 
• Antiseptics, such as tincture of iodine (Betadine) applied on a cut 
• Cough medicines (especially those with red coloring) 
• Supplements such as: 
o 
Ensure 
o 
Boost 
o 
Commercial shakes 
o 
Nutrament 
• Restaurant and processed foods, because they are often high in iodine content. 
• Soy products, such as edamame, tofu, and soy burgers (e.g., Boca) 
• All canned foods, because the lining of the can contains iodine 
 
Do not stop taking any of your medicines unless your doctor tells you to. If you are receiving tube- 
feeding formula, ask your dietitian or doctor what to do. This low-iodine diet does not meet the 
suggested daily allowance for all nutrients. You will be on it for a short time only. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
Drink Plenty of Fluids. 
 
Note: Unless your doctor tells you differently, you must drink at least 8 to 10 8-ounce cups of fluid a 
day. This includes the drinks in the diet guidelines and as much water as you want. 
Low-Iodine Diet Guidelines 
Breads and Cereals 
 
Total number of servings per day: 6-8 
(1 serving equals 1 slice of bread or 1/2 cup of cooked pasta) 
 
Include 
Plain cooked barley, oats, millet, buckwheat, bulgur wheat, quinoa; unsalted, unprocessed, 
preservative-free boxed cereals, such as puffed rice and shredded wheat; rice, plain macaroni, 
spaghetti, noodles; cream of rice or cream of wheat hot cereals; unsalted rice cakes, unsalted plain 
matzah, English muffins, plain unsalted popcorn, homemade breads prepared without commercial 
dough. 
Avoid 
All commercial breads and rolls, processed boxed cereals, salted crackers, potato chips, pretzels, 
bagels, bialys, Melba toast, all other crackers, egg noodles, packaged rice, and pasta mixes. 
Meat and Meat Substitutes 
 
Total number of servings per day: 2-3 
(1 serving equals 3 ounces of meat, fish, poultry, or 2 tablespoons of unsalted peanut or almond 
butter) 
 
Include 
Fresh beef, veal, pork, lamb, chicken and turkey; unsalted peanut or almond butter; fresh-water fish 
such as carp, river bass, lake trout, and river perch; fresh egg whites. 
 
Avoid 
Egg yolks and whole eggs, foods made with eggs; all fast foods; all canned fish such as salmon and 
tuna; seafood, shellfish (clams, crabs, oysters, lobsters), or any food made with fish stock; all 
processed meats; liver and all organ meats; all canned, dried, salted, or cured meats such as bacon, 
sausage, ham, frankfurters, chipped beef, luncheon meats (salami, bologna, pastrami); spicy meats 
such as chili, beef jerky, liverwurst; all canned or processed poultry such as turkey or chicken roll; 
tofu and soy products, such as soy burgers (e.g., Boca); salted peanut butter. 
 
 
Milk and Milk Products 
Total number of servings per day: 0 
Include 
None allowed. 
 
Exception: Only 1 ounce of milk a day in your coffee or tea. 
Avoid 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
All milk (except for 1 ounce daily) and milk products such as condensed or evaporated milk, cheese, 
yogurt, puddings, ice cream, custard; any cream such as heavy or light cream, whipped cream, sour 
cream; any foods made with cream or milk or cheese such as cream soup, pizza, and macaroni and 
cheese. 
Fruits 
 
Total number of servings per day: 5 
(1 serving equals 1 small piece of fruit or 3/4 cup of juice) 
 
Include 
All fresh fruit (exception: limit bananas to 1 serving per day); fresh apple sauce; all natural frozen 
fruits; fresh fruit juices (including bottles or cartons of fruit juice without artificial coloring or 
preservatives); white grape juice. 
 
Avoid 
Cranberries, all dried fruits, all canned fruits and canned fruit juices; jarred applesauce; cranberry 
and grape juice, canned or bottled cherries; rhubarb. 
Vegetables 
Total number of servings per day: 4 
(1 serving equals 1/2 cup of cooked or 1 cup of raw vegetables) 
 
Include 
All fresh vegetables except spinach, fresh potatoes without skin, all plain frozen vegetables without 
added salt, fresh or dried legumes such as lentils and peas. 
 
Avoid 
All canned vegetables and all canned vegetable juices, fresh or dried beans such as red kidney 
beans, lima beans, navy beans, pinto beans and cowpeas; canned legumes (such as beans, peas, 
and lentils); canned soups; sauerkraut, celery; commercially prepared potatoes (e.g., instant 
mashed potatoes); frozen vegetables with added salt; spinach. 
Fat 
Total number of servings per day: 4-6 
(1 serving equals 1 teaspoon of butter or oil) 
 
Include 
Unsalted margarine or sweet butter (not more than 1 teaspoon of each per day), oils, vegetable 
shortening, plain oil and white vinegar dressing. 
 
Avoid 
Salted nuts and seeds, mayonnaise, commercial salad dressings, and lard. 
 
