A Phase II Trial of Ribociclib (LEE011) Plus Letrozole in Women With Recurrent Low-Grade Serous Carcinoma of the Ovary, Fallopian Tube or Peritoneum
Phase: PHASE2
Conditions: Low Grade Serous Carcinoma
Sponsor: Gynecologic Oncology Group

 
Page 1 of 80 
 
 
PROTOCOL GOG-3026  
STUDY TITLE:  A Phase II Trial of Ribociclib (LEE011) plus Letrozole in Women with Recurrent Low-Grade 
Serous Carcinoma of the Ovary, Fallopian Tube or Peritoneum 
PROTOCOL VERSION # 
4.0 
PROTOCOL VERSION DATE 
February 10, 2020 
Administrative Update to title page:  August 16, 2021 
STUDY CHAIR 
Brian Slomovitz, MD 
Director of Gynecologic Oncology 
Mount Sinai Medical Center – Miami Beach 
4306 Alton Road 
Miami Beach, FL 33130 
Email:  bslomovitz@gog.org  
STUDY CO-CHAIR(S) 
David Gershenson, MD 
Professor, Department of Gynecologic Oncology & 
Reproductive Medicine 
  Unit 1362  
MD Anderson Cancer Center 
1155 Herman Pressler Dr  
Houston, TX 
Telephone: 713-745-2565 
Email: DGershen@mdanderson.org 
 
Robert Coleman, MD 
Texas Oncology – The Woodlands 
9180 Pinecroft, Suite 600 
The Woodlands, TX 77380 
Telephone:  281-296-0365 
Email: rcoleman@gog.org  
PATHOLOGIST 
William H. Rodgers, PhD, MD 
Professor, Clinical Pathology and Laboratory Medicine, 
Weill Cornell Medical College 
NYP/Queens Pathology Laboratory 
56-45 Main Street 
Flushing, NY 11355 
Telephone:  718-670-1141 
Email:  whr9001@med.cornell.edu  
BIOSTATISTICIAN 
Wei Deng, PhD 
Wei.deng@roswellpark.org  
DATA MANAGER 
Linda Gedeon 
Linda.gedeon@roswellpark.org  
TRANSLATIONAL RESEARCH SCIENTIST 
Heather Lankes, PhD, MPH 
hlankes@gog.org  
PROTOCOL COORDINATOR 
Jennifer Klein, MEd 

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jklein@gog.org  
FUNDING SOURCE 
Novartis 
GOG Foundation, Inc. 
 
 
Document History 
Closed  
02/24/2023 
Re-activation and Administrative Update 
08/16/2021 
Temporary Closure  
03/25/2021 
Version 4.0 
02/10/2020 
Version 3.0 
08/12/2019 
Version 2.0 
03/01/2019 
Version 1.0/Activation 
06/13/2018 

 
Page 3 of 80 
 
Regulatory Sponsor 
GOG Foundation, Inc. 
Investigational Agent(s) 
Investigational Agent: Ribociclib (formerly LEE011) 
Supplier: Novartis Pharmaceuticals Corporation 
Other Agent(s) 
Other Agent: Letrozole 
Supplier: Novartis Pharmaceuticals Corporation 
IND Status  
IND or IDE #: Exempt 
ClinicalTrials.gov Identifier 
NCT03673124 
 
 
 
 
 

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Table of Contents 
ABBREVIATIONS & DEFINITIONS ........................................................................................................................... 5 
PROTOCOL SYNOPSIS ........................................................................................................................................... 6 
PROTOCOL SCHEMA ........................................................................................................................................... 14 
1.0 
BACKGROUND ...................................................................................................................................... 15 
2.0  
OBJECTIVES ........................................................................................................................................... 22 
3.0  
PATIENT SELECTION .............................................................................................................................. 23 
4.0  
STUDY DESIGN ...................................................................................................................................... 27 
5.0  
PATIENT ENTRY/RANDOMIZATION PROCEDURE ................................................................................... 43 
6.0 
STUDY PARAMETERS ............................................................................................................................. 43 
7.0  
PATHOLOGY/BIOSPECIMEN REQUIREMENTS ........................................................................................ 50 
8.0  
EVALUATION CRITERIA .......................................................................................................................... 52 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES ........................................................................... 60 
11.0  
STATISTICAL CONSIDERATIONS ............................................................................................................. 62 
12.0  
REFERENCES .......................................................................................................................................... 66 
APPENDIX A: PERFORMANCE STATUS SCALES ..................................................................................................... 69 
APPENDIX B: NYHA CLASSIFICATION OF HEART DISEASE ..................................................................................... 70 
APPENDIX C: PROHIBITED MEDICATIONS DURING STUDY DRUG TREATMENT .................................................... 71 
APPENDIX D- PATIENT PILL CALENDAR: .............................................................................................................. 74 
APPENDIX E - DIGITAL PATHOLOGY SCREENING FORM ....................................................................................... 75 
APPENDIX F - TRANSLATIONAL RESEARCH BIOSPECIMEN PROCEDURES .............................................................. 76 
APPENDIX G – BIOPATHOLOGY CENTER FFPE MATERIALS VERIFICATION FORM .................................................. 79 
APPENDIX H - BIOPATHOLOGY PATHOLOGY VERIFICATION FORM ...................................................................... 80 
 
 

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ABBREVIATIONS & DEFINITIONS 
 
Term 
Abbreviation 
Definition 
Dose-Limiting Toxicity 
DLT 
Describes side effects of a drug or other 
treatment that are serious enough to prevent 
an increase in dose or level of that treatment.   
(DLTs are defined before beginning the trial 
and are protocol-specific.)  
Maximum Tolerated Dose 
MTD 
The highest dose of a drug or treatment that 
does not cause unacceptable side effects.  The 
MTD is determined in clinical trials by testing 
increasing doses on different groups of people 
until the highest dose with acceptable side 
effects is found.  
Overall Survival 
OS 
The length of time from either the date of 
diagnosis or the start of treatment for a 
disease, that patients diagnosed with the 
disease are still alive.   
Progression-Free Survival 
PFS 
The length of time during and after the 
treatment of a disease that a patient lives with 
the disease but it does not get worse.   
Time to Progression 
TTP 
The length of time from the date of diagnosis 
or the start of treatment for a disease until the 
disease starts to get worse or spread to other 
parts of the body.   
Clinical Benefit Rate 
CBR 
Summation of response rate and stable disease 
rate 
 
Reference: National Cancer Institute (NCI) Dictionary of Cancer Terms 
http://www.cancer.gov/dictionary   
 

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PROTOCOL SYNOPSIS 
 
Protocol Title  
A Phase II Trial of Letrozole + Ribociclib in Women with 
Recurrent Low-Grade Serous Carcinoma of the Ovary, 
Fallopian Tube or Peritoneum 
Targeted Patient Population 
Histologically confirmed diagnosis of low-grade serous 
carcinoma of ovary, fallopian tube or peritoneum. Patients 
may have been treated with unlimited prior therapies 
excluding aromatase inhibitors. Patients must have 
measurable disease. 
Study Design  
This is an open-label, multi-institution activity phase II trial. 
Eligible subjects with recurrent low-grade serous carcinoma 
who sign informed consent will receive the combination of 
letrozole and Ribociclib until disease progression or until they 
experience significant adverse events. 
Safety Lead-in 
A review of safety will occur after the first 6-10 patients are 
treated and complete one cycle (including starting cycle 2 
within the DLT constraints outlined in Section 4.6) or have a 
DLT prior to completing the first cycle. Within the safety lead-
in, patients who do not have a DLT and who do not complete 
cycle 1 will be replaced.           
Treatment Schema 
Letrozole will be administered at a dose of 2.5 mg by mouth 
daily. Ribociclib will be administered at a dose of 600 mg by 
mouth daily for 21 days followed by 7 days off treatment. 
Treatment will be until progression or toxicity.  
Objectives 
Primary Objective: 
To determine the response rate of patients receiving the 
combination of letrozole + Ribociclib. 
Secondary Objective(s): 
To determine the clinical benefit (CR, PR, and SD) rate of 
patients receiving the combination of letrozole + Ribociclib. 
To determine the nature, frequency, and maximum degree of 
toxicity associated with this combination using CTCAE v5.0. 

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To determine the progression-free survival of women 
receiving the combination of letrozole + Ribociclib. 
To determine the overall survival of women receiving the 
combination of letrozole + Ribociclib. 
Exploratory Objective(s): 
1. To determine the expression of estrogen receptor (ER), 
progesterone receptor (PR), and proliferative index (ki-67) 
and their correlation with response and clinical benefit. 
2. To determine genomic signatures associated with response 
and clinical benefit of the combination of letrozole + 
Ribociclib. 
Expected Number of Patients 
19-51 
Expected Number of Centers 
25  
Expected Duration of the 
Protocol 
22 months 
Inclusion Criteria 
Patients eligible for inclusion in this study must meet all of 
the following criteria: 
1. Patient has signed the Informed Consent (ICF) prior to 
any screening procedures being performed and is able 
to comply with protocol requirements.  
2. Age > 18 years at time of study entry. 
3. Willingness and ability to comply with study and 
follow-up procedures. 
4. Histological confirmation of diagnosis of low-grade 
serous carcinoma of ovary, fallopian tube or 
peritoneum; Original diagnosis of de novo low-grade 
serous carcinoma or Original diagnosis of serous 
borderline tumor with subsequent diagnosis of low-
grade serous carcinoma. 
• In order to prevent inclusion of patients with 
high-grade serous carcinoma, diagnosis of low-
grade serous carcinoma will be verified as part 
of screening review by a gynecologic 
pathologist. Tissue for confirmation can be 
from primary tumor or recurrence. 

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5. Patient must have recurrent, measurable disease by 
RECIST v1.1. 
6. There are no restrictions on number of prior 
therapies. 
7. Patient cannot have previously received a prior cyclin 
dependent kinase inhibitor (CDKi). Patients who were 
treated with letrozole or another aromatase inhibitor 
for other indications must have not taken the drug 
for 6 months prior to initiating letrozole for this trial 
and may not have progressed on treatment. 
8. Patients must not have remaining ovarian function to 
be included. In women who have at least one retained 
ovary, menopause must be confirmed with laboratory 
confirmation. Women who have ovarian function are 
eligible but must be placed on hormonal suppression.  
Menopause must be confirmed with laboratory 
confirmation, to include an estradiol level as this is 
assessed within 8 weeks of patient having been on 
tamoxifen. 
9.  Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) 0-2 
10. Resolution of all acute toxic effects of prior therapy or 
surgical procedures to National Cancer Institute (NCI) 
CTCAE Grade ≤ 1. Patients with grade 1 taxane-
induced neuropathy, any grade alopecia, amenorrhea, 
or other toxicities not considered a safety risk for the 
patient as per investigator’s discretion are eligible.   
11. Patient has adequate bone marrow and organ 
function as defined by the following laboratory values 
at screening:  
• Absolute neutrophil count ≥1.5 × 109/L  
• Platelets ≥100 × 109/L  
• Hemoglobin ≥9.0 g/dL  
• Potassium, total calcium (corrected for serum 
albumin), magnesium, sodium and phosphorus 
within normal limits for the institution or 
corrected to within normal limits with 
supplements before first dose of study 
medication  

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• INR ≤1.5 (unless patient is receiving permitted 
anticoagulants and the INR is within the 
therapeutic range of intended use for that 
anticoagulant within 7 days prior to the first 
dose of study drug). 
Serum creatinine <1.5 mg/dL or creatinine 
clearance ≥50 mL/min  
• In the absence of liver metastases, alanine 
aminotransferase (ALT) and aspartate 
aminotransferase (AST) <2.5 x ULN.  If the 
patient has liver metastases, ALT and AST <5 x 
ULN  
• Total bilirubin < ULN; or total bilirubin ≤3.0 x 
ULN or direct bilirubin ≤1.5 x ULN in patients 
with well-documented Gilbert’s Syndrome.  
12. Patient with available standard 12-lead ECG with the 
following parameters at screening: 
• QTcF interval at screening <450msec (using 
Fridericia’s correction) 
• Resting heart rate 50-90bpm   
13. Must be able to swallow ribociclib and letrozole 
capsules/tablets. 
14. Patients receiving tamoxifen or toremifene must have 
washout period of 5 half-lives prior to randomization. 
Exclusion Criteria 
Patients eligible for this study must not meet any of the 
following criteria:  
1. Patient has a known hypersensitivity to any of the 
excipients of ribociclib or letrozole.  
2. Patient has a concurrent malignancy or malignancy 
within 3 years prior to starting study drug, with the 
exception of adequately treated, basal or squamous 
cell carcinoma, non-melanomatous skin cancer or 
curatively resected cervical cancer. Patients with 
known brain metastases are excluded. 
3. Patients with central nervous system (CNS) 
involvement unless they meet ALL of the following 
criteria:  

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• At least 4 weeks from prior therapy 
completion (including radiation and/or 
surgery) to starting the study treatment  
• Clinically stable CNS tumor at the time of 
screening and not receiving steroids and/or 
enzyme inducing anti-epileptic medications for 
brain metastases.  
4. Patient has impairment of gastrointestinal (GI) 
function or GI disease that may significantly alter the 
absorption of the study drugs (e.g., ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection).   
5. Patient has a known history of HIV infection (testing 
not mandatory).  
6. Patient has any other concurrent severe and/or 
uncontrolled medical condition that would, in the 
investigator’s judgment, cause unacceptable safety 
risks, contraindicate patient participation in the 
clinical study or compromise compliance with the 
protocol (e.g. chronic pancreatitis, chronic active 
hepatitis, active untreated or uncontrolled fungal, 
bacterial or viral infections, etc.).  
7. Clinically significant, uncontrolled heart disease 
and/or cardiac repolarization abnormalities, including 
any of the following:  
• History of acute coronary syndromes (including 
myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary 
angioplasty, or stenting) or symptomatic 
pericarditis within 6 months prior to screening  
• History of documented congestive heart failure 
(New York Heart Association functional 
classification III-IV)  
• Documented cardiomyopathy  
• Left Ventricular Ejection Fraction (LVEF) <50% 
as determined by Multiple Gated acquisition 
(MUGA) scan or echocardiogram (ECHO)  
• Clinically significant cardiac arrhythmias (e.g. 
ventricular tachycardia), complete left bundle 
branch block, high-grade AV block (e.g. 

