Conditions: Breast Cancer
Keywords: Debio 1347 Fulvestrant 17-379
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of a phase Ib study is to find out the best or maximum tolerated dose of a medication or combination of medications. Therefore, the purpose of this study is to decide the best dose of the study drug, Debio 1347, that can be given in combination with the standard hormonal drug, fulvestrant. Debio 1347 and fulvestrant could shrink the cancer but it could also cause side effects. This study tells us about the side effects of these drugs when given in this new combination, and how often they occur.

Detailed description:

Arms:
arm 1: Fulvestrant will be administered according to its approved dose of 500 mg intramuscularly on days 1, 15, 29 and then every 28 days (+/-3 days) thereafter. Debio 1347 will be administered orally daily (1 cycle is 28 days) and the dose of Debio 1347 could be deescalated. The dosage in the phase 2 portion will be the MTD/RP2D determined in the phase 1b portion.

Interventions: intervention 1: Fulvestrant intervention 2: Debio 1347
Intervention descriptions: intervention 1: Fulvestrant will be administered according to its approved dose of 500 mg intramuscularly on days 1, 15, 29 and then every 28 days (+/-3 days) thereafter. intervention 2: Debio 1347 will be administered orally daily (1 cycle is 28 days) and the dose of Debio 1347 could be deescalated.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 1 of 60 
 
 
 
 
 
A Phase Ib/II study of Debio 1347 plus Fulvestrant in Patients with 
FGFR-Amplified Endocrine Receptor Positive Metastatic Breast Cancer 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal 
Investigator/Department: 
Komal Jhaveri, MD, FACP 
Medicine: Breast 
Co-Principal 
Investigator(s)/Department: 
Sarat Chandarlapaty, MD, PhD 
Jorge Reis-Filho, MD, PhD 
Medicine/Breast 
Surgical Pathology 
Investigator(s)/Department: 
Ting Bao, MD 
Victoria S. Blinder, MD 
Jacqueline F. Bromberg, MD, PhD 
Elizabeth Comen, MD 
Gabriella M. D’Andrea, MD 
Chau T. Dang, MD 
Carlos Dos Anjos, MD 
Pamela Drullinsky, MD 
Monica N. Fornier, MD 
Devika Gajria, MD, MPH 
Shari Goldfarb, MD 
Ayca Gucalp, MD 
Neil Iyengar, MD 
Diana E. Lake, MD 
Tomas Lyons, MD 
Shanu Modi, MD 
Larry Norton, MD 
Mark E. Robson, MD 
Rachel Sanford, MD 
Andrew D. Seidman, MD 
Nancy T. Sklarin, MD 
Tiffany A. Traina, MD 
Linda T. Vahdat, MD 
Neil Vasan, MD 
Pedram Razavi, MD, PhD 
Fresia Pareja, MD, PhD 
Pier Selenica 
Carlos Silva Correia, MD 
Joshua Drago, MD 
Dariana Espinal, RN 
Esthefanie Giordano, RN 
Eric Zawacki, RN 
Renee Mercado, RN 
Karen Suarez, RN 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Surgical Pathology 
Surgical Pathology 
Neurology 
Graduate Medical Education 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 


Page 2 of 60 
 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Maureen Cannon, NP 
Karen Drucker, NP 
Odessa Williams, NP 
Danielle Alleva, NP 
Nicole Jimenez, NP 
Melissa Emerzian, NP 
Mikel Ross, NP 
Alexa Segna, NP 
Britni (Walton) Rizzolo, NP 
Amy Deipolyi, MD, PhD 
Kimberly Feigin, MD 
Andrei Holodny, MD 
Mario Lacouture, MD 
Jasmine Francis, MD 
Sujata Patil, PhD 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Radiology 
Radiology 
Radiology 
Medicine/Dermatology 
Surgery 
Epidemiology-Biostatistics 
Consenting 
Professional(s)/Department: 
Ting Bao, MD 
Victoria S. Blinder, MD 
Jacqueline F. Bromberg, MD, PhD 
Sarat Chandarlapaty, MD, PhD 
Elizabeth Comen, MD 
Gabriella M. D’Andrea, MD 
Chau T. Dang, MD 
Carlos Dos Anjos, MD 
Pamela Drullinsky, MD 
Monica N. Fornier, MD 
Devika Gajria, MD, MPH 
Shari Goldfarb, MD 
Ayca Gucalp, MD 
Neil Iyengar, MD 
Komal Jhaveri, MD, FACP 
Diana E. Lake, MD  
Tomas Lyons, MD 
Shanu Modi, MD 
Larry Norton, MD 
Pedram Razavi, MD, PhD 
Mark E. Robson, MD 
Rachel Sanford, MD 
Andrew D. Seidman, MD 
Nancy T. Sklarin, MD 
Tiffany A. Traina, MD 
Linda T. Vahdat, MD 
Neil Vasan, MD 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


Page 3 of 60 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
OneMSK  Sites 
Manhattan 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 4 of 60 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.................................................................................... 6 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................................... 18 
4.1 
Design .................................................................................................................................... 18 
4.2 
Intervention ................................................................................................................................... 19 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 19 
5.1. Debio 1347 (CH5183284) ................................................................................................................... 19 
5.1.1 Chemical Structure, Formula, and Molecular Weight ............................................................. 19 
5.2 Fulvestrant ............................................................................................................................... 21 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................. 21 
6.1 
Subject Inclusion Criteria ........................................................................................................ 21 
6.2 
Subject Exclusion Criteria ....................................................................................................... 23 
7.0 
RECRUITMENT PLAN ........................................................................................................................ 25 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 26 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 27 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................................ 39 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................................ 43 
11.1 
Summary of toxicities of agents .............................................................................................. 43 
11.1.1 
Debio 1347 ............................................................................................................................... 44 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................ 44 
12.1 Measurability of Tumor at Baseline ........................................................................................... 44 
12.1.1 Measurable Lesions ................................................................................................................. 44 
12.1.2 Non-measurable Lesions ......................................................................................................... 45 
12.1.3 Special Considerations Regarding Lesion Measurability .................................................... 45 
12.1.4 Methods of Tumor Measurement ........................................................................................ 46 
12.2 Tumor Response Evaluation .......................................................................................................... 46 
12.2.1 Designation of Target and Non-Target Lesions ...................................................................... 46 
12.2.2 Definitions of Response .................................................................................................. 46 
12.3 Exploratory assessments ..........................................................Error! Bookmark not defined. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 50 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 5 of 60 
 
 
14.0 
BIOSTATISTICS ................................................................................................................... 51 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 53 
15.1 Research Participant Registration ............................................................................................. 53 
15.2 
Randomization ....................................................................................................................... 53 
16.0 
DAT A M ANAGEMENT ISSUES ............................................................................................ 53 
16.1 
Quality Assurance .................................................................................................................. 53 
16.2 
Data and Safety Monitoring ......................................................................................................... 54 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................ 54 
17.1 
Privacy ................................................................................................................................... 54 
17.2 
Serious Adverse Event (SAE) Reporting .................................................................................... 55 
17.2.1 SAE Reporting to Debiopharm International S.A ............................................................ 56 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................................... 56 
19.0 
REFERENCES .......................................................................................................................... 57 
20.0 
APPENDICES ....................................................................................................................... 60 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 6 of 60 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is an open-label, single institution, phase Ib/phase II non-randomized trial that evaluates 
the safety, tolerability and anti-tumor activity of fulvestrant and Debio 1347 in patients with 
ER+/HER2- metastatic breast cancer (MBC) that are FGFR-amplified (as confirmed by a CLIA 
certified laboratory). The phase Ib portion will evaluate 2 dose cohorts (80mg (cohort/dose 
level 1), and one dose de-escalation cohort (60 mg dose level -1) in case dose level 1 is 
deemed to have intolerable toxicity. Only the dose of Debio 1347 will be de-escalated. 
Fulvestrant will be administered intramuscularly at standard doses. Total number of patients 
expected in the phase 1b portion: minimum 4 and maximum 12. 
The phase 2 portion will be comprised of an optimal Simon two-stage design to determine the 
efficacy (defined as clinical benefit rate (CBR): overall response rate (ORR) + Stable disease 
(SD) ≥ 24 weeks) of Debio 1347 plus fulvestrant. Patients enrolled to the phase II portion will 
be treated at the recommended phase 2 doses (RP2D) identified from the phase Ib portion of 
the study. Total number of patients expected in the phase 2 portion: minimum 18, maximum 
43. 
Briefly, patient’s eligibility criteria will include: pre/peri/post-menopausal women and men with 
metastatic ER+/HER2-/FGFR-amplified breast cancer, in first or second line of treatment in the 
metastatic setting (phase II portion) without prior use of a FGFR inhibitor; ECOG performance 
status ≤1, normal baseline blood counts and chemistry laboratory profile; and no intercurrent 
uncontrolled illness. Treatment will be given until disease progression or unacceptable toxicity. 
To assess theanti-tumor effect of therapy, we will estimate the overall tumor burden at baseline 
to which subsequent measurements (performed every 8 weeks for the first 6 months and then 
every 12 weeks thereafter using the Solid Tumor Response Criteria [RECIST] v1.1) will be 
compared. 
Pharmacokinetic and pharmacodynamic data will be obtained throughout the phase Ib/Phase 
II portion of the study. A baseline biopsy of a metastatic site will be required for all the patients 
enrolled on the trial, with the acquisition of at least 3 fragments of a core biopsy and in addition 
archival tissue will also be obtained, whenever available. Tissue will be evaluated for FGFR 
amplifications by FISH and protein and mRNA expression in collaboration with Dr. Jorge Reis- 
Filho. 
Plasma will also be serially obtained, for measurement of plasma cell-free tumor DNA (cfDNA) 
at baseline, Cycle 1 Day15, Cycle 3 D1 and at disease progression). This would allow us to 
determine biomarkers of response and/or resistance associated with FGFR inhibition. 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objectives: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 7 of 60 
 
 
 
 
Phase 1: 
• 
To determine the safety, tolerability,  maximum tolerated dose (MTD)/recommended 
phase 2 dose (RP2D) of Debio 1347 Plus Fulvestrant in patients with ER+/HER2-/FGFR 
amplified metastatic breast cancer 
Phase 2: 
• 
To investigate the anti-tumor activity of Debio 1347 in combination with fulvestrant in 
patients with ER+/HER2-/FGFR-amplified metastatic breast cancer as defined as clinical 
benefit rate (CBR: Objective Response Rate plus Stable disease > 24 weeks) 
Secondary objectives: 
Phase 1: 
 
• 
To obtain a preliminary assessment of the anti-tumor activity (CBR and overall response 
rate (ORR)) of Debio 1347 in combination with fulvestrant in patients with ER+/HER2- 
/FGFR-amplified metastatic breast cancer 
 
Phase 2: 
 
• 
To further characterize the safety and tolerability of Debio 1347 in combination with 
fulvestrant in patients with ER+/HER2-/FGFR- amplified metastatic breast cancer 
 
• 
To determine the overall response rate (ORR), time to progression (TTP), progression- 
free survival (PFS) and overall survival (OS) for the combination of Debio 1347 with 
fulvestrant in patients with ER+/HER2-/FGFR- amplified metastatic breast cancer 
 
 
 
Exploratory Objectives: 
 
Phase 1 and Phase 2: 
 
• 
To measure the pharmacokinetic (PK) parameters of Debio 1347 in combination with 
fulvestrant 
 
• 
To measure pharmacodynamic biomarkers of FGFR inhibition 
 
• 
To make an assessment of biomarkers of response and/or resistance from archival tissue 
and fresh tumor biopsies (using next generation sequencing, FISH, protein and mRNA 
expression) and plasma (cell-free DNA) and correlate with clinical benefit 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Estrogen Receptor positive Breast Cancer 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 8 of 60 
 
 
 
 
Despite advances in early detection and therapeutic options, unresectable or metastatic breast 
cancer (MBC) remains incurable and is one of the leading causes of cancer-related mortality. 
Breast cancer is a molecularly heterogeneous disease with three distinct molecular subtypes 1. 
The first group is characterized by estrogen receptor (ER) expression positivity and/or 
progesterone receptor (PgR) positivity with the absence of over-expression or amplification of 
HER2. The second group is characterized by over-expression or amplification of HER2, with 
more than half of these tumors being positive (+) for expression of ER/PgR. The third group 
lacks detectable ER and PgR, and overexpression of HER2, and is thus referred to as triple- 
negative breast cancer. Approximately 65% of newly diagnosed breast cancers are ER/PgR+ 
and HER2- negative (also referred to as luminal tumors), while an additional 20% of newly 
diagnosed cases are HER2+. ER-targeted drugs, specifically drugs that antagonize estrogen 
binding to the ER (tamoxifen), drugs that block estrogen biosynthesis (non-steroidal and 
steroidal aromatase inhibitors [AI] - only effective in postmenopausal patients), and drugs that 
antagonize and downregulate the ER (fulvestrant), have been the mainstay of systemic 
treatment for patients with both localized and metastatic ER/PgR+ breast cancers 2. 
 
Fulvestrant is the most recent addition to the armamentarium of hormonal therapies available 
to treat these patients. However, acquired resistance (and occasionally primary resistance) to 
antiestrogen therapy universally develops in patients with ER+ MBC3. Interestingly, even after 
acquired resistance develops, breast cancer cells appear to still depend on low-level ER 
activity in addition to signaling through sometimes acquired oncogenic signaling pathways 4. In 
addition, in patients initially diagnosed with ER/PgR+ localized breast cancer who later recur, 
tumors usually demonstrate some degree of resistance to antiestrogen therapy at the time of 
recurrence5. Therefore, improving the efficacy of endocrine therapy would be of great benefit 
to patients with breast cancer and represents a large unmet medical need. 
 
3.1.1 Fulvestrant as first-line or second-line therapy for ER+ MBC 
 
Fulvestrant (a selective estrogen receptor down-regulator or SERD) is currently a standard of 
care hormonal therapy option in patients with ER+ MBC6. Fulvestrant has an affinity for ER 
comparable to estradiol. It blocks the trophic actions of estrogens without any partial agonist 
(estrogen-like) activity and is currently indicated for the treatment of ER+ MBC in 
postmenopausal women with disease progression following primary antiestrogen therapy. 
Clinical trials in postmenopausal women with primary breast cancer have shown that 
fulvestrant significantly downregulates tumor ER protein levels compared with placebo. There 
was also a significant decrease in PgR expression consistent with inhibition of ERα 
transcription. Further, treatment with fulvestrant inhibits tumor cell proliferation as measured 
by Ki67 immunohistochemistry7. 
 
