Phase II Trial to Evaluate the Efficacy of the FASN Inhibitor, TVB-2640, in Combination With Trastuzumab Plus Paclitaxel or Endocrine Therapy in Patients With HER2+ Metastatic Breast Cancer Resistant to Trastuzumab-Based Therapy
Phase: PHASE2
Conditions: Advanced Breast Carcinoma, HER2-Positive Breast Carcinoma, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, HER2-positive Breast Cancer
Sponsor: Mayo Clinic

 
 
 
 
 
MC1633 / 16-010066 
 
 
Phase II Trial to Evaluate the Efficacy of the FASN Inhibitor, TVB-
2640, in Combination with Trastuzumab plus Paclitaxel or 
Endocrine Therapy in Patients with HER2+ Metastatic Breast 
Cancer Resistant to Trastuzumab-based Therapy 
 
 
NCT03179904 
 
 
Document Date: 10/16/2023 

MC1633 
Protocol Version Date: 16Oct2023 
Mayo Clinic Cancer Center 
MC1633 Phase II Trial to Evaluate the Efficacy of the FASN Inhibitor, TVB-2640,  
in Combination with Trastuzumab plus Paclitaxel or Endocrine Therapy in Patients with HER2+ 
Metastatic Breast Cancer Resistant to Trastuzumab-based Therapy 
 
Study Chairs: 
Tufia C Haddad MD* 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
507/284-2511 
 
Study Co-chairs: 
Ruth Lupu PhD√ 
Matthew P Goetz MD 
Alvaro P Moreno MD (Florida) 
Brenda J Ernst MD (Arizona) 
Statistician: 
Vera J Suman PhD√ 
Research Monitor: Yolanda I Garces MD√ 
 
*Investigator having DOD responsibility for this protocol 
√Study contributor(s) not responsible for patient care 
 
Drug Availability 
Commercial Agents: paclitaxel, trastuzumab, anastrozole, exemestane, fulvestrant, letrozole 
Drug Company Supplied: TVB-2640 (IND# 133975) 
 
Document History 
Effective Date 
Activation 
August 3, 2017 
MCCC Amendment 1 
February 20, 2018 
MCCC Amendment 2 
January 25, 2019 
MCCC Amendment 3 
August 27, 2020 
MCCC Amendment 4 
June 9, 2021 
MCCC Amendment 5 
February 4, 2022 
MCCC Amendment 6 
December 14, 2022 
MCCC Amendment 7 
pending 
 
 
 
 
 

MC1633 
2 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Katie A Hervey 
Quality Assurance Specialist 
Phone: 507/266-6117 
E-mail: hervey.katie@mayo.edu  
 
Drug administration, infusion pumps,  
nursing guidelines 
Lisa M La Liberte, RN 
Research Nurse 
Phone: 507/293-4968 
E-mail: laliberte.lisa@mayo.edu 
 
Forms completion and submission (MCR 
only) 
Britni L Anderson 
Clinical Research Coordinator 
Phone: 507-266-3207 
Email: anderson.britni@mayo.edu 
 
Protocol document, consent form, 
regulatory issues 
Lynn M Flickinger MA  
Senior Research Protocol Specialist 
Phone: 507/538-7034 
Email: flickinger.lynn@mayo.edu  
Paraffin-embedded tissue pathology  
Amanda R Sand 
Pathology Coordinator 
Phone: 507/284-3559 
E-mail: sand.amanda@mayo.edu  
  
Non-paraffin biospecimens  
 
Roxann M Neumann CCRP 
Biospecimen Resource Manager 
Phone: 507-538-0602 
Email: neumann.roxann@mayo.edu 
 
Serious Adverse Event Reporting 
FDA Coordination Team 
E-mail: INDSafety@mayo.edu  
*No waivers of eligibility allowed 
 
 

MC1633 
3 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Table of Contents 
MC1633 Phase II Trial to Evaluate the Efficacy of the FASN Inhibitor, TVB-2640,  in Combination with 
Trastuzumab plus Paclitaxel or Endocrine Therapy in Patients with HER2+ Metastatic Breast Cancer 
Resistant to Trastuzumab-based Therapy ..................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 16 
3.0 
Eligibility .................................................................................................................................... 16 
4.0  
Test Schedule .............................................................................................................................. 21 
5.0 
Grouping Factor .......................................................................................................................... 23 
6.0 
Pre-registration/Registration Procedures .................................................................................... 23 
7.0 
Protocol Treatment ...................................................................................................................... 26 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 29 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 36 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 38 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 49 
12.0 
Descriptive Factors:  None .......................................................................................................... 53 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient ............................................................. 53 
14.0 
Body Fluid Biospecimens ........................................................................................................... 54 
15.0 
Drug Information ........................................................................................................................ 58 
16.0  
Statistical Considerations and Methodology ............................................................................... 74 
17.0 
Pathology Considerations/Tissue Biospecimens ......................................................................... 78 
18.0 
Records and Data Collection Procedures .................................................................................... 81 
19.0  
Budget ......................................................................................................................................... 82 
20.0 
References ................................................................................................................................... 83 
Appendix I 
ECOG Performance Status ............................................................................................... 90 
Appendix II 
Patient Medication Diary .................................................................................................. 91 
Appendix III 
Palmar-Plantar Erythrodysesthesia (PPE) Grading Worksheet ........................................ 92 
 

MC1633 
4 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Schema 
For the run-in portion only, prior to discussing protocol entry with the patient, call the MCCC 
Registration Office (507-284-2753) for dose level and to insure that a place on the protocol is open 
to the patient. 
 
Pre-Registration 
 
 
 
↓ 
 
 
 
Central Pathology 
Review 
and/or biopsy for HER2 
HER2− 
→ 
Off 
Study 
 
HER2+↓ 
 
 
 
Registration 
 
 
 
 
 
 
Cohort A:  
Taxane and anti-HER2 therapy-
resistant, advanced HER2-positive 
breast cancer 
 
Cohort B:  
Endocrine therapy and  
anti-HER2 therapy-resistant, 
advanced HER2-positive breast 
cancer 
 
↓ 
 
↓ 
 
TVB-2640 po daily 
Paclitaxel IV Days 1, 8, 15 
Trastuzumab IV Days 1, 8, 15, 22 
 
TVB-2640 po daily 
Trastuzumab IV Days 1, 8, 15, 22 
Endocrine therapy (as chosen 
from allowed list in table below*) 
 
↓ 
 
↓ 
 
At any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
 
At any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
 
↓ 
 
↓ 
 
Event Monitoring 
 
Event Monitoring 
 
Cycle = 28 days ±3 days 
Generic name: TVB-2640 
Brand name(s): N/A 
Mayo Abbreviation: TVB-2640 
Availability: Mayo Clinic Pharmacy 
Generic name: Paclitaxel 
Brand name(s): Taxol 
Mayo Abbreviation: TAXOL 
Availability: Commercial 
Generic name: Trastuzumab 
Brand name(s): Herceptin 
Mayo Abbreviation: HERCEP 
Availability: Commercial 
*Endocrine therapy:  
(only allowed agents are listed) 
Availability: Commercial 
Generic names: 
Anastrozole (ANA) 
Exemestane (EXE) 
Fulvestrant (FULV) 
Letrozole (LET) 
Brand names: 
Arimidex 
Aromasin 
Faslodex 
Femara 

MC1633 
5 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
1.0 
Background  
1.1 
Introduction 
Several agents besides trastuzumab have been developed to target HER2, including the 
monoclonal antibody pertuzumab, tyrosine kinase inhibitors such as lapatinib and 
neratinib, and the antibody-drug conjugate, T-DM11. Unfortunately, none of these drugs 
or other targeted therapies is able to reverse trastuzumab and/or taxane resistance in 
patients2,3. To address this challenge, we seek to develop the untapped potential of 
interrupting the crosstalk between metabolic and oncogenic signaling pathways, as we 
have previously demonstrated that one of the key lipogenic enzymes, fatty acid synthase 
(FASN), is co-regulated with HER2. FASN is a metabolic enzyme required for de novo 
synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH in 
cells4,5. Importantly, FASN is highly expressed in all molecular subtypes of breast 
carcinomas, including luminal A and B, HER2+ and basal-like. In normal epithelia, 
however, the protein is only present at very low or negligible levels, making it an 
excellent therapeutic target. 
1.2 
FASN Inhibition in Breast Cancer and Drug Response 
Most normal cells have low levels of FASN and activity22 in contrast to several cancers, 
including breast cancer23-42. Natural and synthetic FASN inhibitors [Cerulenin (Cer)43-45, 
C7540,46,47, and Orlistat48-50] induce apoptosis specifically in cancer cell lines and delay 
tumor growth in xenograft models; however, the mechanism by which this occurs is still 
unclear. Moreover, FASN inhibition induces synergistic chemosensitization of FASN+ 
breast cancer cells to anticancer therapies51,52,53 including trastuzumab54. Most 
importantly, FASN blockade restores sensitivity to trastuzumab in trastuzumab-resistant, 
HER2+ breast cancer cells55. Thus, it is feasible that patients with FASN+, trastuzumab- 
and chemo-resistant breast cancer may benefit from FASN targeted therapies. 
1.21 
FASN Inhibition Restores Trastuzumab Sensitivity in Trastuzumab-resistant 
Cells: 
Development of trastuzumab-resistance is a significant obstacle for HER2-
targeted therapy, and the underlying mechanisms are still inconclusive59. Thus, it 
is critical to develop strategies to restore trastuzumab sensitivity. Since inhibition 
of FASN down-regulates HER2 expression and inhibits anchorage-independent 
growth of HER2+ breast cancer cells54, and C75 synergizes with trastuzumab22, 
we tested whether FASN inhibition restores trastuzumab sensitivity. BT474S 
(trastuzumab-sensitive) and 
BT474R (trastuzumab-
resistant) cells were treated 
concurrently with a 
combination of TVB-3199 (one 
of the non-clinical forms of 
TVB-2640, 20nM) and 
trastuzumab (3µg/ml) based on 
drug-drug-interaction studies 
and isobologram analysis. As 
shown in Figure 1, FASN 
inhibition sensitizes BT474R to 
trastuzumab (Trz) and restores 

MC1633 
6 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
their sensitivity to levels of the BT474S cells. (In vivo studies show similar 
results, pending confirmation). 
1.22 
FASN inhibition sensitizes breast cancer tumors to chemo- and HER2-targeted 
therapy 
To determine whether FASN inhibition sensitizes breast cancer tumors to 
paclitaxel (PXL) or trastuzumab (Trz) in vivo, we inoculated 4x106 BC cells into 
the mammary fat pad of athymic nude mice, allowed tumors to reach ≤150mm3, 
and then randomized the mice to four arms as indicated. The mean tumor volume 
± SE in each arm (n=10) is reported. The combination of C75+PXL and C75+Trz 
markedly reduced tumor volume compared with either treatment alone (Figure 2). 
Importantly, no weight loss was observed under these conditions. These data 
support the key proposal concept that FASN is a major player in (re)sensitizing 
tumors to chemo- and HER2-targeted therapy. Studies using TVB-3199 are 
underway yielding similar results. 
1.23 
Inhibition of FASN is associated with decreased synthesis of SP1, a key cancer 
metabolic switch 
FASN-related altered lipid metabolism has been recognized to occur in tumor 
cell lines with acquired resistance to chemotherapeutics (e.g., doxorubicin, 
etoposide, cisplatin and paclitaxel) and HER2-targeted therapies (e.g., 
trastuzumab and lapatinib); however, lipid-metabolic traits including FASN 
activity are emerging as key drivers not only of ER signaling, but also of 
resistance to endocrine therapies including tamoxifen and aromatase inhibitors. 
(Benz & et al., 1992) (Pietras & et al., 1995) (Liu & et al., 1995) (Kurokawa & 
Arteaga, 2001) 
Sphingolipid signaling mediators represent a group of extracellular and 
intracellular signaling molecules with pleiotropic effects on important cellular 
processes, including cancer. (Ogretman & Hannun, 2004) Altered sphingolipid 
metabolism contributes to cancer progression (Ryland & et al., 2011). The 
dynamic balance between intracellular sphingosine 1-phosphate, S1P, versus 
sphingosine and ceramide, and the consequent regulation of opposing pathways 
are important factors that determine whether cells survive or die (Nava & et al., 
2002) (Huwiler & Zangemeister-Wittke, 2007). Estradiol (E2) was reported to 
mediate export of S1P from breast cancer cells leading to sphingosine 1-

MC1633 
7 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
phosphate receptor (S1PR) signaling, cell growth and survival (Ogretman, 
Sphingolipid metabolism in cancer signalling and therapy, 2018). It is 
hypothesized that overexpression of FASN promotes a metabolic switch that 
fuels bioenergetics pathways to enhance a hormone-independent breast cancer 
phenotype. 
BT-474 and MCF-7/HER2-18 cell lines are both positive for ER expression and 
HER2 overexpression, and further contain high levels of FASN expression. As 
shown in Figure 1, in both cell lines, the FASN inhibitor, TVB3166, significantly 
blocks the synthesis of S1P. There was no change in S1P levels in response to 
TVB3166 in MCF-7/neo cells that are ER+ but do not express detectable levels 
of either HER2 or FASN (data not shown). Knockdown of FASN expression was 
established using a FASNsh in BT-474, MCF-7/neo and MCF-7/HER2-18 cells. 
FASNsh was associated with a profound decrease S1P in the BT-474 AND mcf-
7/HER2 FASNsh cells (Figure 2), however no change was observed in MCF-
7/neo cells (Gonzalez-Guerrico & et al., 2016). A decrease in S1P synthesis and 
signalling through S1PR can impair cancer cell growth and survival. 
1.24 
Estradiol modules FASN expression and promotes cross talk with PI3K/AKT 
pathways 
Exogenous E2 supplementation at physiological concentrations modulated FASN 
protein levels in ER-positive, endocrine-responsive MCF-7 breast cancer cells. 
Immunoblotting analysis revealed that E2 significantly increased FASN protein 
expression (Fig. 3A, left). Up-regulation of FASN protein was prevented by co-
exposure to the SERD, fulvestrant (Fig. 3A, right). 
 
The stimulatory effects of estradiol on FASN gene promoter activity involves the 
PI3K/AKT/mTOR signaling cascade, a key pathway that is activated in the 
setting of estrogen deprivation and endocrine-resistance.  
1.25 
Pharmacological inhibition of FASN activity fully prevents E2-stimulated breast 
cancer growth (Chung & al., 2002) (Shou & al., 2004) (Menendez & Lupu, 2017) 
The overexpression of HER2 in ER-positive, endocrine-sensitive breast cancer 
has been shown to confer resistance to tamoxifen [24, 77, 78].  In the Lupu lab, 
Figure 1 
Figure 3 

MC1633 
8 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
the rapid growth of MCF-7/HER2-18 cells in the presence of E2 was completely 
prevented in the presence of the FASN inhibitor, C75 (Fig. 4). In subsequent 
studies, ovariectomized nude mice were transplanted subcutaneously with 
tamoxifen-sensitive MCF-7/neo cells and tamoxifen-resistant MCF-7/HER2-18 
counterparts, and then were randomized into four groups (vehicle, tamoxifen, 
C75, and tamoxifen + C75) following estrogen withdrawal (Figure 5, top panels) 
or with continued  E2 supplementation (Figure 5, bottom panels). Growth of 
MCF-7/HER2-18 tumors was stimulated by E2 and inhibited by E2 withdrawal, 
thereby indicating E2 dependency (Figure 5, right panels). Tamoxifen-stimulated 
growth of MCF-7/HER2-18 tumors was strikingly suppressed in mice treated 
with the FASN inhibitor C75. Treatment with tamoxifen failed to cause any 
significant reduction in MCF-7/HER2-18 tumors growing in the presence of E2, 
thereby confirming that HER2 overexpression suffices to drive tamoxifen 
resistance in ER-positive MCF-7/HER2-18 BC cells in vivo. C75 treatment 
drastically antagonized E2-stimulated MCF-7/HER2-18 tumor growth, 
particularly when combined with tamoxifen (Figure 5, right panels). Similar 
findings were observed with C75 was combined with the SERD, fulvestrant (data 
not shown). The data indicate that FASN expression mediates endocrine therapy 
response in advanced ER+/HER2+ tumors, and inhibition of FASN can enhance 
the efficacy and even reverse resistance to endocrine therapy. 
 
1.26 
High FASN expression in Luminal B breast cancer is associated with poor 
clinical outcomes  
The translational impact of FASN expression on clinical outcomes in patients 
with ER+ breast cancer was subsequently assessed utilizing the online Kaplan-
Meier plotter tool (Gyorffy & et al., 2010). ER+ tumors were classified as 
luminal-A (ER+, HER2-, Ki67-low, typically endocrine-sensitive) or luminal-B 
(ER+, HER2-/HER2+, Ki67-high, typically endocrine-resistant), and the 
association of FASN low or high expression was evaluated for an association 
with relapse-free survival (RFS) and distant metastasis-free survival (DMFS) 
outcomes among patients treated with tamoxifen (Fig. 6). There was no 
difference in either RFS (N=466, p=0.11) or DMFS (N=251, p=0.15) between 
the FASN-high and FASN-low groups of patients with ER+ luminal-A breast 
cancer. By contrast, FASN-high, ER+ luminal B-like breast cancer patients had 
significantly poorer outcomes than FASN-low luminal B-like patients in terms of 
both RFS (N=196, p=0.036) and DMFS (N=78, p=0.043). These findings suggest 
that the poor outcomes associated with high FASN expression in breast cancers 
that are ER+ and commonly HER2+/endocrine-resistant may be associated with 
the SP1 metabolic switch, hormone-independent growth, and cancer cell survival.  

MC1633 
9 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Figure 6 
 
1.27 
FASN enables tamoxifen resistance in estrogen receptor-positive (ER+) / HER2-
positive (HER2+) breast cancer cells 
While both genomic and non-genomic cross-talk between the ER and HER2 has 
been associated with endocrine therapy resistance, combined targeting of ER and 
HER2 pathways has failed to improve overall survival in endocrine resistant 
disease (Kaufman, et al., 2009) (Johnston, et al., 2009). The role of FASN has 
been evaluated in the development and maintenance of estrogen-independent 
growth and resistance to endocrine therapy in ER+/HER2+ breast cancer 
(Menendez & Lupu, 2017) (Du, et al., 2018). Estradiol stimulates FASN gene 
promoter activity and protein expression, both of which can be blunted by anti-
estrogens in endocrine-sensitive breast cancer cells. Conversely, a MAPK/AKT-
related constitutive hyperactivation of FASN gene promoter activity was 
unaltered in response to estradiol in endocrine resistant ER+/HER2+ breast 
cancer cells, and could be further enhanced by tamoxifen. Pharmacological 
blockade of FASN activity inhibited estrogen-dependent, tamoxifen-resistant cell 
growth of ER+ MCF-7 cells engineered to overexpress HER2.  
FASN overexpression has been shown to be significantly associated with poor 
response to tamoxifen in patients with luminal B- but not luminal A-like ER+ 
breast cancer (by Kaplan-Meier survival analysis). Overall, these findings reveal 
that FASN can be co-opted by HER2 pathway activation to circumvent the 
inhibition of ER signaling by endocrine therapies. As such, FASN is potentially a 
therapeutically targetable driver of tamoxifen resistance in luminal B-like, 
ER+/HER2+ breast cancer. 
1.28 
Clinical development of the FASN inhibitor TVB-2640 
A first-in-human, first-in-class clinical trial with the only clinically available 
FASN inhibitor, TVB-2640, is currently treating patients with advanced solid 
RF
DMF

MC1633 
10 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
tumor malignancies (NCT 02223247). This phase I trial determined the 
maximum tolerated dose (MTD), recommended phase II dose (RP2D) and 
explored the safety profile of this drug as monotherapy and in combination with 
weekly paclitaxel. TVB-2640 is an oral agent administered once daily. In the 
most recent update of this trial (J Clin Oncol 34, 2016 (suppl; abstr 2512), 121 
patients (15 with breast cancer) were treated with TVB-2640 with doses ranging 
from 60 to 240 mg/m2, as well as with flat doses of 200 and 250 mg. The median 
patient age was 62; 68 (56%) were women and had received 3 or more prior lines 
of therapy. Dose limiting toxicities (DLTs) occurred at dose levels of 120 and 
240 mg/m2 and the 250mg flat dose. These included 3 Grade 3 ocular toxicities 
(2 corneal edema and 1 keratitis), as well as 3 skin toxicities (all hand foot 
syndrome) which were considered on-target effects and were reversible with drug 
discontinuation. Serious GI, hematologic and serum chemistry toxicities were not 
observed at any dose level. There was no QTc prolongation. The 
pharmacokinetic (PK) profile of TVB-2640 has been favorable, with predictable 
exposure, steady state obtained by day 8, and a half-life of approximately 15 
hours (Figure 3). 
 
FASN inhibition modeling at drug exposure of 60 mg/m2 doses and above 
demonstrated that target modulation exceeded the minimum threshold for 
preclinical efficacy in all but one patient (Figure 4). 
 