Page 11 of 80 
bifascicular block, Mobitz type II and third-
degree AV block)  
• Long QT syndrome or family history of 
idiopathic sudden death or congenital long QT 
syndrome, or any of the following:  
o Risk factors for Torsades de Pointe (TdP) 
including uncorrected hypocalcemia, 
hypokalemia or hypomagnesemia, history 
of cardiac failure, or history of clinically 
significant/symptomatic bradycardia.  
o Concomitant use of medication(s) with a 
known risk to prolong the QT interval 
and/or known to cause Torsades de Pointe 
that cannot be discontinued (within 5 half-
lives or 7 days prior to starting study drug) 
or replaced by safe alternative medication   
o Inability to determine the QT interval on 
screening (QTcF, using Fridericia’s 
correction)  
o Systolic blood pressure (SBP) >160 mmHg 
or <90 mmHg at screening  
8. Patient is currently receiving any of the following 
medications and cannot be discontinued 7 days prior 
to starting study drug (see Table 1 for details):  
• Known strong inducers or inhibitors of 
CYP3A4/5, including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville 
oranges  
• That have a narrow therapeutic window and 
are predominantly metabolized through 
CYP3A4/5  
• Herbal preparations/medications, dietary 
supplements.  
9. Participation in other studies involving investigational 
drug(s) within 30 days prior to randomization or 
within 5 half-lives of the investigational product 
(whichever is longer) or participation in any other type 
of medical research judged not to be scientifically or 
medically compatible with this study.  If the patient is 
enrolled or planned to be enrolled in another study 

Page 12 of 80 
that does not involve an investigational drug, the 
agreement of Novartis study medical lead is required 
to establish eligibility. 
10. Patient is currently receiving warfarin or other 
coumadin-derived anticoagulant for treatment, 
prophylaxis or otherwise. Therapy with heparin, low 
molecular weight heparin (LMWH) or fondaparinux is 
allowed. Direct-Acting Oral Anticoagulants (DOACS) 
are permitted. 
11. Patient is currently receiving or has received systemic 
corticosteroids ≤2 weeks prior to starting study drug, 
or who have not fully recovered from side effects of 
such treatment. The following uses of corticosteroids 
are permitted: a short duration (<5 days) of systemic 
corticosteroids; any duration of topical applications 
(e.g., for rash), inhaled sprays (e.g., for obstructive 
airways diseases), eye drops or local injections (e.g., 
intra-articular)  
12. Patient who has received radiotherapy ≤4 weeks or 
limited field radiation for palliation ≤2 weeks prior to 
starting study drug, and who has not recovered to 
grade 1 or better from related side effects of such 
therapy (exceptions include alopecia) and/or in whom 
≥25% of the bone marrow (Ellis, 1961) was irradiated.  
13. Patient has had major surgery within 14 days prior to 
starting study drug or has not recovered from major 
side effects (tumor biopsy is not considered as major 
surgery).  
14. Patient with a Child-Pugh score B or C.  
15. Patients who are pregnant or breastfeeding. 
16. Women of child-bearing potential, defined as all 
women physiologically capable of becoming pregnant, 
unless they are using highly effective methods of 
contraception throughout the study and for 3 weeks 
after study drug discontinuation. Highly effective 
contraception methods include:  
• Total abstinence when this is in line with the 
preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and 

Page 13 of 80 
withdrawal are not acceptable methods of 
contraception  
• Female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy), 
total hysterectomy, or tubal ligation at least six 
weeks before taking study treatment. In case 
of oophorectomy alone, only when the 
reproductive status of the woman has been 
confirmed by follow up hormone level 
assessment . 
Women are considered post-menopausal and not of 
child bearing potential if they have had 12 months of 
natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she 
considered not of child bearing potential. 
17. Current use of food or drugs known to be potent 
CYP3A4 inhibitors, drugs known to be potent CYP3A4 
inducers, and drugs that are known to prolong the QT 
interval unless the prohibited concomitant medication 
can be replaced by other drugs of less potential to 
inhibit or induce CYP3A4 or prolong QT interval (See 
Appendix C for Prohibited Concomitant Medications). 
18. Patients whose tumors contain both low-grade serous 
carcinoma (LGSC) and high-grade serous carcinoma 
(HGSC) 
19. Patients with history of haemopoietic stem cell or 
bone marrow transplant. 
 
 

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PROTOCOL SCHEMA  
 
 
 
Pt with 
recurrent 
LGSC 
meeting 
eligibility 
criteria + 
ICF 
 
3 Weeks on: 
Ribociclib 600 mg oral qd 
1 Week 
OFF 
Radiographic 
Tumor Assessment 
28-Days Cycle 
Cycle until Disease Progression 
Labs every cycle & 
Radiographic 
Tumor Assessment 
Every 3 Cycles 
EOT Follow Up 
Every 3 Cycles (±7days) 
 
Letrozole 2.5 mg oral qd 

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1.0 
BACKGROUND 
1.1 Low-Grade Serous (LGSC) Carcinoma of the Ovary/Peritoneum 
Serous carcinoma represents the most common histologic subtype of epithelial ovarian cancer. 
After almost 20 years of analysis and refinement, investigators proposed a binary grading 
system for serous carcinoma to replace the FIGO 3-tier grading system and subsequently found 
it to be highly reproducible with excellent interobserver and intraobserver agreement (1-3). 
Since 2004, this grading system has been widely accepted and integrated into the 2014 World 
Health Organization classification of ovarian cancer. Concomitantly, several studies indicated 
that ovarian serous tumors of low malignant potential and low-grade serous carcinoma (LGSC) 
exist on a continuum and have molecular signatures and clinical behaviors distinct from high-
grade serous carcinoma (4-12). Thus, LGSC may occur de novo or following a diagnosis of 
serous tumor of low malignant potential.  
Our multidisciplinary team has been at the forefront of clinical and translational research of 
LGSC in elucidating its molecular biology and genetics (13-20) and in describing its clinical 
behavior (21-28).  Compared with high-grade serous carcinoma, LGSC is associated with 
younger age at diagnosis, relative chemoresistance, and prolonged overall survival (median OS 
= 101.7 months) (22, 23, 25-27). However, despite its relatively good prognosis, over 70% of 
women with stage II-IV disease will develop recurrent disease. This observation combined with 
LGSC’s relative chemoresistance underscores the critical need for identifying novel therapies. 
Over the past few years, our investigators have led efforts to identify novel therapies, 
including hormonal therapy (see below), MEK inhibitors, and anti-angiogenesis therapy (13, 
29-31). In addition, there is a NRG Oncology international phase II/III trial, “A randomized 
phase II/III study to assess the efficacy of trametinib (GSK1120212) in patients with recurrent 
or progressive low-grade serous ovarian cancer or peritoneal cancer,” which has thus far 
accrued 200 patients over 37 months. 
1.2 The similarity of LGSC to ER+ Breast Cancer 
Low-grade serous carcinoma shares several characteristics with luminal breast cancer: 1) 
extremely high frequency of ER expression (> 80%), 2) significant clinical benefit from 
hormonal therapies in the maintenance and recurrent settings (clinical benefit > 70%; median 
PFS = 7.4 months), and 3) significantly worse outcome in women < 35 years old (19, 27, 30-32).  
In breast cancer, ribociclib has been shown to have anti-tumor activity in HR-positive pre-
clinical tumor xenograft models.  In addition, ribociclib combined with letrozole has synergistic 
effects with sustained tumor control in PIK3CA-wildtype, ER-positive breast cancer models.   
 

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1.3 Rationale for Studying the Combination of Ribociclib + Letrozole 
Gershenson et al. reported 64 women with recurrent low-grade serous carcinoma who 
received 89 separate hormonal therapy regimens.  The objective response rate was 9%, and an 
additional 62% had stable disease. Of the 50 patients in the study for whom tissue was 
available for immunostaining, all had positive ER expression. In the most recent study using 
hormonal therapy for low-grade serous carcinoma, Gershenson et al. reported on 203 women 
with stage II-IV low-grade serous carcinoma who underwent primary cytoreductive surgery 
followed by platinum-based chemotherapy (30). The 70 women who received hormonal 
maintenance therapy had a significantly improved PFS compared to the 133 women who 
underwent observation (median PFS, 64.9 vs. 26.4 mos; P < .001). Based on information 
indicating relative chemoresistance and response to hormonal therapies in women with low-
grade serous carcinoma, physicians are increasingly replacing conventional chemotherapy with 
hormonal therapy in the first-line, maintenance, and recurrent settings. 
Ribociclib is an orally active potent and highly selective reversible inhibitor of CDK4 and CDK6. 
The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle 
from G1 into the S phase. 
1.4 Pre-Clinical Data 
The effect of ribociclib on pRb phosphorylation, BrdU uptake and cell cycle progression was 
assessed in more than 40 cell lines derived from hematological malignancies, esophageal 
cancer, liposarcoma, colon cancer, melanoma, non-small cell lung cancer, pancreatic cancer, 
and breast cancers.  In 13 pRb-positive breast cancer cell lines, ribociclib inhibited pRb 
phosphorylation with an average IC50 value of 0.413 μM (range: 0.06 to 1.20 μM). Similarly, 
ribociclib interfered with G1 to S phase cell cycle progression in these cells as determined by 
either BrdU uptake or FACS analysis with an average IC50 value of 0.43 μM (range: 0.07 to 0.89 
µM). In contrast, in lineage-matched pRb-negative cell lines no effect of ribociclib on either 
pRb phosphorylation or cell cycle progression was observed [RD-2009-50759]. Thus, ribociclib 
is able to impact cell cycle progression in cell lines derived from a variety of tumor types that 
harbor a diversity of genetic alterations in a manner dependent on intact pRb. 
Ribociclib was further tested in a panel of 47 breast cancer cell lines with known ER status. ER+ 
breast cancer cell lines were most sensitive to ribociclib, with 16 of the 18 cell lines showing 
IC50s < 1 μM, while the majority (21 out of 29) of the ER-negative cell lines had IC50s > 1 μM. 
These data suggest that the majority of ER+ breast cancer cells are dependent on CDK-4/6 
signaling for proliferation (O’Brien et al 2014)[ RD-2016-00052]. 
1.5 Phase I/II Data of Ribociclib in Combination with Letrozole in Advanced Breast 
Cancer 
Study CLEE011X2107 is a phase Ib, multicenter study of the combination of ribociclib and/or 
alpelisib with letrozole in adult patients with advanced HR+ breast cancer. The primary 

Page 17 of 80 
endpoints of the study are to estimate the MTD(s) and/or RP2D(s) for the 3 combinations: 
ribociclib + letrozole, alpelisib + letrozole, ribociclib + alpelisib + letrozole. The dose escalation 
part for ribociclib + letrozole; alpelisib + letrozole and ribociclib + alpelisib+ letrozole 
combination has been completed and patients were also enrolled on dose expansion for these 
doublet and triplet combinations. 
1.6 Doublet ribociclib + letrozole  
Forty-seven patients have been enrolled (cut-off date: 02-May-2017) to receive ribociclib (600 
mg) + letrozole (2.5 mg). The median age of patients was 60 (range: 38–76) years, all the 
patients were female, and the distribution of ECOG performance status of 0/1 at baseline was 
28/19 patients, respectively. Thirty-seven patients were discontinued from the study (29 due 
to progressive disease, 5 due to physician decision, 2 due to adverse events, and 1 due to 
subject decision) and 10 patients were still ongoing.  
Two patients experienced as DLT a grade 4 neutropenia. The RDE for ribociclib + letrozole is 
ribociclib 600 mg 3 weeks on/1 week off schedule and letrozole 2.5 mg.  
All patients experienced at least one AE. The most frequent AEs (≥10%), regardless of grade, 
causality, were: neutropenia (74.5%); nausea (51.1%); diarrhea (40.4%); fatigue (38.3%); 
arthralgia (31.9%); alopecia (29.8%); anemia (27.7%); back pain, constipation, cough, vomiting 
(25.5% for each); asthenia, hot flush, rash (23.4% for each); alanine aminotransferase 
increased, aspartate aminotransferase increased, headache, urinary tract infection (21.3% for 
each); decreased appetite, dry skin (19.1% for each); neutrophil count decreased, pain in 
extremity, pruritus, stomatitis, white blood cell count decreased (17.0% for each); abdominal 
pain, dry eye, oropharyngeal pain (12.8% for each); abdominal pain upper, anxiety, 
hyperglycemia, insomnia, leukopenia, musculoskeletal pain, myalgia, neck pain, pyrexia, and 
upper respiratory tract infection (10.6% for each). 
1.7 Key efficacy results for the combination of ribociclib + letrozole:  
As of 02 May 2017, the best overall response as per local investigator/radiology reports among 
47 patients treated with ribociclib + letrozole was complete response (CR) in two patients 
(4.3%) and partial response (PR) in 12 patients (25.5%). The overall response rate (ORR) was 
29.8%; the clinical benefit rate (CBR) was 59.6%. Seven patients (14.9%) had progressive 
disease (PD).  
1.8 Randomized Phase II and Phase III Data of Ribociclib in Combination with 
Letrozole in Advanced Breast Cancer 
Study CLEE011A2301 is a phase III, multicenter study of the combination of ribociclib or 
placebo with letrozole in postmenopausal women with HR+, HER2-negative advanced 
(metastatic or loco regionally recurrent) breast cancer who have not received prior therapy for 
advanced disease. The study met its primary objective at the pre-planned interim analysis; 