Two phase III clinical trials were completed in a total of 851 postmenopausal women with 
breast cancer who had disease recurrence on or after adjuvant endocrine therapy or 
progression following endocrine therapy for advanced disease8. These trials compared the 
safety and efficacy of monthly administration of fulvestrant 250 mg vs. the non-steroidal AI 
anastrozole at 1 mg/daily. Monthly 250 mg fulvestrant was at least as effective as anastrozole 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 9 of 60 
 
 
 
 
in terms of PFS, OR, and time to death. The combined data showed an objective response 
rate for fulvestrant of 19.2% compared with 16.5% for anastrozole. The median time to death 
was 27.4 months for patients treated with fulvestrant and 27.6 months for patients treated with 
anastrozole. The hazard ratio of fulvestrant 250 mg to anastrozole for time to death was 1.01 
(95% CI 0.86 to 1.19). 
 
Doses of fulvestrant higher than 250 mg have greater pharmacodynamic activity against the 
ER pathway. Thus, a 500 mg monthly dose after an initial load is now the FDA-approved 
standard of care. A phase III clinical trial (CONFIRM)9 was completed in 736 postmenopausal 
women with breast cancer who had disease recurrence on or after adjuvant endocrine therapy 
or progression following endocrine therapy for advanced disease. The study included 423 
patients whose disease had recurred or progressed during antiestrogen therapy and 313 
patients whose disease had recurred or progressed during AI therapy. This trial compared the 
efficacy and safety of fulvestrant 500 mg (n=362) vs. 250 mg (n=374). PFS for fulvestrant 500 
mg was 6.5 months compared to 5.5 months for fulvestrant 250 mg. Overall survival data from 
the time of final analysis showed a median time to death of 26.4 months for fulvestrant 500 mg 
vs. 22.3 months for fulvestrant 250 mg [HR (95%CI) 0.81 (0.69, 0.96), p=0.016]. 
 
More recently results from the randomized, double-blind, multicenter phase III FALCON 
(Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer) 
trial for the treatment of locally-advanced or metastatic breast cancer, in post-menopausal 
women who have not had prior hormonal treatment for hormone-receptor-positive (HR+) 
breast cancer was published in Lancet10. That trial enrolled a total of 462 patients, (n=230) 
were randomized to 500mg intramuscular injections of fulvestrant (Days 0, 14, 28, then every 
28 days), and (n=232) to 1mg of anastrozole daily. Patients were also allowed one prior line of 
chemotherapy. After a median follow-up of 25 months, patients treated with fulvestrant had a 
statistically significant 21% improvement in progression-free survival compared to  those 
treated with anastrozole (16.6 months vs. 13.8 months, p = 0.048). Further, subgroup analysis 
showed an even greater impact on progression-free survival in patients whose disease had 
not spread to the liver or lungs at baseline (22.3 vs. 13.8 months). These data therefore support 
the use of fulvestrant even in the first-line metastatic setting. 
 
3.1.2 Resistance to Endocrine Therapies and CDK 4/6 Inhibitors 
 
Despite the multiple effective treatment options for ER+ breast cancer, many patients progress 
after initial endocrine therapy. Resistance mechanisms are incompletely understood. One 
mechanism known to contribute to resistance is ligand independent ER signaling in the setting 
of acquired ESR1 mutation (ESR1 is the gene which codes for the estrogen receptor). Highly 
recurrent mutations in the ESR1 ligand binding domain (LBD) (p.Tyr537Ser/Asn and 
p.Asp538Gly) are present in approximately 20% of metastatic ER+ breast cancer tumors after 
treatment with endocrine therapy but rarely prior to treatment with endocrine therapy11,12. 
Mutant forms of ER mediate clinical resistance to aromatase inhibitor therapy13. Mutant 
receptors also require higher doses of tamoxifen or fulvestrant to antagonize mutant ER 
signaling. Two other emerging mechanisms of endocrine resistance include a decoupling of 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
Page 10 of 60 
 
 
 
 
the cell cycle control from ER-signaling (e.g. genetic mechanisms such as CCND1 
amplification) and alternate proliferation signals via receptor tyrosine kinases (RTK) and their 
intracellular signaling cascades via phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target 
of rapamycin (mTOR)14-16. These proposed mechanisms of endocrine therapy resistance result 
in tumor cells that have bypassed estrogen control of cell proliferation. 
 
While preclinically, oral serum ER down-regulators are thought to be similar or better than 
fulvestrant against the mutant ESR1 and many agents are in various phases of clinical 
development, none are approved to date. 
 
The introduction of CDK4/6 inhibitors into the treatment of ER+ breast cancer was supported 
by strong preclinical data and rationale17. Cyclin D proteins are critical in cancer cell division 
and complex with the CDK4 and CDK6 protein kinases to promote G1 progression by 
hyperphosphorylating and activating the retinoblastoma protein (pRb)18. Abnormalities that 
result in CDK activation are highly enriched in luminal A and B breast cancer subtypes, ~85% 
of which were ER+/HER2− (Cancer Genome Atlas Network 2012). The luminal subtypes also 
maintain expression of pRb19, which is essential for benefit from treatment with a CDK4/6 
inhibitor. ER+ breast cancer cell lines are among the cancer models most sensitive to single 
agent CDK4/6 inhibition as well as to the combination of endocrine therapy and CDK4/6 
inhibition20. In contrast to the oral SERDs, clinically, CDK4/6 inhibitors have recently 
demonstrated efficacy in ER+ breast cancer and have led to the FDA approval of the first-in- 
class agent, palbociclib. The PALOMA-1 trial demonstrated that the combination of letrozole 
and palbociclib was more effective than letrozole alone (median PFS 20.2 months versus 10.2 
months) in the front line setting21. The confirmatory phase III randomized PALOMA-2 study 
completed accrual and its results corroborate the benefit of CDK4/6 inhibitors in first line. In 
PALOMA 2 a total of 666 post-menopausal patients with no prior systemic therapy for ER+ 
MBC were randomized 2:1 to receive letrozole with palbociclib or letrozole with  placebo. 
Median PFS (primary endpoint) was 24.8 months vs. 14.5 months in favor of the palbociclib 
arm (HR=0.58 [0.46–0.72], p < 0.000001). Response rate was also improved in the palbociclib 
arm (42.1% vs. 34.7%, p=0.031; 55.3% vs. 44.4% in patients with measurable disease 
[p=0.013]), and clinical benefit rate was 84.9% vs. 70.3% (p < 0.0001)22. Similarly, the 
combination of fulvestrant with palbociclib (median PFS = 9.2 months) in the PALOMA-3 trial 
was more effective than single agent fulvestrant (median PFS = 3.8 months) after progression 
on endocrine therapy23. 
 
 
3.2 Fibroblast Growth Factor Receptor Pathway in Cancer ER+ Breast Cancer 
 
The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical role 
in cell behaviours, such as proliferation, differentiation, migration and survival, and are 
fundamental 
to 
embryonic 
development, 
regulation of 
angiogenesis, 
and 
skeletal 
development. 
 
The FGFR family, which is phylogenetically closely related to the VEGFRs and PDGFRs, 
comprises of five members, of which four are receptor-type tyrosine kinases (FGFR1-4)24. By 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
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Page 11 of 60 
 
 
 
 
alternative splicing, they form seven FGFR proteins (FGFR1b, FGFR1c, FGFR2b, FGFR2c, 
FGFR3b, FGFR3c, and FGFR4) which are expressed in a tissue specific manner and with 
differing ligand-binding  specificities. 
 
Each of the 4 FGF receptors have an extracellular domain that contains 3 IG like domain and 
an acidic box, a transmembrane domain and an intracellular TK domain. There are 22 FGF 
ligands that bind to the 2nd and 3rd IG domains of different FGFR receptors and splice variants 
creating ligand binding specificity. Ligand binding causes receptor dimerization, enabling 
transphosphorylation of intracellular kinases and phosphorylation of intracellular signaling 
proteins25. This downstream signaling occurs through two main pathways - the intracellular 
receptor substrates FGFR substrate 2 (FRS2) and phospholipase C γ (PLCγ), leading 
ultimately to upregulation of the Ras-dependent mitogen-activated protein kinase (MAPK) and 
Ras-independent phosphoinositide 3-kinase (PI3K)–Akt signaling pathways26. 
 
FGFR are susceptible to be hijacked by cancer cells and have been shown to have oncogenic 
roles in many cancers. These receptors are also known to be involved in cancer cell 
proliferation, angiogenesis, cell migration, invasion and metastasis. Activation of FGFRs as a 
result of amplification, mutation or translocation of FGFR genes or over-expression of FGFR 
proteins or overproduction of FGF ligands has been shown to be oncogenic. Genes encoding 
FGFRs have been identified as among the most commonly mutated kinase genes in human 
cancer, with mutations in FGFR2 and FGFR3 being most prevalent27. Gene amplification or 
aberrant transcriptional regulation can result in receptor overexpression, whilst a number of 
point mutations have been identified that produce receptors that are either constitutively active 
or exhibit a reduced dependence on ligand binding for activation. In addition translocations can 
result in expression of FGFR-fusion proteins with constitutive FGFR kinase activity28. Finally, 
isoform switching alters the ligand binding specificity of resulting receptors and hence 
sensitizes cells to FGFs that they would not normally be responsive to 29,30. 
 
Activating oncogenic FGFR2 mutations confer sensitivity to FGFR inhibition. Aberrant 
expression, amplification and/or overexpression of FGF proteins, as well as altered gene- 
splicing of FGFRs represent other mechanisms through which FGF/FGFR signaling can 
become deregulated in cancer29,31,32. 
 
Inhibition of FGFR may have clinical utility in cancers that overexpress FGFRs, such as 
breast33,34, esophageal, bladder35, gastric, and lung cancers34,36, or display a prevalence of 
FGFR mutations, such as bladder cancer37,38. FGF/FGFR signaling may also serve as an 
escape pathway in tumours that are being treated with inhibitors of other cellular signaling 
components, such as vascular endothelial  growth factor receptor (VEGFR). 
 
3.2.1 Fibroblast Growth Factor Receptor Pathway in ER+ MBC 
 
FGFR1 amplification (Amplification of a region at chromosome 8p12) is present in up to 17% 
of    all    breast    cancers    and    up    to    27%    of    luminal    B    type    breast    cancer 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-379 A(7) 
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Page 12 of 60 
 
 
 
 
39,40. Based on the TCGA FGFR2 amplifications have been reported in 2-3% and FGFR 3 and 
4 amplifications in 1% of breast cancer. 
 
Furthermore, ER+ luminal B tumors overexpressing FGFR1 exhibited increased proliferation 
and decreased distant metastasis-free survival. FGFR1 amplification was also shown to be an 
independent predictor of overall survival in patients with ER+ breast cancer treated with 
tamoxifen40. In fact, preclinical studies have demonstrated that FGFR1 amplification conferred 
resistance to endocrine-based therapies through activation of the MAPK and PI3K 
pathways.40,41 About 30-40% of breast tumors with FGFR1 amplification also exhibit 
amplification of CCND1, FGF3/4/19 in chromosome 11q29. This co-amplification is also 
associated with a reduction of patients’ survival42. 
 
Based on these data, several pharmaceutical companies have developed selective and non- 
selective FGFR inhibitors, focusing their clinical development on tumor subtypes with a high 
likelihood of dependence on FGFR pathway signaling, including in metastatic breast cancer. 
 
A phase 1/2a clinical trial of lucitanib, a pan VEGFR, PDGFR and FGFR inhibitor in women 
with FGFR1- or 11q (FGF3, FGF4, Cyclin D1, or FGF19)-amplified MBC demonstrated a 
promising objective response rate [ORR] of 50%43. However, the larger, phase 2 trial of 
lucitanib in MBC was just recently reported at the 2016 San Antonio Breast Cancer Symposium 
and showed a modest ORR of 3.5% (6/178) and SD 29.5%. median PFS was 2.9 months (95% 
CI 2.7, 3.8). Toxicities reflected those of a potent anti-angiogenic agent and most frequent 
adverse effects were hypertension, fatigue, nausea, hypothyroidism, and headache. Both 
patients with FGFR1 amplification and/or 11q amplification were enrolled and the clinical 
activity could not be linked to a particular biomarker or selection factor. 
 
3.3 Debio 1347 
 
The orally-active small molecule Debio 1347 is an ATP competitive and highly selective 
inhibitor of FGFR1, FGFR2 and FGFR3 at the low nanomolar level in cell-free systems (IC50: 
7.6 –22 nM). Preclinical studies have shown that Debio 1347 is effective in multiple tumour 
models of different origins with FGFR alterations. 
 
3.3.1 Pharmacology – in vitro 
 
F (IC50: 7.6–22 nM) with less potent inhibitory activity on FGFR4 (290 nM) in cell-free systems. 
The compound is highly selective and does not act on VEGF receptor kinase KDR as 
demonstrated in vascular endothelial cells. 


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Figure 1: Radar plot showing selectivity of Debio 1347 over 234 recombinant kinases (0: 
remaining activity ≥ 50% at 1μM, 1: remaining  activity < 50% at 1μM, 2: remaining  activity 
≤ 10% at 1μM + ≤ 50% at 0.1 μM, 3: remaining  activity ≤ 10% at 1M + < 20% at 0.1μM) 
 
The activity of Debio 1347 was evaluated in vitro in a large panel of human cancer cell lines. 
In cancer cells, Debio 1347 demonstrated a similar potent inhibition of phosphorylation of 
FGFR2 and of its downstream signaling molecules AKT and ERK1/2. In addition, Debio 1347 
selectively inhibits proliferation in cancer cell lines with FGFR alterations. The compound was 
specifically active in gastric cancer cell lines with FGFR2 amplification or high expression, 
endometrial cancer cell lines with FGFR2 mutations, bladder cancer lines with FGFR3 
mutation multiple myeloma cell lines with FGFR3 translocation, breast and colon cancer cell 
lines with FGFR2 amplification, squamous NSCLC cell lines and a small-cell lung cancer cell 
line with FGFR1 amplification (IC50: 12 – 620 nM). Interestingly, Debio 1347 also showed in 
vitro antiproliferative activity in several bladder cancer cell lines with FGFR3 fusions (IC50: 18 
– 350 nM). 
 
3.3.2 Pharmacology – in vivo 
 
Debio 1347 potently inhibits cell growth in a dose-dependent manner in tumour models with 
FGFR genetic alterations when administered orally once a day. When given orally in gastric 
tumours with FGFR2 amplification or high expression, Debio 1347 displayed tumour-shrinking 
effects at non-toxic doses, whereas no anti-tumour activity was observed in a non-amplified 
model. Strong anti-tumour activity was confirmed in endometrial tumour models with FGFR2 
mutations, multiple myeloma models with FGFR3 translocation, SCLC tumour models with 
FGFR1 amplification and breast tumour model with FGFR1 amplification. Debio 1347 showed 
remarkable tumor growth inhibition in the CAL-120 breast cancer xenograft model harboring 
FGFR1 amplification, with an inhibitory value of 87% at 50 mg/kg/day. Potent anti-tumour 
activity was also observed in vivo in several bladder tumour models carrying FGFR3 fusions, 
or mutation. 
These studies show that the small molecule FGFR inhibitor Debio 1347 is effective in multiple 
tumour models of different origins with FGFR alterations. The data provides guidance to the 
future clinical applications of Debio 1347 in the new segment that consists of cancers with 
FGFR genetic alterations (mutations, translocations, amplifications). 