MC1633 
11 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
 
1.29a 
A Phase I evaluation of TVB-2640 in combination with paclitaxel 
In Part B of the phase I trial, the safety and tolerability of TVB-2640 in 
combination with standard dose weekly paclitaxel (80 mg/m2) was explored. Per 
the ASCO 2016 update, 54 heavily pre-treated patients, including 14 with breast 
cancer, have received combination therapy at TVB-2640 dose levels of 60 
mg/m2, 200 mg flat dose, and 100 mg/m2. Importantly, no alterations in PK were 
observed when weekly paclitaxel was combined with TVB-2640.  
Of all patients receiving the combination during dose-escalation, 2 DLTs were 
observed [1 skin (hand foot syndrome), 1 eye (uveitis)] at the 200 mg flat dose 
level, and both were reversible with discontinuation of TVB-2640. The MTD and 
RP2D of TVB-2640 as monotherapy and in combination with PXL (80 mg/m2 
weekly) are 100 mg/m2 oral continuous once daily.  
In all patients receiving combination therapy (n=54), the following adverse 
events were observed regardless of attribution at an incidence of ≥10% but no 
more than 50%: fatigue, alopecia, hand foot syndrome, nausea, peripheral 
neuropathy, anemia, diarrhea, anorexia, dyspnea, vomiting, cough, constipation, 
dry skin, UTI, back pain, peripheral edema, dry eye, increased lacrimation, 
mucosal inflammation, headache, abdominal pain, lower respiratory tract 
infection, pain in extremities and skin exfoliation. Grade 3 toxicities were 
uncommon and occurred in ≤5% of patients, with the exception of anemia, 
cough, and hand foot syndrome which occurred in 13%, 7%, and 7% of patients 
respectively. 
Other adverse events occurring in <10% of patients receiving the combination 
therapy include neutropenia, rash and pneumonitis. Notably, 9% of patients 
receiving the combination therapy experienced pneumonitis, and this was 
identified as a treatment-emergent adverse event (TEAE). For one patient, 
pneumonitis was fatal. There were no cases of pneumonitis reported for patients 
receiving TVB-2640 monotherapy, whereas pneumonitis is a well-described 
toxicity associated with paclitaxel. Beyond this specific TEAE, there were no 
others observed with the combination therapy, nor was there a higher than 
expected incidence of other paclitaxel-associated toxicities (hypersensitivity 

MC1633 
12 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
reaction, alopecia, cytopenias, or neuropathy). Importantly there was no observed 
cardiac toxicity, including no QTc prolongation, by ECG and Holter monitoring. 
Per the ASCO 2016 update, 3 of the 14 (21%) patients with metastatic breast 
cancer experienced a partial response (PR) to therapy. The 16-week clinical 
benefit rate (PR + stable disease for minimum 16 weeks) was 62% (8/13 patients; 
the other patient was still on active therapy after week 10 with stable disease). 
1.29b FASN Expression in Invasive Breast Cancers 
We evaluated FASN expression in breast cancer in a tissue microarray (TMA) 
containing cores of 253 invasive breast cancers from a tumor bank created by the 
Breast SPORE at Northwestern University. The TMAs and corresponding patient 
clinico-pathological data were prepared and analyzed. FASN scoring was 
performed by two pathologists each blinded to the other’s results. This TMA was 
selected for its invasive and highly metastatic tumors. All three major invasive 
histopathological BC types were present in the following distribution: estrogen 
receptor positive, ER+ (n=76, 30%), HER2+ (n=78, 31%), and triple negative, 
TN (n=99, 39%). 
FASN was specifically stained in the breast cancer lesions by 
immunohistochemistry (IHC), with no observed expression in stroma or normal 
breast tissue. FASN expression was interpreted as negative (0), weak (1), positive 
(2), and strongly positive (3), using normal epithelial cells and adipose tissue as 
reference (Figure 5). For a more detailed value for FASN expression among 
invasive 
carcinomas, the scored specimens were separated in two groups, 0/1+ (n= 101, 
40%) and 2+/3+ (n= 152, 60%). We found that high FASN levels (3+) were 
present in all molecular subtypes of BD: 44% of ER+, 38% of HER2+, and 20% 
of TN. Thus, our results demonstrate that 60% of invasive breast cancer were 
FASN+, and high FASN levels (3+) were found in all molecular subtypes, in 
particular ER+ and HER2+. 
1.29c 
FASN Expression as a Prognostic Biomarker 
In rapidly-proliferating cancer cells, de novo fatty acid synthesis is essential to 
provide lipids for membrane formation. FASN is highly expressed in breast, 
prostate, ovarian, endometrial and other cancers (reviewed in 23-42) and is 
prominent in higher grade tumors correlating with poor prognosis60-62. 
Importantly, we demonstrated that FASN expression correlates with high HER2 
levels in aggressive breast cancer 24,63,64. As FASN was implicated as a poor 
prognostic indicator65, we performed a retrospective clinical study of FASN 
expression in a series of 273 breast cancer tumors from patients with early stage 
breast cancer who all received adjuvant chemotherapy. Disease-free survival 

MC1633 
13 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
(DFS) and overall survival (OS) were calculated using the Kaplan-Meier method, 
and patients were segregated by the status of FASN expression in accordance 
with the above described analysis. The analysis revealed that the FASN status 
significantly predicted DFS 
(log rank p=0.0014) and OS 
(log rank p=0.0035) as 
shown in Figure 6. 
Multivariate Cox regression 
analysis showed that FASN 
expression was associated 
with shorter DFS and OS, 
both independent of tumor 
grade, lymph node status, 
Ki67, ER and HER2 
expression status. Thus, in 
this high risk population of 
patients with invasive breast 
cancer treated with adjuvant 
chemotherapy, FASN was an 
independent prognostic factor.  
1.29d FASN Expression is Inversely Correlated with Apoptosis 
To assess whether FASN 
expression is a marker of treatment 
resistance in breast cancer, we 
correlated FASN expression and 
the apoptotic status of the tissue. 
Apoptosis was measured using 
ApopTag® Peroxidase In Situ 
Apoptosis Detection Kit which 
detects apoptotic cells in situ by 
labeling and detecting DNA strand 
breaks by the TUNEL method. For 
this purpose we used the TMAs 
described in Section 1.25. 
Statistical analysis of the study is 
ongoing; however, our preliminary 
results indicate that tumors with 
FASN 2+/3+ overexpression had low number of cells staining for Apoptosis 
(Fig.7). Findings similar to ours have been reported in prostate cancer66. These 
data suggest that FASN overexpression exerts an anti-apoptotic effect and thus 
confers pro-survival properties in breast cancer.  
1.3 
Evolving HER2+ Landscape 
Since initial protocol activation in 2017, there have been four (4) new FDA approved 
drugs for treatment of HER2+ metastatic breast cancer: neratinib with capecitabine 
(February 2020); tucatinib with capecitabine and trastuzumab (April 2020); 
margetuximab with chemotherapy (December 2020); trastuzumab deruxtecan 
(accelerated approval, December 2019 and full approval May 2022) (Exman P, 2021). 
Given more FDA approved options for disease management, accruals to this clinical trial 

MC1633 
14 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
were negatively impacted and more patients were found to be ineligible due to the 
number of lines of prior chemotherapy despite meeting all other requirements. 
Additionally, serial biopsies of tumor tissues have revealed downregulation of the HER2 
receptor as a mechanism of resistance to HER2-directed therapy. Internalization and 
degradation of HER2 has been shown to be dependent on the density of HER2 at the cell 
surface (Ram S, 2014). Whereas high-level expression was associated with rapid 
recycling, increased degradation and cellular depletion of HER2 were observed in cells 
with lower cell surface receptor expressions. Clinical studies also support that at least a 
subset of HER2 breast cancers are susceptible to HER2 degradation and loss. 
Neoadjuvant trastuzumab treatment was associated both with loss of HER2 expression in 
~47% of cases and poorer disease-free survival (Ignatov T, 2019). While it is known that 
tumor cell heterogeneity can result in discordant HER2 results on serial biopsies from 
different sites, this research team further determined that a longer interval between 
treatment and determination of HER2 expression in the second histology was associated 
with better concordance (which supports transient loss due to internalization and 
degradation).  
Emerging research has identified HER2 downregulation as a mechanism of resistance to 
the newly FDA approved agent, trastuzumab deruxtecan. A small study was conducted in 
a HER-low cohort that received trastuzumab deruxtecan in the neoadjuvant setting. 
Results demonstrated that 49% of patients had a change in HER2 status, 88% of which 
had a decrease of HER2 by IHC from 2+ to 1+ or 1+ to 0 (Hurvitz SA, 2021). This too 
suggests that downregulation of the antigen target (HER2) after antibody drug conjugate 
treatment may be contributing to the high volume of screen failures for this clinical trial 
due to HER2-negative disease on the pre-registration biopsy. Despite this phenomenon, it 
is common practice to continue HER2-directed therapy for treatment given the potential 
heterogeneity of HER2 expression across all metastatic tumor sites. 
1.4 
Correlative Studies and Emerging Biomarkers from the Phase I Trial of TVB-2640 
The preliminary biomarker and PK/Pharmacodynamic (PD) studies from the first-in-
human, first-in-class, phase I clinical of TVB-2640 in patients with advanced solid tumor 
malignancies were presented at AACR in April 2015 (abstract #2675); an update and 
expanded findings were shared at the AACR Special Conference on Metabolism and 
Cancer in June 2015 (Abstract #4446). 
Results of the PK studies are per Figure 3. A key PD biomarker that has emerged in the 
development of TVB-2640 is serum malonyl carnitine, reflective of the accumulated 
Malonyl-CoA upon FASN inhibition. As shown in Fig.8, a mean 3.4-fold increase in 
levels of serum malonyl carnitine was observed in 9 out of 10 patients by day 8 after 
initiation of TVB-2640 monotherapy (p<0.05 for D8 pre- versus D1 pre- for dose levels 
120 and 240 mg/m2). In contrast, changes in serum FASN levels after treatment with 
TVB-2640 were more variable (data not shown). Four patients consented to prospectively 
collected biopsies at two time points during the trial (one “pre-dose” prior to treatment and 
one “post-dose” after completing one cycle of TVB-2640). Per Figure 9, one patient with 
PIK3CA-mutant MBC treated at the 240 mg/m2 dose level displayed a marginal change in 
tumor FASN expression after the first cycle of therapy; however, there was a 50% 
decrease in tumor pAKT expression, suggesting that FASN inhibition can modulate cell 
signaling pathways. A 30-45% decrease in pAKT expression after 1 cycle of therapy was 
replicated in all 3 of the additional patients, including one patient with triple negative BC. 

MC1633 
15 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
 
 
 
1.5 
Palmar-Plantar Erythrodysesthesia (PPE) 
Prior to April 28, 2023, 4 (30.8%) of the 13 patients enrolled onto Cohort A (Prior 
Taxane and anti-HER2 Therapy) and one patient enrolled onto Cohort B (Prior Endocrine 
and anti-HER2 Therapy) developed Grade 2 palmar-plantar erythrodysesthesia syndrome 
(PPE) that was considered to be possibly, probably, or definitely related to study 
treatment. This extent of toxicity seen in Cohort A (Prior Taxane and anti-HER2 
Therapy) crossed the safety boundary and triggered a review of all the adverse event data 
by the study PI. Upon reviewing of the five cases with Grade 2 PPE, it became apparent 
that it is difficult for managing clinicians to distinguish among Grade 1 PPE (minimal 
skin changes or dermatitis without pain), Grade 2 PPE (skin changes with pain limiting 
instrumental ADL), and Grade 3 PPE (severe skin changes with pain limiting self-care 
ADL). Within these ‘Grade 2’ events, there were instances of skin changes (erythema) 
without pain. There were also skin changes with discomfort (ranging from mild skin 
peeling and scattered cracks to ‘raw areas’), but it was not clear whether these skin 
changes limited ADLs or self-care. 
The study PI spoke to each of the managing clinicians concerning the signs and 
symptoms observed and the importance of  documenting in the patient’s medical record 
the elements needed for the accurate grading of PPE. Moreover, the study PI developed a 
guide for the grading of PPE (found in Appendix III) to help in this effort. The study PI 
also spoke to the managing clinicians of the need to closely monitor patients with 
Grade 1 PPE who develop Grade 2 peripheral motor neuropathy and/or peripheral 
sensory that required a reduction in their paclitaxel dose as they may experience more 
severe PPE.  
Utilizing the PPE guide for grading PPE, it appears that one (1) patient in Cohort A (Prior 
Taxane and anti-HER2 Therapy) and one (1) patient enrolled onto Cohort B (Prior 
Endocrine and anti-HER2 Therapy) developed Grade 1 PPE. 
 
 
Figure 9: Tumor FASN and pAKT expression 
in response to TVB-2640 
Figure 8: Candidate PD biomarker, malonyl 
carnitine, increases in patient sera after 7 day 
TVB-2640 exposure 

MC1633 
16 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
2.0 
Goals  
2.1 
Primary Goal 
2.11 
To estimate the overall tumor response rate (ORR i.e. CR+PR) of the 
combination of TVB-2640 with paclitaxel and trastuzumab in patients with 
taxane and trastuzumab-resistant, advanced HER2-positive breast cancer  
2.12 
To estimate the ORR of the combination of TVB-2640 with paclitaxel and 
trastuzumab in patients with endocrine and trastuzumab-resistant, advanced 
HER2-positive breast cancer  
2.2 
Secondary Goals 
2.21 
For each patient cohort, to evaluate the safety profile of the combination of TVB-
2640 with paclitaxel and trastuzumab  
2.22 
For each patient cohort, to assess the clinical benefit rate (CBR), duration of 
response, and progression free survival of the combination of TVB-2640 with 
paclitaxel and trastuzumab  
2.23 
To obtain a point and interval estimate of the difference in RR as well as the 
difference in CBR between Cohort A and Cohort B. 
2.3 
Correlative Research 
2.31 
For each patient cohort, to assess the changes in FASN, pAKT, and pS6 
expression in tumor tissue after the first cycle of the combination of TVB-2640 
with paclitaxel and trastuzumab from pre-treatment levels  
2.32 
For each patient cohort, to assess the changes in levels of cellular apoptosis in 
tumor tissue after the first cycle of the combination of TVB-2640 with paclitaxel 
and trastuzumab from pre-treatment levels  
2.33 
For each patient cohort, to assess the changes in serum FASN after the first cycle 
of the combination of TVB-2640 with paclitaxel and trastuzumab from pre-
treatment levels. 
3.0 
Eligibility 
3.1 
Pre-registration – Inclusion and Exclusion Criteria 
Inclusion Criteria 
3.11 
Age ≥18 years. 
3.12 
Measurable disease as defined by RECIST criteria (see Section 11.0) that is: 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥1.0 cm with CT scan, CT component of a PET/CT, or 
MRI and/or 
A malignant lymph node is considered measurable if its short axis is >1.5 cm 
when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  
Note: Tumor lesions in a previously irradiated area are not considered 
measurable disease; Disease that is measurable by physical examination only is 
not eligible.  
 

MC1633 
17 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
3.13 
Prior treatment: 
3.131 Received ≤six (6) prior chemotherapy regimens in the metastatic setting. 
3.132 Cohort A (one of the following must be true): 
(a) Distant disease progression during administration of combination 
therapy with taxane based chemotherapy and anti-HER2 therapy 
(trastuzumab or pertuzumab) for metastatic disease  
Note: patients who began treatment with this combination and 
discontinued taxane-based chemotherapy due to intolerability before 
distant disease progression are eligible. 
(b) Distant disease progression during administration or within 180 days 
of discontinuing combination therapy with taxane based 
chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) 
in the adjuvant disease. 
Note: Patients who began treatment with this combination and 
discontinued taxane-based chemotherapy due to intolerability before 
distant disease progression are eligible. 
(c) For patients who received taxane based chemotherapy and anti-
HER2 therapy (trastuzumab or pertuzumab) in the neo-adjuvant 
setting and underwent surgical resection of primary breast disease: 
Distant disease progression during or within 180 days of 
discontinuing anti-HER2 therapy (trastuzumab or pertuzumab) in the 
adjuvant setting. 
3.133 Cohort B (one of the following must be true): 
• 
Distant disease progression during administration of combination 
therapy with endocrine therapy and anti-HER2 therapy (trastuzumab 
or pertuzumab) for metastatic disease.  
Permissible endocrine therapies include an aromatase inhibitor or 
fulvestrant.  
NOTE: Tamoxifen is not permissible. 
• 
Distant disease progression during administration of combination 
therapy with endocrine therapy and anti-HER2 therapy (trastuzumab 
or pertuzumab) in the adjuvant setting.  
Permissible endocrine therapies include an aromatase inhibitor or 
fulvestrant.  
NOTE: Tamoxifen is not permissible.  
3.14 
Willingness to provide mandatory tumor tissue specimens for correlative 
research (see Section 17.0). 
NOTE: If insufficient or no tissue is obtained by the pre-registration biopsy, an 
archival tissue specimen (preferably from a metastatic site) from procedure 
performed ≤5 years prior to pre-registration must be available to submit for 
Central Laboratory review prior to registration. 
Exception: If there is no medically safe site for biopsy, Study Chair (Dr Haddad) 
may waive this requirement. 

MC1633 
18 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Exclusion criteria 
3.15 
Cardiac Exclusion Criteria: 
- Patients who previously discontinued trastuzumab due to unacceptable 
cardiac toxicity  
- Patients with a history of LVEF decline to below 50% during or after prior 
trastuzumab or other HER2 directed therapy ≤6 months prior to pre-
registration 
- Patients with any class of New York Heart Association (NYHA) CHF or 
heart failure with preserved ejection fraction (HFPEF)  
- Patients with a history of known coronary artery disease or a myocardial 
infarction within 12 months prior to pre-registration 
- Patients with persistently uncontrolled hypertension (systolic BP >160 mm 
Hg or diastolic BP >100 mm Hg) despite optimal medical therapy  
- Patients with known unstable angina pectoris  
- Patients with a known history of serious cardiac arrhythmias requiring 
treatment (exception: controlled atrial fibrillation, paroxysmal 
supraventricular tachycardia)  
- Patients with a prolonged QTc interval (≥450 ms)  
3.16 
Leptomeningeal disease or uncontrolled brain metastasis. 
NOTE: Metastases treated by surgery and/or radiotherapy such that patient is 
neurologically stable and off steroids ≥4 weeks prior to preregistration are 
eligible. 
3.17 
Failure to recover from acute, reversible effects of prior therapy regardless of 
interval since last treatment. 
EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for 
at least 3 months since completion of prior treatment. 
3.18 
Tumors involving spinal cord or heart  
3.19a 
Visceral crisis or lymphangitic spread 
NOTE: Visceral crisis is not the mere presence of visceral metastases, but 
implies severe organ dysfunction as assessed by symptoms and signs, laboratory 
studies, and rapid progression of disease 
3.19b Uncontrolled intercurrent non-cardiac illness including, but not limited to: 
• 
ongoing or active infection 
• 
psychiatric illness/social situations  
• 
dyspnea at rest due to complications of advanced malignancy or other disease 
that requires continuous oxygen therapy  
• 
or any other conditions that would limit compliance with study requirements 
3.19c 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  
NOTE: Patients known to be HIV positive, but without clinical evidence of an 
immunocompromised state, are eligible for this trial. 
3.19d Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
3.19e 
History of myocardial infarction ≤ 6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 

MC1633 
19 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
3.19f 
Prior history of hypersensitivity, drug or radiation-induced, or other immune-
mediated pneumonitis. 
3.19g Patient is unable to swallow oral medications or has impairment of GI function or 
GI disease that may significantly alter drug absorption (e.g., active inflammatory 
bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption 
syndrome). Note: Concomitant therapy with proton pump inhibitors and/or  
H2-receptor antagonists is permissible. 
3.19h Patient has a history of clinically significant dry eye (xerophthalmia) or other 
corneal abnormality, or if a contact lens wearer, does not agree to abstain from 
contact lens use from baseline through the last TVB-2640 dose. 
3.19i 
Patients with a history of intolerance to trastuzumab (i.e., a Grade 3 or 4 infusion 
reaction) are excluded.  
Note: Patients with a history of mild infusion reaction to trastuzumab who have 
previously been successfully re-challenged after an infusion reaction with or 
without prophylactic medication are allowed.  
3.19j 
Other invasive malignancy ≤3 years prior to pre-registration.  
EXCEPTIONS: Non-melanoma skin cancer, papillary thyroid cancer, or 
carcinoma-in-situ of the cervix which has been adequately treated.  
NOTE: If there is a history of prior malignancy, patients must not be receiving 
other antineoplastic treatment for their cancer and the disease must be 
inactive/stable.  
3.2 
Registration - Inclusion Criteria 
3.21 
Registration must be completed ≤28 days of pre-registration. 
3.22 
ECOG Performance Status (PS) 0 or 1 (Appendix I). 
3.23  
Disease characteristics 
3.231 Histological confirmation of HER2 expression (IHC 1-3+) on pre-
registration biopsy. (HER2+ is defined by 2018 ASCO/CAP guidelines.)  
NOTE: If pre-registration biopsy is HER2- by ASCO/CAP guidelines 
then both of the following must be true: 
• 
The patient’s most recent prior biopsy (prior to the pre-registration 
biopsy) must be HER2+,  
AND  
• 
The managing provider must be planning to treat the patient with 
anti-HER2 therapy. 
3.232 For Cohort B only: Histologic confirmation of ERα positive disease 
(≥1% expression). 
3.24 
The following laboratory values obtained ≤14 days prior to registration: 
• 
Hemoglobin ≥9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Direct bilirubin ≤1.5 x ULN  
• 
Aspartate transaminase (AST) ≤3 x ULN (≤5 x ULN for patients with liver 
involvement) 
• 
Calculated creatinine clearance ≥45 ml/min using the Cockcroft-Gault 
formula below: 

MC1633 
20 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  
(140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females =  
(140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 
3.25 
Cardiac ejection fraction (LVEF) ≥50% by echocardiogram ≤28 days prior to 
registration. 
3.26 
Provide written informed consent. 
3.27 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.28 
Negative urine pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
NOTE: If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
3.29a Patient and his/her partner agree to use adequate contraception after providing 
written informed consent through 3 months after the last dose of TVB-2640, as 
follows: 
• 
For women: Compliant with a medically-approved contraceptive regimen 
during and for 3 months after the treatment period or documented to be 
surgically sterile or postmenopausal. 
• 
For men: Compliant with a medically-approved contraceptive regimen 
during and for 3 months after the treatment period or documented to be 
surgically sterile. Men whose sexual partners are of child-bearing potential 
must agree to use 2 methods of contraception prior to study entry, during the 
study, and for 3 months after the treatment period. 
3.29b Willingness to provide mandatory tumor tissue and/or blood specimens for 
correlative research (see Sections 14.0 and 17.0). 
3.3 
Registration – Exclusion Criteria  
3.31 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
3.32 
Any of the following therapies prior to registration: 
• 
Chemotherapy ≤3 weeks 
• 
Immunotherapy ≤3 weeks 
• 
Biologic therapy ≤3 weeks  
• 
Monoclonal antibodies ≤3 weeks  
• 
Radiation therapy ≤2 weeks 
• 
CDK 4/6 inhibitors ≤4 weeks 
• 
mTOR inhibitors ≤4 weeks 
 