Page 18 of 80 
ribociclib in combination with letrozole demonstrated statistically significant benefit over 
placebo in combination with letrozole in prolonging PFS based on investigators assessments.  
In total, 668 patients were randomized; 334 patients each to the ribociclib plus letrozole arm 
and the placebo plus letrozole arm. Median duration of follow up at the second overall survival 
interim analysis (data cut-off 02-Jan-2017) was 26.4 months.  
As of 04-Jan-2017 data cut-off date, 219 (32.8%) patients overall remained on treatment and 
the proportion of patients continuing to receive treatment in the ribociclib plus letrozole arm 
was higher than in placebo plus letrozole arm (39.2% vs. 26.3%, respectively). Disease 
progression was the primary reason for treatment discontinuation and was more frequent in 
the placebo plus letrozole arm compared to the ribociclib plus letrozole arm (60.8% vs. 39.8%). 
Adverse events led to the discontinuation of study treatment in 35 patients ( 5.2%): 27 
patients (8.1%) in ribociclib plus letrozole arm and 8 patients (2.4%) in placebo plus letrozole 
arm.  
As of 04-Jan-2017 cut off date, the majority of patients experienced at least one AE in both 
treatment groups ( 99.1% vs. 97.6%); the most commonly (≥ 30%) reported AEs in ribociclib 
plus letrozole group, irrespective of causality were: neutropenia (64.1%), nausea (53.3%), 
fatigue (41.3%), diarrhea (38.3%), alopecia (34.4%), vomiting (33.5%), and arthralgia (33.2%). 
AEs where a higher proportion of ribociclib plus letrozole-treated patients reported events 
(and where there was a ≥ 10% difference to the placebo plus letrozole group) included: 
neutropenia (+59.3%), nausea (+22.7%), decreased neutrophil count (+20.4%), alopecia 
(+18.3%), decreased white blood cell count (+16.8%), vomiting (+16.8%), anemia (+14.9%), 
diarrhea (+13.8%), leukopenia (+12.9%), increased ALT (+12.9%), increased AST (+11.7%), and 
rash (+10.7%). The incidence of SAEs was 25.4% and 15.5% in the ribociclib plus letrozole and 
placebo plus letrozole arms, respectively. Twenty-eight patients (8.4%) from the ribociclib plus 
letrozole group experienced SAEs that were considered by the Investigator to be related to 
study treatment. The most frequently reported SAE in the ribociclib plus letrozole arm, 
irrespective of causality, was pneumonia in 6 patients (1.8%). Febrile neutropenia was 
reported as suspected in 3 patients (0.9%).  
Permanent discontinuations due to AEs were reported in 16.8% of patients receiving ribociclib 
plus letrozole and 3.9% in patients receiving placebo plus letrozole. The most common AEs 
leading to treatment discontinuation of ribociclib in patients receiving ribociclib plus letrozole 
were ALT increased (4.5%), AST increased (2.7%), vomiting (2.4%) based on data cut off of 4 
Jan 2017.  
AEs led to study drug interruptions in 251 patients (75.1%) in ribociclib + letrozole arm and 57 
patients (17.3%) in placebo + letrozole arm. Neutropenia was the reason for ribociclib 
interruption in 140 patients (41.9%), vomiting in 22 (6.6%), nausea in 18 (5.4%), and diarrhea 
in 16 (4.8%) patients. Dose reductions due to AEs occurred in 160 (47.9%) patients in ribociclib 

Page 19 of 80 
arm, most often due to neutropenia (83 patients, 24.9%), and in 10 patients (3.0%) in placebo 
arm.  
In general, the overall incidence of AEs was similar to that seen at the first interim analysis, 
with no new or unexpected toxicities observed. All events were reversible and managed with 
dose interruption/reduction.  
There were 10 on treatment deaths (7 [2.1%] in the ribociclib group and 3 (0.9%) in the 
placebo group). Two patients in the ribociclib group died from the progression of underlying 
breast cancer; the remaining 5 deaths in the ribociclib group were due to acute respiratory 
failure (2 patients), pneumonia, sudden death and death from an unknown cause. The case of 
sudden death was considered to be related to ribociclib and occurred on day 11 in cycle 2 in 
association with grade 3 hypokalemia (treated with oral potassium supplements) and a grade 2 
prolongation in the QT interval on day 1 of cycle 2. The patient who died from an unknown 
cause received ribociclib for 4 days before withdrawing consent and discontinuing the study 
treatment; her death was reported 19 days later and was not considered to be related to 
ribociclib by the investigator. In the placebo arm, two (2) deaths were attributed to breast 
cancer and one was due to a subdural hematoma.  
1.9 Key efficacy results:  
Study A2301 met its primary objective at the primary analysis (29 Jan 2016 data cut off), with 
compelling evidence of clinical benefit in patients with HR+, HER2-negative advanced breast 
cancer. A 44.4% estimated risk reduction in ribociclib plus letrozole treated patients was 
evident in the primary PFS endpoint as per investigator assessment (HR=0.556, 95% CI: 0.429, 
0.720; one sided p-value =3.29×10-6). Results were consistent across the subgroups of age, 
race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung 
involvement, bone only metastasis disease. Updated PFS analyses (02 Jan 2017 data cut off) 
demonstrated continued treatment benefit for patients receiving ribociclib + letrozole vs 
placebo + letrozole (hazard ratio=0.568; 95% CI: 0.457–0.704; p=9.63×10–8; Figure 5-2). 
Median PFS was prolonged by 9.3 months, from 16.0 months (95% CI: 13.4–18.2) in the 
placebo + letrozole arm to 25.3 months (95% CI: 23.0–30.3) in the ribociclib + letrozole arm. 
The 24-month PFS rates were 54.7% in ribociclib plus letrozole arm vs 35.9% in the placebo 
plus letrozole arm. As of 02-Jan-2017 cut off, overall survival data remain immature, with 
15.0% vs 19.8% of patient deaths in the ribociclib plus letrozole vs placebo plus letrozole arm 
(hazard ratio=0.746; 95% CI: 0.517–1.078; p=0.059).  
Improved ORR of 42.5% versus 28.7% and CBR of 79.9% vs 73.1% were for the ribociclib plus 
letrozole arm relative to placebo plus letrozole arm. The median time to response was not 
achieved in either treatment arm.  Median duration of response is 26.7 months (95% CI: 24.0, 
NE) with ribociclib + letrozole versus 18.6 months (95% CI: 14.8, 23.1) with placebo + letrozole.  

Page 20 of 80 
The ORR (54.5% vs. 38.8%) and CBR (80.2% vs. 71.8%) in the subgroup of patients with 
measurable disease at baseline were consistent with the primary analysis results. 
1.10 FDA Approval 
Ribociclib was approved by the FDA on March 13, 2017 for use in combination with an AI for 
post-menopausal, hormone receptor positive, Her-2/neu negative recurrent breast cancer, 
based on findings from the phase III MONALEESA-2 trial. In that study, the combination of 
ribociclib and letrozole reduced the risk of progression or death by 44% compared with 
letrozole plus placebo in the first-line setting for HR+/HER2- advanced breast cancer (HR, 
0.556; 95% CI, 0.43-0.72; P <.0001). 
1.11 Study Agent 
Ribociclib (formerly LEE011) is an orally bioavailable, highly selective small molecule inhibitor 
of cyclin-dependent kinases 4 and 6 (CDK4/6). Ribociclib has been approved by the United 
States Food and Drug Administration (U.S. FDA) and the European Commission as an initial 
endocrine-based therapy for the treatment of postmenopausal women with hormone 
receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced 
or metastatic breast cancer in combination with an aromatase inhibitor based on a 
randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). 
Additional marketing authorizations are under review by health authorities. Additional phase 
III clinical trials for the treatment of hormone receptor positive (HR+) breast cancer patients, 
as well as several other phase I or II clinical studies are being conducted. 
1.12 Post-marketing experience  
Kisqali® (Ribociclib) in combination with an aromatase inhibitor as initial endocrine-based 
therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, 
human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast 
cancer was approved by the FDA on 13 March 2017, and by the European Commission on 22-
Aug-2017. Other health authority reviews are currently ongoing. Additional marketing 
approvals are expected on an ongoing basis.  
Kisqali® is commercially available as 200 mg film coated tablets in 3 presentations – 63 tablets, 
42 tablets and 21 tablets. On 04-May-2017 the FDA also approved the Kisqali Femara Co-pack 
for the same indication. The Co-pack contains both Kisqali and 26 day supply of Femara 
(letrozole) tablets. 
1.13 Other Agent(s) 
Letrozole is a highly potent, orally active non-steroidal competitive inhibitor of the aromatase 
enzyme system. It effectively inhibits the conversion of androgens to estrogens both in vitro 
and in vivo. It is indicated both as first-line treatment of postmenopausal women with 
hormone receptor positive or hormone receptor unknown locally advanced or metastatic 

Page 21 of 80 
breast cancer as well as for the treatment of advanced breast cancer in postmenopausal 
women with disease progression following antiestrogen therapy. 
Letrozole was initially studied at doses of 0.1mg to 5.0mg daily in six non-comparative Phase 
I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown 
advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients 
had received other hormonal therapies and also may have received cytotoxic therapy. Eight 
(20%) of forty patients treated with letrozole 2.5mg daily in Phase I/II trials achieved objective 
tumor response (complete or partial response). 
A randomized, double-blinded, multinational trial compared Letrozole 2.5mg with tamoxifen 
20mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional 
recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. 
Time to progression (TTP) was the primary endpoint of the trial. Letrozole was superior to 
tamoxifen in TTP and rate of objective tumor response.  
1.14 Rationale 
Based on encouraging results in women with advanced hormone-receptor-positive breast 
cancer, a clinical trial for women with recurrent low-grade serous carcinoma is warranted. 
Furthermore, such a trial would have great appeal to women with recurrent low-grade serous 
carcinoma, a cohort with limited therapeutic options. Although low-grade serous carcinoma is 
a rather uncommon histologic subtype, prolonged overall survival results in a relatively high 
prevalence. 
1.15 Gender and Ethnicity 
This study will be open to women, including members of any minority groups and their 
subpopulations. 
 
 
 

Page 22 of 80 
 
2.0  
OBJECTIVES 
2.1 Primary Objective 
1. To determine the proportion of patients who have objective tumor response (complete or 
partial) within one year from start of study treatment as assessed by RECIST 1.1 in 
patients with recurrent low-grade serous carcinoma of the ovary, fallopian tube or 
peritoneum treated with the combination of ribociclib + letrozole. 
2.2 Secondary Objectives 
1. To examine the proportion of patients who have clinical benefit (complete response [CR], 
partial response [PR], or stable disease [SD]) in patient with recurrent low-grade serous 
carcinoma of the ovary, fallopian tube or peritoneum treated with the combination of 
ribociclib + letrozole. 
2. To estimate the nature, frequency, and maximum degree of toxicity associated with this 
combination using CTCAE v5.  
3. To estimate the progression-free survival of women receiving the combination of 
ribociclib + letrozole. 
4. To estimate the overall survival of women receiving the combination of ribociclib + 
letrozole. 
2.3 Exploratory Objectives 
1.  To determine the expression of Rb, estrogen receptor (ER), progesterone receptor (PR), 
and proliferative index (ki-67) and their correlation with response and clinical benefit. 
2.  To determine genomic signatures associated with response and clinical benefit of the 
combination of ribociclib + letrozole. (Note: for the exploratory objectives, no additional 
tissue biopsy will be required. We will test the recurrent tumor if available. If not we will 
test the primary tumor). 
2.4 Endpoints 
2.4.1 Primary endpoints 
1. Objective Response rate as determined by RECIST 1.1. 
2.4.2 Secondary endpoints 
1. Clinical benefit (CR, PR, SD) rate. 
2. Toxicity using CTCAE v5.0. 
3. Progression-free survival 

Page 23 of 80 
4. Overall survival 
2.4.3 Exploratory endpoints 
1. Expression of ER, PR, and ki-67 and their correlation with response and clinical benefit. 
2. Genomic signatures and their correlation with response and clinical benefit.  
 