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Additional preclinical studies using patient-derived xenograft (PDX) models have recently 
demonstrated that FGFR high mRNA expression levels were better correlated with sensitivity 
to Debio 1347 than amplification only. Debio 1347 induced tumour regressions in gastric PDX 
models with FGFR2 amplification or FGFR2 high expression levels, ESCC PDX models with 
FGFR1 high expression levels and urothelial cancer PDX models with FGFR3 high expression 
levels. 
 
Please refer to the Investigator’s Drug Brochure for more information. 
 
3.3.3 Toxicology and Safety Pharmacology 
 
The toxicology profile of Debio 1347 was assessed after single and repeated oral 
administration of up to four weeks duration in Wistar rats and Cynomolgus monkeys. In the 4- 
week studies, a recovery period of four weeks was included to evaluate the reversibility of any 
findings. The safety of Debio 1347 was also assessed in a battery of safety pharmacology in 
vitro and in vivo tests. 
In the single dose studies in rats, a Debio 1347 dose of 100 mg/kg - the highest dose tested - 
was well tolerated, but slight reductions in body weight and food consumption were observed. 
In monkeys, except for loose stools observed in one animal on the day after dosing, there were 
no observations at 10 mg/kg. 
In the GLP 4 week toxicity study in rats (0, 3, 10, 30 mg/kg/day), no deaths occurred at any 
Debio 1347 dose up to the highest dose, 30 mg/kg/day. At 30 mg/kg/day, thoracic deformity 
was seen in the general condition observations, and changes in cartilage and bone including 
the sternum were seen in the histopathological examinations. Also seen were mineralisation 
in multiple organs, changes in epithelial tissues, and changes in parameters of blood and urine 
related to renal function. At 10 mg/kg/day or less, the above-mentioned histopathological 
changes were not seen; at those doses, mainly changes in parameters of blood and urine that 
suggested effects on bone were observed. At the lowest dose of 3 mg/kg/day, high blood 
TRACP-5b (tartrate-resistant acid phosphatase 5b, a bone resorption marker) was seen, so 
the no observed adverse effect level (NOAEL) was judged to be less than 3 mg/kg/day. The 
NOAEL was considered to be lower than 3 mg/kg/day. 
In the GLP 4-week repeated-dose toxicity study in monkeys (0, 0.4, 1.3, and 4 mg/kg/day), no 
deaths occurred at any Debio 1347 dose up to the highest dose, 4 mg/kg/day. At 4 mg/kg/day, 
very slight histopathological changes in bone and cartilage and related changes in parameters 
of blood and urine were seen, and in one female, very slight histopathological changes in 
kidneys were observed. At the middle dose of 1.3 mg/kg/day, only high urinary excretion of 
inorganic phosphorus in females was seen. No effects were observed at the lowest dose of 
0.4 mg/kg/day, so that was judged to be the no observed adverse effect level in this study. On 
the basis of these results, the highest non-severely toxic dose for monkeys (HNSTD) was set 
at 4 mg/kg/day (NOAEL: 0.4 mg/kg/day). The principal target organs of Debio 1347 toxicity in 
rats and monkeys were bone/cartilage, epithelial tissues and the kidneys. In addition, effects 
on lymphohematopoietic tissues, liver and the gastrointestinal tract 
were observed. 
Mineralisation in multiple organs was also seen, with a broader range of organs and tissues 


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affected in rats than in monkeys. On the other hand, periosteal changes occurred only in 
monkeys but not in rats. Except for thoracic deformity and mineralisation in multiple organs in 
rats, the changes seen in rats and monkeys in the 4-week repeated-dose toxicity studies either 
reversed or tended to reverse over the 4-week recovery period. 
The genotoxic potential of Debio 1347 was assessed in several in vitro and in vivo tests: no 
mutagenic potential was observed in the Ames test and no increases in structural chromosome 
aberrations or in polyploid cells were observed in a chromosomal aberration test using human 
peripheral blood lymphocytes. In an in vivo micronucleus test in rats, however, the numbers of 
micronucleated immature erythrocytes were slightly increased, suggesting a micronucleus- 
inducing potential. In vitro, the principal mechanism of micronucleus induction seems not to be 
due to abnormal chromosome segregation. Based on these results, Debio 1347 is thought to 
be genotoxic to mammalian cells. Debio 1347 may have an in vivo phototoxic risk based on 1) 
an in vitro phototoxicity test using a fibroblast cell line, where the compound was suggested as 
a phototoxic substance (absorbance wavelengths of 200 nm to 400 nm); 2) a whole-body 
autoradiography in rats after single oral dose of 1 mg/kg of [14C] Debio 1347 suggesting a 
slower elimination rate of Debio 1347 from skin compared with blood. Although any 
reproductive and developmental toxicity studies of Debio 1347 have not been conducted, some 
changes in reproductive organs, such as thinning of vaginal mucosal epithelium and atrophic 
changes in testes, epididymides, prostate gland, seminal vesicles and uterus were observed 
at lethal dose in preliminary dose-repeated toxicity in rats. From the above findings and those 
on bone and cartilage, it is inferred that Debio 1347 may affect reproduction and development. 
In the safety pharmacology studies, no effects on the central nervous system or respiratory 
system were seen in rats at Debio 1347 doses up to 100 mg/kg. Debio 1347 was a potent 
hERG inhibitor in vitro (IC50: 677ng/mL). However, in the monkey telemetry study, Debio 1347 
did not modify the blood pressure, heart rate, and ECG or body temperature at doses up to 10 
mg/kg. 
No carcinogenicity studies or local tolerance studies have been conducted to date. 
 
Please refer to the Investigator’s Drug Brochure for more information. 
 
3.3.4. Clinical data 
 
Based on these data a phase 1 first –in-human trial was undertaken, and it has now completed 
the patients’ enrollment in the dose-escalation portion. 
A total of 57 patients with genomically activated advanced solid tumours were included into 
the dose-escalation part up to 06 April 2017. All had received at least one dose of Debio 1347 
and were assessable for safety. Of these, 54 were evaluable for efficacy. Eight dose levels 
had been tested at the time of cut-off (10, 20, 30, 40, 60,80, 110 and 150 mg daily). 
The MTD is 80mg since 2 DLTs were observed at110 mg daily. Five patients experienced 
DLTs: NCI-CTCAE Grade 2 intolerable dry mouth and dry eyes at 60 mg, Grade 3 
hypercalcaemia and Grade 3 hyperamylasaemia both at 80 mg, and Grade 3 bilirubin increase 
and  Grade  3  hyperphosphatemia  and  Grade  3  stomatitis  in  two  patients  at  110  mg, 


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respectively. At cut-off, treatment emergent adverse events (TEAEs) had been reported by all 
patients. At data cut-off, the most common treatment-emergent adverse events (TEAE) were 
hyperphosphatemia (75%), fatigue (40%), diarrhea (39%), nausea (40%), and inappetence 
(32%). Eighteen patients (32%) experienced a grade ≥ 3 related TEAE. Twenty-eight patients 
(49%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. 
Decreased left ventricular ejection fraction (LVEF) was reported in 1 patient (Grade 2) and 2 
patients experienced respectively non-clinically significant Grade 1 and 2 ECG QTc 
prolongation. 
Clinical activity started at the dose of 30 mg. Five patients had a partial response (PR): an 
endometrial cancer patient with FGFR1 amplification (30 mg), a cervical cancer patient with 
FGFR2 mutation (80 mg), an urothelial cancer harbouring a FGFR3-TACC3 translocation (80 
mg), a cholangiocarcinoma patient with FGFR2 mutation (110 mg), and a colon cancer patient 
with FGFR2 fusion (110 mg) and an urothelial cancer with FGFR3 harbouring a FGFR3- 
TACC3 translocation (150 mg). An additional 10 patients had target regression < 30%. Two 
out of these patients had a breast cancer. A triple-negative breast cancer patient with FGFR1 
amplification showed a reduction in the target lesions of 19% (40 mg), while a HR+ Her2- 
breast cancer patient with FGFR1 amplification showed a reduction in the target lesion of 12% 
(60 mg). 
Preliminary PK data from 54 patients treated with 10-150 mg/day during the dose escalation 
part indicate that Debio 1347 was rapidly absorbed after oral administration with a median tmax 
occurring at 3 hours post-dose. Apparent oral clearance (CL/F) and volume of distribution 
(Vz/F) were on average 7 L/hour and 120 L, respectively. Inter-patient variability was moderate 
to high, but PK appeared overall linear. Debio 1347 mean plasma exposure increased with 
dose in an approximately proportional manner in the 10-150 mg range. Half-life was 14 hours 
on average, with a limited accumulation (1.7-fold on average) after 28-day repeated once daily 
dosing. The Debio 1347 PK profiles and plasma exposure of the capsule and tablet 
formulations used in the trial were comparable. 
 
Please refer to the Investigator’s Drug Brochure for other information. 
 
3.4 Study Rationale 
 
As discussed, even after acquired resistance develops, ER+ breast cancer cells appear to still 
depend on low-level ER activity in addition to signaling through sometimes acquired oncogenic 
signaling 
pathways4. FGFR amplification confers resistance  to  endocrine-based 
therapies.40,41 Additionally, in ER+ breast cancers, most FGFR1 amplifications can coexist 
with 11q amplification (CCND1, FGF3/4/19). 
Ongoing clinical trials with FGFR inhibitors are being enriched for tumors harboring specific 
FGFR mutations and amplifications presumed to be highly addicted to this pathway. 
Preliminary clinical data demonstrated that FGFR and/or FGF3/4/19 ligand amplification is 
associated with clinical benefit from FGFR inhibitors43,44, suggesting that these could be 
biomarkers of tumor dependence on the FGF/FGFR pathway. However, the recently presented 


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larger phase 2 trial of lucitanib did not reproduce the promising clinical activity reported in the 
phase 1/IIa study. Additionally, no specific biomarker could be identified that would benefit from 
lucitanib therapy. This could be related to the following: 
1. Lucitanib is a non-selective FGFR inhibitor with toxicity profile similar to anti-angiogenic 
therapy 
2. Patients were treated with monotherapy and not in combination with endocrine therapy 
 
3. Additionally, the amplicon containing FGFR (8p) in lung cancer is more focal; in breast 
cancer this amplicon is rather broad and complex and therefore it remains to be seen if these 
differences influence the degree of addiction to FGFR1. The lucitanib trial allowed patients with 
11q amplification without co-occurring FGFR amplifications to the study. 
We plan to address these issues in our proposed clinical trial with Debio 1347 + Fulvestrant 
as follows: 
1. In 2015, we sequenced tumors from approximately 500 patients with metastatic breast 
cancer using MSK-IMPACT. Specifically, we have a large pool of pre-identified FGFR amplified 
(N=87) and 11q amplified  co-occurring with FGFR1 amplified tumors (N=35) using our in 
house, next generation sequencing assay- MSK-IMPACT. We will exclude patients with 11q 
amplification without co-occurring FGFR amplifications. 
2. We also have a lot of experience with non-specific and specific FGFR inhibitors, including 
Debio 1347 (IRB # 13-131; PI: Martin Voss). Preliminary evidence with FGFR blockade using 
the selective FGFR inhibitor, Debio 1347 has a manageable tolerability profile with promising 
clinical activity including stable disease in metastatic breast cancer patients with FGFR 
amplifications at lower than the RP2D of Debio 1347. In this trial we will be combining Debio 
1347 with Fulvestrant. 
3. Lastly, In situ hybridization scoring techniques for characterizing FGFR1-2 amplification 
have varied in trials reported to date 45. Although amplification of FGF3/4/19 ligands may also 
predict those patients more likely to benefit from FGFR blockade44, the heterogeneity in 
published definitions makes it difficult to assess thetrue significance of these biomarkers given 
the lack of standardized measurement. In order to better understand if the FGFR pathway is 
truly activated, we will not only have the information from a CLIA certified laboratory, but we 
also plan to collaborate with Dr. Jorge Reis-Filho and plan to perform FISH, protein expression 
and mRNA expression from fresh tumor biopsies that we plan to obtain for all patients enrolled 
on to this study. Beyond this, we plan to leverage our state of the art molecular profiling 
program to help further clarify biomarkers of response and/or resistance in this subtype. For 
instance, we could use outlier analyses together with further genomic analyses to attempt to 
better define the subset of tumors for which FGFR amplification represents a driver event. 
Hence, we hypothesize that combination therapies using selective FGFR inhibitors (in this 
case Debio 1347) along with standard endocrine therapy (such as fulvestrant) may lead to 
better responses in patients  with  ER+/ FGFR-amplified breast cancer. This study will also 


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afford us a better understanding of the role of FGFR pathway in endocrine resistant metastatic 
breast cancer. 
 
3.4.1 Rationale for the dose of Debio 1347 
 
Based on the preliminary analysis from the dose escalation portion of the phase 1 study, the 
recommended dose of Debio 1347 to be further explored in the expansion part of the study 
was chosen as 80mg once daily. 60 mg once daily is proposed as reduced dose in the case 
of intolerable toxicity. Due to non-overlapping toxicities with fulvestrant, we plan to start with 
dose level 1/cohort 1 also at 80mg in this study. A dose de-escalation cohort (dose level - 
1/60mg) is also built in if dose level 1 is deemed intolerable. Patients in the phase 2 portion 
will be treated at the MTD/RP2D of Debio 1347 from the phase 1b portion of the study without 
concomitant prophylaxis for hyperphosphatemia (see section 9.2.1). 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is an open-label, single institution, phase Ib/phase II non-randomized trial that evaluates 
the safety, tolerability and anti-tumor activity of fulvestrant and Debio 1347 in patients with 
ER+/HER2- metastatic breast cancer (MBC) that are FGFR-amplified (as confirmed by a CLIA 
certified laboratory). 
The phase I portion of this trial will have 2 dose levels: dose level 1 (80mg) and a de-escalation 
level (60mg) if the 80mg dose level has intolerable toxicities (N= minimum 4 and maximum 
12). Fulvestrant will be administered intramuscularly at standard doses (500 mg loading dose 
on days 1, 14, and 28 of the first month, then maintenance dosing every 28 days, ±3 days) 
with no dose-escalation. Only the dose of Debio 1347 will be de-escalated as shown below. 
There will be no intra-patient dose escalation. 1 cycle = 28 days. 
The Dose Limiting Toxicity (DLT) observation period includes Day 1 to Day 28 of Cycle 1, plus 
the assessments prior to drug administration on Cycle 2, Day1. 
 