MC1633 
21 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
4.0  
Test Schedule 
4.1 
Test schedule for Cohorts 1 and 2 and Cohorts A and B 
 
 
Prior to Registration 
Treatment Phase 
Tests and procedures 
After Pre-
Registration 
≤28 days 
prior to 
registration 
≤14 days 
prior to 
registration 
≤7 days 
prior to 
registration 
Prior to 
Day 1 of 
each 
treatment 
cycle 
Prior to 
treatment on 
Days 8 15, 
and 22 of 
Cycle 1 
Prior to 
treatment 
on Day 15 
of Cycle 2 
End of all 
protocol 
treatment for 
any reason 
Window 
 
 
 
 
-3 days 
±3 days 
±3 days 
±7 days 
History and exam, weight, PS  
 
X 
 
 
X 
 
 
X 
Height 
 
X 
 
 
 
 
 
 
Adverse event assessment 
 
 
X 
 
X 
X 
X 
X 
Urine Pregnancy test1 
 
 
 
X 
 
 
 
 
Hematology group 
Hemoglobin 
White blood cell count 
Absolute neutrophil count 
Platelets 
 
 
X 
 
X 
X 
X 
X 
Chemistry group:  
aspartate aminotransaminase (AST) 
alanine aminotransferase (ALT) 
alkaline phosphatase 
total bilirubin 
direct bilirubin2 
creatinine 
albumin 
calcium 
sodium 
potassium 
magnesium 
glucose 
 
 
X 
 
X 
X 
X 
X 
Tumor measurement3 
 
X 
 
 
X 
 
 
X 
Echocardiogram4 
 
X 
 
 
X 
 
 
 
ECG 
 
X 
 
 
 
 
 
 
Ocular assessment 
 
X 
 
 
 
 
 
 

MC1633 
22 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
 
 
Prior to Registration 
Treatment Phase 
Tests and procedures 
After Pre-
Registration 
≤28 days 
prior to 
registration 
≤14 days 
prior to 
registration 
≤7 days 
prior to 
registration 
Prior to 
Day 1 of 
each 
treatment 
cycle 
Prior to 
treatment on 
Days 8 15, 
and 22 of 
Cycle 1 
Prior to 
treatment 
on Day 15 
of Cycle 2 
End of all 
protocol 
treatment for 
any reason 
Window 
 
 
 
 
-3 days 
±3 days 
±3 days 
±7 days 
Patient Medication Diary (Appendix II)5 
 
 
 
 
X 
 
 
X 
Mandatory research blood specimens 
(see Section 14.0)R,6 
 
 
 
 
X6 
X6 
 
 
Mandatory research tissue specimens 
(see Section 17.0) R 
X7 
 
 
 
X8 
 
 
 
NOTE: Protocol minimums are specified in the table. Additional clinical testing may be done at the discretion of the treating provider. 
Cycle = 28 days 
R Research funded (see Section 19.0) 
1. For women of childbearing potential only. Must be done ≤7 days prior to registration. 
2. Direct bilirubin is only needed ≤14 days prior to registration. 
3. Tumor measurements (CT or MRI) are to be done at the completion of Cycles 2, 4, 6, etc until disease progression or treatment 
discontinuation. Use same imaging throughout the study. 
4. Echocardiogram will be performed for left ventricular ejection fraction (LVEF) assessment. The LVEF assessments are to be performed at 
the completion of Cycle 1 and then after each odd numbered cycle of therapy (i.e. Cycles 3, 5, 7, etc.). 
5. The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution OR compliance must be documented in the medical record by any member of the care team. 
6. Blood specimens will be collected prior to treatment on D1and D8 of Cycle 1 and D1 of Cycle 2 only. Kits will be provided for MCA and 
MCF.  
7. The pre-registration biopsy will be utilized for local HER2 evaluation and correlative studies. NOTE: If pre-registration biopsy is attempted 
and fails to obtain evaluable tissue, archival specimens may be allowed if there is available tissue obtained ≤5 years prior to pre-registration 
(See Section 17.0) 
8. Tissue specimens must be collected and submitted on D1 of Cycle 2 only (prior to treatment). 
 

MC1633 
23 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
4.2 
Event Monitoring/Survival Follow-up 
NOTE: All timelines are approximate and not meant to represent exact dates 
 
Event Monitoring Phase1 
q. 6 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
5.0 
Grouping Factor 
Group: Cohort A (prior taxane and anti-HER2 therapy) vs. Cohort B (endocrine and anti-HER2 
therapy) 
6.0 
Pre-registration/Registration Procedures 
6.1 
Pre-Registration (Step 1) 
For the run-in portion of the trial, Call the Mayo Clinic Research Site Management 
Office (507-284-2753) prior to discussing protocol entry with the patient to ensure 
that a place on the protocol is open to the patient. 
6.11 
Patient preregistration 
To pre-register a patient, access the Mayo Clinic Research Registration 
Application web page at  https://registration.mayo.edu/. The Research Registration 
Application is available 24 hours a day, 7 days a week. Back up and/or system 
support contact information is available on the website. If unable to access the 
website, call the Research Site Management Office at (507) 284-2753 between the 
hours of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 
The instructions for the Research Registration Application are available on the 
Office of Clinical Trials web page (https://www.mayo.edu/research/centers-
programs/center-clinical-translational-science/offices/office-of-clinical-
trials/research-registration-application) and detail the process for completing and 
confirming patient registration. Prior to initiation of protocol treatment, this 
process must be completed in its entirety and a MCCC subject ID number must 
be available as noted in the instructions. It is the responsibility of the individual 
and institution registering the patient to confirm the process has been 
successfully completed prior to release of the study agent. Patient registration via 
the registration/randomization application can be confirmed in any of the 
following ways: 
• 
Contact the Research Site Management Office (507) 284-2753. If the 
patient was fully pre-registered, the Research Site Management Office 
staff can access the information from the centralized database and 
confirm the pre-registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
IRB approval(s) is required for each treating site.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually). If the necessary 
documentation is not submitted in advance of attempting patient registration, the 

MC1633 
24 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
registration will not be accepted and the patient may not be enrolled in the 
protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals is no longer necessary. 
6.13 
Verification 
Prior to accepting the pre-registration, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient pre-registration eligibility  
• 
Existence of a signed consent form  
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.14 
The site has reviewed and understands the process listed in Sections 14 and 17 and 
must account for sufficient time to complete pre-registration and registration steps. 
6.15 
Correlative studies 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.14,  and 17.0). 
6.2 
Registration (Step 2) 
6.21 
For the run-in portion 
To register a patient, fax (507-284-0885) a completed eligibility checklist to the 
Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through Friday. 
6.22 
Following the completion of the run-in portion 
To register a patient access the Mayo Clinic Research Registration Application 
web page at https://registration.mayo.edu/ and enter the remote registration 
application. The Research Registration/ Application is available 24 hours a day, 7 
days a week. Back up and/or system support contact information is available on 
the website. If unable to access the website, call the Research Site Management 
Office at (507) 284-2753 between the hours of 8 a.m. and 5:00 p.m. Central Time 
(Monday through Friday). 
The instructions for the registration application are available on the Mayo Clinic 
Office of Clinical Trials web page (https://www.mayo.edu/research/centers-
programs/center-clinical-translational-science/offices/office-of-clinical-
trials/research-registration-application) and detail the process for completing and 
confirming patient registration. Prior to initiation of protocol treatment, this 
process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual and 
institution registering the patient to confirm the process has been successfully 
completed prior to release of the study agent. Patient registration via the Research 
Registration Application can be confirmed in any of the following ways: 
• 
Contact the Mayo Clinic Research Site Management Office (507) 284-2753. 
If the patient was fully registered, the Research Site Management Office staff 
can access the information from the centralized database and confirm the 
registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 

MC1633 
25 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
6.23 
Verification 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval of the study 
• 
Patient eligibility 
• 
Grouping factor 
6.24 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Research site Management 
Office before an investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Research Site 
Management Office (fax: 507-284-0885 or email 
RESEARCHSITEMANAGEMENT@mayo.edu). If the necessary documentation 
is not submitted in advance of attempting patient registration, the registration will 
not be accepted and the patient may not be enrolled in the protocol until the 
situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Research Site Management Office is no longer 
necessary. 
6.25 
Correlative studies 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.30, 14.0 and 
17.0). 
6.26 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision 
of a medical oncologist or endocrinologist  
6.27 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after 
registration. 
6.28 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.29a 
Baseline symptoms 
All required baseline symptoms (see Section 10.0) must be documented and 
graded. 
6.29b Study drug is available on site  
Study drug is available on site for this patient. 
6.29c 
Kits 
Blood draw kits are available on site 
 
 

MC1633 
26 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
Use actual weight or estimated dry weight if fluid retention 
7.11 
Pre-treatment medications allowed for paclitaxel and trastuzumab  
(or per institutional guidelines) 
Cohort Agent 
Dose 
Route 
When given 
A 
Dexamethasone 
20 mg 
IV or PO 
30 minutes prior to 
paclitaxel 
A 
Diphenhydramine 
25-50 mg 
IV 
30 minutes prior to 
paclitaxel 
A 
Famotidine 
20 mg 
IV 
30 minutes prior to 
paclitaxel 
A and B Acetaminophen 
650 mg 
PO 
30 minutes prior to 
trastuzumab 
7.12 
Cohort A: Treatment medication table 
Agent 
Dose Level 
Route 
Day 
ReRx 
TVB-2640 
100mg/m2* 
PO 
1-28 (continuous) 
Q4w 
Paclitaxel 
80 mg/m2 
IV 
Days 1, 8, 15 
Q4w 
Trastuzumab 
4 mg/kg load† 
then 2mg/kg thereafter 
IV 
Days 1, 8, 15, 22 
Q4w 
*Dose rounding down to the nearest 50 mg TVB-2640 capsule 
†The loading dose of trastuzumab is required if the last dose of trastuzumab or 
T-DM1 was administered >4 weeks prior to Day 1 of Cycle 1. 
7.13 
Cohort B: Treatment medication table 
Agent 
Dose Level 
Route 
Day 
ReRx 
TVB-2640 
100mg/m2* 
PO 
1-28 (continuous) 
Q4w 
Trastuzumab 
4 mg/kg load† 
then 2mg/kg thereafter 
IV 
Days 1, 8, 15, 22 
Q4w 
Endocrine 
Therapy 
Continue previously 
prescribed treatment 
 
1-28 (continuous) 
Q4w 
*Dose rounding down to the nearest 50 mg TVB-2640 capsule 
†The loading dose of trastuzumab is required if the last dose of trastuzumab or 
T-DM1 was administered >4 weeks prior to Day 1 of Cycle 1. 
7.131 Endocrine Therapy allowed 
• 
Standard doses of letrozole, anastrozole, exemestane, or fulvestrant 
Permissible agents include:  
o Anastrozole 1 mg PO daily;  
o Exemestane 25 mg PO daily;  
o Fulvestrant 500 mg IM Day 1 and 14 q 28 days for first 
cycle, then Day 1 q 28 days for all subsequent cycles  
(NOTE: 250 mg may be used if clinically indicated) 
o Letrozole 2.5 mg PO daily;  
o NOTE: Tamoxifen is NOT allowed 
• 
28-day cycles will apply for all agents 

MC1633 
27 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
• 
There are no dose modifications for these agents 
• 
If chosen aromatase inhibitor changes during the study, the change 
must be documented in the medical record and in Medidata Rave 
7.14 
Optional treatment medication tables after completion of 3 or more cycles 
The patient may be changed to an alternate trastuzumab dosing schedule if both 
of the following conditions are met: 
• 
Patient has completed 3 or more cycles of combination treatment 
• 
Paclitaxel has been discontinued (if applicable) 
7.141 
Cohort A – Alternate trastuzumab dosing (Cycle 4 and beyond) 
Agent 
Dose Level 
Route 
Day 
ReRx 
TVB-2640 
100mg/m2* 
PO 
1-28 (continuous) 
Q4w 
Trastuzumab 
8 mg/kg load† 
then 6mg/kg thereafter 
IV 
Day 1 
Q3w 
*Dose rounding down to the nearest 50 mg TVB-2640 capsule 
†The loading dose of trastuzumab should be administered as needed per local 
institutional guidelines 
7.142 
Cohort B – Alternate trastuzumab dosing (Cycle 4 and beyond) 
Agent 
Dose Level 
Route 
Day 
ReRx 
TVB-2640 
100mg/m2* 
PO 
1-28 (continuous) 
Q4w 
Trastuzumab 
8 mg/kg load† 
then 6mg/kg thereafter 
IV 
Day 1 
Q3w 
Endocrine 
Therapy 
Continue previously 
prescribed treatment 
Per agent 1-28 (continuous) 
Q4w 
*Dose rounding down to the nearest 50 mg TVB-2640 capsule 
†The loading dose of trastuzumab should be administered as needed per local 
institutional guidelines 
7.2 
Administration 
7.21 
For the purposes of this study, a treatment cycle is 28 days. 
Patient must return to Mayo Clinic once every 28 ±3 days for testing and 
prescription refill. 
7.22 
TVB-2640 
Each QD TVB-2640 dose is to be taken at the same time of the day under fasting 
conditions (i.e., at least 2 hours after last food consumption and at least 1 hour 
before next food consumption), with each dose separated by 24 hours (±4 hours).  
Cohort A only: TVB-2640 is to be taken 1 hour prior to initiation of paclitaxel. It 
is permissible to administer paclitaxel pre-medications during this time. 
7.3 
Treatment by local medical doctor (LMD) 
7.31 
Administration of TVB-2640 by a local medical doctor (LMD) is not allowed.  

MC1633 
28 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
7.32 
Administration of trastuzumab (both cohorts) and paclitaxel (Cohort A only)* is 
allowed by LMD as follows: 
• 
Cycle 1: none 
• 
Cycle 2: Days 8 and 22 only 
• 
Cycle 3 and beyond: Days 8, 15, and 22 
OR  
May change trastuzumab to 21-day cycle and give trastuzumab once every 
21 ±3 days (see Section 7.14 above for conditions) 
*If paclitaxel is discontinued, LMD may administer trastuzumab according to 
restrictions stated above. 
7.33 
Administration of endocrine therapy by LMD is allowed as follows: 
• 
Standard doses of aromatase inhibitors per Section 7.131 with no dose 
modifications allowed 
• 
Fulvestrant cannot be given by LMD due to the need to align cycles with 
TVB-2640 
• 
If chosen aromatase inhibitor changes during the study, the change must be 
documented in the medical record and in Medidata Rave 
• 
Tamoxifen use is NOT allowed 
7.34 
Any serious adverse events must be reported to Mayo Clinic immediately upon 
discovery by LMD. 
7.4 
Safety Run-in 
For Cohort B: An initial six patients will be enrolled at the planned starting dose level in 
Section 7.1 and observed for one cycle for evaluation of the safety analysis. See Section 
16 for specifics. 
 
 

MC1633 
29 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the 
start of the next cycle, then the dose will remain lowered for that entire subsequent cycle.  
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
TVB-2640** 
Trastuzumab 
Paclitaxel 
Weekly 
Q3W  
(see Section 7.14) 
0* 
100 mg/m2 
4mg/kg loading dose† 
then 2mg/kg thereafter 
8mg/kg loading dose† 
then 6mg/kg thereafter 
80mg/m2 
-1 
 Starting dose reduced 
by 50 mg 
No dose reduction 
No dose reduction 
60 mg/m2 
-2 
Starting dose reduced 
by 100 mg 
No dose reduction 
No dose reduction 
Discontinue 
*Dose level 0 refers to the starting dose. 
** Dose rounding down to the nearest 50 mg TVB-2640 capsule. 
†The loading dose of trastuzumab should be administered as needed per local institutional 
guidelines 
NOTES: 
• 
If TVB-2640 is discontinued, the patient will stop all study treatment and go to Event 
Monitoring/Survival Follow-up. 
• 
If paclitaxel or trastuzumab or both are discontinued, the patient remains on study 
treatment with TVB-2640. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current  
version 4.03* unless otherwise specified   
*Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
 
 

MC1633 
30 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
8.2 
Dose Modifications for TVB-2640 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Eye Disorders 
≥Grade 2 
Blurred vision 
Eye Pain 
Dry eye 
Conjunctivitis 
TVB-2640 
Omit TVB-2640 until AE returns to 
≤Grade 1 or baseline.  
Once resolved resume TVB-2640 at next 
lower dose. 
If drug is withheld for 7 days and the AE 
does not return to at least Grade 1 or 
baseline, then discontinue TVB-2640 and 
continue on paclitaxel and trastuzumab. 
≥Grade 2 
Cataract 
Keratitis 
Papilledema 
Retinopathy 
Uveitis 
 
Discontinue TVB-2640 
Skin and subcutaneous 
tissue disorders 
≥Grade 2 
Palmar-plantar 
erythrodysesthesia 
syndrome 
TVB-2640 
Omit TVB-2640 until AE resolves or 
returns to ≤Grade 1.  
Once resolved resume TVB-2640 at next 
lower dose. 
If drug is withheld for 14 days and the AE 
does not return to at least Grade 1 or 
baseline, then discontinue TVB-2640 and 
continue on paclitaxel and trastuzumab. 
Respiratory, thoracic, 
and mediastinal 
disorders 
Pneumonitis Grade 2 
TVB-2640 
paclitaxel 
Omit TVB-2640, permanently discontinue 
paclitaxel, and consider immediate 
initiation of systemic steroids for 
management 
Treatment with TVB-2640 is to be 
omitted until symptoms and signs of 
possible pneumonitis resolve to ≤Grade 1. 
Then TVB-2640 may be resumed 
 
If symptoms do not resolve to ≤Grade 1 
within 8 weeks or prednisone (or 
equivalent corticosteroid) is not reduced 
to ≤10 mg/day within 12 weeks, then 
treatment with TVB-2640 is to be 
permanently discontinued 
Second event: If a second pneumonitis 
event occurs, discontinue TVB-2640  
It is at the discretion of the treating 
physician to maintain trastuzumab 
monotherapy or have the patient 
discontinue all study treatment 

MC1633 
31 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Respiratory, thoracic, 
and mediastinal 
disorders 
Pneumonitis Grade ≥3 
TVB-2640 
paclitaxel 
Treatment with TVB-2640 and paclitaxel 
is to be permanently discontinued for 
patients who experience Grade 3 or 4 
pneumonitis (see Section 9.8).  
It is at the discretion of the treating 
physician to maintain trastuzumab 
monotherapy or have the patient 
discontinue all study treatment. 
 
 
8.3 
Recommended Dose Modifications for Paclitaxel 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Neutrophil count 
decreased 
≥Grade 3 (<1,000/mm3) 
paclitaxel 
Day 1 AE: 
• 
Omit paclitaxel administration  
• 
If counts recover within 4 weeks, 
decrease paclitaxel by 1 dose level 
and maintain for all subsequent doses. 
• 
If a second dose reduction is needed, 
discontinue paclitaxel 
• 
If counts do not recover within 
4 weeks discontinue paclitaxel  
 
Day 8 or 15 AE: 
• 
Omit the Day 8 and/or 15 
administration of paclitaxel (doses are 
not made up) 
• 
If paclitaxel is skipped, decrease 
paclitaxel by 1 dose level and 
maintain for all subsequent doses.  
• 
If a second dose reduction is needed, 
discontinue paclitaxel 

MC1633 
32 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Platelet count decreased 
Grade 2 (50,000 -
<75,000/mm3) 
paclitaxel 
Day 1 AE: 
• 
Omit paclitaxel administration  
• 
If counts recover to ≥75,000/mm3 
within 4 weeks, resume paclitaxel 
without dose reduction 
• 
If counts do not recover within 
4 weeks discontinue paclitaxel 
Day 8 or 15 AE: 
• 
Omit Day 8 and/or 15 administration 
of paclitaxel (doses are not made up) 
• 
If paclitaxel is omitted no dose 
reduction is required for subsequent 
doses 
Platelet count decreased 
≥Grade 3 
(<50,000/mm3) 
paclitaxel 
Day 1 AE: 
• 
Omit paclitaxel administration  
• 
If counts recover to ≥75,000/mm3 
within 4 weeks, decrease paclitaxel 
by 1 dose level and maintain for all 
subsequent doses 
• 
If counts do not recover within 4 
weeks discontinue paclitaxel 
Day 8 or 15 AE: 
• 
Omit Day 8 and/or 15 administration 
of paclitaxel (doses are not made up) 
• 
If treatment is omitted decreased 
paclitaxel by 1 dose level and 
maintain for all subsequent doses 
Investigations 
Alanine 
aminotransferase 
increased 
paclitaxel See Table 8.31  
Investigations 
Aspartate 
aminotransferase 
increased 
paclitaxel See Table 8.31  
Investigations 
Total bilirubin increased paclitaxel See Table 8.31  

MC1633 
33 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Nervous system 
disorders 
Peripheral sensory 
neuropathy 
paclitaxel 
For Grade 2 peripheral neuropathy, 
decrease paclitaxel by one dose level and 
maintain for all subsequent doses. 
Omit paclitaxel administration for 
Grade 3 peripheral neuropathy. When the 
symptoms improve to ≤Grade 1, 
paclitaxel may resume with one dose 
level reduction for all subsequent doses 
If a second dose reduction is needed, 
discontinue paclitaxel 
Discontinue paclitaxel if Grade 4 
peripheral neuropathy develops 
Peripheral motor 
neuropathy 
paclitaxel 
For Grade 2 peripheral neuropathy, 
decrease paclitaxel by one dose level and 
maintain for all subsequent doses. 
Omit paclitaxel administration for 
Grade 3 peripheral neuropathy. When the 
symptoms improve to ≤Grade 2, 
treatment may resume with one dose level 
reduction for all subsequent doses. 
If a second dose reduction is needed, 
discontinue paclitaxel 
Discontinue paclitaxel if Grade 4 
peripheral neuropathy develops. 
Other non-
hematologic toxicity  ≥Grade 3 
paclitaxel 
Omit until recovery to ≤Grade 1 or back 
to baseline then decrease by 1 dose level. 
If not recovered within 14 days 
discontinue paclitaxel. 
Grade ≥3 nausea, vomiting, or diarrhea 
with maximal supportive treatment(s) 
resolving ≤3 days will not necessitate a 
dose reduction. 
 