 
3.0  
PATIENT SELECTION 
3.1 Inclusion Criteria 
1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being 
performed and is able to comply with protocol requirements.  
2. Age > 18 years at time of study entry. 
3. Willingness and ability to comply with study and follow-up procedures. 
4. Histological confirmation of diagnosis of low-grade serous carcinoma of ovary, fallopian 
tube or peritoneum; Original diagnosis of de novo low-grade serous carcinoma or 
Original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade 
serous carcinoma 
• In order to prevent inclusion of patients with high-grade serous carcinoma, 
diagnosis of low-grade serous carcinoma will be verified as part of a screening 
review by a gynecologic pathologist. Tissue for confirmation can be from primary 
tumor or recurrence. 
5. Patient must have recurrent, measurable disease by RECIST v1.1. 
6. There are no restrictions on number of prior therapies. 
7. Patient cannot have previously received a prior cyclin dependent kinase inhibitor (CDKi). 
Patients who were treated with letrozole or another aromatase inhibitor for other 
indications must have not taken the drug for 6 months prior to initiating letrozole for 
this trial and may not have progressed on treatment.  
8. Patients must not have remaining ovarian function to be included. In women who have 
at least one retained ovary, menopause must be confirmed with laboratory 
confirmation. Women who have ovarian function are eligible but must be placed on 
hormonal suppression. Menopause must be confirmed with laboratory confirmation, to 
include an estradiol level as this is assessed within 8 weeks of patient having been on 
tamoxifen.  
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 
10. Resolution of all acute toxic effects of prior therapy or surgical procedures to National 
Cancer Institute (NCI) CTCAE Grade ≤ 1.  Patients with grade 1 taxane-induced 
neuropathy, any grade alopecia, amenorrhea, or other toxicities not considered a safety 
risk for the patient as per investigator’s discretion are eligible.   

Page 24 of 80 
11. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values at screening:  
a. Absolute neutrophil count ≥1.5 × 109/L  
b. Platelets ≥100 × 109/L  
c. Hemoglobin ≥9.0 g/dL  
d. Potassium, total calcium (corrected for serum albumin), magnesium, sodium and 
phosphorus within normal limits for the institution or corrected to within normal 
limits with supplements before first dose of study medication  
e. INR ≤1.5 (unless patient is receiving permitted anticoagulants and the INR is 
within the therapeutic range of intended use for that anticoagulant within 7 days 
prior to the first dose of study drug). 
f. Serum creatinine <1.5 mg/dL or creatinine clearance ≥50 mL/min  
g. In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) <2.5 x ULN.  If the patient has liver metastases, ALT and 
AST <5 x ULN  
h. Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in 
patients with well-documented Gilbert’s Syndrome.  
12. Patient with available standard 12-lead ECG with the following parameters at screening:  
a. QTcF interval at screening <450msec (using Fridericia’s correction)  
b. Resting heart rate 50-90bpm   
13. Must be able to swallow ribociclib and letrozole capsules/tablets. 
14. Patients receiving tamoxifen or toremifene must have washout period of 5 half-lives 
prior to randomization. 
3.2 Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria:  
1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole.  
2. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study 
drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer. Patients with known 
brain metastases are excluded. 
3. Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria:  
a. At least 4 weeks from prior therapy completion (including radiation and/or 
surgery) to starting the study treatment  
b. Clinically stable CNS tumor at the time of screening and not receiving steroids 
and/or enzyme inducing anti-epileptic medications for brain metastases.  
4. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection).   

Page 25 of 80 
5. Patient has a known history of HIV infection (testing not mandatory).  
6. Patient has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate 
patient participation in the clinical study or compromise compliance with the protocol (e.g. 
chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, 
bacterial or viral infections, etc.).  
7. Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormalities, including any of the following:  
a. History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or 
symptomatic pericarditis within 6 months prior to screening  
b. History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)  
c. Documented cardiomyopathy  
d. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated 
acquisition (MUGA) scan or echocardiogram (ECHO)  
e. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete 
left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz 
type II and third-degree AV block)  
f. Long QT syndrome or family history of idiopathic sudden death or congenital 
long QT syndrome, or any of the following:  
i. Risk factors for Torsades de Pointe (TdP) including uncorrected 
hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac 
failure, or history of clinically significant/symptomatic bradycardia.  
ii. Concomitant use of medication(s) with a known risk to prolong the QT 
interval and/or known to cause Torsades de Pointe that cannot be 
discontinued (within 5 half-lives or 7 days prior to starting study drug) or 
replaced by safe alternative medication   
iii. Inability to determine the QT interval on screening (QTcF, using 
Fridericia’s correction)  
iv. Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening  
8. Patient is currently receiving any of the following medications and cannot be discontinued 
7 days prior to starting study drug (see Table 1 for details):  
a. Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville oranges  
b. That have a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5  
c. Herbal preparations/medications, dietary supplements.  
9. Participation in other studies involving investigational drug(s) within 30 days prior to 
randomization or within 5 half-lives of the investigational product (whichever is longer) or 

Page 26 of 80 
participation in any other type of medical research judged not to be scientifically or medically 
compatible with this study. If the patient is enrolled or planned to be enrolled in another 
study that does not involve an investigational drug, the agreement of the Novartis study 
medical lead is required to establish eligibility. 
10. Patient is currently receiving warfarin or other coumadin-derived anticoagulant for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH) or fondaparinux is allowed. Direct-Acting Oral Anticoagulants (DOACs) are 
permitted.   
11. Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to 
starting study drug, or who have not fully recovered from side effects of such treatment.  
The following uses of corticosteroids are permitted: a short duration (< 5 days) of systemic 
corticosteroids; any duration of topical applications (e.g., for rash), inhaled sprays (e.g., for 
obstructive airways diseases), eye drops or local injections (e.g., intra-articular). 
12. Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 
weeks prior to starting study drug, and who has not recovered to grade 1 or better from 
related side effects of such therapy (exceptions include alopecia) and/or in whom ≥25% of 
the bone marrow (Ellis, 1961) was irradiated.  
13. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects (tumor biopsy is not considered as major surgery).  
14. Patient with a Child-Pugh score B or C.  
15. Patients who are pregnant or breastfeeding 
16. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
throughout the study and for 3 weeks after study drug discontinuation.   Highly effective 
contraception methods include:  
• Total abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception  
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment  
 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential. 

Page 27 of 80 
17. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be 
potent CYP3A4 inducers, and drugs that are known to prolong the QT interval (see 
Appendix C for Prohibited Concomittant Medications).  
18. Patients whose tumors contain both low-grade serous carcinoma (LGSC) and high-grade 
serous carcinoma (HGSC). 
19. Patients with history of haemopoietic stem cell or bone marrow transplant. 
 
 
 
4.0  
STUDY DESIGN 
This is an open-label, multi-institution, phase II trial. Eligible subjects with recurrent low-grade 
serous carcinoma who sign informed consent will receive the combination of letrozole and 
Ribociclib until disease progression or until they experience significant adverse events. 
Table 1. Dose and Treatment Schedule 
Agent 
Dose 
Route 
Schedule 
Ribociblib 
600 mg 
Capsules/tablets 
for oral use 
Daily for 
21 days 
then 7 
days off 
Letrozole 
2.5 mg 
Capsules for oral 
use 
Daily 
**Doses as appropriate for assigned dose level. 
• Letrozole will be administered at a dose of 2.5 mg by mouth daily with 
continuous treatment until progression or unacceptable toxicity. The dose of 
letrozole will not be modified.  
• Ribociclib will be administered at a dose of 600 mg by mouth daily for 21 days 
followed by 7 days off treatment. Treatment will be until progression or 
unacceptable toxicity.  
 
4.1 TREATMENT PLAN: Ribociclib 
Ribociclib will be supplied by Novartis or its designee in the form of 200 mg hard gelatin 
capsules or tablets as individual patient supply packaged in bottles. Storage conditions are 
described in the medication label.   

Page 28 of 80 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded. 
Ribociclib will be administered as a flat-fixed dose of 600 mg daily, and not by body weight or 
body surface area.  
Patients must be instructed to return unused study drugs to the site at discontinuation or 
completion of treatment. The site personnel must ensure that the appropriate dose of each 
study drug is administered and that the drug accountability is performed.  
Ribociclib must be taken as follows:  
• Patients should be instructed to take the ribociclib capsules/tablets with a large 
glass of water (~250 ml) at the same time each day.  
• Ribociclib can be taken without regard to meals; however dietary habits around 
the time of dosing should be as consistent as possible throughout the study  
• Patients should be instructed to swallow the ribociclib capsules/tablets whole 
and not to chew, crush or open them.  
• If vomiting occurs during the course of treatment, no re-dosing of the patient is 
allowed before the next scheduled dose  
• Any doses that are missed (not taken within 6 hours of the intended time) should 
be skipped and should not be replaced or made up on a subsequent day.  
• Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, 
star-fruit, Seville oranges or products containing the juice of each during the 
entire study and preferably 7 days before the first dose of study medication, due 
to potential CYP3A4 interaction with the study medications. Orange juice is 
allowed.  
• No herbal or dietary supplements are permitted, due to potential interactions 
with ribociclib; multivitamins are allowed. 
 
4.2 TREATMENT PLAN: Letrozole 
Letrozole is formulated as tablets of 2.5 mg and supplied in bottles. The dose of letrozole is one 
2.5 mg tablet administered orally once daily. The oral single dose of ribociblib should be taken 
together with the daily dose of letrozole 2.5 mg as per schedule below. 
  
4.3 Treatment Dispensation, Compliance and Accountability 
4.3.1 Ribociclib will be provided and dispensed by the pharmacy. Study medication will be 
supplied in an open label fashion. Patients will self-administer both medications at 
home.  
 
4.3.2  Patients will be instructed to take the study medication at an approximately consistent 
time each day.  

Page 29 of 80 
 
The use of a patient pill calendar (See Appendix C) during study therapy will be utilized 
by the patient and the treating clinic to help promote and monitor compliance with 
Ribociclib and letrozole. 
4.4 Concomitant Medications  
In general, the use of any concomitant medication deemed necessary for the care of the 
patient is permitted in this study, except as specifically prohibited below. Combination 
administration of study drugs could result in drug-drug interactions (DDI) that could potentially 
lead to reduced activity or enhanced toxicity of the concomitant medication and/or ribociclib.  
 The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Oncology Clinical Pharmacology  guidance, Drug-Drug Interaction and Co-
medication Consideration (v05, release date: 2015), which was compiled from the Indiana 
University School of Medicine’s P450 Drug Interaction Table 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and  
Implications for Dosing and Labeling (February 2012) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm292362.pdf), and the University of Washington’s Drug Interaction Database 
(http://www.druginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(www.qtdrugs.org). 
 
4.5 AGENTS (DRUG FORMULATION AND PROCUREMENT) 
4.5.1 Investigational Agent: Ribociclib 
Ribociclib will be supplied by Novartis or its designee in the form of 200 mg hard gelatin 
capsules or tablets as individual patient supply packaged in bottles. Storage conditions are 
described in the medication label.  

Page 30 of 80 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded. Ribociclib will be administered as a flat-fixed dose (e.g. 400 mg or 600 mg daily), 
and not by body weight or body surface area. 
Patients must be instructed to return unused study drugs to the site at discontinuation or 
completion of treatment. The site personnel must ensure that the appropriate dose of each 
study drug is administered and that the drug accountability is performed. 
Refer to the Ribociclib Investigator’s Brochure (IB) for more information.  IB requests should be 
sent via email to GOGRegulatory@gog.org with GOG-3026 Request for IB in the subject line.    
4.5.1.1 Source and Pharmacology: Also known by its tradename Kisqali® and its clinical 
trials name LEE011, is a kinase inhibitor indicated in combination with an aromatase 
inhibitor as initial endocrine-based therapy for the treatment of postmenopausal 
women with hormone receptor (HR)-positive, human epidermal growth factor receptor 
2 (HER2)-negative advanced or metastatic breast cancer 
 
4.5.1.2 Adverse Events and Drug Interactions 
Most common adverse reactions (incidence ≥ 20%) are neutropenia, nausea, fatigue, diarrhea, 
leukopenia, alopecia, vomiting, constipation, headache and back pain. 
See Appendix D for prohibited concomitant medications 
Drugs known to prolong QT interval: Avoid concomitant use of drugs known to prolong QT 
interval such as anti-arrhythmic medicines. 
4.5.1.3 Guidelines for Administration 
Ribociclib must be taken as follows:  
• Patients should be instructed to take the ribociclib capsules/tablets with a large 
glass of water (~250 ml) at the same time each day.  
• Ribociclib can be taken without regard to meals; however dietary habits around 
the time of dosing should be as consistent as possible throughout the study  
• Patients should be instructed to swallow the ribociclib capsules/tablets whole 
and not to chew, crush or open them.  
• If vomiting occurs during the course of treatment, no re-dosing of the patient is 
allowed before the next scheduled dose  
• Any doses that are missed (not taken within 6 hours of the intended time) should 
be skipped and should not be replaced or made up on a subsequent day. 
• Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, 
star-fruit, Seville oranges or products containing the juice of each during the 
entire study and preferably 7 days before the first dose of study medication, due 
to potential CYP3A4 interaction with the study medications. Orange juice is 
allowed. 

Page 31 of 80 
• No herbal or dietary supplements are permitted, due to potential interactions 
with ribociclib; multivitamins are allowed.  
 