Beverages 
Total number of servings per day: No restrictions 
(1 serving equals 12 ounces of a carbonated beverage or 1 cup [8 ounces] of any of the other 
beverages listed) 
 
Include 
Water; bottled carbonated beverages without added coloring (such as Sprite, 7-Up, sodium-free 
seltzer); brewed coffee, tea steeped from tea leaves; white tea bags; fresh lemonade or fresh 
orangeade. 
 
Avoid 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Mineral water containing sodium; all bottled, canned, or powdered iced tea, lemonade, instant 
coffee, instant tea, instant iced tea, fruit punch, and other powdered or commercial drinks such as 
Hi-C and Kool-Aid; tea steeped from tea bags; soy milk and rice milk (which contain sea salt); ginger 
ale, Coke, Pepsi, or any other carbonated beverages with added coloring. 
Desserts and sweets 
Total number of servings per day: 2 
(See below for serving equivalents) 
 
Include 
Each of the following equals 1 serving: 
• 1 cup Knox clear gelatin 
• 2 tablespoons sugar 
• 2 tablespoons honey 
• 2 tablespoons maple syrup 
• 2 regular size marshmallows 
• 1/2 cup natural sorbets with no coloring or added salt 
 
Avoid 
All bakery products such as pies, cakes, pastries, danishes, muffins, donuts and cookies; graham 
crackers; Jell-0, colored gelatins; chocolate and chocolate desserts; candy. 
 
Miscellaneous 
Total number of servings per day: Unlimited 
 
Include 
Pepper, spices such as cinnamon; herbs such as oregano; white vinegar, and noniodized salt 
(contains trace amounts of iodine, use sparingly). 
 
Avoid 
All salted foods such as salted nuts, Chinese food, soy sauce, catsup, Worcestershire sauce, chili 
sauce, all commercial sauces, tomato sauce, all gravies, olives, pickles, relish, bouillon cubes, soup 
bases, iodized salt, sea salt, onion salt, garlic salt, celery salt, seasoned salt, kelp (seaweed); 
molasses; any food containing food coloring, iodates, iodides, iodate dough conditioners or 
stabilizers, algin, alginate, carrageens, agar, or nori (seaweed); all sushi; red wine vinegar, balsamic 
vinegar (with caramel coloring); all additives, preservatives, or artificial colorings. 
Sample Menu for a Low-Iodine Diet 
 
BREAKFAST 
1 fruit 112 cup orange juice 
3 breads 112 cup oatmeal (no milk) 
1 plain unsalted matzah 
1 meat 1 egg white omelet 
Misc. 2 teaspoons sugar 
1 beverage 1 cup brewed coffee 
 
MIDMORNING SNACK 
1 fruit 2 rice cakes 
1 teaspoon unsalted butter 
1 cup water 
 
LUNCH 
1 meat 3-oz fresh turkey breast 
2 fats 2 teaspoons oil 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
2 breads 2 slices homemade white bread 
1 vegetable 1 cup romaine lettuce 
1 beverage 1 cup fresh lemonade 
 
MIDAFTERNOON SNACK 
1 fruit 1 fresh apple 
1 meat 2 tablespoons unsalted peanut butter 
 
DINNER 
1 meat 3-oz roast beef 
2 breads 1 baked potato (no skin) 
2 vegetables 1 cup fresh broccoli 
2 fats 2 teaspoons oil (used in cooking) 
1 fruit 1 orange 
1 beverage 1 cup white tea 
 
BEDTIME SNACK 
1 fruit 1 small pear 
1 beverage 1 cup tea made from fresh tea leaves 
 
©1997 Memorial Sloan-Kettering Cancer Center 
1275 York Avenue, New York, New York 10065 
Revised 2002, 2004, 2006, 2008 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
Appendix D: Glycemic Index Foods 
Foods are categorized as having a low glycemic index if the glucose reference index is 55. High- 
glycemic-index foods have a glucose reference index >55. The summary table below contains 
glucose references for common foods. 
 
GI = glycemic index. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix E: Permeability Glycoprotein (Pg-p) Substrates, Breast 
Cancer Resistance Protein (BCRP) Substrates, and Multidrug and Toxin 
Extrusion Protein 2 (MATE2K) Substrates 
A list of drugs to be used with caution. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-053 A(4) 
Approval date: 09-Nov-2021 
 
 
Copanlisib is an inhibitor of 
BCRP, P-gp and MATE2K in 
vitro. Therefore substrates, 
especially those with a narrow 
therapeutic range, should be used 
with caution.Pgp-Substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxina", everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, tolvaptan, topotecan 
BCRP substrates 
Zidovudine, pantoprazole, cirnetidine, sulfasalazine, 
nitrofurantoin, ands everal s tatins (lovas tatin, s irnvas tatin, 
cerivastatin, pitavastatin), mitoxantrone, methotrexate, topotecan, 
irnatinib, and irinotecan 
MATE2K substrates 
Metforrnin, cimetidine, procainamide and N methylnicotinamide 
BCRP = Breast cancer resistance protein; MATE2K = Multidrug and toxin extrusion protein 2, 
P-gp = Perrneability glycoprotein 
a:Narrow therapeutic window