 
 

MC1633 
34 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
8.31 
Liver Function dose modifications for paclitaxel 
Transaminase level 
 
Bilirubin level 
Dose modification 
AST or ALT ≥2.5  
and 
T. bilirubin ≥1.5 x ULN, but ≤3 x ULN 
Reduce one dose level♦ 
AST or ALT ≥2.5, but ≤10 x ULN  
and 
T. bilirubin ≤1.5 x ULN  
Reduce one dose level♦ 
AST or ALT ≥2.5 but ≤10 x ULN  
and 
T. bilirubin ≥1.5 x ULN, but ≤3 x ULN 
Reduce two dose levels*♦ 
AST or ALT >10 x ULN  
or 
T. bilirubin >3 x ULN 
Discontinue paclitaxel 
* No reductions below dose level -2. 
♦ Dose reductions stay at the same level unless hepatic function worsens (i.e., for abnormal LFTs that remain at the 
same level, another dose reduction should not be made). 
 
8.4 
Dose Modifications for Trastuzumab 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Cardiac disorders 
Left ventricular systolic 
dysfunction 
trastuzumab See Figure 8.4.1  
General disorders and 
administration site 
conditions 
Infusion related 
reaction, Grade >3 
trastuzumab 
Infusion related reactions should be 
managed per institutional protocol 
For Grade 3 infusion reaction, 
trastuzumab will be discontinued if: 
• 
the infusion reaction lasts more than 
24 hours, or  
• 
the patient cannot receive the entire 
dose due to the infusion reaction, or  
• 
a Grade 3 infusion reaction occurs in 
spite of pre-medication  
For Grade 4 infusion reaction, 
trastuzumab will be discontinued. 
If the patient misses a dose (or doses) of trastuzumab, a re-loading dose of trastuzumab should be given as 
outlined in Section 8.1.  
Trastuzumab can be held for a maximum of 42 days from last administered dose. Patients who require 
longer dose delays may not restart trastuzumab. Patients who discontinue trastuzumab may continue 
treatment with paclitaxel and/or TVB-2640 or discontinue all study treatment. 
Any patient who develops clinical signs and symptoms suggesting congestive heart failure or adverse 
events that may be related to cardiac dysfunction should have LVEF measurement preformed. If CHF is 
confirmed, the patient should discontinue all protocol treatment and go to event monitoring.  CHF should 
be treated and monitored according to institutional guidelines  
 
 

MC1633 
35 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
8.41 
Management of cardiac toxicity related to trastuzumab 
Asymptomatic decrease in left ventricular ejection fraction (LVEF):  The 
decision to continue or stop trastuzumab is based on: measured ejection fraction 
as it relates to the radiology facility’s lower limit of normal (LLN) and change in 
ejection fraction from baseline. Guidelines for performing MUGA 
scan/echocardiogram and management of HERCEP patients who have an 
asymptomatic decrease in LVEF from baseline are in the table below:  
Asymptomatic decrease in LVEF percentage points from baseline 
Relationship of LVEF 
to the radiology 
facility’s LLN  
Decrease of <10 
percentage points 
Decrease of 10 to 15 
percentage points 
Decrease of ≥16 
percentage points 
Within normal limits  
Continue  
Continue  
Hold and repeat 
echocardiogram after 
4 weeks  
1 to 5 percentage points 
below the LLN  
Continue and repeat 
echocardiogram after 
4 weeks  
Hold and repeat 
echocardiogram after 
4 weeks  
Hold and repeat 
echocardiogram after 
4 weeks  
≥6 percentage points 
below the LLN  
Continue and repeat 
echocardiogram after 
4 weeks  
Hold and repeat 
echocardiogram after 
4 weeks 
Hold and repeat 
echocardiogram after 
4 weeks 
 
- Trastuzumab must be permanently discontinued when two consecutive “hold” categories 
occur.  
- Trastuzumab must be permanently discontinued when three intermittent “hold” categories 
occur. (At the discretion of the investigator, trastuzumab may also be permanently 
discontinued prior to the occurrence of three intermittent “hold” categories.)  
- If LVEF is maintained at a “continue and repeat echocardiogram” or improves from a “hold” 
to a “continue and repeat echocardiogram” category, additional echocardiogram prior to the 
next scheduled echocardiogram will be at the discretion of the investigator. 
 
 

MC1633 
36 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care  
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
9.5 
Hand-foot syndrome (palmar-plantar dysesthesia) 
Prophylaxis: patient can use a daily moisturizing cream on hands and feet with a high 
emollient factor such as Eucerin,  Vanicream, O’Keefe’s Working Hands (or similar 
product), 4-6 times a day.  Patient can also use a non-drying daily wash on hands and feet 
such as Cetaphil or Vanicream Soap (or similar product). 
If hand-foot symptoms/signs are detected despite the above prophylaxis 
recommendations: 
Treatment: to be symptomatic. At the first sign (deemed a grade 1; per CTCAE 4.03; 
minimal skin changes or dermatitis (e.g. erythema, edema, or hyperkeratosis without 
pain): 
• 
Moisturizing:  daily cream on hands and feet to continue;   
• 
Urea cream: can be considered if scaling, peeling present;  
• 
Antihistamines: oral antihistamine medication to be considered for reduction of 
itchiness. 
If hand-foot symptoms/signs present at or escalate to Grade 2 or above: 
• 
Steroid Ointment (N.B. not cream): patient can apply ointment based barrier 
layer of topical steroid cream Diprolene (or similar product) once daily. 

MC1633 
37 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
• 
Dermatologist consult: should be considered for further evaluation and 
treatment recommendations. 
9.6 
Dry Eye 
Treatment: to be symptomatic. At the first sign (deemed a grade 1 per Common 
Terminology Criteria for Adverse Events CTCAE 4.03; asymptomatic, clinical or 
diagnostic observations only, mild symptoms relieved by lubricants) of dryness, 
itchiness, redness or otherwise “gritty” eye.  
• 
Eye drops: soothe XP-Xtra Protection Emollient (Lubricant) Eye Drops (or 
similar product) can be used 4-6 times daily. If the patient finds this to be too 
cumbersome and/or altering to his/her vision, then a less oily eye drop such as 
Soothe Hydration Lubricant Eye drop or Visine (or similar product) can be used 
during the day with the mineral oil based [Soothe XP-Xtra Protection Emollient 
(Lubricant) Eye Drops or similar products] drops to be used nightly before bed.  
• 
Warm compresses: patient can apply warm compresses to eyes 4-6 times a day 
or as needed to unblock tear ducts and reduce inflammation. Patient should be 
instructed to place a warm, wet washcloth over the eyelids (a fresh/sterile cloth to 
be used with each compress application) for up to 10 minutes. 
• 
Azasite: patient can apply to eyelid with a cotton swab such as Q-Tip once daily 
to reduce inflammation (as needed).  
• 
Ophthalmologist consult: should be considered for further evaluation and 
treatment recommendations. 
9.7 
Bone Modifying Agents 
Zolendronic acid, pamidronate, or denosumab may be administered per institutional 
guidelines as appropriate for patients with bone metastases. 
9.8 
Pneumonitis 
9.81 
Grade 1-2 
It is the treating provider’s choice whether empiric antibiotic therapy should be instituted, 
even in the absence of a causative organism being isolated.  
 
9.82 
Grade 3-4 
For patients who experience Grade 3 or 4 pneumonitis, intravenous steroid treatment as 
well as additional anti-inflammatory measures should be considered and administered, as 
needed. It is the treating provider’s choice whether empiric antibiotic therapy should be 
instituted, even in the absence of a causative organism being isolated. Prophylactic 
antibiotics for opportunistic infections should be considered in the case of prolonged 
steroid administration. 
 
 
 

MC1633 
38 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events and 
adverse events of special interest to the sponsor as described within the protocol, regardless of 
attribution to study agent or treatment procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA, 3-V Biosciences, Inc., and all 
participating investigators in a written safety report of any of the following: 
a. Any suspected adverse reaction that is both serious and unexpected. 
b. Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
c. Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND and whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug 
d. Any clinically important increase in the rate of a serious suspected adverse reaction over the 
rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic_a
pplications/docs/PregnancyReportFormUpdated.pdf 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
http://livecycle2.mayo.edu/workspace/?startEndpoint=
MC4158-56/Processes/MC4158-56-Process.MC4158-
56 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo
.edu 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
 
 

MC1633 
39 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
o Identify the grade and severity of the event using the CTCAE version 4.0. 
o Determine whether the event is expected or unexpected (see Section 10.2). 
o Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
o Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
o Determine if other reporting is required (see Section 10.5). 
o Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
 
 

MC1633 
40 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• 
An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for investigational agents/interventions.  
• 
An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent 
require an expedited report, unless hospitalization is required. Refer to Section 
10.4 for specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• 
An increased incidence of an expected adverse event (AE) is based on the patients 
treated for this study at their site. A list of known/expected AEs is reported in the 
package insert or the literature, including AEs resulting from a drug overdose. 
• 
Commercial agent expedited reports must be submitted to the FDA via 
MedWatch 3500A for Health Professionals (complete all three pages of the 
form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/UCM387002.pdf 
 
 
 

MC1633 
41 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an expedited 
manner1 
General disorders and 
administrations site 
conditions 
Fatigue  
≤Grade 3 
Malaise 
≤Grade 3 
Skin and subcutaneous 
tissue disorders 
Alopecia 
Any Grade 
 
 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on 
this trial 
● Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the 
cancer. 
 
 

MC1633 
42 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
10.4 
Expedited Reporting Requirements for IND/IDE Agents  
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
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 for ≥ 
24 hours  
• 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
• “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
• “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 
 
 

MC1633 
43 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
10.42 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing 
of expedited adverse events and forwarding of suspected unexpected serious 
adverse reactions (SUSARs) to the FDA and IRB plus Sagimet Biosciences Inc. 
(formerly 3-V Biosciences, Inc.). 
Use Mayo Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56 for investigational agents or 
commercial/investigational agents on the same arm. 
For commercial agents (Trastuzumab and Paclitaxel):  
Submit form MedWatch 3500A to the FDA, 5600 Fishers Lane, Rockville, MD 
20852-9787, by fax at 1-800-332-0178 or online at 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm. 
 
Submit SAEs to Industry Partner Contacts: 
dsafety@sagimet.com 
Katharine Grimmer (Katharine.Grommer@sagimet.com) 
Dr. Bill McCulloch (Bill.McCulloch@sagimet.com) 
George Kemble (George.Kemble@sagimet.com) 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table 10.41 
MUST be immediately reported to 3-V Biosciences within the timeframes 
detailed in the corresponding table. This reporting includes, but is not limited to 
SAEs that re-occur again after resolution. 
10.5 
Other Required Reporting 
The following study events must be promptly reported to the HRPO in one of the 
following manners: 
• 
Phone: 301-619-2165 
• 
Email: usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil 
• 
Fax: 301-619-7803 
• 
Mail: US Army Medical Research and Materiel Command 
ATTN: MCMR-RP 
810 Schreider St 
Fort Detrick, MD 21702-5000 
a) All unanticipated problems involving risk to subjects or others. 
b) Suspensions, clinical holds (voluntary or involuntary), or terminations of this research    
by the IRB, the institution, the sponsor, or regulatory agencies. 
c) Any instances of serious or continuing noncompliance with the federal regulations or 
IRB requirements. 
d) The knowledge of any pending compliance inspection/visit by the Food and Drug 
Administration (FDA), Office for Human Research Protections, or other government 
agency concerning this clinical investigation or research. 
e) The issuance of inspection reports, FDA Form 483, warning letters, or actions taken by 
any government regulatory agencies. 

MC1633 
44 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
f) Change in subject status when a previously enrolled human subject becomes a prisoner 
must be promptly reported to the USAMRMC ORP HRPO.  The report must include 
actions taken by the institution and the IRB. 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56, to submit to 
CANCERCROSAFETYIN@mayo.edu. The Mayo Regulatory Affairs Office 
will review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 

MC1633 
45 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 

MC1633 
46 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancies occurring in the patient or patient’s partner while the 
patient is receiving study drug or within 3 months after the patient’s 
last dose of study drug will not be considered serious, but are to be 
reported in an expedited manner as Grade 3 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy)” under 
the Pregnancy, puerperium and perinatal conditions SOC. Study drug 
must be discontinued immediately in the event of a pregnancy in the 
patient.  The patient should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and 
counseling. Pregnancy should be followed until the outcome is known 
and must be reported to the Medical Monitor within 5 days. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. In addition, any 
infant death after 28 days that the Investigator suspects is related to the 
in utero exposure to the study drug should also be reported. 
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
 
 

MC1633 
47 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.03 unless alternate grading is indicated in the table 
below: 
CTCAE 
System Organ 
Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and 
Lymphatic 
System Disorders 
Anemia 
X 
X 
Eye Disorders 
Dry Eye 
X 
X 
 
Eye Pain 
X 
X 
Gastrointestinal 
Disorders 
# of stools 
X 
 
Diarrhea 
 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Mucositis Oral 
X 
X 
General disorders 
and administration 
site conditions 
Fatigue 
X 
X 
Investigations 
Platelet Count Decreased  
X 
X 
 
Neutrophil Count Decreased 
X 
X 
 
White Blood Cell Decreased 
X 
X 
Nervous system  
Peripheral motor neuropathy 
X 
X 
disorders 
Peripheral sensory neuropathy 
X 
X 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Pneumonitis 
X 
X 
Skin and 
subcutaneous  
Rash maculo-papular 
X 
X 
tissue disorders 
Palmar-plantar 
erythrodysesthesia syndrome* 
X 
X 
*See Appendix III for PPE Grading Worksheet 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 

MC1633 
48 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
3V Biosciences Inc. Additional Event Reporting Instructions 
Adverse Events of Special Interest 
Any pneumonitis AE and/or treatment-emergent respiratory symptoms or signs 
experienced by patients receiving TVB-2640 are to be reported as adverse events of 
special interest (AESI). All AESIs that occur after any patient has been enrolled, before 
treatment, during treatment, or within 28 days following the cessation of treatment, 
whether or not they are related to the study drug, must be reported within 24 hours of 
discovery using the procedures as described for SAEs  
 
 
 

MC1633 
49 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
11.0 
Treatment Evaluation/Measurement of Effect  
11.1 
Schedule of Evaluations 
Evaluations using RECIST will then be performed at completion of Cycles 2, 4, 6, etc 
until disease progression or discontinuation of all protocol treatment. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21  Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
11.212 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 
NOTE: Tumor lesions in a previously irradiated area are not considered measurable 
disease.  
11.22 Non-Measurable Disease 
o All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone 
lesions, leptomeningeal disease, ascites, pleural/ pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable as well. 
Note: ‘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. In addition, lymph nodes that have a short axis 
<1.0 cm are considered non- pathological (i.e., normal) and should not be 
recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
11.32 Acceptable Modalities for Measurable Disease: 
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.  
• 
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. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 

MC1633 
50 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
• 
PET-CT: 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.  
11.33 Measurement at Follow-up Evaluation:  
• 
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. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in ATC after chemoradiation can 
represent fibrotic tissue) 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.  
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.  
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.  
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the post-baseline sum of 
dimensions (PBSD). If the radiologist is able to provide an actual measure 
for the target lesion (or target lymph node), that should be recorded, even if it 
is below 0.5 cm. If the target lesion (or target lymph node) is believed to be 
present and is faintly seen but too small to measure, a default value of 0.5 cm 
should be assigned. If it is the opinion of the radiologist that the target lesion 
or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 

MC1633 
51 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at  
baseline. These lesions and lymph nodes should be followed in accord with 
11.433. 
11.43 Response Criteria 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-
CT must be measured on re-evaluation Specifically, a change in 
objective status to either a PR or CR cannot be done without re-
measuring target lesions and target lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment,  
11.432 
Evaluation of Target Lesions 
Complete Response (CR):All of the following must be true: 
• 
Disappearance of all target lesions. 
• 
Each target lymph node must have reduction in short axis to 
<1.0 cm. 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis 
of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.41). 
Progression (PD): At least one of the following must be true: 
• 
At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) and 
increased to ≥1.0 cm short axis during follow-up.  
• 
At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference the 
MSD (Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
MSD.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Complete Response (CR): 
All of the following must be true: 
a. Disappearance of all non-target 
lesions. 
b. Each non-target lymph node must 
have a reduction in short axis to 
<1.0 cm. 
Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 

MC1633 
52 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Progression (PD): 
At least one of the following must be 
true: 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (<1.0 cm 
short axis) and increased to ≥1.0 cm 
short axis during follow-up.  
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status. It must be representative 
of overall disease status change.)  
11.44 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following tables:  
 
11.441 
For Patients with Measurable Disease 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
11.45 Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time, and not 
either related to study treatment or other medical conditions, should be reported 

MC1633 
53 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
as PD due to “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. 
12.0 
Descriptive Factors:  None  
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who have not had disease progression and have experienced acceptable toxicity 
are to continue treatment per protocol until documentation of progressive disease, 
unacceptable toxicity or refusal. 
13.2 
Criteria for discontinuation of all protocol treatment 
- Disease progression 
- Request by patient to discontinue all protocol treatment 
- Unacceptable toxicity 
- Intercurrent illness that would, in the judgment of the investigator, affect 
assessments of clinical status to a significant degree or require 
discontinuation of all protocol treatment 
- Administration of radiotherapy, non-protocol chemotherapy, 
immunotherapy, biological agents, or an experimental drug  
- Development of new primary cancer 
- Ineligibility 
Patients who discontinue protocol treatment due to any of the above reasons will proceed 
to event monitoring phase of the trial where patient and disease status until death or a 
maximum of 3 years post-registration.  Further treatment is at the discretion of the 
patient’s medical team. 
13.3 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.   
• 
If the patient received protocol treatment and is deriving benefit, the patient may 
continue on study per protocol as if the patient was eligible.  If the patient chooses to 
end protocol treatment, then all data (except biospecimens) up until the point of 
treatment discontinuation must be submitted.   No further data submission is 
necessary. 
• 
If the patient never received any protocol treatment, on-study material (except 
biospecimens) and the End of Active Treatment/Cancel Notification Form must be 
submitted. No further data submission is necessary. 
13.4 
Cancel 
A patient who withdraws consent before any study treatment is given.  On-study material 
(except biospecimens) and the End of Active Treatment/Cancel Notification Form must 
be submitted.  No further data submission is necessary. 
 