Cohort/Dose  level 
Debio 1347 
Fulvestrant 
-1 
60mg 
500mg IM 
1 (Starting dose cohort) 
80mg 
500mg IM 
 
 
If none or one of the initial 3 patients in dose level 1 has DLT, 3 additional patients will be 
treated at the same dose level. If 2 or more patients experience DLT at this dose level, then 
dose level -1 will be evaluated. Should 2 or more patients experience DLT at dose level -1, the 
study will stop accrual. If only 1 of the 3 initial patients experiences a DLT at dose level -1, 3 


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additional patients will be evaluated at this dose level. Patients who withdraw before 
completing a full cycle of treatment for reasons other than development of a DLT will be 
replaced. 
The phase 2 portion will be comprised of an optimal Simon two-stage design to determine the 
efficacy (defined as clinical benefit rate (CBR): proportion of patients who have a best overall 
response of a complete response, a partial response, or stable disease (SD) for at least 24 
weeks (SD ≥ 24 weeks) of Debio 1347 plus fulvestrant (N: 18 in the first stage with possibility 
of going on to 43 if 3 out of the first 18 have a CBR ≥ 24 weeks). The dosage in the phase 2 
portion will be the RP2D determined in the phase 1b dose-escalation portion. The treatment 
schedule and duration in the phase 2 portion will be identical to the phase 1b part except that 
concomitant prophylaxis for hyperphosphatemia will not be required. Patients enrolled in the 
phase 1b portion will not be eligible for the phase 2 component. 
4.3 
Intervention 
 
Fulvestrant will be administered according to its approved dose of 500 mg intramuscularly on 
days 1, 15, 28 and then every 28 days (+/-3 days) thereafter. Debio 1347 will be administered 
orally daily (1 cycle is 28 days) and the dose of Debio 1347 could be de-escalated as detailed 
in section 4.1. The dosage in the phase 2 portion will be the MTD/RP2D determined in the 
phase 1b portion. 
Pharmacokinetic and pharmacodynamic data will be obtained throughout the phase Ib/Phase 
II portion of the study. A baseline biopsy of a metastatic site will be required, with the acquisition 
of at least 3 fragments on a core biopsy for all the patients enrolled on the trial and in addition 
archival tissue will also be obtained, whenever available. Tissue will be evaluated for FGFR 
amplifications by FISH and protein and mRNA expression in collaboration with Dr. Jorge Reis- 
Filho. 
Plasma will also be serially obtained, for measurement of plasma cell-free tumor DNA (cfDNA) 
at baseline, at Cycle 1 Day 15, Cycle 3 Day 1 and at disease progression. This would allow us 
to determine biomarkers of response and/or resistance associated with FGFR inhibition. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. Debio 1347 
 
5.1.1 Chemical Structure, Formula, and Molecular Weight 
 
Structural formula: 
 
 


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Chemical name: 5-amino-1-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-4-yl  1H-indol-2- 
yl ketone mono[(S)-2-hydroxysuccinate] 
 
Molecular weight: 490.47l 
 
Molecular  formula: C20H16N6O•C4H6O5 
 
5.1.2 International Non-proprietary Name, Brand Name, and Code Name 
 
INN (International  Non-proprietary Name) Not applicable 
Brand name: Not applicable 
Company code name: Debio 1347 malate (malate salt) 
 
Debio 1347 (free base) 
Former code name: CH5183284 
5.1.3 Finished product 
 
Tablets: Debio 1347 20mg and 50mg coated tablets contain the following excipients: lactose 
hydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium 
lauryl sulfate, and magnesium stearate. 
5.1.4 Stability 
 
Expiry date: 36 months after the manufacturing date (the shelf life may be extended when 
new stability data are available). 
Storage: mentioned on labels 
 
A certificate of analysis (CoA) will be provided with the product. 
 
5.1.5 Packaging 
 
Fifty-six capsules or tablets in HDPE bottles. 
 
5.1.6 Storage and handling 
 
Debio 1347 capsules or tablets should be stored at 15-25°C. 
 
5.1.7 Other 
 
The in vitro, in vivo, toxicology and clinical data to date are detailed in section 3.3.1-3.3.4. 
 
Debio 1347 will be provided by Debiopharm International SA. Please refer to the Investigator 
Brochure for any further details. 


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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
5.2 Fulvestrant 
 
Fulvestrant 500 mg should be administered intramuscularly into the buttocks slowly (1 - 2 
minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 28 and 
once every 28 days as per standard of care. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Males and Females, Age > 18 years 
• 
Written informed consent and authorization obtained from the subject/HIPAA- 
appointed legal representative prior to performing any protocol-related procedures 
including screening evaluations. 
• 
Patients with metastatic histologically or cytologically confirmed invasive breast 
cancer. 
• 
Female patients of postmenopausal status 
Postmenopausal status will be defined as following: 
o Age ≥ 60 years 
o Age < 60 years and 12 months of amenorrhea plus follicle stimulating 
hormone and plasma estradiol levels within postmenopausal range by local 
laboratory assessment in the absence of oral contraceptive pills, hormone 
replacement therapy, or gonadotropin-releasing hormone (GnRH) agonist or 
antagonist 
o Prior bilateral oophorectomy 
Pre or perimenopausal women allowed with the addition of goserelin. 
• 
ECOG performance status 0 -1 
• 
Tumor must be estrogen receptor and/or progesterone receptor positive (i.e. Hormone 
receptor positive (HR+) and HER-2 negative as defined by the ASCO-CAP guidelines: 
HR+ is defined as expression of ER and/PR in ≥ 1% of cells, or HR+ by local laboratory 
or regional definition. HER2− is defined as a HER2 IHC score of 0 or 1+, or an IHC 
score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ 
hybridization test indicating the absence of HER2 gene amplification, or a 
HER2/CEP17 ratio of < 2.0, or local clinical guidelines. 


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• 
Tumors must have FGFR amplifications as determined by a CLIA certified laboratory. 
Patients with FGFR amplifications co-occurring with 11q amplification (CCND1, 
FGF3,4, 19 amplifications) are also eligible. 
• 
Measurable or evaluable disease per RECIST1.1 or pure lytic or mixed lytic-blastic 
bone lesions 
• 
No more than 1 prior chemotherapy regimen in the metastatic setting for the phase 2 
portion. Patients in the phase 1 portion could have received any number of prior lines 
of therapy. 
• 
Willing to undergo a new core or excisional biopsy from a metastatic, not previously 
irradiated tumor lesion during screening 
• 
Life expectancy of greater than 3 months 
• 
Archival Tumor (up to 10 unstained slides) will be obtained, whenever available for 
additional biomarker analyses 
• 
Hematologic  parameters: 
o White blood cell (WBC) count of > 3000/ul 
o Absolute neutrophil count (ANC) > 1000/ul 
o Platelets > 100,000/ul, hemoglobin > 9.0 g/dl 
• 
Non-hematologic  parameters: 
o Corrected calcium value ≤1.1 x ULN 
o Total bilirubin ≤1.5 x ULN (upper limit of normal) except subject with 
documented Gilbert’s syndrome (≤5 x ULN) or liver metastasis, who must 
have a baseline total bilirubin ≤3.0 mg/dL 
o AST and ALT ≤ 3 x ULN, unless associated with hepatobiliary  metastases, in 
that case ≤5 x ULN 
o ALP ≤ 2.5 x ULN or ≤ 5.o x ULN for patients with bone metastases 
o Gamma-glutamyltransferase ≤ 2.5 x ULN 
o Albumin ≥ 2.5 g/dL 
o Phosphate ≤ 1.1 x ULN 
o Prothrombin time (PT) and/or prothrombin time international normalized ratio 
(PT-INR) and/or activated partial thromboplastin time (APTT) ≤ 1.3 x ULN 
o Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the 
basis of the 
Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85 if female, 1.00 if male) 
72 × (serum creatinine in mg/dL) 


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• 
Patients with “treated and stable” brain lesions for a duration of > 4 weeks may be 
enrolled. 
• 
Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication and 
agree to use effective contraception. If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required. Note: Abstinence is acceptable if 
this is the usual lifestyle and preferred contraception for the subject. 
 
 
6.3 
Subject Exclusion Criteria 
 
• 
Prior Fulvestrant for metastatic breast cancer will be allowed for phase 1 portion but 
not for the phase 2 portion 
• 
History of hypersensitivity to any of the excipients in the Debio 1347 formulation 
(lactose hydrate,  microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, sodium lauryl sulfate, and magnesium stearate). 
 
• 
Other malignancies requiring active treatment in the last 6 months. 
 
• 
Brain tumors and/or brain metastases unless they are asymptomatic, stable on recent 
imaging (not dated more than 30 days from the inclusion date) and have not required 
active treatment in the last 6 months. 
• 
History and/or current evidence of endocrine alteration of calcium-phosphate 
homeostasis. 
• 
History of myocardial infarction or stroke within 6 months, congestive heart failure 
greater than NYHA class II, unstable angina pectoris, unexplained recurrent syncope, 
cardiac arrhythmia requiring treatment or family history of sudden death from cardiac - 
related causes. 
• 
Baseline Frederica’s corrected QT (QTcF) interval greater than 470 msec (female) or 
greater than 450 msec (male), history of congenital long QT syndrome, the presence 
in the screening ECG of a conduction abnormality that in the opinion of the 
Investigator would preclude safe participation in this study. 
 
• 
Concomitant use of a drug with a known risk of QTc prolongation 
 
• 
Current anticoagulation therapy with therapeutic doses of warfarin (low-dose warfarin 
≤ 1mg/day or low molecular-weight heparin are permitted). 
 
• 
History and or current evidence of ectopic mineralisation/calcification including but not 
limited to the soft tissue, kidneys, intestine, myocardium and lung with the exception 
of calcified lymph nodes and asymptomatic coronary calcification. 


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• 
Concomitant use of high dose systemic steroids and other drugs such as calcitonin 
preparations, active Vitamin D3 preparations, estrogen preparations, selective 
estrogen receptor modulators, Vitamin K2 preparations, parathyroid hormones, 
phosphorus absorbers. Note, inhaled, topical steroids and low tapering doses of 
steroid especially in patients treated recently for brain metastases will be included. 
• 
Corneal disease, such as bullous or band keratopathy, corneal desquamation, 
keratitis, corneal ulcer, or keratoconjunctivitis. 
• 
Known infection requiring the systemic use of, for example, an antibiotic or antiviral 
agent. 
• 
Known HIV, HBV or HCV infection. 
 
• 
Known untreated or uncontrolled acute infection, including urinary tract infection, 
within 7 days of study entry. 
• 
History of organ, bone marrow, or stem cell transplantation. 
 
• 
Pregnant or lactating woman (any woman of childbearing potential who has 
menstruated within the year prior to enrolment will undergo pregnancy testing within 
72 hours prior to receiving the first dose of study medication). 
• 
Women of childbearing potential or men who are unwilling to use an appropriate 
method of contraception during the study period and for 6 months after completing 
treatment with Debio 1347. Oral or injectable contraceptive agents cannot be the sole 
method of contraception. Note: Abstinence is acceptable if this is the usual lifestyle 
and preferred contraception for the subject. 
• 
Poorly controlled diabetes mellitus or hypertension (e.g., systolic > 180 mmHg or 
diastolic > 100 mmHg). 
 
• 
Inability or unwillingness to swallow oral medications. 
 
• 
Clinically significant gastrointestinal abnormality that would affect the absorption of 
drug such as gastrointestinal dysfunction, malabsorption syndrome, major resection 
of the small bowel or total gastrectomy or inflammatory bowel disease. 
 
• 
Uncontrolled  hydropericardium. 
 
• 
Chemotherapy or radiotherapy within 14 days prior to starting study treatment. In 
case of monoclonal antibodies/biologics, within 28 days prior to starting study 
treatment. 
• 
Administration of investigational agents within 28 days prior to treatment initiation. 
 
• 
Major surgery and surgery for brain metastases within 28 days prior to screening 
start. Of note, Intravenous port placement is not considered as a major surgery. 


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• 
Not recovered from AEs or toxicities due to previous treatments to a Grade 1 or less 
specified in NCI-CTCAE version 4.0 excepting, albumin (< 2.5 g/dL), AST and ALT in 
patients with liver metastases (> 5 × ULN) ALP in patients with bone metastases (> 5 
× ULN) and alopecia. 
 
• 
Prior use of a drug targeting FGF or FGFR. Patients previously treated with 
medications that affect FGFR signaling as a secondary target (e.g., multi-tyrosine 
kinase inhibitors that primarily inhibit VEGF, but to a lesser extent also affect FGFR 
signaling) can be considered after discussion with the Principal Investigator. 
 
• 
Currently under alcohol or drug abuse rehabilitation  or treatment program. 
 
• 
Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit 
compliance with study requirements. 
Eligibility Note: Patients could have progressed on prior aromatase inhibitors 
7.0 
RECRUITMENT PLAN 
 
The Evelyn H. Lauder Breast Center, in the Breast and Imaging Center at MSKCC provides a 
large referral base, with approximately 2000 patients with metastatic breast cancer consults 
each year. In 2015, we sequenced tumors from approximately 500 patients with metastatic 
breast cancer using MSK-IMPACT. Specifically, we have a large pool of pre-identified FGFR 
amplified (N=87) and 11q amplified co-occurring with FGFR1 amplified tumors (N=35) using 
our in house, next generation sequencing assay- MSK-IMPACT.  This study will be available 
to all patients seen at Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY), who 
meet the eligibility criteria outlined in section 6.0. Dr. Komal Jhaveri will facilitate accrual within 
Breast Medicine Service. 
The investigators take due notice of the NIH policy  concerning inclusion of women and 
minorities in clinical research populations. There will be no limitation to access with regard to 
race or gender. Patients will be required to read, agree to, and sign an IRB-approved informed 
consent form prior to registration on this trial. Participants will also be asked to sign a 
procedural consent form, detailing standard of care risks. Patients will then be registered by 
study research staff. The registration procedure will be conducted as described in section 15.0. 
Patients’ clinical details will become part of an outcomes database for future analysis. Patients 
will not receive payment for their participation on this study. 
7.1       LIMITED WAIVER OF AUTHORIZATION 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC). 
If the investigator is a member of the treatment team, s/he will screen their patient’s medical 
records for suitable research study participants and discuss the study and their potential for 
enrolling in the research study. Potential subjects contacted by their treating physician will be 
referred to the investigator/research staff of the study. 