4.5.1.4. Drug Supply and Storage  
Please refer to the Regulatory Manual for Drug Ordering Instructions and Forms. 
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the medication label. Medication labels will comply 
with the legal requirements of each country and be printed in the local language.   
Study Drug Compliance and Accountability  
Compliance should be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver. Records of study medication used, 
dosages administered, and intervals between visits and the completion of the study should be 
captured in the Drug Accountability Form. This information must be captured in the source 
document at each patient visit. 
4.5.2 Commercial Agent:  Letrozole 
4.5.2.1  
Refer to the FDA-approved package insert for more information: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82b77d74-085f-
45ac-a7dd-1f5c038bf406   
4.5.2.2 
Source and Pharmacology: Also known by its tradename Femara®, letrozole is an 
aromatase inhibitor indicated for adjuvant treatment of postmenopausal women 
with breast cancer. 
4.5.2.3 Adverse Events and Drug Interactions 
The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, 
asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, 
bone pain; and musculoskeletal. 
4.5.2.4 Guidelines for Administration 
Letrozole tablets are taken orally without regard to meals. 
Recommended dose: 2.5.mg once daily. 
Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day 

Page 32 of 80 
4.5.2.5 Supplier: Letrozole will be supplied by Novartis or its designee.  Please refer 
to the Regulatory Manual for drug ordering instructions and forms. 
4.6 
Safety Lead-in 
A review of safety will occur after the first 6-10 patients are treated and complete 
one cycle (including starting cycle 2 within the DLT constraints below) or have a DLT 
prior to completing the first cycle. Within the safety lead-in, patients who do not 
have a DLT and who do not complete cycle 1 will be replaced.  
 
A dose limiting toxicity (DLT) is defined as an AE or clinically significant abnormal 
laboratory value assessed as unrelated to disease, disease progression, inter-current 
illness, or concomitant medications that occurs within the first 28 days of treatment 
with ribociclib and meets any of the criteria included in the table below. NCI CTCAE 
version 5.0 should be used for all grading.   
 
Criteria for Defining Dose-Limiting Toxicities 
Toxicity  
DLT Criteria  
Hematology  
CTCAE grade 4 neutropenia lasting more than 7 consecutive days  
CTCAE grade 4 thrombocytopenia  
CTCAE grade 3 thrombocytopenia with bleeding  
CTCAE grade 3 or 4 febrile neutropenia   
ECG QT interval  
QTc interval ≥501 ms on at least 2 separate ECGs  
Cardiac  
Cardiac toxicity ≥ CTCAE grade 3  
Clinical signs of cardiac disease, such as unstable angina or myocardial 
infarction, or Troponin ≥ CTCAE grade 3  
Gastro-intestinal  
≥ CTCAE grade 3 vomiting ≥48 hours despite optimal anti-emetic therapy  
≥ CTCAE grade 3 diarrhea ≥48 hours despite optimal anti-diarrhea 
treatment  
Hepato-biliary  
≥ CTCAE grade 2 total bilirubin for more than 7 consecutive days  
≥ CTCAE grade 3 total bilirubin  
≥ CTCAE grade 2 ALT with a ≥grade 2 bilirubin elevation of any duration 
in the absence of liver metastases  
≥ CTCAE grade 3 ALT for >4 consecutive days   
CTCAE grade 4 ALT or AST  
Grade 4 serum alkaline phosphatase >7 consecutive days  
Renal   
≥ CTCAE grade 3 serum creatinine  

Page 33 of 80 
ILD/pneumonitis 
≥ CTCAE grade 3 
Any drug-related death 
 
Non-hematologic events  
≥ CTCAE grade 3, except for the exclusions noted below:  
Exceptions to DLT criteria  Grade 3 alopecia  
<5 days of CTCAE grade 3 fatigue  
Grade 3 fever or infection without neutropenia <5 days duration  
Grade 3 laboratory abnormalities that are responsive to oral 
supplementation or deemed by the investigator to be clinically 
insignificant  
CTCAE version 5.0 should be used for grading.  
Optimal therapy for vomiting and diarrhea should be based on institutional guidelines with 
consideration of the prohibited medications listed in these protocol guidelines.  
 
4.7 
TREATMENT/ DOSE MODIFICATIONS 
 
4.7.1 Ribociclib - Dose Modification Guidelines 
Management of severe or intolerable adverse reactions requires temporary dose reduction 
and/or interruption of ribociclib therapy. For patients who do not tolerate the dosing schedule, 
dose adjustments are permitted in order to allow the patient to continue the study treatment. 
 
  
Ribociclib 
dose  
Number of 
capsules/tablets 
& strength  
Starting dose  
600 mg  
3 x 200 mg 
capsules/tablets  
First dose reduction  
400 mg  
2 x 200 mg 
capsules/tablets  
Second dose reduction  
200 mg  
1 x 200 mg  
capsules/tablets  
4.7.1.1 Ribociclib Dose Adjustment/Management Recommendation for Hematological Adverse 
Reactions 
Toxicity/Grade  
Dose Adjustment and Management 
Recommendations  
Thrombocytopenia  
 
Grade 1(≥75 x109/L)  
No dose adjustment required.  

Page 34 of 80 
Grade 2 (≥50 x 109/L – <75 x 109/L)  
Dose interruption until recovery to grade <2 
Re-initiate ribociclib at the same dose.  
Grade 3 (≥25 x 109/L - <50 x 109/L)  
Dose interruption until recovery to grade <2.  
Re-initiate ribociclib at the same dose level.  
If toxicity recurs at grade 3: temporary dose 
interruption until recovery to grade 1 and reduce 
ribociclib to the next lower dose level.  
Grade 4(<25 x 109/L)  
Dose interruption until recovery to grade <2.  
Re-initiate ribociclib at the next lower dose level.  
If toxicity recurs at grade 4: discontinue ribociclib  
Absolute neutrophil count (ANC)  
 
Grade 1 (≥1.5 x109/L)  
  No dose adjustment required.  
Grade 2 (≥1.0 - <1.5 x 109/L)  
  No dose adjustment required.  
Grade 3 (≥0.5 - <1.0 x 109/L)  
Dose interruption until recovery to ≥ 1.0 x 109/L. 
Re-initiate ribociclib at the same dose level.  
If toxicity recurs at grade 3: temporary dose 
interruption until recovery to ≥1.0 x 109/L.  
If resolved in ≤7 days, then maintain dose level.  
If resolved in >7 days, then reduce ribociclib dose 
to the next lower dose level.  
Grade 4 (<0.5 x 109/L)  
Dose interruption until recovery to ≥1.0 x 
109 /L.  
Re-initiate ribociclib at the next lower dose level.  
If toxicity recurs at grade 4: temporary dose 
interruption until  
recovery to ≥1.0 x 109 /L and reduce ribociclib 
at the next lower dose level.  
 
Febrile neutropenia  
 
Grade 3  
ANC <1.0 x 109/L with a single 
temperature of >38.3  
ºC (101 ºF) or a sustained temperature of 
≥38 ºC  
(100.4 ºF) for more than one hour  
 
Dose interruption until improvement of ANC ≥1.0 
x 109 /L and no fever. Restart at the next lower 
dose level.  
If febrile neutropenia recurs, discontinue 
ribociclib.  
Grade 4  
Discontinue ribociclib.  

Page 35 of 80 
Life-threatening 
consequences; urgent 
intervention indicated  
Anemia  
(Hemoglobin)  
 
Grade 1 (≥10.0 – LLN g/dL)  
No dose adjustment required.  
Grade 2 (≥8.0 – <10.0 g/dL)  
No dose adjustment required.  
Grade 3 (<8.0 g/dL)  
Dose interruption until recovery to grade <2. 
Re-initiate ribociclib at the same dose.  
Grade 4  
Life-threatening 
consequences; urgent 
intervention indicated  
Discontinue ribociclib.  
 
4.7.1.2 Recommendations for Ribociclib Dose Modification in Case of Hepatic Toxicities 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)  
TOTAL BILIRUBIN without ALT/AST increase above baseline value  
Grade 1 (> ULN – 1.5 x ULN) 
(confirmed 48 to 72hrs later)  
Maintain dose level with LFTs monitored every 
two weeks  
Grade 2 (>1.5 – 3.0 x ULN)  
Dose interruption of ribociclib  
If resolved to ≤ grade 1 in ≤21 days, then 
maintain dose level  
If resolved to ≤ grade 1 in >21 days or toxicity 
recurs, then reduce 1 dose level  
Repeat liver enzymes and bilirubin tests twice 
weekly for 2 weeks after dose resumption  
  
If toxicity recurs after two dose reductions, 
discontinue ribociclib  
Grade 3 (>3.0 – 10.0 x ULN)  
Dose interruption of ribociclib  
If resolved to ≤ grade 1 in ≤21 days, lower 1 
dose level of ribociclib  
Repeat liver enzymes and bilirubin tests twice 
weekly for 2 weeks after dose resumption  
  
If resolved to ≤ grade 1 in >21 days or toxicity 
recurs, discontinue ribociclib  
Grade 4 (>10.0 x ULN)  
Discontinue ribociclib  

Page 36 of 80 
Confounding factors and/or alternative causes for increase of total bilirubin should be 
excluded before dose interruption/reduction. They include but are not limited to: evidence of 
obstruction, such as elevated ALP and GGT typical of gall bladder or bile duct disease, 
hyperbilirubinemia due to the indirect component only (i.e. direct bilirubin component ≤1 x 
ULN) due to hemolysis or Gilbert Syndrome, pharmacologic treatment, viral hepatitis, 
alcoholic or autoimmune hepatitis, other hepatotoxic drugs.  
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct 
bilirubin only. Bilirubin will be fractionated if elevated.  
 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)  
AST or ALT  
AST or ALT without bilirubin elevation >2 x ULN  
Same grade as baseline or increase from 
baseline grade 0 to grade 1  
(confirmed 48 to 72 hrs later)  
No dose adjustment required with LFTs 
monitored per protocol if same grade as 
baseline or every two weeks in case of 
increase from baseline grade 0 to 1  
Increase from baseline grade 0 or 1 to grade 
2 (>3.0  
– 5.0 x ULN)  
  
Dose interruption of ribociclib  
If resolved to ≤ baseline value in ≤21 days, 
then maintain dose level  
If resolved to ≤ baseline value in >21 days or 
toxicity recurs, then reduce 1 dose level  
Repeat liver enzymes and bilirubin tests twice 
weekly for 2 weeks after dose resumption  
  
If toxicity recurs after two dose reductions or 
recovery to   
≤ baseline value is >28 days, discontinue 
ribociclib  
Increase from baseline grade 0 or 1 to grade 
3 (>5.0 – 20.0 x ULN)  
Dose interruption of ribociclib until resolved 
to ≤ baseline value, then lower 1 dose level of 
ribociclib Repeat liver enzymes and bilirubin 
tests twice weekly for 2 weeks after dose 
resumption  
  
If recovery to ≤ baseline value is >28 days, 
discontinue ribociclib  
If toxicity recurs, discontinue ribociclib  

Page 37 of 80 
Increase from baseline grade 2 to grade 3 
(>5.0 –   
20.0 x ULN)  
Dose interruption of ribociclib until resolved to 
< baseline value, then lower 1 dose level of 
ribociclib  
Repeat liver enzymes and bilirubin tests twice 
weekly for 2 weeks after dose resumption  
  
If toxicity reoccurs after 2 dose reductions or 
recovery to < baseline value is > 28 days, 
discontinue ribociclib  
Grade 4 (>20.0 x ULN)  
Discontinue ribociclib  
AST or ALT and concurrent Bilirubin  
For patients with normal ALT or AST or 
total bilirubin at baseline: AST or ALT ≥ 
grade 2 combined with total bilirubin  >2 
x ULN without evidence of cholestasis  
or  
For patient with elevated AST or ALT or total 
bilirubin at baseline: baseline: [AST or ALT >2 
x baseline AND >3.0x ULN] OR [AST or ALT 
8.0x ULN]- whichever is lower-combined with 
[total bilirubin 2x baseline AND >2.0 x ULN]  
  
  
  
Discontinue ribociclib  
Confounding factors and/or alternative causes for increased transaminases should be 
excluded before dose interruption/reduction. They include but are not limited to: 
concomitant medications, herbal preparations or dietary supplements, infection, hepato-
biliary disorder or obstruction, new or progressive liver metastasis, and alcohol intake.  
 
Additional Follow-up for Hepatic Toxicities  
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug induced liver injury (DILI), and should be considered as clinically important events.   
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value; 
patients meeting any of the following criteria will require further follow-up as outlined below:  
• For patients with normal ALT or AST or TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN   

Page 38 of 80 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]  
Medical review needs to ensure that liver test elevations are not caused by cholestasis, 
defined as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis.  
 Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for 
both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic or 
hepatocellular liver injury or mixed type injury)  
 In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, 
detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.  
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, 
direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is grade 
2 or higher), creatine kinase, protrombine time (PT/INR) and GGT. For patients with Gilbert 
Syndrome: total and direct  bilirubin  must  be  monitored,  intensified  monitoring  applies  to  
changes  in  direct bilirubin only.  
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring dose 
interruption, which involves:  
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or return to normal values.  
• Obtaining a more detailed history of current symptoms.  
• Obtaining a more detailed history of prior and/or concurrent diseases, including 
history of any preexisting liver conditions or risk factors.  
• Obtaining a history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplements), alcohol use, recreational drug 
use, and special diets.  
• Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus 
infections (CMV, EBV or HSV); autoimmune or alcoholic hepatitis; NASH; 
hypoxic/ischemic hepatopathy; and biliary tract disease.  
• Obtaining a history of exposure to environmental chemical agents.  
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, 
direct bilirubin).  
• Considering gastroenterology or hepatology consultations.  
• Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction.  