 

MC1633 
54 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory or 
Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
C1D1  
C1D8  
C2D1 
Process at 
site?  
(Yes or No) 
Temperature 
Conditions for 
Storage 
/Shipping 
FASN 
Mandatory 
Serum 
Gold top SST 
tube 
5mL 
X 
X 
X 
yes 
Freeze 
 
 

MC1633 
55 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
14.2 
Collection and Processing 
14.21 Serum FASN 
• 
NOTE: all pre-dose samples should be collected BEFORE daily TVB-2640 
administration. 
• 
The steps listed should be performed as quickly as possible after each blood 
draw:  
1. Label one serum separator vacutainer tube (Gold top (SST tube)), and 
two storage tubes (Sample A and Sample B) 
2. Collect 3 mL of blood into the SST vacutainer. 
3. Immediately and gently, invert the tube 5 times to mix. 
4. Stand the tube upright in a vertical rack for 30 to 60 minutes at room 
temperature to allow clotting to occur. 
5. Record the actual sampling date and time (hours and minutes using 24 
hour clock time) for each sample collected onto the appropriate CRF. 
6. Centrifuge at 1300 g for 15 min. While directing away from your face, 
remove the rubber top from the tube.  Two separate layers should be 
readily visible. 
7. Transfer ~half of serum (approx. 0.6 ml) into a clean storage tube 
(labeled as “Sample A”, and transfer the remaining serum into another 
clean storage tube labeled as “Sample B”.  (“Sample B” is the back-up 
sample.) 
8. Store serum samples in an upright position in a frost-free freezer, at 
approximately 70°C or lower. 
9. The time between blood collection and freezing the serum should not 
exceed 4 hours. Following collection if processing will take longer than 2 
hours the sample will need to be refrigerated until processing can occur. 
10. Ship specimens on dry ice according to instructions below. Ship “Sample 
A” serum samples every month by the 15th on Monday, Tuesday or 
Wednesday for US sites. 
11. Store “Sample B” specimens at -70°C or lower, and ship to the storage 
facility (EPL) every month by the 15th on Monday, Tuesday or 
Wednesday for US sites.  
14.3 
Shipping and Handling 
14.31 Kits will be used for this study. 
14.311 Kits will be supplied to MCA and MCF by the Biospecimen 
Accessioning and Processing Shared Resource (BAP). Cards will be 
generated for MCR. 
14.312 The kit contains supplies and instructions for collecting, processing and 
shipping specimens. 
14.313 Participating institutions may obtain kits by faxing the Supply Order 
Form to the number listed on the form. Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry. Supply Order Forms must 
be filled in completely and legibly for quick processing. 
14.314 Kits will be sent via Fed Ex Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 

MC1633 
56 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
14.315 Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex account number or alternate 
billing number for express mail. Cost for rush delivery of kits will not 
be covered by the study. 
14.316 All specimens must be collected and shipped Monday – Thursday 
ONLY. 
14.32 Shipping 
14.321 Staff from MCA and MCF should ship all their serum FASN samples to: 
BAP Freezer 
Mayo Clinic 
St SL-16 
150 Third Street SW 
Rochester, MN 55902 
507-538-0602 
Fed-Ex is the selected courier for Serum (for free FASN) samples. 
All “Sample A” serum samples should be shipped frozen on dry ice using 
appropriate packaging to avoid damage and maintain temperature. 
1. Unless other arrangements are made, samples should be shipped on 
Monday, Tuesday or Wednesday for US sites for next day delivery, 
excluding holidays. 
2. Complete one requisition form per sample type and per patient. Note any 
missing samples. 
3. Place the frozen samples for each patient in Cryoboxes, and label box 
with patient numbers. Include the requisition form with the shipment. 
4. Pack the frozen samples in a sufficient quantity of dry ice in shipping 
containers to maintain a frozen state for approximately 2-3 days. 
5. Label the package with 3-V Biosciences, Inc., and study number 
(MC1633). 
6. Include a return address (which includes the investigator’s name) on the 
outside of each shipping container. 
7. Comply with all courier regulations for the shipment of biological 
specimens (include all paperwork). 
8. Retain all documents indicating date, time, and signature(s) of person(s) 
making the shipment, in the study files. 
9. As soon as shipment day and air bill number(s) are available, fax, or e-
mail the completed requisition form to the recipient, including the 
shipment tracking or reference number. 
Shipping address: 
Leslie Couch 
BioRepository Archivist 
EPL BioRepository 
615 Davis Drive 
Suite 300 
Durham, NC  27713 USA 
Tel:  1-919-998-9009 Ext 653 
Fax: 1-919-998-9008 
e-mail:  LCouch@epl-inc.com  

MC1633 
57 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
14.33 Reminder: Sample A’s should always be shipped independently of Sample B’s. 
14.34  Handling Specimens 
RSTP tickets should be completed for each time samples are shipped 
14.4 
Background and Methodology 
Evaluation of Serum FASN Levels:  We hypothesize that levels of serum FASN are 
strongly correlated with tumor tissue levels of FASN. This would be an important finding 
should tumor FASN emerge as a relevant biomarker of response, as a serum study (as 
opposed to a tumor biopsy) for FASN determination would eliminate the need for an 
invasive procedure. These studies will be performed at the 3-V Biosciences laboratories 
(or by a contracting site TBD). For the FASN ELISA, a commercially available human 
FASN kits from Immtech will be used. FAS-detect ELISA is an enzyme-linked 
immunosorbent assay that can be used to detect soluble FASN in human serum. We run 
serum of neat, 1/5 and 1/20 dilutions in duplicate. Developed by FASgen Diagnostics 
LLC, FAS-detect ELISA is a highly sensitive, specific, and quantitative enzyme-linked 
immunosorbent assay that can be used to detect soluble FASN in human serum, 
secondary to production and release by FASN-positive tumors.  
 

MC1633 
58 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.0 
Drug Information 
15.1 
TVB-2640 
15.11 Background 
TVB-2640 is a small-molecule, orally-bioavailable, reversible inhibitor of the 
human FASN enzyme. Many solid and hematopoietic tumors overexpress FASN, 
including breast, ovarian, prostate, colon, and pancreatic cancers as well as non-
Hodgkin lymphoma. FASN tumor expression has been found to be increased in a 
stage-dependent manner that is associated with diminished patient survival. This 
expression-prognosis relationship suggests that FASN plays an important role in 
affecting tumor cell biology and therapeutic response. 
15.12 Formulation 
TVB-2640 is currently supplied for oral administration as immediate release 50 
mg strength capsules. 
15.13 Preparation and storage 
TVB-2640 should be stored in a secure, limited access storage area at room 
temperature, 20-25°C (77°F). Excursions to 15°C - 30°C (59°F - 86°F) are 
permitted. TVB-2640 should not be refrigerated or frozen. 
15.14 Administration 
Administer on an empty stomach, one hour before or two hours after a meal. 
Swallow the capsules whole, do not chew, crush, or open. Dose should be taken 
at the same time each day, ±4 hours. 
15.15 Pharmacokinetic information 
There is limited PK data in humans.  The half –life has been determined to be 
approximately 15 hours at steady state.  
15.16 Potential Drug Interactions 
TVB-2640 showed no significant inhibition of CYP1A2, CYP2B6, CYP2C8, 
CYP2C19, or CYP2D6. It showed weak inhibition of CYP2C9 and CYP3A4 
with testosterone as a substrate.  In a screening assay in human hepatocytes from 
3 donors, TVB-2640 at a concentration of 1 and 10 μM caused little or no 
significant induction of catalytic activity of CYP1A2, CYP2B6, and CYP3A4; 
the extent of induction was less than 40% of the positive controls. These data 
suggest that TVB-2640 is not an inducer of drug-metabolizing enzymes. TVB-
2640 is a time-dependent inhibitor of CYP3A4 and may reduce the clearance of 
substrates of this enzyme. 
15.17 Known potential toxicities 
Of 73 patients treated with TVB-2640 as monotherapy, the most common 
(incidence ≥ 10%) adverse events reported were alopecia (56%), palmar-plantar 
erythrodysesthesia syndrome (40%), fatigue (33%), decreased appetite (25%), 
dry skin (22%), constipation (18%), nausea (18%), diarrhea (17%), vomiting 
(17%), cough (15%), dry eyes (15%), abdominal pain (14%), conjunctivitis 
(14%), anemia (13%), asthenia (13%), skin exfoliation (13%),  urinary tract 
infection (13%), dehydration (11%), dyspnea (11%), increased lacrimation 
(11%), dysgeusia (10%), peripheral edema (10%), pyrexia (10%), rash (10%).   

MC1633 
59 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Six dose-limiting toxicities (DLTs) were observed, including corneal edema 
(Grade 3, n = 2), keratitis (Grade 2, n = 1) and palmar-plantar erythrodysesthesia 
(PPE) syndrome (Grade 3, n = 2; Grade 2, n = 1), across a range of doses.  
With TVB-2640 in combination with paclitaxel, the most common TEAEs were 
fatigue (49%), alopecia (45%), PPE syndrome (44%); nausea (38%), and 
peripheral neuropathy (36%).  2 DLTs were observed, uveitis (Grade 2, n=1) 
and PPE syndrome (Grade 3, n=1), both at a flat dose of 200 mg. Serious cases of 
pneumonitis in 9% of patients (5/55) have been reported with TVB-2640 in 
combination with paclitaxel, which were all considered by the Investigator to be 
study drug-related, including 1 fatal case that occurred ~6 months after initiation 
of TVB-2640 and paclitaxel. Pneumonitis is known to be associated with 
paclitaxel, but any contribution of TVB-2640 is not clear. No cases of 
pneumonitis have occurred among patients treated with TVB-2640 monotherapy.  
Nonetheless, respiratory symptoms, and specifically pneumonitis, constitute 
Adverse Events of Special Interest (AESI) which should be reported to the FDA 
as such, should they occur.   
No Carcinogenicity, reproductive, developmental, local tolerance or other special 
toxicity studies have been conducted with TVB-2640.   
15.18 Drug procurement 
TVB-2640 is supplied by 3-V Biosciences, Inc. An initial supply is provided 
once the study is finalized and contracts have been signed.  TVB-2640 will then 
be proactively supplied by 3-V Biosciences based on enrollment, dose and 
patient duration on study.  If an intermediate drug resupply is needed, an order 
request must be made through an appropriate 3-V Biosciences contact, either 
Clinical Operations or CMC representatives.    A list of 3-V Biosciences 
authorized drug resupply contacts will be maintained with the site study 
coordinator. 
15.19 Nursing guidelines 
15.19a 
Agent must be administered on an empty stomach. Instruct patients to 
take one hour before or two hours after a meal. Do no crunch, chew, or 
open capsules, they must be swallowed whole. 
15.19b 
Instruct patients to take agent at the same time each day. 
15.19c 
Due to the early investigational nature of this agent, not all side effects 
can be known at this time. Instruct patients to report all side effects to 
the study team. 
15.19d 
Warn patients of possible hair loss. 
15.19e 
PPE (hand-foot syndrome) is common.  Instruct patients to report any 
redness, swelling, pain, numbness, tingling, blistering and/or peeling of 
the hands/feet to study team immediately. Patients should be 
encouraged to keep areas well moisturized with alcohol free lotion, and 
to  avoid harsh soaps. Additional skin toxicities may occur, including 
dermatitis, dry skin, and nail disorders. Assess patient’s skin and 
instruct them to report any changes to the team. 
15.19f 
Fatigue can be seen. Encourage patient in energy-conserving lifestyle. 

MC1633 
60 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.19g 
GI side effects can be seen – diarrhea, constipation, vomiting, nausea, 
etc. Treat symptomatically and assess for effectiveness. 
15.19h 
Monitor CBC w/diff as cytopenias have been seen. 
15.19i 
Patients may experience ocular toxicity. Instruct them to report any 
changes in vision, or pain to the study team immediately. 
15.19j 
Mild LFT elevation may occur. Monitor liver function tests. 
15.19k 
Arthralgias and musculoskeletal pain can be seen. Treat 
symptomatically and monitor for effectiveness. 
15.19l 
Pneumonitis has been reported when TVB-2640 has been given in 
conjunction with paclitaxel. The exact relationship is not clear.  
Instruct patients to report any shortness of breath, DOE or chest pain to 
study team immediately. 
15.2 
Trastuzumab (Herceptin®) 
15.21 Background: Trastuzumab is a monoclonal antibody which binds to the 
extracellular domain of the human epidermal growth factor receptor 2 protein 
(HER-2); it mediates antibody-dependent cellular cytotoxicity by inhibiting 
proliferation of cells which over express HER-2 protein. 
15.22 Formulation: Commercially available injection, powder for reconstitution: 440 
mg [packaged with bacteriostatic water for injection; diluent contains benzyl 
alcohol] 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Prior to reconstitution, store intact vials 
under refrigeration at 2ºC to 8ºC (36ºF to 46ºF). Reconstitute each vial with 20 
mL of bacteriostatic sterile water for injection (SWFI) to a concentration of 21 
mg/mL. Swirl gently; do not shake. Allow vial to rest for ~5 minutes. The 
solution in the vial (reconstituted with bacteriostatic SWFI) is stable refrigerated 
for 28 days from the date of reconstitution; do not freeze. If the patient has a 
known hypersensitivity to benzyl alcohol, trastuzumab may be reconstituted with 
sterile water for injection without preservatives, which must be used 
immediately. Determine the appropriate volume for the trastuzumab dose and 
further dilute in 250 mL 0.9% Sodium Chloride for injection prior to 
administration. Refer to the treatment section of the protocol for any changes in 
dilution or dispensing instructions. Avoid rapid expulsion from the syringe; 
gently invert bag to mix. The solution for infusion is stable for 24 hours 
refrigerated; do not freeze. 
15.24 Administration:  Administered by I.V. infusion; loading doses are infused over 
90 minutes; maintenance doses may be infused over 30 minutes if tolerated. Do 
not administer with D5W. Do not administer I.V. push or by rapid bolus. 
Treatment with acetaminophen, diphenhydramine, and/or meperidine is usually 
effective for managing infusion-related events. Do not mix with any other 
medications. 
15.25 Pharmacokinetic information: 
Distribution: Vd: 44 mL/kg; not likely to cross the (intact) blood brain barrier 
(due to the large molecule size) 
Half-life elimination: Weekly dosing: Mean: 6 days (range: 1-32 days); every 3 
week regimen: Mean: 16 days (range: 11-23 days) 

MC1633 
61 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.26 Potential Drug Interactions:   
Increased Effect/Toxicity: Paclitaxel may result in a decrease in clearance of 
trastuzumab, increasing serum concentrations. Combined use with anthracyclines 
may increase the incidence/severity of cardiac dysfunction. Monoclonal 
antibodies/abciximab may enhance the potential for allergic or hypersensitivity 
reactions to trastuzumab due to the presence of human antichimeric antibodies 
(HACA); may also cause thrombocytopenia or diminished effects. Trastuzumab 
may increase the incidence of neutropenia and/or febrile neutropenia when used 
in combination with Myelosuppressive chemotherapy. 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. Refer to the package insert pertaining to the 
following boxed warnings: Trastuzumab is associated with symptomatic and 
asymptomatic reductions in left ventricular ejection fraction (LVEF) and severe 
heart failure (HF) and may result in mural thrombus formation and stroke, and 
even cardiac death. Serious adverse events, including hypersensitivity reaction, 
infusion reactions, have been associated with trastuzumab. 
Common known potential toxicities, >10%:   
Cardiovascular: LVEF decreased 
Central nervous system: Pain, fever, chills, headache, insomnia, dizziness 
Dermatologic: Rash 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, anorexia 
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Cough, dyspnea, rhinitis, pharyngitis 
Miscellaneous: Infusion reactions (chills, fever), infection. 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Peripheral edema, CHF, tachycardia, hypertension, arrhythmia, 
palpitation 
Central nervous system: Depression, paresthesia, peripheral neuritis, neuropathy 
Dermatologic: Acne, nail disorder, pruritus 
Gastrointestinal: Constipation, dyspepsia 
Genitourinary: Urinary tract infection 
Hematologic: Anemia, leukopenia 
Neuromuscular & skeletal: Paresthesia, bone pain, arthralgia, myalgia, muscle 
spasm, peripheral neuritis, neuropathy 
Respiratory: Sinusitis, nasopharyngitis, upper respiratory infection, epistaxis, 
pharyngolaryngeal pain 
Miscellaneous: Flu-like syndrome, accidental injury, influenza, allergic reaction, 
herpes simplex 
Rare known potential toxicities, <1%: Acute respiratory distress syndrome 
(ARDS), amblyopia, anaphylaxis, anaphylactoid reaction, angioedema, apnea, 
ascites, asthma, ataxia, bone necrosis, bronchospasm, cardiac arrest, 
cardiomyopathy, cellulitis, coagulopathy, colitis, confusion, deafness, esophageal 
ulcer, gastroenteritis, glomerulo-nephritis, glomerulopathy, glomerulosclerosis, 
hematemesis, hemorrhage, hemorrhagic cystitis, hepatic failure, hepatitis, herpes 
zoster, hydrocephalus, hydronephrosis, Hypercalcemia, hypersensitivity, 
hypotension, hypothyroidism, hypoxia, ileus, intestinal obstruction, interstitial 
pneumonitis, laryngitis, leukemia, lymphangitis, mania, mural thrombosis, 
sympathy, nephrotic syndrome, neutropenia, pancreatitis, pancytopenia, 
paroxysmal nocturnal dyspnea, pathological fracture, pericardial effusion, pleural 

MC1633 
62 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
effusion, pneumonitis, pneumothorax, pulmonary edema, pulmonary fibrosis, 
pulmonary hypertension, pulmona5ry infiltrate, pyelonephritis, radiation injury, 
renal failure, respiratory distress, respiratory failure, seizure, sepsis, shock, skin 
ulcers, stroke, syncope, stomatitis, thyroiditis, vascular thrombosis, ventricular 
dysfunction, volume overload. 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.29 Nursing Guidelines:  
15.291 
The most common adverse events related to trastuzumab are fever 
(>38°C), chills, and occasional rigors, most often infusion-related after 
the initial dose.  Treat with acetaminophen as necessary.  Meperidine 
may be needed for rigors.  Instruct patient and family to report any 
fever >101°F.  Patients with underlying pulmonary pathology should 
be closely monitored. 
15.292 
Transient, localized tumor-site pain may be experienced within 8 hours 
of infusion.  Advise patient that acetaminophen is helpful. 
15.293 
Provide symptomatic management of the possible mild-to-moderate 
nausea/vomiting/diarrhea. 
15.294 
Assess heart and lung sounds.  Monitor vital signs (resting pulse, BP).  
Be alert to early signs to cardiotoxicity, i.e., dyspnea, steady weight 
gain, nonproductive cough, arrhythmias, tachycardia, and pulmonary 
rales.  Cardiotoxicity is increased when co-administered with 
doxorubicin/cyclophosphamide (AC). 
15.295 
Advise patient of possible fatigue, loss of strength, and weakness.  
Have patient pace activities with frequent rest periods. 
15.296 
Allergic reactions may occur, therefore emergency equipment should 
be easily accessible especially during initial infusion.  Monitor VS at 
baseline and frequently throughout infusion.  Patient should be 
observed for one hour after the initial dose. 
 
 
 

MC1633 
63 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.3 
Paclitaxel (Taxol) 
15.31 Background: Antineoplastic Agent, Antimicrotubular, Taxane derivative. 
Paclitaxel promotes microtubule assembly by enhancing the action of tubulin 
dimers, stabilizing existing microtubules, and inhibiting their disassembly, 
interfering with the late G2 mitotic phase, and inhibiting cell replication. In 
addition, the drug can distort mitotic spindles, resulting in the breakage of 
chromosomes. Paclitaxel may also suppress cell proliferation and modulate 
immune response. 
15.32 Formulation: Commercially available for injection 6 mg/mL (5 mL, 16.7 mL, 
25 mL, and 50 mL) [contains alcohol and purified Cremophor EL 
(polyoxyethylated castor oil)]. 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at room temperature 
and protect from light. Dilute in 250-1000 mL D5W or 0.9% NaCL to a 
concentration of 0.3 – 1.2 mg/mL. Solutions in D5W and 0.9% NaCl are stable 
for up to 3 days at room temperature. Chemotherapy dispensing devices (e.g., 
Chemo Dispensing Pin) should not be used to withdraw paclitaxel from the vial. 
Paclitaxel should be dispensed in either glass or non-PVC containers (e.g., 
Excel/PAB). Use nonpolyvinyl (non-PVC) tubing (e.g., polyethylene) to 
minimize leaching.  
15.34 Administration:  Infuse IV over 1-96 hours. When administered as sequential 
infusions, taxane derivatives should be administered before platinum derivatives 
(cisplatin, carboplatin) to limit myelosuppression and to enhance efficacy. Infuse 
through a 0.22 micron in-line filter and nonsorbing administration set. 
15.35 Pharmacokinetic information: 
Distribution: Vd: Widely distributed into body fluids and tissues; affected by 
dose and duration of infusion 
Vdss: 1- to 6-hour infusion: 67.1 L/m2 
Vdss: 24-hour infusion: 227-688 L/m2 
Metabolism: Hepatic via CYP2C8 and 3A4; forms metabolites (primarily 6α-
hydroxypaclitaxel). 
Half-life elimination: 1- to 6-hour infusion: Mean (beta): 6.4 hours, 
3-hour infusion: Mean (terminal): 13.1-20.2 hours 
24-hour infusion: Mean (terminal): 15.7-52.7 hours 
Excretion: Feces (~70%, 5% as unchanged drug); Urine (14%) 
Clearance: Mean: Total body: After 1- and 6-hour infusions: 5.8-16.3 
L/hour/m2; after 24-hour infusions: 14.2-17.2 L/hour/m2 
15.36 Potential Drug Interactions:   
Cytochrome P450 Effect: Substrate (major) of CYP2C8, CYP3A4; Induces 
CYP3A4 (weak).  
Increased Effect/Toxicity: CYP2C8 inhibitors may increase the levels/effects of 
paclitaxel. Refer to the package insert or LexiComp1 for example inhibitors. 
Decreased Effect: CYP2C8 inducers may decrease the levels/effects of 
paclitaxel. Refer to the package insert or LexiComp1 for example inducers. 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in estrogen-
dependent tumors. Avoid valerian, St John’s wort (may decrease paclitaxel 
levels), kava kava, gotu kola (may increase CNS depression). 