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The principal investigator may also screen the medical records of patients with whom they do 
not have a treatment relationship for the limited purpose of identifying patients who would be 
eligible to enroll in the study and to record appropriate contact information in order to approach 
these patients regarding the possibility of enrolling in the study. For the majority of the potential 
research participants, most will have a treatment relationship with the investigators and 
consenting professionals listed on the front sheet of protocol. We plan to maintain a screening 
log for all patients considered for this study. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the recruitment 
and enrollment process. The investigator/research staff may also review portions of their 
medical records at MSKCC in order to further assess eligibility. They will use the information 
provided by the patient and/or medical record to confirm that the patient is eligible and to 
contact the patient regarding study enrollment. If the patient turns out to be ineligible for the 
research study, the research staff will destroy all information collected on the patient during 
the initial conversation and medical records review, except for any information that must be 
maintained for screening log purposes. 
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team. The recruitment process outlined presents no more than minimal risk to the privacy of 
the patients who are screened and minimal PHI will be maintained as part of a screening log. 
For these reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) 
reviewing medical records to identify potential research subjects and obtain information 
relevant to the enrollment process; (2) conversing with patients regarding possible enrollment; 
(3) handling of PHI contained within those records and provided by the potential subjects; and 
(4) maintaining information in a screening log of patients approached (if applicable). 
 
8.1 
PRETREATMENT EVALUATION 
 
To be completed within 28 days of starting Cycle 1 Day1 (unless otherwise indicated): 
 
• 
Signed informed consent for study participation 
• 
History and physical examination including height, weight, vital signs (temperature, 
pulse rate, respiratory rate, blood pressure, pulse oximetry), performance status 
(ECOG), and review of pathology and concomitant medications: medications taken 
within 28 days of starting Debio 1347 and fulvestrant 
• 
Urine or serum pregnancy test for all women of childbearing potential. If the test result 
is positive related to pregnancy, the patient will not be allowed to participate in this 
study 
• 
CBC with differential and platelet count 
• 
Complete metabolic panel (sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, total protein, albumin, bilirubin, alkaline phosphatase, AST, ALT, 
calcium) 
• 
Magnesium 


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• 
Phosphorous 
• 
γGTP 
• 
CPK 
• 
CRP 
• 
Uric Acid 
• 
LDH 
• 
Calcium regulating hormones (whole-PTH, 1,25(OH)2D, PTHrP) 
• 
PT/INR & aPTT 
• 
Serology for HepBsAg, HepBcAb, HIV and hepatitis C antibody (negative test 
acceptable prior to screening period) 
• 
Tumor markers: CEA and Ca 15-3 
• 
Urinalysis including urinary protein, blood, glucose, urobilinogen,  pH, sediment, 
creatinine, calcium (CA), phosphate 
• 
12-lead Electrocardiogram (EKG) 
• 
ECHO 
• 
Complete ophthalmologic examination. The examination will be interpreted by a 
qualified ophthalmologist, including visual acuity testing, slit-lamp ophthalmoscopy 
and indirect ophthalmoscopy. 
• 
CT scan with contrast (chest, abdomen and pelvis). If patient is unable to receive CT 
contrast, or the abdominal/pelvic target lesion is indeterminate on CT scan, then MRI 
with contrast (abdomen and pelvis) plus CT chest without contrast may be performed. 
• 
A baseline brain MRI or CT scan with contrast (the same method of imaging done at 
baseline should be done throughout the study at indicated time points) is required 
only for patients with a history of brain metastases 
• 
Research blood samples: for PK and cfDNA as detailed in section 12.0 
 
• 
Baseline tumor biopsies will be obtained during screening for all patients enrolled in the 
study 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
This is an open-label, single institution, phase Ib/phase II non-randomized trial that evaluates 
the safety, tolerability and anti-tumor activity of fulvestrant and Debio 1347 in patients with 
ER+/HER2- metastatic breast cancer (MBC) that are FGFR-amplified (as confirmed by a CLIA 
certified laboratory). 


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Page 28 of 60 
 
 
 
 
The phase I portion of this trial will evaluate 2 dose cohorts (dose level 1 (starting dose level) 
80mg Debio 1347, and dose level -1, 60mg Debio 1347). Fulvestrant will be administered at 
standard doses. Only the dose of Debio 1347 will be de-escalated as per section 4.1. 
Phase 2 portion: The phase 2 portion will be comprised of an optimal Simon two-stage design 
to determine the efficacy of Debio 1347 plus fulvestrant (N: 18 in the first stage with possibility 
of going on to 43 if 3 out of the first 18 have a CBR ≥ 24 weeks). The dosage in the phase 2 
portion will be the MTD/RP2D determined in the phase 1b portion (80mg daily), except that 
concomitant prophylaxis for hyperphosphatemia will not be required. 
 
1 cycle: 28 days. Patients will be on treatment until progression of disease or unacceptable 
toxicity. 
 
9.1 
Concomitant  Medications 
 
Administration of concomitant when administered between the date of informed consent 
signature and the last visit (including follow-up) will be recorded. 
9.1.1 
Permitted Concomitant Medication 
 
Supportive therapies against pain, nausea, vomiting, constipation and diarrhea, and 
granulocyte colony-stimulating factors (G-CSF) are allowed as per the Investigator’s decision. 
Since drugs that alter gastric pH (e.g., proton pump inhibitors, histamine receptors antagonists, 
antacids) may interfere with the absorption of Debio 1347, they should be administered at least 
2 hours after Debio 1347 administration. 
Treatment of pain should be done according to severity and recommended drugs. Study- 
specific guidelines will be provided separately. 
Concomitant radiotherapy may only be given for the control of bone pain or as indicated to 
30% of the bone marrow. Irradiated lesions will not be evaluable for response. Radiotherapy 
should start no sooner than 24 hours after the previous dose of Debio 1347, and study 
treatment may be resumed with the resolution of any radiation toxicity to ≤ grade 1. 
Any other medication necessary for the well-being of the patient (with the exception of those 
mentioned as prohibited/excluded concomitant medications, see Section below) may be given 
at the Investigator’s discretion. Particular attention should be paid to treatment that could 
influence the intended effects or mask side effects of treatment. 
9.1.2 
Excluded Concomitant Medications 
 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications are considered exclusionary during the study. The Principal 
Investigator must be notified if a subject receives any of these during the study. 
• 
Any investigational anticancer therapy. 


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Page 29 of 60 
 
 
 
 
• 
Any concurrent chemotherapy, immunotherapy, or biologic therapy. Note: concurrent use 
of bone-directed therapies (such as bisphosphonates or denosumab) is permitted. 
• 
Other antineoplastic agents are prohibited except GnHR agonists and GnHR antagonists 
for premenopausal women. 
• 
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes) 
is acceptable. 
• 
Immunosuppressive medications including, but not limited to systemic corticosteroids 
(>10 mg/day prednisone or equivalent), methotrexate, azathioprine, and tumor necrosis 
factor alpha (TNF-α) blockers. \ In addition, use of inhaled and intranasal corticosteroids 
is permitted. 
• 
Fibroblast growth factors injections, cosmetics containing FGF. 
• 
High dose systemic steroids, calcitonin preparations, active Vitamin D3 preparations, 
estrogen preparations, selective estrogen receptor modulators, Vitamin K2 preparations, 
parathyroid hormones, phosphorus absorbers 
In nonclinical studies, Debio 1347 has been seen to affect the cornea. Since corneal disorders 
may occur when contact lenses are being worn, and the use of Debio 1347 may exacerbate 
these symptoms, caution should be exercised when using Debio 1347 in a patient wearing 
contact lenses, and the patient should be monitored. 
 
Although the possibility of Debio 1347 affecting cardiac function in nonclinical studies is low, 
caution should be exercised when using Debio 1347 with drugs with a known risk of QTc 
prolongation (see Arizona CERT database at website ttp://www.crediblemeds.org/). 
The hepatic oxidative metabolism of Debio 1347 has been shown in vitro to be mainly mediated 
by CYP 4F3b, with no or only minor contribution of other metabolic enzymes. Furthermore, 
according to bi-directional permeability experiments in Caco-2 cells, Debio 1347 is not a 
substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) efflux 
transporters. Therefore, based on current knowledge, Debio 1347 appears to have a low risk 
of being victim of PK interaction from other drugs. In contrast, as per in vitro results available 
so far and Debio 1347 plasma exposure achieved in patients, Debio 1347 is considered at 
possible risk of perpetrating drug-drug interactions through CYP3A inhibition, CYP3A induction 
(some transporters such as P-gp might also be co-induced), CYP1A2 repression, or inhibition 
of several transporters (P-gp, BCRP, multidrug and toxin extrusion protein 1 [MATE1], organic 
cation transporter 2 [OCT2]; bile salt export pump [BSEP] is also 
inhibited). 
The clinical impact of these in vitro observations is not known. While patients are not 
precluded from receiving any drugs  based upon the potential for a PK drug interaction, 
patients who are taking concurrent drugs that are known substrates of either CYP3A, 
CYP1A2, P-gp, BCRP, MATE1 or OCT2 should be  carefully monitored. 
Notably, due to the irreversible nature of CYP3A inhibition by Debio 1347 and also its in vitro 
potential   for  enzyme  induction,  it  should  be  noticed  that  the  potential   for  drug-drug 


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Page 30 of 60 
 
 
 
 
interactions with CYP3A substrates (and possibly also with P-gp substrates) is time- 
dependent; it may increase with time as patients continue to take Debio 1347, and it may 
persist for some days after Debio 1347 discontinuation. 
A list of drugs that are sensitive or narrow-therapeutic-range substrates of CYP3A, CYP1A2, 
and substrates of P-gp, BCRP, MATE1 or OCT2 can be consulted in: 
• 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University 
School of Medicine (2007): http://medicine.iupui.edu/clinpharm/ddis/table.aspx,  and 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInt  
eractionsLabeling/ucm093664.htm 
If treatment with a prohibited medication is necessary, the patient will be withdrawn from the 
study. 
 
 
9.2 
Supportive Care 
 
The following are the supportive care guidelines for the study: 
 
9.2.1 Hyperphosphataemia  prevention 
 
• 
All treated patients should receive adequate instructions concerning dietary phosphate 
restriction. The main natural sources of phosphate are: 
▪ 
Dairy products (milk, cheese, ice-cream, yogurt) 
▪ 
Meat 
▪ 
Dried beans 
▪ 
Peas 
▪ 
Nuts and peanut butter 
▪ 
Wholegrains 
▪ 
Cola 
• 
During the dose-escalation phase of the debio 1347 trial, only 50% of patients 
needed to be treated with phosphate chelators. In the expansion phase, three 
patients did recieve prophylactic sevelamer, and there was no clear difference with 
regard phosphate levels in these patients. In view of the side-effects associated with 
use of phosphate chelators, prophylaxis will not be required in phase 2 portion of the 
study. Phosphate levels will be measured on cycle 1 D4 (+/-1 day), and treated 
according to the guidelines provided in section 9.4.2. At the time of this amendment, 
all patients on the phase 1 cohort were off study. 
 
9.2.2 Gastrointestinal disorders 
 
For nausea, vomiting, diarrhea or constipation, treatment may include anti-emetics, anti- 
diarrheas or laxative bowel regimen consistent with standard of care. Since drugs that alter 
gastric  pH  (e.g.,  proton  pump  inhibitors,  histamine  receptors  antagonists,  antacids) may 


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Page 31 of 60 
 
 
 
 
interfere with the absorption of Debio 1347, they should be administered at least 2 hours after 
Debio 1347 administration. 
9.2.3 Haematological support 
 
• 
The use of red blood cell transfusions will be permitted as clinically indicated during the 
study. 
• 
The use of bone marrow colony stimulating factors (such as granulocyte colony- 
stimulating factor or granulocyte-macrophage colony-stimulating factor) is permitted as 
clinically indicated. Prophylactic use is prohibited. 
9.2.4 Infections 
 
• 
CR-BSI (Catheter-Related Bloodstream Infection) should be managed according 
current Clinical Practice Guidelines46. 
• 
Febrile neutropenia: Antibacterial and antifungal prophylaxis for fever and treatment of 
neutropenia should be managed according the current Clinical Practice Guidelines 47,48 . 
• 
MSRA (Methicillin-Resistant Staphylococcus Aureus) infection should be managed 
according the current Clinical Practice Guidelines49. 
9.2.5 Pain 
 
• 
The management of pain should be done according to severity and recommended 
drugs. 
9.2.6 Hypercalcaemia  prophylaxis 
 
Patients with asymptomatic hypercalcaemia do not require immediate treatment if calcium 
remains < 12 mg/dL (3 mmol/L). However, the patient should be advised to avoid factors that 
can aggravate hypercalcaemia (such as thiazide diuretics, volume depletion,  prolonged bed 
rest or inactivity, and a high calcium diet [> 1000 mg/day]). 
Adequate hydration (at least 6 to 6 glasses of water per day) is recommended to minimise the 
risk of nephrolithiasis. 
9.2.7 Prophylaxis for skin toxicity and alopecia 
 
Guidelines for prophylaxis are detailed in Appendix A. 
 
9.3 Dose-limiting toxicity during Phase 1 
 
The following AEs or laboratory abnormalities, graded according to NCI-CTCAE version 4, 
are considered to be DLTs when occurring during the DLT evaluation period (Day 1 to Day 
28 of Cycle 1, plus the assessments prior to drug administration on Cycle 2, Day 1 and the 
Investigator feels  are possibly, probably, or definitely related to Debio 1347 excluding those 
that are clearly and incontrovertibly due to disease progression or extraneous causes.: 
• 
Febrile neutropenia (ANC < 1.0 X 109/L and fever ≥ 38.2°C [101° F]) 


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• 
Grade 3 or higher neutropenia with infection. 
• 
Grade 4 neutropenia persisting for more than 7 days. 
• 
Grade 4 thrombocytopenia persisting for more than 7 days or Grade 3 
thrombocytopenia requiring platelet transfusion. 
• 
Grade 3 diarrhea, constipation, nausea, vomiting or skin toxicity that lasts longer than 
72 hours despite optimal symptomatic therapy. 
• 
Any Grade 4 diarrhea, constipation, nausea, vomiting or skin toxicity. 
• 
Grade 3 or higher liver function tests (ALT, AST, ɣGPT) and ALP unless as clarified 
below 
• 
Grade 3 or higher non-hematologic toxicity including Hy’s law: AST and/or ALT > 3x 
ULN and bilirubin > 2x ULN, and without initial findings of cholestasis (serum alkaline 
phosphatase (ALP) activity < 2x ULN) and no other reason that could explain the 
combination of increased transaminases and serum total bilirubin, such as viral 
hepatitis A, B, or C, preexisting or acute liver disease (including preexisting liver 
metastases), or another drug capable of causing the observed injury. 
• 
The following non-hematologic AEs are not considered DLTs: 
a. Grade 3 electrolyte abnormalities lasting <24 to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions; and ≥ Grade 3 amylase or lipase that is not associated with symptoms 
or clinical manifestations of pancreatitis. 
b. Grade 3 or higher of ALP clearly related to bone metastases evolution. The 
relationship should be discussed with the study Medical Monitor on a case by case 
basis. 
• 
Hyperphosphataemia: 
a. Serum Pi > 7.0 mg/dL for > 7 consecutive days despite phosphorus lowering 
therapy for at least 14 days. 
b. Serum Pi > 9.0 mg/dL, despite phosphorus lowering therapy for at least 14 days. 
c. Serum Pi > 10.0 mg/dL. 
• 
Any treatment delay more than 7 days because of treatment-related AEs or 
laboratory abnormalities occurring during the DLT period. 
• 
Any other life-threatening toxicity. 
• 
Other AEs considered intolerable by the Investigator. 
• 
Death not clearly due to the underlying disease or extraneous causes 
 
Patients experiencing a DLT during the DLT period may continue treatment after treatment 
adjustments if there is a potential benefit from treatment. 
9. 4 Dose Modifications or Scheduling Delays 
 
• 
This study will use the NCI Common Toxicity Criteria (CTC) AE version 4.0 for toxicity. 
• 
Study treatment will be temporarily or permanently discontinued due to the 
occurrence of AEs as specified in Table 1 below, for both the phase 1 and 2 portions 
of this study. 
• 
Additionally,  non-treatment related or unexpected toxicities may require interruption of 
therapy at the discretion of the Investigator. 