Page 39 of 80 
• Liver biopsy as clinically indicated to assess pathological change and degree of 
potential liver injury.  
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant”, thus met the definition of SAE (Section 7.02), and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
4.7.1.3 Dose Modification Guidance in Case of QT Prolongation 
 
Grade 
Dose Modification 
For All Grades 
1. 
Check the quality of the ECG and the QT value and repeat if needed. 
2. 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If outside of the normal 
range, interrupt ribociclib administration, correct with supplements or appropriate therapy 
as soon as possible, and repeat electrolytes until documented as normal. 
3. 
Review concomitant medication usage for the potential to inhibit CYP3A4 and/or to prolong 
the QT interval. 
4. 
Check compliance with correct dose and administration of ribociclib. 
Consider collecting a time matched PK sample; record date and time of last study drug intake 
1 
QTcF 450-480 ms 
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment required. 
2 
QTcF 481-500 ms 
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.” 
Perform a repeat ECG within one hour of the first QTcF of ≥ 481 ms. 
Repeat ECG as clinically indicated until the QTcF returns to < 481 ms, Restart ribociclib with 
dose reduced by 1 dose level. Refer to Section 4.7.1 for dosing schedule. 
If QTcF ≥ 481 ms recurs, ribociclib should be reduced again by 1 dose level. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated)  for any 
patients who had therapy interrupted due to QTcF ≥ 481 ms. 
3 
QTcF ≥ 501 ms on at least two 
separate ECGs 
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.” 
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and repeat cardiac 
monitoring as indicated until the QTcF returns to < 481 ms. 
• If QTcF returns to < 481 ms, ribociclib will be reduced by 1 dose level. Refer to Section 4.7.1 
for dosing schedule. 
• If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in “For All Grades,” 
discontinue ribociclib. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) for any 
patients who had therapy interrupted due to QTcF ≥ 501 ms 
If QTcF of ≥ 501 ms recurs, discontinue ribociclib. 
4 
[QT/QTcF ≥ 501 or > 60 ms change 
from baseline] 
and 
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms of 
serious arrhythmia] 
Discontinue ribociclib. Perform steps 1-4 as directed in “For All Grades.” 
• 
Obtain local cardiologist (or qualified specialist) consultation and repeat cardiac monitoring 
as indicated until the QTcF returns to <481 ms. 
 
 

Page 40 of 80 
 
4.7.1.4 Dose Adjustment and Management Recommendation for ILD/pneumonitis (CTCAE 
v4.03) 
Grade 
Dose Adjustment and Management Recommendations 
1 
(asymptomatic) 
No dose adjustment required.  Initiate appropriate medical therapy and monitor as clinically 
indicated. 
2 
(symptomatic) 
Interrupt ribociclib dose until recovery to Grade ≤1, then resume ribociclib at the next lower 
dose level*.  
 
3 and 4 
(severe) 
Discontinue ribociclib 
* An individualized benefit-risk assessment should be performed before resuming ribociclib  
      
4.7.1.5 Guidance for Management of All Other Adverse Reactions 
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium 
for all adverse reactions that are potentially associated/aggravated with electrolyte 
imbalance (e.g. diarrhea, nausea/vomiting, non-QT related cardiovascular events). If 
electrolyte values are below the lower limit of normal, interrupt ribociclib administration, 
correct electrolytes with supplements as soon as possible, and repeat electrolyte testing 
until documented normalization of the electrolytes. 
Ribociclib Dose Adjustment and Management Recommendation for All Other Adverse 
Reactions 
Grade  Dose Adjustment and Management Recommendations  
1  
No dose adjustment recommended. Initiate appropriate medical therapy and 
monitor.  
2  
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy 
and monitor.  
Re-initiate ribociclib at the same dose.  
• If the same toxicity recurs at grade 2, interrupt ribociclib until recovery 
to grade ≤1. Reinitiate ribociclib at the next lower dose level.  
3  
Dose interruption until recovery to grade ≤1.  
Initiate appropriate medical therapy and monitor.  
Re-initiate ribociclib at the next lower dose level.  
• If toxicity recurs at grade 2: temporary dose interruption until 
recovery to grade ≤1 and reduce ribociclib dose the next lower dose 
level.  
• If toxicity recurs at grade 3, discontinue ribociclib.  
4  
Discontinue ribociclib and treat with appropriate medical therapy.  
 

Page 41 of 80 
4.7.1.6 Adjustment of Starting Dose in Special Populations  
Renal impairment  
Insufficient data are available to provide a dosage recommendation for ribociclib in patients 
with renal impairment.   
Patients with baseline renal impairment are excluded from the study (serum creatinine > ULN 
or creatinine clearance <50 mL/min). Patients who experience renal impairment of grade 2 or 
higher during the treatment period should discontinue treatment and should be followed for 
safety assessments.  
 
 
Elderly  
Physicians should exercise caution in monitoring the effects of ribociclib in the elderly. 
Insufficient data are available to provide a dosage recommendation.  
4.7.1.7  Concomitant Medications  
Permitted concomitant therapy  
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheal are allowed. 
Please consult the list of prohibited medications and the list of use with caution medications 
for further guidance.   
The patient must be told to notify the investigational site about any new medications she takes 
after the start of the study treatment.  All medications (other than study drugs) and significant 
non-drug therapies (including vitamins, herbal medications, physical therapy and blood 
transfusions) administered within 30 days of study entry and during the study must be listed 
on the Concomitant medications/Significant nondrug therapies section of the patient record.  
Bisphosphonates and denosumab  
Adjuvant bisphosphonate/denosumab therapy is allowed per local and ASCO guidelines.  
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis and 
prevention of skeletal related events for patients with bone metastases. Chronic concomitant 
bisphosphonate/denosumab therapy for the prevention of bone metastasis is not permitted.   
Hematopoietic growth factors  
Hematopoietic growth factors may be used according to ASCO guidelines.  
Selective radiotherapy  

Page 42 of 80 
Selective radiotherapy is permitted.  It should not be delivered to a target lesion   Cumulative 
courses of RT should not encompass > 25% of irradiated bone marrow.  No dose modification 
of study treatment is needed during selective radiotherapy.  
Permitted concomitant therapy requiring caution  
Medications to be used with caution during ribociclib and [If applicable: and co-treatment] in 
this study are listed below (see Table 2). This list is not comprehensive and is only meant to be 
used as a guide. These medications should be excluded from patient use if possible. If they 
must be given, then use with caution and consider a ribociclib interruption if the concomitant 
medication is only needed for a short time.  
• Moderate inhibitors or inducers of CYP3A4/5  
• Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index  
• Strong inhibitors of BSEP  
• Sensitive substrates of the renal transporters, MATE1 and OCT2  
• Sensitive substrates of BCRP  
• Medications that carry a possible risk for QT prolongation  
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially increasing the risk of reducing ribociclib drug 
exposure to subtherapeutic levels. Systemic corticosteroid treatment should not be given during 
the study, except for: 
• Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular); 
• A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency of 
4 mg dexamethasone (e.g. for chronic obstructive   pulmonary disease, or as an antiemetic)  
 
Prohibited concomitant therapy  
The following medications are prohibited during study treatment in the study (see Table 1). 
This list is not comprehensive and is only meant to be used as a guide.   
• Strong inhibitors or inducers of CYP3A4/5  
• Substrates of CYP3A4/5 with a narrow therapeutic index  
• Medications that carry a known risk for QT prolongation  
• Other investigational and antineoplastic therapies not part of the study  
• Herbal medications/preparations, dietary supplements (except for vitamins) 
including, but not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh 
and ginseng. Patients should stop using all herbal medications and dietary 
supplements at least 7 days prior to first dose of study treatment.  
 

Page 43 of 80 
Drugs with QT prolongation  
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the 
potential to increase the risk of drug-related QT prolongation (e.g., via a potential DDI that 
increases the exposure of ribociclib or the exposure of the QT prolonging drug). A definitive list 
of drugs with a known risk, possible risk, or conditional risk of QT prolongation and/or 
Torsades de Pointes (TdP) is available online at www.qtdrug.org.   
Medications with a known risk for QT prolongation are prohibited during study treatment. 
For complete information, refer to the ribociclib (LEE011) Investigator’s Brochure and other 
drug package insert.  See Appendix C for information on possible interactions with other 
drugs.  
 
 
4.7.2 Letrozole - Dose Modification Guidelines 
 
Toxicity Site 
Observation 
Management 
Bone Effects 
Use of Letrozole may cause decreases in 
bone mineral density (BMD) 
Consideration should be 
given to monitoring BMD 
Grade 3-4 
hypercholesterolemia 
 Hypercholesterolemia was reported in 
52.3% of letrozole patients and 28.6% 
of tamoxifen patients.  
Consideration should be 
given to monitoring 
serum cholesterol. 
Subjects with 
cirrhosis and severe 
hepatic impairment 
 
Reduce dose to 2.5mg 
every other day 
 
 
5.0  
PATIENT ENTRY/RANDOMIZATION PROCEDURE  
Regulatory Requirements:  Please see the Regulatory Manual for site requirements prior 
to screening and enrollment of patient. 
 
Patient Entry and Registration:  The GOG Partners’ IRT System (https://partners.gog.org) 
will be used for patient registration following the completion of the Pathology Screening 
(see Section 6.1 for instruction for obtaining a Screening ID). 
6.0 
Study Parameters 

Page 44 of 80 
6.1 
Pre-Treatment Evaluations (Screening) 
The following must be collected/ performed within 28 days prior to Cycle 1, day 1 of 
treatment.  Clinical and laboratory evaluations performed as part of routine standard of 
care do not need to be repeated if performed within the appropriate window.  
• Voluntary, written, dated, and signed informed consent must be obtained before 
any study specific procedures are performed (with the exception of certain 
imaging assessments if meeting the criteria defined in this section).  
• Radiographic tumor assessments that were performed before the signing of the 
informed consent form as routine procedures (but within 28 days prior to study 
enrollment) do not need to be repeated and may be used as baseline 
assessments, as long as: 
o The tests were performed per the method requirements outlined in the 
Tumor Assessment Requirement Flowchart, the Efficacy Assessments 
sections. 
o Appropriate documentation indicating that these radiographic tumor 
assessments were performed as standard of care is available in the 
patient’s source notes 
• Complete medical history and disease treatment history.  
• UPT in WOCBP 
• ECOG PS  
• Baseline AE assessment 
• Physical exam with vital signs 
• Labs: CMP, CPK, CBC with differential (diff), Uric acid, Urinalysis  
• ECG 
• Tumor assessment – CT chest, abdomen, and pelvis, or MRI 
• Concomitant medication 
• CA-125 
• Lipid panel (total cholesterol, HDL, LDL, triglycerides) fasting preferred 
• Coagulation (PT and INR) 
• Submission of an H&E stained slide for pathology review to confirm eligibility.  
• Obtain a Screening ID (format: XXXX-3026-YYYY) from the GOG Partners’ IRT 
System (https://partners.gog.org). 
• Print IRT Screening Confirmation 
• Send H&E stained slide (labeled with Screening ID) along with a completed copy 
of the Digital Pathology Screening Form (Appendix E) and printout of the IRT 
Screening Confirmation to: 
GOG 3026 Pathology Review 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 

Page 45 of 80 
Columbus, OH 43205 
Phone: (614) 722-2865 
• Receive results of pathology review via email to registrar patient. 
• If pathology review results indicate patient is eligible (and all other eligibility 
criteria are met), return to the GOG Partners’ IRT System to complete patient 
registration. Once completed, proceed to Rave for patient data entry. 
• If pathology review results indicate patient is not eligible, no further action is 
required in the GOG Partners’ IRT System. 
 
Special Note Regarding the Safety Lead-In 
For the Safety Lead-in portion, the assigned Screening ID also serves as a slot 
reservation. These reservations are not transferrable to other patients, and if the 
patient is not enrolled within the required timeframe, the reservation is 
cancelled and the slot is then made available to other patients and sites. If all 
slots for the lead-in are reserved, including existing enrollments, patients can be 
added to a waiting list. Patients on the waiting list can begin the pathology 
screening process noted above, but may be unable to be enrolled during the 
Safety Lead-in if accrual is met in the interim. 
 
To mitigate the risk of over-accrual, the number of active screening patients will 
be limited in that the sum of patients enrolled and active screening patients 
cannot exceed the total for phase or study accrual. If a patient in screening is 
found to not be eligible, or has elected to seek other treatment, this information 
should be reported in the IRT system as soon as possible. Any “stale” screening 
patient records will be marked as inactive after 30 days to help in the monitoring 
of accrual. 
 
 
 
Treatment should be initiated within 7 days of registration. 
 
Please refer to the Regulatory Manual for more information regarding the safety 
 
lead-in.  
 