MC1633 
64 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information. Percentages reported with single-agent 
therapy. U.S. Boxed Warning: Bone marrow suppression is the dose-limiting 
toxicity; do not administer if baseline absolute neutrophil count (ANC) is <1500 
cells/mm3 (1000 cells/mm3 for patients with AIDS-related KS); reduce future 
doses by 20% for severe neutropenia. U.S. Boxed Warning: Severe 
hypersensitivity reactions have been reported. 
Common known potential toxicities, >10%:   
Cardiovascular: Flushing, ECG abnormal, edema, hypotension. 
Dermatologic: Alopecia, rash. 
Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, stomatitis, abdominal 
pain (with intraperitoneal paclitaxel)  
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, bleeding. 
Hepatic: Alkaline phosphatase increased, AST increased. 
Local: Injection site reaction (Erythema, tenderness, skin discoloration, 
swelling). 
Neuromuscular & skeletal: Peripheral neuropathy, arthralgia, myalgia, weakness. 
Renal: Creatinine increased. 
Miscellaneous: Hypersensitivity reaction, infection. 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Bradycardia, tachycardia, hypertension, rhythm abnormalities, 
syncope, venous thrombosis. 
Dermatologic: Nail changes. 
Hematologic: Febrile neutropenia. 
Hepatic: Bilirubin increased. 
Respiratory: Dyspnea. 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anaphylaxis, ataxia, atrial fibrillation, AV block, back pain, cardiac conduction 
abnormalities, cellulitis, CHF, chills, conjunctivitis, dehydration, enterocolitis, 
extravasation recall, hepatic encephalopathy, hepatic necrosis, induration, 
intestinal obstruction, intestinal perforation, interstitial pneumonia, ischemic 
colitis, lacrimation increased, maculopapular rash, malaise, MI, necrotic changes 
and ulceration following extravasation, neuroencephalopathy, neutropenic 
enterocolitis, ototoxicity, pancreatitis, paralytic ileus, phlebitis, pruritus, 
pulmonary embolism, pulmonary fibrosis, radiation recall, radiation pneumonitis, 
pruritus, renal insufficiency, seizure, skin exfoliation, skin fibrosis, skin necrosis, 
Stevens-Johnson syndrome, supraventricular tachycardia, toxic epidermal 
necrolysis, ventricular tachycardia  (asymptomatic), visual disturbances. 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.39 Nursing Guidelines 
15.391 
Premedicate with steroids, antihistamines, and H2 blockers as per 
institutional guidelines. 
15.392 
Mix the infusion bag well.  Thorough admixture of this drug often 
prevents a hypersensitivity reaction.  An inline filter of <0.22 micron 
must be used distal to the infusion pump.  Filter may need to be 

MC1633 
65 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
changed if infusion is to be prolonged >12 hours.  Inspect solution for 
excessive particulate matter, if present do not use. 
15.393 
Caution patients that the alcohol contained in the infusion may cause 
impairment in operating heavy equipment or in driving a vehicle and to 
assess their ability before trying either.  Advise avoidance of any 
alcohol or depressants such as sedatives and opiates if not necessary. 
15.394 
Assess the patient frequently for the first 30 minutes. Taxol® 
hypersensitivity reactions, which may include chest pain, back pain, 
flushing, diaphoresis, dyspnea, pruritus, hypotension, hypertension, 
bronchospasm and/or urticaria, usually occur early in the infusion.  
Have the anaphylaxis tray available. 
15.395 
If a reaction occurs, stop the infusion immediately.  Epinephrine, IV 
fluids, diphenhydramine, and methylprednisolone may be used as per 
MD’s order. 
15.396 
Approximately 60% of patients experience peripheral sensory 
neuropathy (numbness, tingling, burning pain, fine motor skills 
impairment, paresthesias, distal sensory loss).  Patients receiving 
higher doses at shorter infusion times are at greater risk.  Most cases 
have been reported at doses >170 mg/m2/day and with cumulative 
doses over multiple courses of therapy.  The nerve damage may take 
months to resolve.  Nonsteroidal anti-inflammatory agents and opiates 
have not been effective in treating neuropathic pain.  Consult MD 
about trying tricyclic antidepressants or possibly Neurontin.   
15.397 
Increased risk of cardiotoxicity when given in combination with 
doxorubicin, with a sharp increase in risk of CHF once cumulative 
dose of doxorubicin is > 380 mg/m2.  At this point taxol should be 
continued as a single agent only.  Monitor for sign/symptoms of CHF. 
Instruct patient to report any swelling in the hands, arms, feet, or legs, 
and any chest pain. 
15.398 
Mucositis can usually be managed with a salt and soda mouthwash (1 
tsp. Salt, 1 tsp. Soda and 1 quart boiled water) or try OTC oral Lysine 
or Vitamin E. 
15.399a Narcotics and nonsteroidal anti-inflammatory drugs may be used to 
manage the myalgias. 
15.399b Monitor CBC closely.  Neutropenia is most severe in patients who 
have had previous chemotherapy.  Instruct patient to report signs or 
symptoms of infection, unusual bruising or bleeding to the health care 
team. 
15.399c There is an increased risk of neutropenia and stomatitis when given  
prior to doxorubicin.  Therefore Taxol should always be given after 
doxorubicin administration. 
15.399d Monitor IV site closely and establish patency before administration.  
Paclitaxel is an irritant, however rarely rash, radiation recall, and 
ulceration have occurred with infiltration of drug. 
15.399e Monitor liver function tests 

MC1633 
66 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.399f Inform patient about total alopecia. 
15.399g If given on the same day as a platinum agent, paclitaxel should be 
administered first to limit myelosuppression and enhance efficacy of 
agent. 
15.4 
Endocrine Therapy 
NOTE: Cohort B patients will be on one of these agents. 
15.41 Anastrozole commercial supply (Arimidex®) 
15.411 
Formulation and storage 
Anastrozole is commercially available from AstraZeneca as 1 mg 
tablets. Store at 15 C to 30 C (59 F to 86 F). 
15.412 
Category and mechanism of action 
Anastrozole is a potent and selective nonsteroidal aromatase inhibitor. 
It significantly lowers serum estradiol concentrations and has no 
detectable effect o formation of adrenal corticosteroids or aldosterone. 
In postmenopausal women, the principal source of circulating estrogen 
is conversion of adrenally generated androstenedione to estrone b 
aromatase in peripheral tissues. 
15.413 
Administration 
Oral. Anastrozole is well absorbed and not affected by food. 
15.414 
Dose:  
1 mg PO once daily without regard to meals. 
15.415 
Known potential adverse events: 
Likely (occurring greater than 20% of the time): 
Cardiovascular: Flushing 
Less Likely (occurring less than or equal to 20% of the time): 
Cardiovascular:  peripheral edema, chest pain, hypertension 
Central nervous system: Headache, dizziness, anxiety, 
depression, insomnia,  
Dermatologic: Rash, pruritus 
Endocrine & metabolic: Increased cholesterol levels 
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, 
anorexia, constipation, gas and cramping 
General effects:  Asthenia, weakness, flu-like symptoms, back 
pain, arthralgia, carpal tunnel syndrome 
Neuromuscular & skeletal: Osteoporosis, pathological fracture, 
breast pain 
Respiratory: Dyspnea, cough, pharyngitis, sore throat 
Rare but serious (occurring less than 2-3% of the time): 
Cardiovascular: Thrombophlebitis, heart attack, stroke, low 
supply of blood to the heart and brain, blood clots 
Central nervous system: Confusion 
Dermatologic: Hair thinning   
Endocrine & metabolic: Increase in liver enzymes 
Gastrointestinal: Weight gain or loss 

MC1633 
67 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
General effects:  Allergic reaction (Stevens Johnson 
Syndrome) 
Genitourinary: Vaginal dryness or bleeding 
Hematologic: Anemia, leukopenia 
Neuromuscular & skeletal: Paresthesia 
15.416 
Drug procurement 
Commercially available. 
15.417 
Nursing guidelines 
15.4171 May take with food if needed for nausea.  Instruct patient to 
report unrelieved nausea or vomiting. 
15.4172 Instruct patient that hot flashes may occur.  Manage hot 
flashes with non-hormonal interventions (ie: venlafaxine XR 
75 mg daily). 
15.4173 Assess for changes in bowel patterns. Manage diarrhea with 
non-prescription drugs. Instruct patient to report unrelieved 
diarrhea. 
15.4174 Headache may occur. Can be managed with non-prescription 
analgesics. Instruct patient to report headaches that are not 
relieved. 
15.4175 Vaginal dryness may occur. Instruct patient in the use of 
lubricating agents. 
15.4176 Mild swelling may occur in the arms and legs. Instruct 
patient to elevate extremities when at rest to relieve the 
swelling. 
15.4177 While thrombophlebitis is rare, instruct patient to report any 
pain, redness, marked swelling in the arms and/or legs, 
dizziness, or shortness of breath to their health care provider 
immediately or seek medical attention in an emergency 
room. 
15.42 Exemestane (Aromasin) 
15.421 
Background:  
Exemestane is an irreversible, steroidal aromatase inactivator. It 
prevents conversion of androgens to estrogens by tying up the enzyme 
aromatase. In breast cancers where growth is estrogen-dependent, this 
medicine will lower circulating estrogens. 
15.422 
Formulation 
Commercially available in 25 mg tablets for oral administration. 
15.423 
Preparation, storage, and stability 
Store at room temperature of 25ºC. 
15.424 
Administration 
Administer after a meal. Patients on aromatase inhibitor therapy should 
receive vitamin D and calcium supplements. 

MC1633 
68 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.425 
Pharmacokinetic information: 
Absorption: Rapid and moderate (~42&) following oral 
administration; absorption increases ~40% following high-fat meal 
Protein Binding: 90%, primarily to albumin and α1-acid glycoprotein 
Metabolism: Extensively hepatic; oxidation (CYP3A4) of methylene 
group, reduction of 17-keto group with formation of many secondary 
metabolites; metabolites are inactive 
Distribution: Extensive 
Half-life elimination: 24 hours 
Time to peak: Women with breast cancer: 1.2 hours 
Excretion: Urine (<1% as unchanged drug, 39% to 45% as 
metabolites); feces (36% to 48%) 
15.426 
Potential Drug Interactions:   
Cytochrome P450 Effect: Substrate of CYP3A4 (major) 
Decreased Effect: CYP3A4 inducers may decrease the levels/effects 
of Exemestane. See package insert for example CYP3A4 inducers. 
Adjustment of dosage required with potent inducers. 
Ethanol/Nutrition/Herb Interactions:  
Food: Plasma levels increased by 40% when Exemestane was taken 
with a fatty meal. 
Herb/Nutraceutical: St John’s wort may decrease Exemestane levels. 
Avoid black cohosh, dong quai in estrogen-dependent tumors. 
15.427 
Known potential adverse events 
Consult the package insert for the most current and complete 
information.  
Common known potential adverse events, > 10%:   
Cardiovascular: Hypertension 
Central nervous system: Fatigue, pain, headache, depression 
Dermatologic: Hyperhidrosis, alopecia 
Endocrine & metabolic: Hot flashes 
Gastrointestinal: Nausea, abdominal pain 
Hepatic: Alkaline phosphatase increased 
Neuromuscular & skeletal: Arthralgia 
Less common known potential adverse events, 1% - 10%:  
Cardiovascular: Edema, cardiac ischemic events, chest pain 
Central Nervous System: Dizziness, anxiety, fever, confusion, 
hypoesthesia 
Dermatologic: Dermatitis, itching, rash 
Endocrine& metabolic: Weight gain 
Gastrointestinal: Diarrhea, vomiting, anorexia, constipation, appetite 
increased, dyspepsia 
Genitourinary: Urinary tract infection 
Hepatic: Bilirubin increased 
Neuromuscular & skeletal: Back pain, limb pain, osteoarthritis, 
weakness, osteoporosis, pathological fracture, paresthesia, carpal 
tunnel syndrome, cramps 
Ocular: Visual disturbances 
Renal: Creatinine increased 

MC1633 
69 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Respiratory: Dyspnea, cough, bronchitis, pharyngitis, rhinitis, sinusitis, 
upper respiratory infection 
Miscellaneous: Influenza-like symptoms, diaphoresis, lymphedema, 
infection 
Rare known potential adverse events, <1% (Limited to important 
or life-threatening):  
Cardiac failure, endometrial hyperplasia, GGT increased, neuropathy, 
osteochondrosis, thromboembolism, transaminases increased, uterine 
polyps 
15.428 
Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
15.429 
Nursing Guidelines 
15.4291 Advise patients to take after a meal. 
15.4292 Manage hot flashes with non-hormonal interventions (ie. 
venlafaxine XR 75 mg daily). 
15.4293 Instruct patient to report uncontrolled nausea, insomnia. 
15.4294 Assess for changes in bowel patterns and manage diarrhea or 
constipation. Instruct patient to report unrelieved diarrhea or 
constipation. 
15.4295 Monitor for drug interactions. Aromasin is metabolized by 
the P450 3A4 system. While it is unlikely that inhibitors of 
this system will significantly increase aromasin level, the 
manufacturer cautions about concommitent use with 
inducers of the CYP3A4 system as this may decrease serum 
levels, and thereby it’s effectivness. Assess all of patients 
prescription and non-prescription medications. Instruct 
patient to check with physician before starting any new 
medications, including OTC. 
15.43 Fulvestrant (Faslodex®) 
15.431 
Background 
Fulvestrant is an estrogen receptor antagonist. Fulvestrant 
competitively binds to estrogen receptors on tumors and other tissue 
targets, producing a nuclear complex that causes a dose-related down-
regulation of estrogen receptors and inhibits tumor growth. 
15.432 
Formulation:  
Commercially available for injection as:  
Injection, solution: 50 mg/mL (5 mL) [contains benzyl alcohol, benzyl 
benzoate, castor oil, ethanol 10% w/v] 
15.433 
Preparation, storage, and stability 
Refer to package insert for complete preparation and dispensing 
instructions. Store in original carton under refrigeration at 2°C to 8°C 
(36°F to 46°F). Protect from light. 

MC1633 
70 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.434 
Administration 
Refer to the treatment section for specific administration instructions. 
Administer IM only; do not administer IV, SubQ, or intra-arterially. 
Administer 500 mg dose as two 5 mL injections (one in each buttocks) 
slowly over 1-2 minutes per injection.  
15.435 
Pharmacokinetic information: 
Distribution: Vd: ~3-5 L/kg 
Protein binding: 99%; to plasma proteins (FLDL, LDL and HDL 
lipoprotein fractions) 
Metabolism: Hepatic via multiple biotransformation pathways 
(CYP3A4 substrate involved in oxidation pathway, although relative 
contribution to metabolism unknown); metabolites formed are either 
less active or have similar activity to parent compound. 
Half-life elimination: 250 mg: ~40 days 
Excretion: Feces (~90%); urine (<1%) 
15.436 
Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (minor). There are 
no known interactions where it is recommended to avoid concomitant 
use. 
15.437 
Known potential adverse events 
Consult the package insert for the most current and complete 
information.  
Common known potential toxicities, > 10%:   
Endocrine & metabolic: Fertility: Hot flushes 
Hepatic: Alkaline phosphatase increased, transaminases increased 
Local: Injection site pain 
Neuromuscular & skeletal: Joint disorders 
Less common known potential adverse events, 1% - 10%:  
Cardiovascular: Ischemic disorder 
Central nervous system: Fatigue, headache 
Gastrointestinal: Nausea, anorexia, vomiting, constipation, weight gain 
Genitourinary: Urinary tract infection 
Neuromuscular & skeletal: Bone pain, arthralgia, back pain, extremity 
pain, musculoskeletal pain, weakness 
Respiratory: Cough, dyspnea 
Rare known potential adverse events, <1% (Limited to important 
or life-threatening):  
Angioedema, hypersensitivity reactions, leukopenia, myalgia, 
osteoporosis, thrombosis, urticaria, vaginal bleeding 
15.438 
Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
15.439 
Nursing guidelines: 
15.4391 Rarely a blood-tinged vaginal discharge has been reported 
infrequently during therapy.  Advise patients that this is a 

MC1633 
71 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
possibility and that studies have shown no effects on vagina 
or endometrium.   
15.4392 Monitor LFTs based on protocol requirements. Report 
increased LFTs to treating physician. 
15.4393 Hot packing the injection site for a short while after injection 
may prevent the possible bruising, tenderness, and/or 
erythema at the IM injection site.  
15.4393 It is recommended that pregnancy be avoided during 
treatment. Instruct patient and partner on adequate methods 
of birth control. 
15.4393 Instruct patient to report any signs or symptoms of blood 
clots. Patients with calf tenderness or burning, and/or chest 
pain (pulmonary embolus) should be evaluated by a 
physician immediately. 
15.4393 Warn patient of possible hot flashes. Assess severity and 
discuss non-hormonal treatments with treating physician. 
Assess treatment for efficacy.  
15.4393 May cause mild GI symptoms (nausea, anorexia, vomiting, 
constipation). Treat symptomatically and monitor for 
effectiveness of intervention. 
15.44 Letrozole for Oral Administration (Femara®) 
15.441 
Background 
Letrozole is an aromatase inhibitor. Letrozole is a nonsteroidal, 
competitive inhibitor of the aromatase enzyme system which binds to 
the heme group of aromatase, a cytochrome P450 enzyme which 
catalyzes conversion of androgens to estrogens. This process leads to 
inhibition of the enzyme and a significant reduction in plasma estrogen 
levels. Letrozole does not affect synthesis of adrenal or thyroid 
hormones, aldosterone, or androgens.  Patients treated with letrozole 
do not require glucocorticoid or mineralocorticoid replacement 
therapy. 
15.442 
Formulation 
Commercially available for oral administration as: Tablets: 2.5 mg  
15.443 
Preparation, storage, and stability 
Refer to package insert for complete preparation and dispensing 
instructions. Store letrozole at room temperature of 77°F (25°C); 
excursions permitted to 59°F to 86°F (15°C to 30°C).  
15.444 
Administration 
Refer to the treatment section for specific administration instructions. 
Administer orally with or without food.  
15.445 
Pharmacokinetic information: 
Distribution: Vd: ~1.9 L/kg 
Protein binding: weak 
Metabolism: Hepatic via CYP3A4 and CYP2A6 into an inactive 
carbinol metabolite 

MC1633 
72 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Half-life elimination: Terminal:  ~ 2 days 
Excretion: Urine (90%; 6% as unchanged drug, 75% as glucuronide 
carbinol metabolite, 9% as unidentified metabolites) 
15.446 
Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CY2A6 (minor) CYP3A4 
(minor).  Inhibitor of CYP2A6 (strong), CYP2C19 (weak) 
Increased Effect/Toxicity:  CYP2A6 substrates, methadone, vitamin 
K antagonists (eg, warfarin) 
Decreased Effect:  digoxin, tegafur, vitamin K antagonists (eg, 
warfarin) 
15.447 
Known potential adverse events 
Consult the package insert for the most current and complete 
information.  
Common known potential adverse events, > 10%:   
Cardiovascular: Edema 
Central nervous system: Headache, dizziness, fatigue 
Endocrine & metabolic: Hypercholesterolemia, hot flashes 
Gastrointestinal: Nausea, weight gain, constipation 
Neuromuscular & skeletal: Weakness, arthralgia, arthritis, bone pain, 
back pain, bone mineral density decreased/osteoporosis, bone fracture 
Respiratory: Dyspnea, cough 
Miscellaneous:  Diaphoresis, night sweats 
Less common known potential adverse events, 1% - 10%:  
Cardiovascular: Chest pain, hypertension, chest wall pain, peripheral 
edema, cerebrovascular accident including hemorrhagic stroke, 
thrombotic stroke, thromboembolic event including venous 
thrombosis, thrombophlebitis, MI, angina, transient ischemic attack 
Central nervous system: Insomnia, pain, anxiety, depression, vertigo, 
somnolence 
Dermatologic: Rash, alopecia, pruritis 
Endocrine & metabolic:  Breast pain, hypercalcemia 
Gastrointestinal:  Diarrhea, vomiting, weight loss, abdominal pain, 
anorexia, dyspepsia 
Genitourinary: Urinary tract infection, vaginal bleeding, vaginal 
dryness, vaginal hemorrhage, vaginal irritation 
Neuromuscular & skeletal: Limb pain, myalgia 
Ocular:  Cataract 
Renal:  Renal disorder 
Respiratory:  Pleural effusion 
Miscellaneous:  Infection, influenza, viral infection, secondary 
malignancy 
Rare known potential adverse events, <1% (Limited to important 
or life-threatening):  
Anaphylactic reaction, angioedema, arterial thrombosis, cardiac 
failure, carpal tunnel syndrome, endometrial cancer, endometrial 
hyperplasia, endometrial proliferation, erythema multiforme, hepatitis, 
leukopenia, memory impairment, stomatitis, tachycardia, 
thrombocytopenia, toxic epidermal necrolysis, trigger finger 

MC1633 
73 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
15.448 
Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
15.449 
Nursing Guidelines  
15.4491 Manage hot flashes with non-hormonal interventions (e.g., 
venlafaxine XR 75 mg daily). 
15.4492 Manage pain (arthralgias). Instruct patient to report 
unrelieved pain. 
15.4493 May take with food if needed for nausea. Instruct patient to 
report unrelieved nausea or vomiting. 
15.4494 Assess for changes in bowel patterns. Manage diarrhea or 
constipation with non-prescription drugs. Tell patients to 
report unrelieved diarrhea or constipation. 
15.4495 If patient experiences difficulty breathing or sudden onset 
chest pain, instruct them to seek emergency medical 
attention immediately. 
15.4496 Monitor for signs of edema, instruct patient to report any 
swelling in legs, feet, or hands. 
 