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• 
Failure to recover to the specified levels following temporary discontinuation within 7 
days in the phase 1b portion and 14 days in the phase 2 portion will result in 
permanent treatment discontinuation. The treating Investigator and the PI will discuss 
the case of any patient whose treatment has been delayed for more than 7 or 14 
days, respectively, who they think may benefit from continued treatment, prior to 
resuming treatment. 
• 
In addition, if Grade 2 or higher toxicity occurs, treatment may be temporarily 
discontinued at the discretion of the Investigator. The patients may resume at the 
same dose level when toxicity has resolved to Grade 1 or below or the baseline level 
if resolution is achieved within 7 days in the phase 1b part and 14 days in the phase 2 
part. 
• 
In the event the patient requires temporary treatment discontinuation, the Investigator 
may choose to increase the frequency of the assessments performed to weekly 
collections until resolution. 
• 
Only in the phase 2 portion, one dose reduction can be undertaken except for dose 
level -1 (60mg). Patients resuming treatment following a temporary discontinuation 
can do so at their original dose level or at one lower dose level. 
• 
Patients experiencing a DLT during the DLT period may continue treatment after 
dose adjustments if there is a potential benefit from treatment after discussion with 
the PI 
• 
Patients will be permanently discontinued if reduction beyond <60mg/day is 
necessary in both phase 1 and phase 2 portions of the study 
• 
Reduced doses may not be re-escalated. 
• 
If a patient discontinues Debio 1347 purely due to toxicity, they can stay on study and 
continue to receive fulvestrant. The patient will be captured as coming off of Debio 
1347 due to toxicity and report TTF. 
Table 1: Dose Modifications and Delays during Phase 1 and Phase 2 
 
Adverse Event 
Grade 
Action 
Phase I part: 
DLT evaluation period only 
Phase I part: 
non-DLT evaluation period 
Phase 2 portion 
Febrile neutropenia, 
Neutropenia w ith infection 
4 
Permanent  discontinuation Permanent 
discontinuation 
Permanent  discontinuation 
Permanent  discontinuation 
3 
Permanent  discontinuation 
Temporary discontinuation 
until recovery to 
Grade 0 
Neutropenia 
3, 4 
Temporary discontinuation  until recovery to 
Grade 2 
Temporary discontinuation 
until recovery to 
Grade 2 
Thrombocytopenia 
4 
Permanent  discontinuation 
Temporary discontinuation 
until recovery to 
Grade 1 
3 
Temporary discontinuation  until recovery to 
Grade 1 
Permanent  discontinuation if a platelet 
If a platelet transfusion is 
required, temporary 


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Adverse Event 
Grade 
Action 
transfusion is required 
discontinuation  until 
recovery to Grade 1 
Diarrhea, constipation, nausea, 
vomiting 
3,4 
Permanent  discontinuation,  if not manageable 
by optimal symptomatic  therapy 
Temporary discontinuation 
until recovery to 
Grade 2, or baseline 
Skin toxicity 
(See additional guidelines in 9.4.1) 
3,4 
Permanent  discontinuation,  if not manageable 
despite prophylaxis and optimal symptomatic  therapy 
Temporary discontinuation 
until recovery to 
Grade 2, or baseline 
Hyperphosphataemia 
Please use the treatment guidelines  per 9.4.2 
Please use the treatment 
guidelines per 9.4.3 
Hypertension 
4 
Permanent  discontinuation 
Permanent  discontinuation 
3 
Permanent  discontinuation 
If uncontrolled,  temporary 
discontinuation 
until control is achieved 
Hepatotoxicity 
(AST, ALT, ALP, γGTP 
increased) 
4 
Permanent  discontinuation 
Permanent  discontinuation 
3 
Temporary discontinuation,  until recovery to 
Grade 2 
Temporary discontinuation, 
until recovery to 
Grade 2 
Other non-haemotoxicity 
(except for transient electrolyte 
abnormalities) 
4 
Permanent  discontinuation 
Permanent  discontinuation 
3 
Permanent  discontinuation 
Temporary discontinuation 
until recovery to 
Grade 1 or baseline 
Recovery from above AEs 
Permanent  discontinuation,  if failure to 
recover w ithin 7 days, Otherw ise treatment at same 
dose level. Dose reduction during the DLT has to be 
discussed w ith the PI 
Permanent  discontinuation, 
if failure to 
recover w ithin 14 days, 
otherw ise retreatment at 
next low est dose level 
 
 
9.4.1 Skin Toxicity, nail toxicity and alopecia 
 
Patients will be referred to Dr. Mario Lacouture (Dermatology) for management of alopecia, 
skin, nail toxicity and stomatitis as needed. Of note, patients will be allowed to receive 
prophylaxis for skin toxicity and alopecia per section 9.2.7 and Appendix A. Specific 
treatment guidelines are also detailed in Appendix A. 
 
 
9.4.2 Hyperphosphatemia (Phase I) 
1. Initial Modifications on Treatment: 
 
Serum  phosphorus 
level 
5.5 – 6.9 mg/dL 
1. 
Continue Debio 1347 
2. 
Continue (or increase) sevelamer  powder 2400mg TID 
3. 
Add Fosrenol 1g TID 
4. 
Recheck within 7 days 


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*If sevelamer is not available or tolerable, alternate phosphate reducing agents or preparations can be utilized. 
 
2. Second Modification on Treatment 
 
Serum  phosphorus 
level 
5.5 – 6.5 mg/dL 
1. 
Cont Debio 1347 
2. 
Cont sevelamer  powder  to 2400mg TID  increase Fosrenol to 
1.5mg TID 
3. 
recheck within 7 days 
6.6-6.9mg/dL 
1. 
Cont Debio 1347 
2. 
Cont sevelamer  powder  to 2400mg TID 
3. 
Cont Fosrenol 1g TID 
4. 
add acetazolamide  250mg BID 
5. 
recheck within 7 days 
≥ 7 mg/dL 
1. 
Hold Debio 1347 – consider dose reduction 
2. 
Cont sevelamer  powder  to 2400mg TID 
3. 
increase Fosrenol  to 1.5g TID 
4. 
add acetazolamide 250mg BID 
5. 
check within 7 days -> resume if Ph < 5.5 
*If sevelamer is not available or tolerable, alternate phosphate reducing agents or preparations can be utilized. 
 
3. Subsequent Modifications: 
 
Serum 
phosphorus 
level 
> 5.5 mg/dL-6.9mg/dL 
1. 
If not already,  maximize regimen to include: 
sevelamer  powder  to 2400mg TID 
fosrenol to 1.5g TID 
acetazolamide  250mg BID 
2. If already maximized, consider dose reduction (without interrupting 
drug) 
3. Recheck within 7 days 
≥ 7 mg/dL 
1. 
Hold Debio 1347 – dose reduction needed 
2. 
Maximize regimen  to include: 
sevelamer  powder  to 2400mg TID 
fosrenol to 1.5g TID 
acetazolamide  250mg BID 
≥ 7 mg/dL 
1. 
Hold Debio 1347 
2. 
Continue (or increase) sevelamer  powder 2400mg TID 
3. 
Add Fosrenol 1g TID 
4. 
check within 7 days -> resume if Ph < 5.5 and 
recheck within 7 days of resumption 


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IRB Number: 17-379 A(7) 
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*If sevelamer is not available or tolerable, alternate phosphate reducing agents or preparations can be utilized. 
 
4. For patients whose phosphorous control improves after Debio 1347 dose reductions, de- 
escalation of the phosphorus regimen can be considered at the discretion of the investigator. 
Subsequent to any such adjustment, phosphorous level should be rechecked within 7 days. 
5. In case of patients with hepatic or renal impairment, it is recommended not to change 
hyperphosphatemia treatment even in the case of Debio 1347 dose reduction. 
 
9.4.3 Hyperphosphatemia (Phase II) 
 
INITIAL TREATMENT MODIFICATION 
Serum 
Phosphorous  Level 
Intervention/Modi fication 
5.5 – 6.9 mg/dL 
• 
Continue treatment with Debio 1347 at current  dose AND 
• 
Start on sevelamer  oral POWDER 1200mg three times a day (subjects 
may use tablets if preferred,  but tends to have  more gastrointestinal 
toxicity) 
• 
Escalate to sevelamer  oral POWDER or tablets 2400mg three times a 
day if tolerated. 
• 
Reassess serum phosphorus  within 7 days 
≥ 7 mg/dL 
• 
Hold treatment with Debio1347 
• 
Start sevelamer  oral POWDER or tablets 2400mg three times a day 
• 
Add treatment with lanthanum  carbonate (Fosrenol®) 1g three times a 
day 
• 
Reassess serum phosphorus  level  within 7 days: 
o If serum phosphorus  level < 5.5 mg/dL, resume Debio 1347 at 
same dose and recheck within 7 days of resumption 
Note: 
• 
Sevelamer  should be preferably  taken in the middle of meals 
• 
Lanthanum  carbonate should be taken just after meals 
• 
Sevelamer  and lanthanum must be administered at least 2 hours after or 
4 hours before  Debio 1347 
 
SECOND TREATMENT MODIFICATION 
Serum 
Phosphorous  Level 
Intervention/Modi fication 
5.5 – 6.5 mg/dL 
• 
Continue treatment with Debio 1347 at a current  dose AND 
• 
Continue sevelamer  oral POWDER or tablets 2400mg three times a day 
• 
Introduce treatment with lanthanum  carbonate (Fosrenol®) to 1.0g three 
times a day or increase to 1.5g three times a day 
• 
Reassess serum phosphorus  level  within 7 days 
6.6-6.9 mg/dL 
• 
Continue treatment with Debio 1347 at current  dose AND 
• 
Continue sevelamer  oral POWDER or tablets 2400mg three times a day 
• 
Introduce treatment with lanthanum  carbonate (Fosrenol®) to 1.0g three 
times a day or increase the dose to 1.5g three times a day 
• 
Add treatment with oral acetazolamide 250mg twice a day 
• 
Reassess serum phosphorus  level  within 7 days 
≥ 7 mg/dL 
• 
Hold treatment with Debio 1347  – consider dose reduction 
• 
Continue sevelamer  oral POWDER or tablets 2400mg three times a day 
• 
Increase treatment with lanthanum  carbonate (Fosrenol®)  to 1.5g three 
times a day AND 
3. 
check within 7days -> resume with dose reduction if Ph < 5.5 


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GENERAL  RECOMMENDATIONS 
• 
In subjects whose serum phosphorus  control improves  after Debio 1347 dose reduction,  de- 
escalation of the hyperphosphatemia  treatment can be considered at the discretion of the 
Investigator.  Subsequent  to any such adjustment, serum phosphorus  level  should be 
reassessed within 7 days. 
• 
In case of subjects with hepatic or renal impairment,  it is recommended  not to change 
hyperphosphatemia  treatment even  in the case of Debio 1347 dose reduction. 
 
 
 
• 
Add treatment with oral acetazolamide 250mg twice a day 
• 
Reassess serum phosphorus  level  within 7 days: 
o If serum phosphorus  level < 5.5 mg/dL, resume Debio 1347 with 
dose reduction 
Note: 
• 
Sevelamer  should be preferably  taken in the mid of meals 
• 
Lanthanum  carbonate should be taken just after meals 
• 
Sevelamer  and lanthanum must be administered at least 2 hours after or 
4 hours before  Debio 1347 
• 
Acetazolamide should be preferably  taken just after breakfast  and dinner 
 
SUBSEQUENT TREATMENT MODIFICATIONS 
Serum 
Phosphorous  Level 
Intervention/Modi fication 
5.5 – 6.9 mg/dL 
• 
If not already  done, maximize regimen to include: 
o 
Sevelamer  oral POWDER or tablets to 2400mg three times a 
day 
o 
Lanthanum  carbonate (Fosrenol®)  to 1.5g three times a day 
o 
Oral acetazolamide 250mg twice a day 
• 
If regimen already maximized, consider dose reduction (without 
interrupting  Debio  1347 assumption) 
• 
Reassess serum phosphorus  level  within 7 days 
≥ 7 mg/dL 
• 
Hold treatment with Debio1347  – dose reduction  needed 
• 
Maximize regimen  to include: 
o 
Sevelamer  oral POWDER or tablets to 2400mg three times a 
day 
o 
Lanthanum  carbonate (Fosrenol®)  to 1.5g three times a day 
o 
Oral acetazolamide 250mg twice a day 
• 
Reassess serum phosphorus  level  within 7 days: 
o 
If serum phosphorus  level < 5.5 mg/dL, resume Debio 1347 with 
dose reduction 
Note: 
• 
Sevelamer  should be preferably  taken in the mid of meals 
• 
Lanthanum  carbonate should be taken just after meals 
• 
Sevelamer  and lanthanum must be administered at least 2 hours after or 
4 hours before  Debio 1347 
• 
Acetazolamide should be preferably  taken just after breakfast  and dinner 
 
 
 
 
 
 
 
 
 
9.4.4 Guidelines for significant QTc prolongation 
 
Significant QTc prolongation is defined as an interval > 500 ms or an interval which increases 
by 60 ms over baseline. 
If the prolongation is confirmed on 2 out of the 3 ECGs by either criteria (i.e., QTc interval > 
500 ms or > 60 ms increase from baseline) treatment with Debio 1347 should be stopped 
and the following actions will be taken: 


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• 
The patient will be withdrawn from Debio 1347 treatment. 
• 
The patient will be monitored, treated appropriately, and closely followed (ECGs at 
least three times per week) until the QT and QTc interval return to within 30 ms of 
baseline. 
If an ECG shows significant QTc prolongation the patient should be referred to a cardiologist. 
 