6.2 
Evaluations on Treatment 
Collection of Concomitant Medications and Adverse Events (AEs) should occur 
throughout the study, as described.  Pre-treatment (Screening) evaluations do not need 
to be repeated if within 28 days of Cycle 1 Day 1. 
Day 1 (±3 days) 
• History and physical exam with vital signs 
• Labs: CMP, CPK, CBC with differential (diff), Uric acid, Urinalysis  
• If WOCBP, pregnancy test within 3 days of treatment for Cycle 1 only 
• AEs 

Page 46 of 80 
• ECG (if clinically indicated) 
• Study drugs to be taken daily at the same time every day for 21-consecutive 
days. 
• CA-125 
• Lipid panel (total cholesterol, HDL, LDL, triglycerides) fasting preferred 
• Coagulation (PT and INR) 
 
Day 21 (±3 days) 
• Ribociclib –start of 1-week off period. 
• Letrozole – Continue taking through the week off period of Ribociclib. 
6.3 
Off-Treatment Evaluations (End of Treatment or EOT visit) 
The end of treatment visit will be performed as soon as possible but no later than 4 
weeks (i.e., 28 days) ± 7 days from last dose of investigational product and prior to the 
initiation of any new anticancer therapy.  
6.4 
Follow-up Evaluations  
After discontinuation of study treatment, post-study survival status (including post study 
anticancer therapies) will be collected approximately every 3 months for the first two 
years and then every six months for the next three years. from the last dose of study 
treatment. Telephone contact is acceptable. 
If patient comes off study treatment prior to progression, continue tumor 
measurements and radiologic evaluations on schedule until progression or initiation of a 
subsequent cancer therapy. Toxicity assessments will be continued until resolution or 
return to baseline. Patients will be followed after last drug dose until toxicity resolution 
or return to baseline, until progression if patient withdraws before progressive disease, 
or until study withdrawal if it occurs before this time.  
Patients who discontinue study treatment for reasons other than radiographically 
and/or clinically (i.e., for photographed or palpable lesions) documented disease 
progression as per RECIST v1.1 definitions will continue to have tumor assessment 
performed during the follow-up visits every 3 months (± 7 days) from the date of 
starting protocol therapy until disease progression, initiation of new anticancer therapy 
or discontinuation of patient from overall study participation (eg, death, patient's 
request, lost to follow-up), whichever occurs first. 

 
Page 47 of 80 
 
6.5. Schedule of Assessments 
 
Screening 
Phasea 
Treatment Phase: 28-day cyclesf 
Post Treatment 
Follow up Phase e 
Visit Name  
Screening 
Cycle 
1* 
Cycle 2 
Cycle 3  
Cycle 4 - n  
End of Treatment  
  
Treatment Days 
Prior to 
Day 1 
1 
 
1 
 
1 
1 
 
 
Physical Assessments 
History & Physical Exam with vital 
signs 
X 
X 
X 
X 
X 
 
 
Review of Concomitant 
Medications 
Continuous – up to 30 days after last dose of study treatment  
Performance Status 
X 
 
 
 
 
 
 
Laboratory Assessments 
Hematology: CBC 
X 
X 
Xg 
Xg 
Xg 
X 
 
Chemistry (including LFTs):  K, Ca, 
Mg, Na, P, CPK, Uric Acid, AST, 
ALT, total bilirubin, BUN 
X 
X 
X 
X 
X 
X 
 
Coagulation:  PT and INR 
X 
X 
X 
X 
X 
X 
 
Lipid Panel:  Total cholesterol, 
HDL, LDL, triglycerides (fasting 
preferred) 
X 
X 
 
 
Xh 
 
 
CA-125 
X 
X 
X 
X 
X 
 
X 
 
 
 
 

Page 48 of 80 
 
Screening 
Phasea 
Treatment Phase: 28-day cyclesf 
Post Treatment 
Follow up Phase e 
Visit Name  
Screening 
Cycle 
1 
Cycle 2 
Cycle 3  
Cycle 4 - n  
End of Treatment  
 
Urinalysis  
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test (WOCBP 
only) 
X 
X 
 
 
 
 
 
Cardiac Assessments 
ECG (12-Lead)j 
X 
Xi 
Xi 
As clinically indicated 
 
Safety & Imaging 
Toxicity Assessment/Adverse 
Events 
Continuous  
Tumor Imagingb 
X 
 
Xd 
 
 
X 
H&E for Pathology Reviewc 
X 
 
 
Survival Follow Up 
 
 
X 
Legend: 
* Pre-treatment (Screening) evaluations do not need to be repeated if within 28 days of Cycle 1 Day 1. 
a. Within 28 days of first dose of letrozole + ribociclib 
b. CT or MRI of chest, abdomen, and pelvis 
c. H&E stained slide must be submitted for pathology review to confirm eligibility 
d. Every 3 cycles 
e. The end of treatment visit will be performed as soon as possible but no later than 4 weeks (i.e., 28 days) ± 7 days from last dose of investigational product 
and prior to the initiation of any new anticancer therapy. After discontinuation of study treatment, post-treatment follow-up, including survival status, will 
be collected every 3 months for the first 2 years and then every 6 months for 3 year for a total of 5 years. Telephone contact is acceptable.  If patient comes 
off study treatment prior to progression, continue tumor measurements and radiologic evaluations on schedule until disease progression or initiation of a 
subsequent cancer therapy.  Toxicity assessments continue until resolution or return to baseline.  Patients who discontinue study treatment for reasons 
other than disease progression should have tumor assessments performed during follow-up visits every 3 months until disease progression, initiation of 
new anticancer therapy or discontinuation from participation on study.   

Page 49 of 80 
f. Due to scheduling, these visits may occur +/- 3 days from the required time point. Additionally, it may be necessary to perform these procedures at 
unscheduled time points if deemed clinically necessary by the Investigator or in order to accommodate patient/physician scheduling logistics. 
g.  Must be performed within 3 days of re-treatment. 
h.  Every 4th cycle 
i. Predose and 2-4 hours postdose at investigator’s discretion if clinically indicated. 
j. For patients with QTcF ≥ 481 ms at any time, interrupt study treatment and follow the procedures described in the “Ribociclib Dose Modification section”. 
If treatment is resumed, repeat ECGs 7 days and 14 days after dose resumption (and then as clinically indicated). During subsequent cycles, perform 
predose ECG for every cycle starting at cycle 6, and predose and 2-4 postdose starting at cycle 9 and every 3rd cycle thereafter.  

Page 50 of 80 
 
7.0  
PATHOLOGY/BIOSPECIMEN REQUIREMENTS 
7.1 
Pathology Review for Confirmation of Eligibility 
This protocol requires a digital pathology review to confirm eligibility. 
Regardless of whether the patient’s original diagnosis was ovarian or peritoneal serous tumor of low 
malignant potential or low-grade serous carcinoma, eligible patients include those with recurrent low-
grade serous carcinoma of the ovary, fallopian tube or peritoneum. 
One H&E stained slide from the recurrent tumor (obtained at secondary surgery, prior biopsy, or SOC 
image-guided fine needle/core biopsy) or from the original diagnostic specimen documenting low-
grade serous carcinoma must be obtained from the pathology department and sent by overnight 
courier at the institution’s expense to the Biopathology Center:  
GOG 3026 Pathology Review 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
A completed copy of the Digital Pathology Screening Form (Appendix E), printout of the IRT Screening 
Confirmation, and a copy of the corresponding pathology report must be submitted with the H&E. All 
items shipped must be labeled with the Screening ID (format: XXXX-3026-YYYY; see Section 6.1 for 
details). Slides must also be labeled with the surgical pathology accession number and block number 
from the corresponding pathology report. 
7.2 Protocol for digital review of pathology slides  
The representative H&E stained slide will be scanned at the Biopathology Center into a tissue review 
database. A gynecologic pathologist will be provided the case for central prospective review using 
VIPER (Virtual Imaging for Pathology Education and Research). The institution will be notified of patient 
eligibility by email within five business days of: 
(1) receipt at the Biopathology Center of the 
a. H&E, 
b. corresponding pathology report, 
c. completed Digital Pathology Screening Form (Appendix E), and 
d. printout of the IRT Screening Confirmation; and 
(2) pathologist review. 
Failure to send the required materials and/or improper labelling could delay the results review.  
7.3 
Translational Research  

Page 51 of 80 
 
Next generation sequencing will be performed on all pre-treatment tissue specimens. These results will be 
correlated to response and clinical benefit. In addition, we will evaluate estrogen receptor (ER) signaling and 
correlate these findings with response. 
 Specimen Requirements  
If the patient gives permission for her specimens to be collected and used for this optional translational 
research component, then participating institutions are required to submit the patient’s translational 
research specimens as outlined below (unless otherwise specified). Refer to Appendix F for details. 
Required Specimen (Specimen Code) 
Collection Time Point 
Ship To 
FFPE Tumor Tissue (Submit at least one tumor type – Listed in order of preference) 
Archival FFPE Recurrent Primary (FRP01) 
or Recurrent Metastatic (FRM01) Tumor1 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment 
Biopathology Center 
within 8 weeks of 
registration2 
Archival FFPE Primary (FP01) or 
Metastatic (FM01) Tumor1 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) 
tube(s) and frozen3 
Prior to starting study treatment 
Biopathology Center 
within 1 week of 
registration2 
1 A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the Biopathology Center. 
2 Biopathology Center / Protocol GOG 3026, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 43205, 
Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
3 Do not use glass blood collection tubes. 
 
7.4 
Laboratory Testing 
 
7.41 
Hormone Receptor Immunohistochemistry   
Unstained sections of formalin-fixed, paraffin-embedded (FFPE) tumor will be used for 
hormone receptor (e.g., estrogen receptor [ER]-alpha, ER-beta, progesterone receptor 
[PR]-alpha, PR-beta, G protein-coupled ER [GPR-30]) immunohistochemistry (IHC). 
 
7.42 
Mutation Analysis 
Unstained sections of FFPE tumor and DNA extracted from whole blood will be used for 
mutational analysis (e.g., PTEN, PIK3CA, KRAS, CTNNB1 [beta-catenin], Rb). 
 

Page 52 of 80 
7.43 
Next-Generation Sequencing (NGS) 
Unstained sections of FFPE tumor will be used for next-generation sequencing (NGS) 
mutational analysis.  
8.0  
Evaluation Criteria 
8.1 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria.  
In the present study, tumors will be re-evaluated by CT scan of the chest, abdomen, and pelvis every 
12 weeks during treatment and at least 4 weeks after the first observation of a complete or partial 
response. After discontinuation of protocol treatment, patients who have not progressed will still be 
re-evaluated every 12 weeks.  
8.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first treatment 
with ribociclib and letrozole 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of 
cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or unequivocal progression of the lesions.  
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.  If the investigator thinks it appropriate to include them, the conditions under which such 
lesions should be considered must be defined in the protocol. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 

Page 53 of 80 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
8.1.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ³10 mm diameter as assessed using calipers (e.g., skin 
nodules).  In the case of skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended.  

Page 54 of 80 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans), but NOT lung.  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. 
As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should 
be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality 
used at follow-up should be the same as was used at baseline, and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, 
subsequent image acquisitions should use the same type of scanner and follow the baseline imaging 
protocol as closely as possible. If possible, body scans should be performed with breath-hold scanning 
techniques.  
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. PET-CT scans are not always 
done with oral and IV contrast. In addition, the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. For these reasons, the GOG will not 
allow PET-CT use for RECIST 1.1 response criteria.  
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-PET at follow-
up is not confirmed as a new site of disease on CT, additional follow-up CT  scans are needed to 
determine if there is truly progression occurring at that site (if so, the date of PD will be the date of 
the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where 
a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-PET 
in this circumstance should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 

Page 55 of 80 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances.  
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint.  
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): CA-125 cannot be used to assess 
response or progression in this study. If CA-125 is initially above the upper normal limit, it must 
normalize for a patient to be considered in complete clinical response. Specific guidelines for CA-125 
response (in recurrent ovarian cancer) have been published [JNCI 96:487-488, 2004]. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria that are to be integrated with 
objective tumor assessment for use only in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].  
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases, e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain.  
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when measurable disease has met criteria for response or stable disease. 
This confirmation is necessary to differentiate response or stable disease versus progressive disease, as 
an effusion may be a side effect of the treatment.  
8.1.3 Response Criteria  
 
8.1.3.1 
Evaluation of Target Lesions  
Response Criteria - Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 
<10 mm 
Partial Response (PR) 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference 
the baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference 
the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the 

Page 56 of 80 
sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
Clinical Benefit 
CR+PR+SD Progression-free survival  
 
8.1.3.2 Evaluation of Non-Target Lesions  
Response Criteria - Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level 
above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
Not evaluable (NE) 
When at least one non-target lesion is not 
evaluated at a particular time point 
 
8.1.3.3 Evaluation of Biomarkers 
If serum CA-125 is initially above the upper normal limit, it must normalize for a patient to be 
considered in complete clinical response.  
Progression cannot be based upon biomarkers, such as serum CA- 125, for this study.  
8.1.3.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria. 

Page 57 of 80 
For Patients with Measurable Disease (i.e., Target Disease): 
Evaluation of Overall Response 
Target Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after 
discontinuation of treatment. 