MC1633 
74 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
16.0  
Statistical Considerations and Methodology  
16.1 
Study Design 
A two-stage phase II trial will be conducted to assess the tumor response rate and safety 
profile of TVB-2640 in combination with paclitaxel and trastuzumab in two patient 
cohorts, namely, patients with HER2+ MBC resistant to taxane and HER2-directed 
therapy and patients with ER+/HER2+ MBC resistant to endocrine and HER2-directed 
therapy  
For each cohort, the primary endpoint is overall response rate (ORR) defined as the 
number of patients whose disease meets the RECIST criteria for a partial (PR) or 
complete (CR) on two consecutive evaluations at least 8 weeks apart divided by the total 
number of patients in that cohort who started protocol treatment. 
For each cohort, the following two-stage Simon minimax design with a safety run-in 
period will be used to test the null hypothesis that the true tumor response rate is at most 
5% against the alternative it is at least 20%.   
For each cohort, a maximum of 6 patients may be enrolled in the run-in period before 
accrual is temporarily suspended. If 2 or more run-in patients develops one of the 
following toxicities during the first two  cycles of treatment: febrile neutropenia 
Grade ≥3, neutropenia Grade 4, thrombocytopenia with any Grade ≥3 bleeding, 
thrombocytopenia Grade ≥4, hand/foot syndrome Grade 3, ocular toxicity Grade ≥3, and 
Grade 3 CHF, accrual will be suspended to that cohort. All toxicity data will be reviewed 
by the study team and consideration will be given to changing the dosing schedule for 
that cohort.  Study recommendations will be forwarded to the IRB for approval. If the 
dosing schedule is changed and enrollment reopened to the cohort, the initial 6 patients 
will be not included in the assessment of tumor response (but will be included in all 
safety reports) and another run-in period of 6 patients will be undertaken. 
After the 6 patient run-in demonstrates patient tolerability, another 12 patients will be 
enrolled to that cohort. If none of the 18 patients has a partial response (PR) or complete 
response (CR) on two consecutive evaluations at least 8 weeks, further enrollment to that 
cohort will be closed and the treatment regimen will not be considered promising in that 
patient cohort.  If at least one tumor response is documented among the 18 patients from 
a given cohort, an additional 14 patients will be enrolled onto that cohort. If at least 
4 tumor responses are seen among the total 32 patients enrolled onto that cohort, we will 
conclude that the tumor response rate is at least 20% in that patient cohort. The proposed 
design has a 90% chance of rejecting the true response rate is less than 5% when the true 
response rate is 20% or more, at a 0.10 level of significance. 
NOTE: If the second run-in period does not demonstrate tolerability, enrollment to that 
cohort will be closed. 
16.11 Secondary Endpoints:  
Secondary endpoints will be evaluated for each cohort independently. 
16.111 
Duration of response is defined as the time from the first radiologic 
finding of a PR or CR to  disease progression among those patients 
whose disease meets the RECIST criteria for CR or PR on 
2 consecutive evaluations approximately 8 weeks apart.  
16.112 
Clinical Benefit Rate (CBR) is defined as the proportion of patients 
who have completed 6 cycles of treatment without disease progression 

MC1633 
75 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
(that is, their objective disease status is a CR, PR, or stable for 6 cycles 
or more)  
16.113  
Progression-free survival (PFS) - time from randomization to the first 
of these disease events: local/regional or distant breast recurrence, 
DCIS or invasive breast disease in contralateral breast, non-breast 
second primary, or death due to any cause. 
16.12 Analysis Plans for each cohort independently 
A point and interval estimate of the response rate as well as the clinical benefit 
rate will be constructed using the Duffy-Santner approach to take into account 
the sequential nature of the study design. 
The distribution of response times and progression-free survival times will be 
estimated using the Kaplan-Meier approach. 
Toxicities will be tabulated by severity. 
16.13 Adverse Event Stopping Rules 
The adverse event stopping rule will be applied to each cohort independently. 
Enrollment to a given cohort will be temporarily suspended for close 
examination of treatment safety and tolerability: 
- at each instance of a treatment related death; 
- if 2 or more of the first 6 patients develops one of the following toxicities 
that is considered to be possibly, probably, or definitely related to protocol 
treatment with TVB-2640: a Grade 4 neutropenia, or any clinically 
significant Grade 4 event (other than expected cytopenias or transient 
laboratory abnormalities); or Grade 3 or worse fatigue, malaise, mucositis, 
pneumonitis; or any Grade 2 or worse eye disorder or Grade 3 or worse 
palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome); 
- or at any time after the first 6 patients have been enrolled, if 25% or more 
patients develops one of the following toxicities that is considered to be 
possibly, probably or definitely related to protocol treatment with TVB-2640: 
a Grade 4 neutropenia, or any clinically significant Grade 4 event (other than 
expected cytopenias or transient laboratory abnormalities); or Grade 3 or 
worse fatigue, malaise, mucositis, pneumonitis; or any Grade 2 or worse eye 
disorder, or Grade 3 or worse palmar-plantar erythrodysesthesia syndrome 
(hand-foot syndrome). 
NOTE: Adverse events normally associated with treatment with paclitaxel (e.g., 
peripheral neuropathy) and/or trastuzumab (e.g., LVEF decreased) will not count 
toward the stopping rules, as these events are expected. 
All toxicity data will be examined to assess whether changes should be made in 
the treatment or eligibility criteria to increase the tolerability of the treatment. All 
modifications to the protocol will be forwarded to the IRB for review. 
16.14 Correlative Endpoints 
The changes in H score FASN, pAKT, and pS6 expression and levels of cellular 
apoptosis in tumor tissue after the first cycle of the combination of TVB-2640 
with paclitaxel and trastuzumab will be examined graphically by plotting the 
difference in pre and post levels against pre-levels of the biomarker, with patients 
who derived clinical benefit represented by dashed line and those who did not by 
solid line. 

MC1633 
76 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
For each patient cohort, Wilcoxon signed rank tests will be used to assess the 
changes in serum FASN after the first cycle of the combination of TVB-2640 
with paclitaxel and trastuzumab from pre-treatment levels. 
16.2 
Research Monitoring 
Specific to meeting Department of Defense requirements 
An independent research monitor will be designated for complying with Department of 
Defense funding regulations. This designee will monitor protocol deviations, adverse 
events and data analysis. 
16.21 Research Monitor Tasks 
1. Receive and review expedited adverse event reports as defined in section 
10.0 of the protocol. 
2. Receive and review unanticipated problems and major protocol violations 
meeting the criteria for real-time reporting 
3. Receive and review Mayo Clinic Cancer Center data and safety monitoring 
board reports 
4. Receive and approve the content of continuing review reports prior to IRB 
submission 
5. Receive and review protocol data analyses 
6. Is required to review all unanticipated problems involving risks to subjects or 
others, serious adverse events and all subject deaths associated with the 
protocol and provide an unbiased written report of the event. At a minimum, 
the research monitor must comment on the outcomes of the event or problem 
and in the case of a serious adverse event or death, comment on the 
relationship to participation in the study. The research monitor must also 
indicate whether he/she concurs with the details of the report provided by the 
principal investigator. Reports for events determined by either the 
investigator or research monitor to be possibly or definitely related to 
participation and report of events resulting in death must be promptly 
forwarded to the USAMRMC ORP HRPO. 
16.22 Research Monitor Responsibilities 
1. The research monitor will agree to promptly report problems or discrepancies 
found to the IRB. 
2. The research monitor will agree to have the authority to stop the study’s 
research in progress, remove individual subjects from the research study, and 
take whatever steps deemed necessary to ensure the safety and well-being of 
the study subjects until the IRB can make a determination based upon the 
monitor’s report. 
3. May discuss the protocol with the investigators, interview subjects, and 
consult with others outside the study about the research. 
4. Shall have the authority to stop the protocol, remove subjects from the 
protocol, and take any necessary steps to protect the safety and well-being of 
subjects until the IRB can assess the Monitor's report. 
5. Shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official. 
Assuming one cohort will require an additional run-in period and as many as 5 patients 
may be needed to account for patients found to be ineligible or cancel participation: 
 
 

MC1633 
77 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
16.3 
Gender and Minority Accrual 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
4 
 
 
Not Hispanic or Latino 
76 
 
 
Ethnic Category: Total of all subjects 
80 
 
 
Racial Category 
American Indian or Alaskan Native 
1 
 
 
Asian 
3 
 
 
Black or African American 
2 
 
 
Native Hawaiian or other Pacific Islander 
 
 
 
White 
74 
 
 
Racial Category: Total of all subjects 
80 
 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

MC1633 
78 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
17.0 
Pathology Considerations/Tissue Biospecimens  
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc. (# 
of each to 
submit) 
Following 
Pre-
registration* 
C2D1 
Process at 
site?  
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
Tumor FASN Expression 
Mandatory 
FFPE 
3 unstained 
slides 
X 
X 
 
 
Tumor pAKT and pS6 
Mandatory 
FFPE 
2 unstained 
slides 
X 
X 
 
 
Tumor HER2 Expression 
Mandatory 
FFPE 
2 unstained 
slides 
X 
X 
 
 
Tumor ER and PR 
expression 
Mandatory 
FFPE 
2 unstained 
slides 
X 
 
 
 
Tumor Apoptosis 
Evaluation 
Mandatory 
FFPE 
3 unstained 
slides 
X 
X 
 
 
H&E 
Mandatory 
 
1 slide 
X 
X 
 
 
 
A: All tumor specimens will be collected prior to administration of therapy on Cycle 2 Day 1. 
Note: Please submit a pathology report with the pre-registration biopsy in which HER2 status will be tested. HER2 status can be tested and 
confirmed at local site. 
*If pre-registration biopsy is attempted and either aborted or insufficient tissue is obtained, the patient may still be eligible. In this case, 
the site may submit slides from archival specimens (preferably from a metastatic site) from biopsy or surgery completed ≤5 years prior to 
pre-registration for central lab review.  
NOTE: If biopsy does not obtain evaluable tissue AND no recent archived tissue is available for Central Laboratory review, patient is not 
eligible. A repeat biopsy may be attempted at the discretion of the treating physician and patient.  
 
 

MC1633 
79 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
Along with original diagnostic slides, include pathology reporting form, surgical 
pathology report and operative report. 
17.3 
Correlative Tissue Collection  
17.31 Tissue Kits will not be provided for this protocol. 
17.32 Paraffin Embedded Tissue 
17.321 
For both the pre-registration and C2D1 biopsies, collection should 
occur per standard site procedures and at the radiologist discretion. 
One core will be formalin-fixed, paraffin-embedded (FFPE) and 
sections (5 micron) will be cut from the tumor tissue block to obtain 10 
unstained slides that contain at least 75% tumor tissue. These slides 
will be used for FASN expression, pAKT and pS6 expression, HER2 
expression, and apoptosis evaluation. One slide from each biopsy will 
also be cut for H&E. 
17.322 
 All slides should be shipped to the pathology coordinator at the 
following address: 
Mayo Clinic Cancer Center Operations Office 
Attn: PC Office (MC1633) 
RO_FF_03_24-CC/NW Clinic 
200 First Street SW 
Rochester, MN 55905  
17.4 
Background and Methodology 
17.41 Evaluation of Tumor FASN Expression 
We hypothesize that tumor expression of FASN is associated with clinical benefit 
from targeted treatment with TVB-2640. Paraffin-embedded tissue biospecimens 
will be processed and assessed by immunohistochemistry (IHC) for total 
expression of FASN. Staining will be performed by the Lupu laboratory with 
scoring and interpretation by Dr. Visscher. Results will be utilized to evaluate an 
association between the changes in FASN levels after 1 cycle of treatment and 
subject response to treatment.   
17.42 Evaluation of Tumor pAKT and pS6 
We hypothesize that a reduction in tumor expression of pAKT and pS6 are 
associated with clinical benefit from targeted treatment with TVB-2640. Paraffin-
embedded tissue biospecimens will be processed and assessed by IHC for 
phosphorylated expression of AKT and ribosomal protein S6. Staining will be 
performed by 3V-Biosciences, Inc. with pAKTS473 (Dako, rabbit clone 14-5) 
(CST rabbit Ab C20G5) using a validated IHC method. H-score in tumor will be 
quantitated by standard pathology review (staining intensity graded 0-3+ and % 
cells positive). Results will be utilized to evaluate an association between the 
change in these biomarker levels after 1 cycle of treatment and subject response 
to treatment. Scoring and interpretation of the IHC analysis will be performed by 
Dr. Visscher. 
17.43 Evaluation of Tumor HER2 Expression: 
As HER2 levels are positively correlated with FASN levels, and we have 
previously shown that inhibition of FASN results in decrease in HER2 
expression. We hypothesize that tumor expression of HER2 will decrease after 

MC1633 
80 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
treatment with TVB-2640. Paraffin-embedded tissue biospecimens will be 
processed and assessed by IHC for HER2 expression at the MCCC PRC. Testing 
is performed using FDA-approved Ventana Pathway HER2 (4B5) rabbit 
monoclonal primary antibody and a proprietary detection system. The percentage 
of invasive cancer cells exhibiting complete membrane staining and the 
uniformity of staining will be reported. Final scoring (0 – 3+) and interpretation 
per ASCO/CAP guidelines will be performed by Dr. Visscher . For equivocal 
results by IHC (2+), standard reflex testing by FISH will be performed using 
probes for HER2 (17q12) and a D17Z1 control probe. Two technologists will 
score signals in 60 total nuclei from tumor and concurrent controls. Dr. Visscher 
will oversee interpretation of results. 
17.44 valuation of Tumor Apoptosis:  
We hypothesize that Apoptosis (the percentage of apoptotic cells) will be 
inversely correlated with the expression of FASN. Apoptosis will be detected 
using the ApopTag Peroxidase In Situ Apoptosis Detection Kit from Millipore. 
This evaluation will be conducted in the Lupu laboratory. The assay detects 
apoptotic cells in situ by labeling & detecting DNA strand breaks by the TUNEL 
method. It is important to note that ApopTag Kits detect single-stranded and 
double-stranded breaks associated with apoptosis. Drug-induced DNA damage is 
not identified by the TUNEL assay unless it is coupled to the apoptotic response. 
In addition, this technique can detect early-stage apoptosis in systems where 
chromatin condensation has begun and strand breaks are fewer, even before the 
nucleus undergoes major morphological changes. The association between FASN 
and apoptosis will serve for future correlative and clinical studies. 
 

MC1633 
81 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.0 and data submission table for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis prior to study entry. 
Supporting documentation for diagnosis will include either a pathology report or a 
laboratory report. These reports should be submitted within 14 days of registration. 
A copy of the report stating the size of the lesions being followed for tumor response 
should be provided prior to start of treatment and at time disease progression is first 
documented. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 
information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to the 
appropriate site to make the correction and return the query and documentation of 
correction back to the QAS.  
 
 

MC1633 
82 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
19.0  
Budget 
19.1 
Costs charged to patient:  
Routine clinical care; every other echocardiogram; tumor assessment scans; blood work 
(labs) related to toxicity assessment 
19.2 
Tests to be research funded:  
Baseline ocular assessment and ECG; tumor biopsies; all research-related serum (FASN) 
and tumor tissue studies; every other echocardiogram 
19.3 
Other budget concerns: None. 
 
 
 

MC1633 
83 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
20.0 
References 
1. 
Dawood, S., Broglio, K., Buzdar, A.U., Hortobagyi, G.N. & Giordano, S.H. Prognosis of women 
with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based 
review. J Clin Oncol 28, 92-98 (2010). 
2. 
Berns, K., Horlings, H.M., Hennessy, B.T., Madiredjo, M., Hijmans, E.M., Beelen, K., Linn, S.C., 
Gonzalez-Angulo, A.M., Stemke-Hale, K., Hauptmann, M., Beijersbergen, R.L., Mills, G.B., van 
de Vijver, M.J. & Bernards, R. A functional genetic approach identifies the PI3K pathway as a 
major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395-402 (2007). 
3. 
Elster, N., Collins, D.M., Toomey, S., Crown, J., Eustace, A.J. & Hennessy, B.T. HER2-family 
signalling mechanisms, clinical implications and targeting in breast cancer. Breast Cancer Res 
Treat 149, 5-15 (2015). 
4. 
Menendez, J.A. & Lupu, R. Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from 
anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells. Arch 
Immunol Ther Exp (Warsz) 52, 414-426 (2004). 
5. 
Kuhajda, F.P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. 
Nutrition 16, 202-208 (2000). 
6. 
Cohen, G.M. Caspases: the executioners of apoptosis. Biochem J 326 ( Pt 1), 1-16 (1997). 
7. 
Gnesutta, N. & Minden, A. Death receptor-induced activation of initiator caspase 8 is antagonized 
by serine/threonine kinase PAK4. Mol Cell Biol 23, 7838-7848 (2003). 
8. 
Peter, M.E. & Krammer, P.H. Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr Opin 
Immunol 10, 545-551 (1998). 
9. 
Chen, M. & Wang, J. Initiator caspases in apoptosis signaling pathways. Apoptosis 7, 313-319 
(2002). 
10. 
Kaufmann, S.H. & Hengartner, M.O. Programmed cell death: alive and well in the new millennium. 
Trends Cell Biol 11, 526-534 (2001). 
11. 
Ricci, J.E., Munoz-Pinedo, C., Fitzgerald, P., Bailly-Maitre, B., Perkins, G.A., Yadava, N., 
Scheffler, I.E., Ellisman, M.H. & Green, D.R. Disruption of mitochondrial function during 
apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport 
chain. Cell 117, 773-786 (2004). 
12. 
Newmeyer, D.D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the 
machineries of death. Cell 112, 481-490 (2003). 
13. 
Ricci, J.E., Waterhouse, N. & Green, D.R. Mitochondrial functions during cell death, a complex 
(I-V) dilemma. Cell Death Differ 10, 488-492 (2003). 
14. 
Chipuk, J.E. & Green, D.R. How do BCL-2 proteins induce mitochondrial outer membrane 
permeabilization? Trends Cell Biol 18, 157-164 (2008). 
15. 
Cory, S. & Adams, J.M. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev 
Cancer 2, 647-656 (2002). 
16. 
Chittenden, T. BH3 domains: intracellular death-ligands critical for initiating apoptosis. Cancer 
Cell 2, 165-166 (2002). 
17. 
van Delft, M.F. & Huang, D.C. How the Bcl-2 family of proteins interact to regulate apoptosis. 
Cell Res 16, 203-213 (2006). 
18. 
Willis, S.N. & Adams, J.M. Life in the balance: how BH3-only proteins induce apoptosis. Curr 
Opin Cell Biol 17, 617-625 (2005). 
19. 
Lessene, G., Czabotar, P.E. & Colman, P.M. BCL-2 family antagonists for cancer therapy. Nat Rev 
Drug Discov 7, 989-1000 (2008). 
20. 
Jin, J., Hou, Q., Mullen, T.D., Zeidan, Y.H., Bielawski, J., Kraveka, J.M., Bielawska, A., Obeid, 
L.M., Hannun, Y.A. & Hsu, Y.T. Ceramide generated by sphingomyelin hydrolysis and the salvage 
pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-
2 cells. J Biol Chem 283, 26509-26517 (2008). 

MC1633 
84 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
21. 
Siskind, L.J., Kolesnick, R.N. & Colombini, M. Ceramide channels increase the permeability of 
the mitochondrial outer membrane to small proteins. J Biol Chem 277, 26796-26803 (2002). 
22. 
Menendez, J.A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. 
Nat Rev Cancer 7, 763-777 (2007). 
23. 
Alo, P.L., Visca, P., Botti, C., Galati, G.M., Sebastiani, V., Andreano, T., Di Tondo, U. & Pizer, 
E.S. Immunohistochemical expression of human erythrocyte glucose transporter and fatty acid 
synthase in infiltrating breast carcinomas and adjacent typical/atypical hyperplastic or normal 
breast tissue. Am J Clin Pathol 116, 129-134 (2001). 
24. 
Milgraum, L.Z., Witters, L.A., Pasternack, G.R. & Kuhajda, F.P. Enzymes of the fatty acid 
synthesis pathway are highly expressed in in situ breast carcinoma. Clin Cancer Res 3, 2115-2120 
(1997). 
25. 
Welsh, J.B., Sapinoso, L.M., Su, A.I., Kern, S.G., Wang-Rodriguez, J., Moskaluk, C.A., Frierson, 
H.F., Jr. & Hampton, G.M. Analysis of gene expression identifies candidate markers and 
pharmacological targets in prostate cancer. Cancer Res 61, 5974-5978 (2001). 
26. 
Shurbaji, M.S., Kuhajda, F.P., Pasternack, G.R. & Thurmond, T.S. Expression of oncogenic 
antigen 519 (OA-519) in prostate cancer is a potential prognostic indicator. Am J Clin Pathol 97, 
686-691 (1992). 
27. 
Epstein, J.I., Carmichael, M. & Partin, A.W. OA-519 (fatty acid synthase) as an independent 
predictor of pathologic state in adenocarcinoma of the prostate. Urology 45, 81-86 (1995). 
28. 
Gansler, T.S., Hardman, W., 3rd, Hunt, D.A., Schaffel, S. & Hennigar, R.A. Increased expression 
of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Hum Pathol 28, 
686-692 (1997). 
29. 
Pizer, E.S., Jackisch, C., Wood, F.D., Pasternack, G.R., Davidson, N.E. & Kuhajda, F.P. Inhibition 
of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res 56, 
2745-2747 (1996). 
30. 
Pizer, E.S., Lax, S.F., Kuhajda, F.P., Pasternack, G.R. & Kurman, R.J. Fatty acid synthase 
expression in endometrial carcinoma: correlation with cell proliferation and hormone receptors. 
Cancer 83, 528-537 (1998). 
31. 
Sebastiani, V., Visca, P., Botti, C., Santeusanio, G., Galati, G.M., Piccini, V., Capezzone de 
Joannon, B., Di Tondo, U. & Alo, P.L. Fatty acid synthase is a marker of increased risk of 
recurrence in endometrial carcinoma. Gynecol Oncol 92, 101-105 (2004). 
32. 
Visca P, S.V., Pizer ES,  Botti C, DeCarli P, Filippi S, Monaco S, Alo PL. Immunochemical 
expression and prognostic significance of FAS and GLUT1 in bladder carcinoma. Anticancer Res 
23, 335-339 (2003). 
33. 
Nemoto, T., Terashima, S., Kogure, M., Hoshino, Y., Kusakabe, T., Suzuki, T. & Gotoh, M. 
Overexpression of fatty acid synthase in oesophageal squamous cell dysplasia and carcinoma. 
Pathobiology 69, 297-303 (2001). 
34. 
Kusakabe T, N.A., Honma K, Suzuki T. Fatty acid synthase is highly expressed in carcinoma, 
adenoma and in regenerative epithelium and intestinal metaplasia of the stomach. Histopathology 
40, 71-79 (2002). 
35. 
Piyathilake, C.J., Frost, A.R., Manne, U., Bell, W.C., Weiss, H., Heimburger, D.C. & Grizzle, W.E. 
The expression of fatty acid synthase (FASE) is an early event in the development and progression 
of squamous cell carcinoma of the lung. Hum Pathol 31, 1068-1073 (2000). 
36. 
Krontiras, H., Roye, G.D., Beenken, S.E., Myers, R.B., Mayo, M.S., Peters, G.E. & Grizzle, W.E. 
Fatty acid synthase expression is increased in neoplastic lesions of the oral tongue. Head Neck 21, 
325-329 (1999). 
37. 
Guo, C.B., Cui, N.H., Yu, G.Y., Liu, D.X., Meng, S.C. & Song, Q. Effects of cerulenin on the 
endogenous fatty acid synthetic activity in squamous cell carcinoma of the oral cavity. J Oral 
Maxillofac Surg 61, 909-912 (2003). 