 
9.5 Subject replacement strategy 
 
• 
Patients not eligible for the MTD/RP2D determination of the phase 1b portion will be 
replaced (see section 12.3.3) 
• 
Patients not eligible for efficacy evaluation for the Phase II portion of the study will 
also be replaced 


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10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
 
 
Screening 
Treatment 
EOT 
F/Ua 
Cycle 
1 
2 
3+ 
Every 
12 weeks 
Day 
-28 to -1 
1 
4 
8 
15 
28 
1 
15 
1 
 
±2 
±1 
±2 
±2 
-4 
±3 
±3 
±3 
±7 
±14 
Written Informed 
Consent 
X 
Review of 
Eligibility Criteria 
X 
Demographic 
Information 
X 
Vital Signs, ECOG 
PSb 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Physical Exam and 
Weight 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGc 
X 
X 
X 
X 
X 
ECHOc 
X 
X 
X 
Haematology and 
Chemistry  blood 
work d 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor markers 
(CEA and CA15-3) 
X 
X 
X 
X 
X 
Other Bloodwork 
(CRP LDH, uric 
acid and γGTP) 
X 
X 
X 
X 
X 
X 
X 
X 
Phosphate  (P) 
X 
Blood coagulation 
(PT (INR), APTT) 
X 
X 
X 
X 
X 
Urinalysise 
X 
X 
X 
X 
X 
X 
X 
X 
Calcium  regulating 
hormones 
bloodworkf 
X 
X 
X 
X 
X 
Serum pregnancy 
test 
X 
X 
Ophthalmological 
testingg 
X 
X 
Adverse  events 
X 
X 
X 
X 
X 
X 
X 
X 


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Fulvestrant 
X 
X 
X 
X 
Tumour 
assessmenth 
X 
X 
X 
Plasma sample for 
CfDNAi 
X 
X 
X 
X 
Pharmacokineticsj 
Xj 
X 
X 
X 
Tumor Biopsyk 
X 
HepBsAg, 
HepBcAb, HIV and 
hepatitis C 
antibodyl 
X 
 
 
Abbreviations: DEXA, dual-energy X-ray  absorptiometry;  ECHO,  echocardiogram;  ECOG,  Eastern 
Cooperative Oncology Group; EOS, end-of-study;  EOT,  end-of-treatment  (any  study  treatment);  IV, 
intravenous;  PS, performance  status. 
a) Survival and disease status will be assessed every 12 weeks (+/- 14 days) until death,  withdrawal  of 
consent, or end of the study, whichever is first. Assessments can be collected through phone call or review of 
patient records. 
b) Blood pressure and heart rate to be collected. BP and pulse rate to be taken after at least 5 minutes  of 
supine rest. 
c) ECG recorded every 3RD cycle after Cycle 3. If an ECG shows QTc prolongation (> 470 msec.), the ECG 
must be repeated twice additionally to obtain values in triplicate. ECHO will be done at baseline, every 3 cycles 
and at EOT during the phase 1 portion of the study. 
d) Haematology: red blood cells, haemoglobin, hematocrit, platelet count, white blood cells, neutrophils, 
lymphocytes, monocytes, eosinophils,  basophils. 
Blood chemistry(Fasting): total protein, albumin, total bilirubin, AST, ALT, LDH, ALP, γGTP, CK, total 
cholesterol, sodium (Na), potassium (K), calcium (Ca), chloride (Cl), phosphate (P), magnesium (Mg), 
creatinine, BUN, CRP, uric acid, glucose. 
e) Urinalysis: protein, blood, glucose, urobilinogen,  pH, sediment, creatinine, calcium (Ca), phosphate (P). 
f) Calcium regulating hormone assessments (whole-PTH, 1,25(OH) 2D, PTHrP) will be performed every cycle 
until Cycle 3 and every  3 cycles thereafter. 
g) Ophthalmological tests to be repeated as clinically indicated during treatment. Complete ophthalmologic 
examinations will be performed at screening and, as soon as clinically indicated, if a patient reports any visual 
abnormality. Complete ophthalmologic examination will be performed and interpreted by a qualified 
ophthalmologist, including visual acuity testing, slit-lamp ophthalmoscopy and indirect ophthalmoscopy. At the 
final visit and 28 days after the last dose, slit-lamp ophthalmoscopy  will be performed. 
h) Tumor assessments (patients with a history of brain mets will be required to have brain CT scans with 
contrast or MRIs) to be performed every 8 weeks for 48 weeks (i.e. cycle 2, 4, 6 between days 22 and 28) and 
then every  12 weeks thereafter  (i.e.  cycle 9, 12, 15 again between days 22 and 28 etc.). 
i) Plasma samples for cfDNA analysis will be collected prior to dosing on cycle 1, cycle 1 day 15, day 1 of C3 
and then at EOT. 
j) Plasma samples for PK will be collected both during phase 1 and 2. Phase 1 PK will be collected prior to 
dosing on day 1 and 15 of cycle 1 and then day 1 of each cycle thereafter.  Phase 2 PK will be collected prior 
to dosing on day 15 of cycle 1 and day 1 of cycle 2. 


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k) Baseline tumor biopsies will be obtained during screening for all patients enrolled in the study, at least three 
fragments  on a core biopsy 
l) Documented negative  tests prior to screening period  is acceptable. 
 
 
 
10.1 Follow up visits 
 
The mandatory End of Treatment Visit should be conducted approximately 2-4 weeks after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the End of Treatment Visit should be recorded. Subjects 
with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 30 
days of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded. 
 
10.1.2 Survival Follow-up 
 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone or 
review of patient records every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
10.1.3 End-of-Treatment Criteria 
 
Treatment with Debio 1347 will continue until any of the following occur: 
 
• 
Patient withdraws consent. 
• 
Disease progression documented by CT scan, physical exam or other objective 
method of measurement. An exception could be made for patients who progressed 
due to brain metastases; patients may continue treatment with Debio 1347 if, in the 
Investigator’s opinion, there was reasonable evidence of ongoing clinical benefit. 
• 
Unacceptable toxicity. 
• 
Pregnancy. 
• 
Patient's interests as judged by the Investigator. 
• 
In the event of a Debiopharm International SA decision to no longer supply study 
drug, ample notification will be provided so that appropriate adjustments to subject 
treatment can be made. 
Patients who are removed from study treatment due to AEs are to be treated and followed-up 
according to accepted medical practice. All pertinent information concerning the outcome of 
such treatment will be recorded. 
 
 
 
10.1.4 End-of-Treatment Visit 


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Patients will undergo the EOT assessment and exit from the study, unless they are prematurely 
discontinued from the study for any of the following reasons: 
1. Patient requests to leave the study. 
 
2. Adverse event, e.g. intercurrent illness that would, in the judgment of the Investigator, affect 
assessments of clinical status to a significant degree; or intercurrent illness that, in the opinion 
of the Investigator compromises the patients safety. 
 
3. Patient non-compliance. 
 
4. Patient lost to follow-up. 
 
5. If, in the Investigators opinion, continuation in the trial would be detrimental to the patient’s 
wellbeing. 
6. A major protocol violation occurs. 
 
7. Prohibited medication as indicated in Section 9 is required/used during the course of the 
trial. In the event a patient is found to be taking a prohibited medication during the trial, the site 
should immediately contact the Medical Monitor. The decision to withdraw the patient will be 
made in conjunction with the Sponsor. 
 
8. Non-drug related reason; e.g. patient relocates too far from study centre. 
 
9. Study is terminated. 
 
Should a patient be withdrawn, EOT assessments should be performed prior to any further 
therapeutic intervention whenever possible. Results of these assessments will be recorded 
together with a description of the reasons for study discontinuation. 
10.1.5 Correlative analyses 
 
Plasma samples for pharmacokinetics (PK) will be collected during both phase 1 and 2. Phase 
1 PK will be collected prior to dosing on day 1 and 15 of cycle 1 and then day 1 of each cycle 
thereafter. Phase 2 PK will be collected prior to dosing on day 15 of cycle 1 and day 1 of cycle 
2. These samples may be analyzed by LC-MS/MS to assess the PK (trough levels at steady- 
state) of both fulvestrant and Debio 1347 in combination. These data will be compared with 
historical PK data in monotherapy (Faslodex® prescribing information; PK results from Study 
Debio 1347-101), in order to investigate potential PK interactions and to support interpretation 
of safety and/or efficacy results in the trial, and tumor specimens will be studied. 
Archival tissue will be obtained, whenever available as well. 
 
Baseline tumor biopsies will be obtained. We will perform FISH, protein and mRNA expression 
analyses from formalin-fixed paraffin-embedded tissue samples in the laboratory of Dr. Jorge 
Reis-Filho along with the MSKCC Integrated Genomics Operation (IGO) and MSKCC Molecular 
Cytogenetics Core facilities. 


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1) FGFR1 FISH will be performed as follows: FGFR1 amplification will be assessed using the 
ZytoLight SPEC FGFR1/CEN 8 Dual Color Probe (ZytoVision, Bremerhaven, Germany). Tissue 
processing, hybridization, post-hybridization washing, and fluorescence detection will be 
performed according to standard lab procedures. Slides will be scanned using a Zeiss Axioplan 
2i epifluorescence microscope equipped with a CCD camera (CV-M4+CL, JAI) controlled by Isis 
5.5.9 (MetaSystems Group Inc.). Marked region(s) within a given tissue section will be scanned 
at 63X or 100X and at least five images per representative region captured, each image being a 
compressed stack of 12 z-section images taken at 0.5 µm intervals. Signal counts will be 
performed on the captured images and a minimum of 100 discrete nuclei scored. Amplification 
will be defined as >10 copies of discrete MYB or NFIB signals or small cluster of signals (>4 
copies; representing tandem duplications/repeats). Tumors will be considered as FGFR1- 
amplified under one of the following conditions: a) The FGFR1/CEN8 ratio is ≥2.0; b) Average 
number of FGFR1 signals per tumor cell nucleus is ≥6; or c) Presence of large or small cluster 
of signals FGFR1/CEN8 ratio will be also reported as a continuous variable. 
2) Immunohistochemistry: the expression of FGFR1 at the protein level will be assessedusing 
immunohistochemistry, using the monoclonal D8E4 antibody (Cell Signaling, Boston, MA). 
Antibody dilution and antigen retrieval is currently  being optimized. Stained slides  will be 
analyzed in a semi quantitative manner using the H score method. 
3) mRNA expression: We will quantify the mRNA expression levels of FGFR1 along with other 
key targets using Nanostring. RNA will be extracted the RNAeasy Mini Kit (Qiagen) according to 
the manufacturers' instructions. One hundred ng of total RNA will be hybridized to a custom 
designed gene CodeSet (non-enzymatic RNA profiling using barcoded fluorescent probes) 
according to the manufacturers protocol (Nanostring Technologies). Barcodes will be counted 
(600 fields of view per sample) on an nCounter Digital Analyzer following the manufacturer’s 
instructions (NanoString® Technologies) and normalized to housekeeping transcripts. Further 
analysis will follow previously published methods to identify the range of FGFR1 expression 
levels, which will be compared to IHC and FISH findings. 
 
 
11.1 
TOXICITIES/SIDE EFFECTS 
 
11.1 
Debio 1347 
Expected side effects include: 
• 
Constitutional: asthenia, fatigue,  decreased appetite 
• 
Musculoskeletal: myalgia, back pain 
• 
Neurologic: dizziness 
• 
Cardiovascular: hypertension, decline in LVEF, QTc prolongation 
• 
ENT: blurry vision, diplopia, dry eyes 
• 
Respiratory: dyspnea, cough 
• 
Dermatologic: maculo papular rash, nail changes, alopecia, hand foot syndrome, dry 
skin 


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• 
Gastrointestinal: elevations in AST/ALT/Alk  Phos/bilirubin/amylasemia, 
nausea/vomiting, constipation, diarrhea, abdominal pain, dry mouth, dysgeusia, 
stomatitis 
• 
Renal/Electrolyte abnormalities: hyperphosphatemia, increased creatinine, 
hypomagnesemia, hypokalemia 
 
 
Please refer to Section 3.3.4 and the Investigator’s Drug Brochure for more information. 
 
 
11.2 Fulvestrant 
The most commonadverse reactions occurring in ≥5% of patients receiving 500 mg fulvestrant 
were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in 
extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and 
constipation. 
 
Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were 
not dose-dependent. 
 
Because Fulvestrant is administered intramuscularly, it should be given with caution in patients 
with bleeding diathesis, thrombocytopenia, or anticoagulant use. For further details regarding 
the safety profile of fulvestrant, refer to the fulvestrant package insert. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Tumor response is based on the RECIST v.1.1. A copy of the full article is provided as 
Appendix B. Key elements of the criteria are summarized below. 
 
12.1 Measurability of Tumor at Baseline 
 
RECIST v.1.1 provides the following definitions for designating the tumor lesion/lymph node 
as measurable or non-measurable at baseline. 
 
12.1.1 Measurable Lesions 
 
12.1.1.1 Tumor Lesions 
 
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size as follows: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II of 
Eisenhauer et al, 2009 for imaging guidance) 
o 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with caliper should be recorded as non-measurable) 
o 20 mm by chest X-ray 


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12.1.1.2 Malignant  Lymph Nodes 
 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessedby CT scan (CT scan slicethickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
For additional information on lymph node measurement, see notes in Eisenhauer et al, 2009 
under the heading “Baseline documentation of target and non-target lesions,” as well as a 
companion paper on lymph node assessment using RECIST 50. 
 
12.1.2 Non-measurable Lesions 
 
Non-measurable lesions are all other lesions, including small lesions (longest diameter < 10 
mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non- 
measurable lesions. Truly non-measurable lesions include leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement of skin 
or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
12.1.3 Special Considerations Regarding Lesion Measurability 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment. 
 
12.1.3.1 Bone Lesions 
 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
 
Blastic bone lesions are non-measurable. 
 
12.1.3.2 Cystic Lesions 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (i.e., neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same individual, these are preferred for selection as target lesions. 


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12.1.3.3 Lesions with Prior Local Treatment 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco- 
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
 
12.1.4 Methods of Tumor Measurement 
 
Please refer to Eisenhauer et al, 2009, Section 3.2 for details concerning details of how 
measurements of lesions/lymph nodes should be done. For the current study, CT is the only 
acceptable measurement method. 
 
12.2 Tumor Response  Evaluation 
 
12.2.1 Designation of Target and Non-Target Lesions 
 
When more than one measurable lesion is present at baseline, all lesions, up to a maximum 
of 5 lesions (and a maximum of 2 lesions per involved organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
In the current study, the baseline measurement will be based on the scans and measurements 
taken at the end of the pre-study standard chemotherapy, as submitted by the investigator. 
Target lesions should be selected on the basis of their size (lesions with longest diameter) and 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the casethat on occasion, the largest lesion 
does not lend itself to reproducible measurement; in such cases, the next largest lesion that 
can be reproducibly measured should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as the reference to characterize any objective changes in the 
measurable dimension of disease. 
All other lesions or sites of disease (i.e., non-measurable lesions), including pathological lymph 
nodes, should be identified as non-target lesions. Measurements of non-target lesions, even if 
measurable, are not required, as they are intended to be assessed qualitatively and should be 
designated as present or absent at baseline. It is also possible to record multiple non-target 
lesions in the same organ as a single item, e.g., “multiple enlarged pelvic lymph nodes.” 
 