MC1633 
85 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
38. 
Silva, S.D., Agostini, M., Nishimoto, I.N., Coletta, R.D., Alves, F.A., Lopes, M.A., Kowalski, L.P. 
& Graner, E. Expression of fatty acid synthase, ErbB2 and Ki-67 in head and neck squamous cell 
carcinoma. A clinicopathological study. Oral Oncol 40, 688-696 (2004). 
39. 
Vlad LD, A.C., Merino MJ. Fatty acid synthase is highly expressed in aggressive thyroid tumors. 
Mod Pathol 12(1999). 
40. 
Gabrielson, E.W., Pinn, M.L., Testa, J.R. & Kuhajda, F.P. Increased fatty acid synthase is a 
therapeutic target in mesothelioma. Clin Cancer Res 7, 153-157 (2001). 
41. 
Camassei, F.D., Jenkner, A., Rava, L., Bosman, C., Francalanci, P., Donfrancesco, A., Alo, P.L. & 
Boldrini, R. Expression of the lipogenic enzyme fatty acid synthase (FAS) as a predictor of poor 
outcome in nephroblastoma: an interinstitutional study. Med Pediatr Oncol 40, 302-308 (2003). 
42. 
Innocenzi, D., Alo, P.L., Balzani, A., Sebastiani, V., Silipo, V., La Torre, G., Ricciardi, G., 
Bosman, C. & Calvieri, S. Fatty acid synthase expression in melanoma. J Cutan Pathol 30, 23-28 
(2003). 
43. 
Pizer, E.S., Wood, F.D., Pasternack, G.R. & Kuhajda, F.P. Fatty acid synthase (FAS): a target for 
cytotoxic antimetabolites in HL60 promyelocytic leukemia cells. Cancer Res 56, 745-751 (1996). 
44. 
Pizer, E.S., Chrest, F.J., DiGiuseppe, J.A. & Han, W.F. Pharmacological inhibitors of mammalian 
fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res 
58, 4611-4615 (1998). 
45. 
Heiligtag, S.J., Bredehorst, R. & David, K.A. Key role of mitochondria in cerulenin-mediated 
apoptosis. Cell Death Differ 9, 1017-1025 (2002). 
46. 
Pizer, E.S., Thupari, J., Han, W.F., Pinn, M.L., Chrest, F.J., Frehywot, G.L., Townsend, C.A. & 
Kuhajda, F.P. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid 
synthase inhibition in human breast cancer cells and xenografts. Cancer Res 60, 213-218 (2000). 
47. 
Kuhajda, F.P., Pizer, E.S., Li, J.N., Mani, N.S., Frehywot, G.L. & Townsend, C.A. Synthesis and 
antitumor activity of an inhibitor of fatty acid synthase. Proc Natl Acad Sci U S A 97, 3450-3454 
(2000). 
48. 
Kridel, S.J., Axelrod, F., Rozenkrantz, N. & Smith, J.W. Orlistat is a novel inhibitor of fatty acid 
synthase with antitumor activity. Cancer Res 64, 2070-2075 (2004). 
49. 
Knowles, L.M., Axelrod, F., Browne, C.D. & Smith, J.W. A fatty acid synthase blockade induces 
tumor cell-cycle arrest by down-regulating Skp2. J Biol Chem 279, 30540-30545 (2004). 
50. 
Menendez, J.A., Vellon, L. & Lupu, R. Orlistat: from antiobesity drug to anticancer agent in Her-
2/neu (erbB-2)-overexpressing gastrointestinal tumors? Exp Biol Med (Maywood) 230, 151-154 
(2005). 
51. 
Liu, H., Liu, Y. & Zhang, J.T. A new mechanism of drug resistance in breast cancer cells: fatty 
acid synthase overexpression-mediated palmitate overproduction. Mol Cancer Ther 7, 263-270 
(2008). 
52. 
Menendez, J.A., Vellon, L., Colomer, R. & Lupu, R. Pharmacological and small interference RNA-
mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) 
synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. Int J Cancer 115, 19-35 (2005). 
53. 
Menendez, J.A., Lupu, R. & Colomer, R. Inhibition of tumor-associated fatty acid synthase 
hyperactivity induces synergistic chemosensitization of HER -2/ neu -overexpressing human breast 
cancer cells to docetaxel (taxotere). Breast Cancer Res Treat 84, 183-195 (2004). 
54. 
Menendez, J.A., Vellon, L., Mehmi, I., Oza, B.P., Ropero, S., Colomer, R. & Lupu, R. Inhibition 
of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer 
cells. Proc Natl Acad Sci U S A 101, 10715-10720 (2004). 
55. 
Vazquez-Martin, A., Colomer, R., Brunet, J. & Menendez, J.A. Pharmacological blockade of fatty 
acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by 
transcriptionally inhibiting 'HER2 super-expression' occurring in high-dose trastuzumab-
conditioned SKBR3/Tzb100 breast cancer cells. Int J Oncol 31, 769-776 (2007). 

MC1633 
86 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
56. 
Loftus, T.M., Jaworsky, D.E., Frehywot, G.L., Townsend, C.A., Ronnett, G.V., Lane, M.D. & 
Kuhajda, F.P. Reduced food intake and body weight in mice treated with fatty acid synthase 
inhibitors. Science 288, 2379-2381 (2000). 
57. 
Brusselmans, K., De Schrijver, E., Heyns, W., Verhoeven, G. & Swinnen, J.V. Epigallocatechin-
3-gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces 
apoptosis in prostate cancer cells. Int J Cancer 106, 856-862 (2003). 
58. 
Puig, T., Turrado, C., Benhamu, B., Aguilar, H., Relat, J., Ortega-Gutierrez, S., Casals, G., Marrero, 
P.F., Urruticoechea, A., Haro, D., Lopez-Rodriguez, M.L. & Colomer, R. Novel Inhibitors of Fatty 
Acid Synthase with Anticancer Activity. Clin Cancer Res 15, 7608-7615 (2009). 
59. 
Bertelsen, V. & Stang, E. The Mysterious Ways of ErbB2/HER2 Trafficking. Membranes (Basel) 
4, 424-446 (2014). 
60. 
Kuhajda, F.P., Jenner, K., Wood, F.D., Hennigar, R.A., Jacobs, L.B., Dick, J.D. & Pasternack, G.R. 
Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proceedings of the 
National Academy of Sciences of the United States of America 91, 6379-6383 (1994). 
61. 
Kuhajda, F.P., Katumuluwa, A.I. & Pasternack, G.R. Expression of haptoglobin-related protein and 
its potential role as a tumor antigen. Proc Natl Acad Sci U S A 86, 1188-1192 (1989). 
62. 
Kuhajda, F.P., Piantadosi, S. & Pasternack, G.R. Haptoglobin-related protein (Hpr) epitopes in 
breast cancer as a predictor of recurrence of the disease. N Engl J Med 321, 636-641 (1989). 
63. 
Alo, P.L., Visca, P., Marci, A., Mangoni, A., Botti, C. & Di Tondo, U. Expression of fatty acid 
synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77, 474-
482 (1996). 
64. 
Alo, P.L., Visca, P., Trombetta, G., Mangoni, A., Lenti, L., Monaco, S., Botti, C., Serpieri, D.E. & 
Di Tondo, U. Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast 
carcinomas. Tumori 85, 35-40 (1999). 
65. 
Wang, Y., Kuhajda, F.P., Li, J.N., Pizer, E.S., Han, W.F., Sokoll, L.J. & Chan, D.W. Fatty acid 
synthase (FAS) expression in human breast cancer cell culture supernatants and in breast cancer 
patients. Cancer Lett 167, 99-104 (2001). 
66. 
Migita, T., Ruiz, S., Fornari, A., Fiorentino, M., Priolo, C., Zadra, G., Inazuka, F., Grisanzio, C., 
Palescandolo, E., Shin, E., Fiore, C., Xie, W., Kung, A.L., Febbo, P.G., Subramanian, A., Mucci, 
L., Ma, J., Signoretti, S., Stampfer, M., Hahn, W.C., Finn, S. & Loda, M. Fatty acid synthase: a 
metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst 101, 519-532 
(2009). 
67. 
Le Rhun, Y., Kirkland, J.B. & Shah, G.M. Cellular responses to DNA damage in the absence of 
Poly(ADP-ribose) polymerase. Biochem Biophys Res Commun 245, 1-10 (1998). 
68. 
Youle, R.J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. 
Nat Rev Mol Cell Biol 9, 47-59 (2008). 
69. 
Puthalakath, H. & Strasser, A. Keeping killers on a tight leash: transcriptional and post-translational 
control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 9, 505-512 (2002). 
70. 
Menendez, J.A., Ropero, S., Mehmi, I., Atlas, E., Colomer, R. & Lupu, R. Overexpression and 
hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive 
to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively 
inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by 
which dietary fat can alter mammary tumorigenesis. Int J Oncol 24, 1369-1383 (2004). 
71. 
Menendez, J.A., Vellon, L. & Lupu, R. Targeting fatty acid synthase-driven lipid rafts: a novel 
strategy to overcome trastuzumab resistance in breast cancer cells. Med Hypotheses 64, 997-1001 
(2005). 
72. 
Vazquez-Martin, A., Ropero, S., Brunet, J., Colomer, R. & Menendez, J.A. Inhibition of Fatty Acid 
Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. 
Oncol Rep 18, 973-980 (2007). 
73. 
Mitchell, D., Hruska, C.B., Boughey, J.C., Wahner-Roedler, D.L., Jones, K.N., Tortorelli, C., 
Conners, A.L. & O'Connor, M.K. 99mTc-sestamibi using a direct conversion molecular breast 

MC1633 
87 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
imaging system to assess tumor response to neoadjuvant chemotherapy in women with locally 
advanced breast cancer. Clin Nucl Med 38, 949-956 (2013). 
74. 
Symmans, W.F., Peintinger, F., Hatzis, C., Rajan, R., Kuerer, H., Valero, V., Assad, L., Poniecka, 
A., Hennessy, B., Green, M., Buzdar, A.U., Singletary, S.E., Hortobagyi, G.N. & Pusztai, L. 
Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. 
J Clin Oncol 25, 4414-4422 (2007). 
75. 
Baselga, J., Cortes, J., Kim, S.B., Im, S.A., Hegg, R., Im, Y.H., Roman, L., Pedrini, J.L., 
Pienkowski, T., Knott, A., Clark, E., Benyunes, M.C., Ross, G. & Swain, S.M. Pertuzumab plus 
trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366, 109-119 (2012). 
76. 
Gianni, L., Pienkowski, T., Im, Y.H., Roman, L., Tseng, L.M., Liu, M.C., Lluch, A., Staroslawska, 
E., de la Haba-Rodriguez, J., Im, S.A., Pedrini, J.L., Poirier, B., Morandi, P., Semiglazov, V., 
Srimuninnimit, V., Bianchi, G., Szado, T., Ratnayake, J., Ross, G. & Valagussa, P. Efficacy and 
safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, 
or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 
trial. Lancet Oncol 13, 25-32 (2012). 
77. 
Ellis PA, Barrios CH, Eiermann W, Toi M, Im YH, Conte P-F, Martin M, Pienkowski T, Pivot 
XB, Burris HA, Strasak A, Patre M, Perez EA.  Phase III, randomized study of trastuzumab 
emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of 
HER2-positive MBC: Primary results from the MARIANNE study. J Clin Oncol 33, 2015; suppl; 
abstr 507. 
78. 
Sunters, A., Fernandez de Mattos, S., Stahl, M., Brosens, J.J., Zoumpoulidou, G., Saunders, C.A., 
Coffer, P.J., Medema, R.H., Coombes, R.C. & Lam, E.W. FoxO3a transcriptional regulation of 
Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278, 49795-49805 
(2003). 
79. 
Janssen, K., Pohlmann, S., Janicke, R.U., Schulze-Osthoff, K. & Fischer, U. Apaf-1 and caspase-9 
deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival 
during paclitaxel treatment. Blood 110, 3662-3672 (2007). 
80. 
Czernick, M., Rieger, A. & Goping, I.S. Bim is reversibly phosphorylated but plays a limited role 
in paclitaxel cytotoxicity of breast cancer cell lines. Biochem Biophys Res Commun 379, 145-150 
(2009). 
81. 
Wertz, I.E., Kusam, S., Lam, C., Okamoto, T., Sandoval, W., Anderson, D.J., Helgason, E., Ernst, 
J.A., Eby, M., Liu, J., Belmont, L.D., Kaminker, J.S., O'Rourke, K.M., Pujara, K., Kohli, P.B., 
Johnson, A.R., Chiu, M.L., Lill, J.R., Jackson, P.K., Fairbrother, W.J., Seshagiri, S., Ludlam, M.J., 
Leong, K.G., Dueber, E.C., Maecker, H., Huang, D.C. & Dixit, V.M. Sensitivity to antitubulin 
chemotherapeutics is regulated by MCL1 and FBW7. Nature 471, 110-114 (2011). 
82. 
Inuzuka, H., Shaik, S., Onoyama, I., Gao, D., Tseng, A., Maser, R.S., Zhai, B., Wan, L., Gutierrez, 
A., Lau, A.W., Xiao, Y., Christie, A.L., Aster, J., Settleman, J., Gygi, S.P., Kung, A.L., Look, T., 
Nakayama, K.I., DePinho, R.A. & Wei, W. SCF(FBW7) regulates cellular apoptosis by targeting 
MCL1 for ubiquitylation and destruction. Nature 471, 104-109 (2011). 
83. 
Meng, X.W., Lee, S.H., Dai, H., Loegering, D., Yu, C., Flatten, K., Schneider, P., Dai, N.T., Kumar, 
S.K., Smith, B.D., Karp, J.E., Adjei, A.A. & Kaufmann, S.H. Mcl-1 as a buffer for proapoptotic 
Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 
43-9006)-induced TRAIL sensitization. J Biol Chem 282, 29831-29846 (2007). 
84. 
Dai, H., Meng, X.W., Lee, S.H., Schneider, P.A. & Kaufmann, S.H. Context-dependent Bcl-2/Bak 
interactions regulate lymphoid cell apoptosis. J Biol Chem 284, 18311-18322 (2009). 
85. 
Yu, C., Bruzek, L.M., Meng, X.W., Gores, G.J., Carter, C.A., Kaufmann, S.H. & Adjei, A.A. The 
role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-
9006. Oncogene 24, 6861-6869 (2005). 
86. 
El-Kouhen, K. & Tremblay, M.L. PTPMT1: Connecting Cardiolipin Biosynthesis to Mitochondrial 
Function. Cell Metab 13, 615-617 (2011). 

MC1633 
88 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
87. 
Abedin, M.J., Wang, D., McDonnell, M.A., Lehmann, U. & Kelekar, A. Autophagy delays 
apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 14, 500-510 
(2007). 
88. 
Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino, T., Taniguchi, T. 
& Tanaka, N. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-
induced apoptosis. Science 288, 1053-1058 (2000). 
89. 
Shibue, T., Takeda, K., Oda, E., Tanaka, H., Murasawa, H., Takaoka, A., Morishita, Y., Akira, S., 
Taniguchi, T. & Tanaka, N. Integral role of Noxa in p53-mediated apoptotic response. Genes Dev 
17, 2233-2238 (2003). 
90. 
Hassan, M., Alaoui, A., Feyen, O., Mirmohammadsadegh, A., Essmann, F., Tannapfel, A., Gulbins, 
E., Schulze-Osthoff, K. & Hengge, U.R. The BH3-only member Noxa causes apoptosis in 
melanoma cells by multiple pathways. Oncogene 27, 4557-4568 (2008). 
 
 
20.1 
Additional Works Cited 
Benz, C. C., & et al. (1992). Estrogen-Dependent, Tamoxifen-Resistant Tumorigenic Growth of Mcf-7 
Cells Transfected with HER2/Neu. Breast Cancer Research and Treatment, 24(2): 85-95. 
Chung, Y., & al., e. (2002). Resistance to tamoxifen-induced apoptosis is associated with direct 
interaction between Her2/neu and cell membrane estrogen receptor in breast cancer. International 
Journal of Cancer, 97(3):306-312. 
Du, T., Sikora, M. J., Levine, K. M., Tasdemir, N., Riggins, R. B., Wendell, S. G., et al. (2018). Key 
regulators of lipid metabolism drive endocrine resistance in invasive lobular breast cancer. Breast 
Cancer Res, 20(1):106 PMID 30180878. 
Gonzalez-Guerrico, A. M., & et al. (2016). Suppression of endogenous lipogenesis induces reversion of 
the malignant phenotype and normalized differentiation in breast cancer. Oncotarget, 
7(44):71151-71168. 
Gyorffy, B., & et al. (2010). An online survival analysis tool to rapidly assess the effect of 22,277 genes 
on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Research and 
Treatment, 123(3):725-731. 
Huwiler, A., & Zangemeister-Wittke, U. (2007). Targeting the conversion of ceramide to sphingosine 1-
phosphate as a novel strategy for cancer therapy. Critical Reviews in Oncology-Hematology, 
63(2):150-159. 
Johnston, S., Pippen Jr, J., Pivot, X., Lichinitser, M., Sadeghi, S., Dieras, V., et al. (2009). Lapatinib 
combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal 
hormone receptor-positive metastatic breast cancer. J Clin Oncol, Nov 20;27(33):5538-46 
PMID19786658. 
Kaufman, B., Mackey, J. R., Clemens, M. R., Bapsy, P. P., Vaid, A., Wardley, A., et al. (2009). 
Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal 
women with human epidermal growth factor receptor 2-positive, hormone receptor-positive 
metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol, 
Nov 20;27(33):5529-37 PMID 19786670. 
Kurokawa, L., & Arteaga, C. L. (2001). Inhibition of erbB receptor (HER) tyrosine kinases as a strategy 
to abrogate antiestrogen resistance in human breast cancer. Clinical Cancer Research, 
7(12):4436s4442s. 

MC1633 
89 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Liu, Y. L., & et al. (1995). Mcf-7 Breast-Cancer Cells Overexpressing Transfected C-Erbb-2 Have an in-
Vitro Growth Advantage in Estrogen-Depleted Conditions and Reduced Estrogen-Dependence 
and Tamoxifen-Sensitivity in-Vivo. Breast Cancer Research and Treatment, 34(2):97-117. 
Menendez, J. A., & Lupu, R. (2017). Fatty acid synthase regulates estrogen receptor-α signaling in breast 
cancer cells. Oncogenesis, 6:e299. 
Nava, V. E., & et al. (2002). Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of 
breast cancer MCF-7 cells. Experimental Cell Research, 281(1):115-127. 
Ogretman, B. (2018). Sphingolipid metabolism in cancer signalling and therapy. Nature Reviews Cancer, 
18(1):33-50. 
Ogretman, B., & Hannun, Y. A. (2004). Biologically active sphingolipids in cancer pathogenesis and 
treatment. Nature Reviews Cancer, 4(8):604-616. 
Pietras, R. J., & et al. (1995). Her-3 Tyrosine Kinase Pathway Targets Estrogen-Receptor and Promotes 
Hormone-Independent Growth in Human Breast-Cancer Cells. Oncogene, 10(12):2435-2446. 
Ryland, L. K., & et al. (2011). Dysregulation of sphingolipid metabolism in cancer. Cancer Biology & 
Therapy, 11(2):138-149. 
Shou, J., & al., e. (2004). Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2/neu 
cross-talk in ER/HER2-positive breast cancer. Journal of the National Cancer Institute, 
96(12):926-935. 
 
 
20.2 
Additional References from Amendment 7 
Exman P, T. S. (2021). HER2-positive metastatic breast cancer: a comprehensive review. Clinically 
Advanced Hematological Oncology, 19(1), 40-50. 
Hurvitz SA, P. P. (2021). TRIO-US B-12 TALENT: Phase II neoadjuvant trial evaluating trastuzumab 
deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. Journal of 
Clinical Oncology, 39, no. 15_suppl. doi:10.1200/JCO.2021.39.15_suppl.TPS603 
Huwiler, A., & Zangemeister-Wittke, U. (2007). Targeting the conversion of ceramide to sphingosine 1-
phosphate as a novel strategy for cancer therapy. Critical Reviews in Oncology-Hematology, 
63(2):150-159. 
Ignatov T, G. F. (2019). Loss of HER2 after HER2-targeted treatment. Breast Cancer Research and 
Treatment, 175(2), 401-408. doi:10.1007/s10549-019-05173-4 
Ram S, K. D. (2014). The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior 
in cancer cells. MAbs, 6(5), 1211-9. 
 
 

MC1633 
90 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf_stat.html 
 
 

MC1633 
91 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Appendix II 
Patient Medication Diary 
The Patient Medication Diary is provided as a standalone document as required by the IRB. 
 

MC1633 
92 
MCCC Amendment 7 
Protocol Version Date: 16Oct2023 
Appendix III Palmar-Plantar Erythrodysesthesia (PPE) Grading Worksheet 
For each PPE event, please use this worksheet for AE grading, per CTCAE v4.03. 
Grade 1: Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain 
Interpretation – Skin changes such as erythema, edema or peeling that does not cause pain or 
interfere with self-care and/or ADLs. If neuropathic pain from taxane-chemotherapy is present 
without pain associated with the skin changes, then PPE would be grade 1.  
Grade 2: Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
Interpretation – skin peeling, bleeding, blistering, fissures, or edema, with pain that is associated 
with PPE. If neuropathic pain from taxane-chemotherapy is present without pain associated with 
the skin changes, then PPE would be grade 1. The skin changes with PPE-associated pain may or 
may not limit ADLs. If self-care is constrained, then PPE would be grade 3. 
Grade 3: Severe skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; 
limiting self care ADL 
Interpretation – skin bleeding, blistering, fissures, or edema constraining the patient’s ability to 
perform self-care (dressing, bathing, grooming, eating, toileting, and mobility). 
Are the following present (Y/N)? 
Signs & Symptoms Present 
YES 
NO 
Erythema 
 
 
Edema (not due to lymphedema) 
 
 
Peeling 
 
 
Blisters 
 
 
Fissures 
 
 
Bleeding 
 
 
Pain in hands and/or feet that is neuropathic and/or due to 
taxane-induced neuropathy 
 
 
Pain in hands and/or feet that is due to PPE (skin changes)* 
 
 
PPE constrains ability to perform self-care (dressing, bathing, 
grooming, eating, toileting, mobility)** 
 
 
 
*If yes, then grade is 2 
**If yes, then grade is 3