12.2.2 Definitions of Response 
 
12.2.2.1 Target Lesions 
 
Definitions of response for individual patients at each assessment time point for target 
lesions are shown in Table 2. 
Table 2 Evaluation of Response in Target Lesions 


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Response  Category 
Definition 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non- 
target) must have reduction in short axis  to < 10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative  increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm.  (Note: the appearance of one or more new lesions is also considered 
progression). For this study, PD should be confirmed at least 4 weeks later. 
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study 
Abbreviations:    CR, complete response;  PR, partial response; PD, progressive  disease; SD, stable 
disease 
 
12.2.2.1.1 Lymph Nodes as Target Lesions 
 
Please refer to RECIST v.1.1 in Appendix B for special notes on the assessment of lymph 
nodes as target lesions, lesions that become too small to measure, and lesions that split or 
coalesce after treatment. 
 
12.2.2.2 Non-target  Lesions 
 
Definitions of response for individual patients at each assessment time point for non-target 
lesions are shown in Table 18. Non-target lesions, even if measurable, are to be evaluated 
qualitatively, as noted above, and are to be designated as CR, non-CR/non-PD, or PD, as 
defined in Table 3. 


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Table 3 Evaluation of Response at Each Time Point in Non-target Lesions 
 
Response  Category 
Definition 
CR 
Disappearance of all non-target lesions and normalization  of tumor marker  level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more  non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
PD 
Unequivocal progression (see comments  below) of existing non-target lesions. (Note: 
the appearance of one or more  new lesions is also considered progression).a 
Abbreviations:   CR, complete response;  SD, stable disease; PD, progressive  disease. 
a    Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the opinion of the 
treating physician should prevail. 
 
12.2.2.2.1 Special Notes on Designation of Progression in Non-Target Disease 
 
The concept of progression of non-target disease in the setting of concurrent measurable 
disease as in this study requires further explanation. In this setting, to assign unequivocal 
progression on the basis of the non-target disease (see determination of overall response in 
Section 0), there must be an overall level of substantial worsening in non-target disease such 
that, even in the presence of SD or PR in the target disease, the overall tumor burden has 
increased sufficiently to warrant discontinuation of therapy (see examples in the RECIST v.1.1 
guidelines in Appendix B). A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for a designation as unequivocal progression. The designation 
of overall progression solely on the basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
 
12.2.2.3 New Lesions 
 
The appearance of new malignant lesions denotes disease progression. Refer to RECIST 
v.1.1 in Appendix B for notes concerning the detection of new lesions. 
 
12.2.2.4 Missing Data 
 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missinglesions would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a subject had a baseline sum of 50 mm with three measured lesions and at the 
assessment only two lesions were assessed, but those gave a sum of 80 mm, the subject will 
have achieved PD status regardless of the contribution of the missing lesion measurement. 
 
12.2.2.4.1 Additional  Notes Relevant to Designations of Disease Progression 
 
Per RECIST v.1.1, patients with a global deterioration of health status requiring discontinuation 
of  treatment  without  objective  evidence  of  disease  progression  should  be  reported  as 


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“symptomatic deterioration,” and every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy. The objective 
response of such subjects is to be determined by evaluation of target and non-target disease 
as shown in Table 17 and Table 18. In the current study, scans are to be done every 3 cycles 
and at any time deemed appropriate by the investigator (i.e., when progression is suspected). 
PD at first response scan must be confirmed at least 4 weeks later. 
 
12.2.2.5 Overall Response for Each Subject at Each Assessment Time Point 
 
Overall response at each assessment time point is based on the totality of the responses for 
target and non-target lesions, as shown in Table 19. 
Table 4 Rubric for Determination of Overall Response at Each Assessment Time Point for Each 
Patient 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations:  CR,  complete  response; PR, partial response; SD, stable disease; PD, progressive disease 
 
12.2.2.6 Additional  Information Concerning RECIST v1.1 
 
Full details concerning the use of RECIST v.1.1 may be found in the full article by 
Eisenhauer et al. (2009), which is attached as Appendix B. 
 
 
12.3 Evaluable patients 
 
12.3.1 Safety Population 
 
Patients who received any dose of the study drug. 
 
12.3.2 MTD/RP2D Determination Population during Phase 1b portion 
 
The population evaluable for MTD/RP2D determination will consist of all patients who 
received at least 75% of the planned Debio 1347 dose during the DLT period (Day 1 to Day 
28 of Cycle 1 and assessments prior to drug administration on C2D1). Patients who 
experienced a DLT will be included in the MTD/RP2D determination population regardless of 
the dose of Debio 1347 received. 


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Patients who fulfill any of the following situations will be excluded from the MTD/RP2D 
determination population: 
1. Administration during the DLT period of non-permitted concomitant treatments with 
impact on DLT evaluation. 
2. 
Proper DLT/safety evaluation is judged to be difficult because of protocol violation(s). 
 
12.3.3 Efficacy population 
 
Patients who have measurable and/or non-measurable disease, according to RECIST 
version 1.1. criteria, undergo a baseline disease assessment, at least one on-treatment 
assessment, but excluding those who fulfill any of the following conditions: 
1. Violation  of clinically relevant inclusion/exclusion criteria. 
2. Administration of non-permitted concomitant treatments. 
 
13.1 
CRITERIAFOR REMOVAL FROM STUDY 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• 
Confirmed radiographic disease progression 
 
Note: A subject may continue on treatment with confirmed radiographic progression if 
clinically stable or clinically improved. 
• 
Unacceptable adverse experiences 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Investigator’s decision to withdraw the subject 
 
• 
Subject death 
 
• 
The subject has a confirmed positive serum pregnancy test 
 
• 
Noncompliance with trial treatment or procedure requirements 
 
• 
The subject is lost to follow-up 
 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment). 


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Subjects who discontinue for reasons other than progressive disease will have post- 
treatment follow-up for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up, for up to 2 years. After 
documented disease progression, each subject will be followed by telephone for overall 
survival until death, withdrawal of consent, the end of the study, or 2 years, whichever occurs 
first. 
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation. 
 
 
14.0 
BIOSTATISTICS 
 
Phase I: The phase I portion of this trial will evaluate 2 dose cohorts including 1 de-escalation 
cohort (N= minimum 4 and maximum 12) as shown in the table below. Only the dose of Debio 
1347 will be de-escalated. There will be no intra-patient dose escalation. 1 cycle = 28 days. 
The Dose Limiting Toxicity (DLT) observation period includes Day 1 to Day 28 of Cycle 1, plus 
the assessments prior to drug administration on Cycle 2, Day1. 
 
Cohort/Dose  level 
Debio 1347 
Fulvestrant 
-1 
60mg 
500mg IM 
1 (Starting dose cohort) 
80mg 
500mg IM 
 
 
If none or one of the initial 3 patients in dose level 1 has DLT, 3 additional patients will be 
treated at the same dose level. If 2 or more patients experience DLT at this dose level, then 
dose level -1 will be evaluated. Should 2 or more patients experience DLT at dose level -1, the 
study will stop accrual. If only 1 of the 3 initial patients experiences a DLT at dose level -1, 3 
additional patients will be evaluated at this dose level. Patients who withdraw before 
completing a full cycle of treatment for reasons other than development of a DLT will be 
replaced. 
Selected non-hematologic and hematologic toxicities, as measured by the NCI CTCAE 
Version 4.0, will be described by frequency and grade, by cycle and over all cycles, with the 
maximum grade over all cycles used as the summary measure per patient.   In a descriptive 
secondary analysis, clinical benefit rate will be estimated by dose. 
 
We anticipate accruing 1-2 patients/month in the phase 1b portion of the study. 
 
Phase II:  The purpose of the phase II portion of the study is to evaluate the efficacy of this 
regimen, using the MTD/RP2D as determined in the Phase Ib part of the trial.  Efficacy will be 
measured by the clinical benefit rate: proportion of patients who have a best overall response 


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of a complete response, a partial response, or stable disease (SD) for at least 24 weeks (SD 
≥ 24 weeks) i.e. (CR+PR+SD >=24 weeks).  In the PALOMA-3 trial where ER+ MBC patients 
were randomized to fulvestrant plus palbociclib versus fulvestrant, the CBR (ORR + SD > 24 
weeks) was 34%(95% CI, 29.0 to 39.3)  vs 19% (95% CI, 13.4 to 25.6).  There is no historic 
data available for patients who have progressed on palbociclib. Since this trial will allow 
patients who have received prior palbociclib, it was decided that a target clinical benefit rate 
below 10% will not be worthy of further consideration and a response rate of 25% will be 
considered promising. 
Simon’s two-stage optimal design will be used to study the treatment efficacy since it permits 
early termination of the study. We will allow early termination only if the data at the first stage 
indicate that the treatment is highly inactive.  18 patients will initially enter the study.  If there 
are 2 or fewer patients with clinical benefit (CR, PR or SD>=24) observed, the study will be 
terminated early and declared to have a negative result.  If 3 or more patients have clinical 
benefit, enrollment will be extended to 43 patients.   Note, we will halt the trial after the first 
stage while awaiting results from the first 18 patients. 
If 8 or more patients with clinical benefit are observed among the 43 patients, the study will be 
considered to have a positive result and this regimen would be considered worthy of further 
testing in this disease. The probability of early termination is 0.73 if the true clinical benefit 
probability is < 10%. This design would effectively discriminate between true clinical benefit 
rates of < 10% and > 25%.  This design has 80% power and a type I error of 5%. 
 
Upon completion of the study, the true clinical benefit rate will be estimated via the observed 
rate and an exact confidence interval will be constructed. 
The maximum of 43 patients requires about 2 years of patient accrual with an anticipated 
enrollment of 1-2 patients per month. 
In secondary analyses for the Phase Ib portion of the trial, the ORR will be summarized as a 
proportion with a 95% exact confidence interval. TTP, PFS and OS will be evaluated using 
Kaplan-Meier methods.  All toxicities as measured by the NCI CTCAE Version 4.0, will be 
described by frequency and grade, by cycle and over all cycles, with the maximum grade over 
all cycles used as the summary measure per patient. All patients will be included in the safety 
analyses regardless of whether a patient is not evaluable for the efficacy endpoint. 
All exploratory analyses will be conducted for each phase of the trial separately.  PK/PD 
measures such as AUC, Cmax, and Cmin will be calculated and summarized. Exploratory 
endpoints that aim to investigate biomarkers of clinical benefit and/or resistance will be 
evaluated descriptively and graphically. If there are a sufficient number of clinical benefit 
events, nonparametric tests (Fisher’s exact or Wilcoxon rank sum) will be used to test the 
exploratory hypotheses depending on the distribution of the biomarker. 
Deaths will be censored for the TTP endpoint in secondary analyses. However, we will also 
evaluate  PFS  which  treated  deaths  and  progression  as  events.    These  are  secondary 


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analyses, and if there are a sufficient number of events and types of events, we can consider 
other approaches, such as the calculation of cumulative incidence functions. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to complete 
a protocol specific  Eligibility Checklist. The individual signing the Eligibility Checklist is 
confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
15.3 
Randomization 
 
If the research study requires randomization procedures, this section should be referenced by 
the Biostatistics section (14.0). Describe in detail the process of randomization, when it should 
occur, how it is being conducted and who is responsible for carrying it out. 
16.1 
DATA MANAGEMENT ISSUES 
 
A MSKCC Research Study Assistant (RSA) and Research Project Coordinator (RPC) will 
assist the PI, Dr. Komal Jhaveri with the oversight and conduct of this study. The RSA will be 
responsible for protocol compliance, data collection, data reporting, AE tracking and reporting, 
SAE reporting, regulatory submissions, and for coordinating all study participant research 
activities. The RPC will be responsible for regulatory compliance, overall project compliance, 
data quality assurance, SAE review, and Medidata database management. Both the RSA and 
RPC will report to and regularly meet with the PI to review study, data and enrollment status; 
protocol aberrations, regulatory requirements and any participant toxicities on study. 
16.2 
Quality Assurance 
 
Throughout the life of the study, the study team comprising of the PI, research fellows, research 
nurses, RSA, and RPC will meet regularly. During these meetings, they will address accrual 
rates, review adverse events, and discuss any  challenges with using the device in this 
population. Regular registration reports will be generated to monitor patient accruals and 
completeness of data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study and potential problems will be brought to the attention of the 
PI and CRM for discussion and action. 
Random sample data quality audits will be performed by the RPC and evaluated at the study 
team meetings. 


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16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute 
for Data 
and 
Safety Monitoring of Clinical  Trials” which can  be  found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Officeof Clinical Research. The MSKCC Data and Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
 
at:  
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional  Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Participants will be informed that information collected during their participation in this study is 
considered confidential. All data gathered will be kept in a secured location and available only 
to members of the research study team. Findings will be presented in aggregate form only - 
with no references made to the individual participant’s data. Confidentiality of each participant’s 
data will be protected with utmost care; data will be identified solely by a code number. A list 
matching participant’s names and code numbers will be maintained on a secureand password 
protected database in MSKCC servers. Participation in this study is entirely voluntary. All 
participants will be required to sign a statement of informed consent that adheres to MSKCC 
guidelines. Should a patient decide not to participate in this study or to withdraw their consent 
to participate at any time during the study, their treatment at MSKCC or participating institutions 
will in no way be compromised. 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 


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The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researc hers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified  researchers. 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention.  SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event.  All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 


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• 
An explanation of how the AE was handled 
• 
A description of the participant’s condition 
• 
Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
17.3.1 SAE Reporting to Debiopharm International S.A. 
 
All SAEs, irrespective of their cause, that occur between signature of informed 
consent and 30 days after the last IMP administration, have to be reported by the 
Institution to Debiopharm International SA within 24 hours after being informed of 
their occurrence. 
 
• Serious AEs will be reported to Debiopharm by FAX, e-mail, or phone. 
• When reported by FAX, SAEs will be transmitted via the “Serious Adverse 
Event Report transmittal form” to: 
 
Debiopharm International SA 
Fax: + 41 21 321 06 97 
• When reported by e-mail, SAEs will be transmitted to: 
• Safety-Debio-1347-101@debiopharm.com 
• When reported by phone, SAEs will be notified to the Pharmacovigilance 
Manager of Debiopharm International  SA as specified in the site study file. 
• All SAEs shall be promptly confirmed in writing at the latest within 3 days of 
being informed using the “Serious Adverse Event Report transmittal form” of 
Debiopharm International SA 
 
17.2.1 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 


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5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In addition 
to signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
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IRB Number: 17-379 A(7) 
Approval date: 10-Mar-2020 
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20.0 
APPENDICES 
 
Appendix A: Guidelines for prophylaxis and Treatment of Dermatologic Toxicity 
Appendix B:  Recist 1. 1 Guideline