Page 58 of 80 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent time point 
at least 4 weeks later.  
8.1.4 Frequency of Tumor Re-evaluation 
In the present study, tumors will be re-evaluated by CT scan of the chest, abdomen, and pelvis every 
12 weeks during treatment and at least 4 weeks after the first observation of a complete or partial 
response. After discontinuation of protocol treatment, patients who have not progressed will still be 
re-evaluated every 12 weeks.  
8.1.5  Date of Progression 
Date of progression is defined as the first day when the RECIST (version 1.1) criteria for PD are met. CA 
125 (GCIG) progression alone is not sufficient for progression to be defined.  
8.1.6 Reporting of tumor response 
All patients included in the study must be assessed for response to treatment, even if there is a major 
protocol deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned 
one of the following categories: complete response, partial response, stable disease, progressive 
disease, early death from malignant disease, early death from toxicity, early death from other cause or 
unknown (not assessable, insufficient data).  
Early death is defined as any death occurring before the first per protocol time point of tumor re-
evaluation. The responsible investigator will decide if the cause of death is malignant disease, toxicity, 
or other cause.  
Patients for whom response is not confirmed will be classified as “unknown” unless they meet the 
criteria for stable disease (or the criteria for partial response in case of an unconfirmed complete 
response). Patients’ response will also be classified as “unknown” if insufficient data were collected to 
allow evaluation per these criteria. See table above for further detail.  

Page 59 of 80 
8.1.7 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive disease 
the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that progressive disease is objectively documented.  
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 
8.1.8 Progression-free survival: Progression-free survival (PFS) is defined as the duration of time from study 
entry to time of progression or death or the date of last contact, whichever occurs first.  
8.1.9 Overall Survival 
Overall survival is defined as the time from study entry to time of death or date of last contact.  
9.0  
DURATION OF STUDY 
9.1 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies:  
• Disease progression,  
• Intercurrent illness that prevents further administration of treatment,  
• Unacceptable adverse event(s),  
• Patient withdraws consent for the study,  
• Patient non-compliance with the protocol, 
• Death, 
• Pregnancy, or  
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator.  
 
9.1.1 If patient comes off study treatment prior to progression, continue tumor measurements and 
radiologic evaluations on schedule until progression or initiation of a subsequent cancer therapy. 
Toxicity assessments will be continued until resolution or return to baseline. Patients will be followed 
after last drug dose until toxicity resolution or return to baseline, until progression if patient withdraws 
before progressive disease, or until study withdrawal if it occurs before this time.  
 
9.1.2 All patients will be treated (with completion of all required case report forms) until disease 
progression or study withdrawal. Patients will then be followed every three months for the first two 
years and then every six months for the next three years. Patients will be monitored for delayed 
toxicity and survival for this 5-year period with Follow-Up Forms submitted to the GOG Statistical and 

Page 60 of 80 
Data Center, unless consent is withdrawn. Follow-Up Forms will no longer be required if the study is 
terminated prior to the completion of the 5-year follow-up period.  
 
9.1.3  A patient is considered off study therapy when the patient has progressed or died, a non-
protocol drug or therapy (directed at the disease) is initiated or all study therapy is totally 
discontinued. Report all treatment received on Cycle Drug Information Forms and adverse events on 
Adverse Event Forms up until the patient qualifies as being off study therapy.  
 
10.0 
Study Monitoring and Reporting Procedures 
 
10.1 
Adverse Event Reporting 
 
10.1.1 Definitions 
 
Adverse Event (AE):  Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. Progression of disease is considered the natural development 
of cancer in this study; therefore it is not considered as an adverse event. 
 
Suspected Adverse Reaction (SAR):  Adverse event for which there is a reasonable possibility that the 
investigational drug caused the adverse event (i.e., attribution to study drug of possible, probable, or 
definite).   
 
 
Serious Adverse Event (SAE):  An adverse event or suspected adverse reaction is considered “serious” if 
in the view of either the Investigator or sponsor, it results in any of the following outcomes: 
1) Death, 
2) A life-threatening adverse event, 
3) Inpatient hospitalization or prolongation or existing hospitalization, 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions,  
5) A congenital anomaly/birth defect. 
 
6) Important medical events that may not result in death, be life-threatening, or require 
 
hospitalization may be considered serious when, based upon appropriate 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. 
 
Unexpected Adverse Event:  An adverse event is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed. 
 
10.1.2 GOG Reporting Requirements:   

Page 61 of 80 
 
All investigators and ultimately the protocol Principal Investigator (PI) have the primary responsibility 
for AE identification, documentation, grading, and assignment of attribution to the study drug.  It is the 
responsibility of the investigator to supply the medical documentation needed to support expedited AE 
reports in a timely manner.  Investigators MUST immediately report to the sponsor any serious adverse 
event, whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is reasonable possibility that the drug 
caused the event (21 CFR 312.64(b)).  Please refer to Section 10.15 for reporting procedures. 
 
Information regarding AEs and SAEs will be collected from the time of informed consent until 30 days 
from the last dose administered.   
 
When possible, adverse events should be described in terms of a change in the baseline status or with 
a diagnosis or summary term rather than as individual symptoms.  The Investigator is responsible for 
reporting SAEs to the appropriate Institutional Review Board (IRB) or other committees in accordance 
with local institutional and IRB policies.   
 
10.1.3 Criteria for Determining Adverse Event Severity:   
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting.  
 
10.1.4 Criteria for Determining Adverse Event Causality:   
 
The following attribution categories will be  used in assessing the relationship between the AE and the 
study drug: 
 
 
 
 
 
 
 
 
 
 
 
10.1.5 SAE Reporting to GOG and Novartis:   
 
The investigator must report to GOG any serious adverse  event, whether or not considered drug-
related, within 24 hours of any site personnel becoming  aware of the event.  Please see the Data 
Management Manual for instructions for submitting SAE reports to GOG in Medidata Rave.  
 
 
RELATIONSHIP  
ATTRIBUTION 
DESCRIPTION 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 

Page 62 of 80 
The GOG Regulatory Compliance Department will forward all SAE reports to Novartis within 24  hours 
of first awareness. 
 
10.2 
GOG Data Management Forms 
 
The Case Report Forms (CRFs) noted in the Data Management Form Manual must be submitted 
through the Medidata Rave Electronic Data Entry System (www.imedidata.com). All amendments to 
CRFs must also be submitted through Medidata Rave. 
 
Please refer to the Data Management Form Manual. 
 
10.3  Safety Monitoring for Safety Lead-In 
 
The formal safety monitoring process for the safety lead-in for this protocol includes bi-weekly 
teleconferences which will be scheduled with participating sites to discuss the patients enrolled on 
the safety lead-in.  The site investigator or MD delegate is required to participate on the calls.  In 
addition, it is recommended that the responsible Clinical Research Coordinator participate as well. 
 
During the teleconference, each patient’s drug doses, treatment delays, abnormal blood counts, and 
AEs/SAEs as documented on the Case Report Forms (CRFs) in Medidata Rave.  The CRF data should be 
updated prior to each call.  Sites should be prepared to discuss the following topics for each enrolled 
patient: 
• 
Drug dosing (including total number of cycles) 
• 
Treatment delays 
• 
Dose modifications 
• 
Adverse Events, Serious Adverse Events, DLTs 
• 
Abnormal laboratory values 
• 
Response evaluations 
• 
Number of potentially eligible patients awaiting study 
 
Please refer to the Regulatory Manual for more information regarding the safety lead-in.  
 
11.0  
Statistical Considerations 
The intent of this this study is to assess the anti-tumor activity of the combination of letrozole + ribociclib in 
women with recurrent low-grade serous carcinoma of the ovary, fallopian tube or peritoneum measured by 
objective tumor response.  This is a single-arm, open-label phase II study with a safety lead-in using an 
optimal flexible 2-stage design (33).  
The targeted accrual for the first stage of the study will be 23 eligible and evaluable patients but permitted to 
range from 19 to 26 for administrative reasons. The cumulative targeted accrual for the second stage will be 
48 eligible and evaluable patients but permitted to range from 44 to 51 for administrative reasons.   
      11.1 Study endpoints 
11.1.1 Primary endpoints 
                               The frequency of objective tumor response as assessed by RECIST 1.1. 

Page 63 of 80 
                    11.1.2 Secondary endpoints 
                              The frequency of clinical benefit (CR, PR, or SD). 
                              The frequency and severity of adverse events as assessed by CTCAE v5.0. 
                               Progression-free survival 
                               Overall survival 
11.1.3 Exploratory endpoints 
Measurements of expression of ER, PR, and ki-67 and objective tumor response and clinical 
benefit. 
Measurements of genomic signatures and objective tumor response and clinical benefit.  
11.2 Anticipated annual accrual is approximately 31-39 patients based on GOG-0239. 
 
The accrual duration will take approximate 7-9 months for the first stage without suspension of 
safety lead-in and 8-10 months for the second stage, separately. Additionally, the evaluation of 
patients with complete/partial response takes at least 16 weeks, and it can take even longer to 
evaluate patients with stable disease to determine whether they respond or not. Therefore, the 
duration for completion of primary endpoint will be approximately 13-15 months from activation 
of the study for the first stage, and 14-16 months from activation of the second stage for the 
second stage if the study advances to the second stage. 
 
11.3 Study plan 
                    Safety lead-in 
                     The purpose of the safety lead-in phase is not to identify the MTD of the combination regimen. 
Rather it is being conducted to assure the safety of this regimen in the population of interest 
through the determination of cycle 1 DLTs. Patients will be dichotomized as either experiencing at 
least one DLT in cycle 1 (including delays in cycle 2 administration) or experiencing no DLTs at all in 
cycle 1. 
                    After six patients have received a full cycle of treatment and are observed for the whole first cycle, 
the safety of the regimen will be assessed based on the dose limiting toxicities (DLTs) listed in 
Section 4.6.   At most ten patients will be accrued before this safety evaluation takes place, and if 
necessary, accrual will be suspended at 10 patients in order to do this evaluation. 
The probability of DLT (θ) will be assessed using a Bayesian interpretation of θ, in which θ is 
considered to be a random variable with a probability distribution. We combine the data observed 
in our trial with a prior probability distribution for θ to obtain a posterior distribution for θ. The DLT 
data is binomially distributed (DLT yes/no). The conjugate prior for the binomial distribution is the 
beta distribution, so we assume the prior for θ, f(θ), to be Beta(α, β). We specify our prior to have 
α=2 and β=6 which reflects the belief that the θ for the regimen is most likely around 0.1 to 0.25. 
Our interested target for the probability of DLT is 0.25. 

Page 64 of 80 
Let n be the number of DLT-evaluable patients (i.e., had a DLT or treated for a full cycle), and x be 
the number of patients experiencing DLTs. The posterior for θ at the end of the safety lead-in is 
thus Beta(α + x, β + n  − x).  Consideration will be given to stopping the study if Pr(θ > 0.25|x, n) > 
0.5, which corresponds to stopping if the number of patients with DLTs is greater or equal to critical 
value, r, i.e., 2 or more out of 6 or 7 patients, or 3 or more out of 8-10 patients. Table 11.1 shows 
the posterior probabilities of θ exceeding the target of 0.25 at the end of safety lead-in and 
corresponding critical values.  These critical values are guidelines, but clinical judgment will be 
exercised, taking into account the nature of the toxicities and the likelihood of the toxicity being 
related to treatment. 
Table 11.1: Posterior Probabilities of θ [Pr(DLT)] Exceeding the Target of 0.25 and Corresponding Critical 
Values for Consideration of Stopping for Toxicity  
        x   
n           
Pr(θ > 0.25|x,n)  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
6 
0.13 
0.33 
0.58 
0.79 
0.92 
0.98 
0.99 
 
 
 
  
7 
0.10 
0.28 
0.52 
0.74 
0.89 
0.96 
0.99 
1.00 
 
 
  
8 
0.08 
0.24 
0.46 
0.69 
0.85 
0.94 
0.98 
1.00 
1.00 
 
  
9 
0.06 
0.20 
0.41 
0.63 
0.81 
0.92 
0.97 
0.99 
1.00 
1.00 
  
10 
0.05 
0.16 
0.35 
0.57 
0.77 
0.89 
0.96 
0.99 
1.00 
1.00 
1.00 
 
                    Phase II 
The intent of this study is to assess the anti-tumor activity of the combination of letrozole + 
ribociclib measured by objective tumor response. Tumor response is dichotomized as response (i.e., 
complete or partial response) vs. non-response (i.e., stable disease, progressive disease, or unknown) 
and is assumed to have a Bernoulli distribution with a probability equal to π. Given a sample size, the 
number of tumor responses is binomially distributed with a given sample size and probability equal to 
π. Statistically, the evaluation of the study regimen efficacy measured by tumor response will be 
formulated through hypothesis testing via tumor response. 
 
If combination proposed here has a true response rate of 10% or less, it would be considered of 
little clinical significance. Alternatively, if the true response rate were at least 25%, further 
investigation would be clearly indicated. Therefore, the primary hypotheses for this study can be 
formulated as follow:  
H0: π ≤ 0.10, 
H1: π ≥ 0.25, 
where π is the probability of true tumor response, H0 is the null hypothesis and H1 is the 
alternative hypothesis. An optimal flexible two-stage design will be implemented to evaluate the 
primary hypotheses with average type I and type II error rates at 0.1 level, respectively (33).  This 
design has early stopping guidelines that intends to limit patient accrual to inactive treatments and 
it permits the actual number of patients entered in each stage to vary slightly in order to 

Page 65 of 80 
accommodate the challenges of coordinating a multicenter clinical trial while maintaining the levels 
of average type I and type II errors.  
 
We will target an accrual of 23 eligible and evaluable patients in the first stage of this study, but in 
practice permit accrual to range from 19 to 26 patients due to administrative coordination. If there are 
more than 2 out of 19-25, or 3 out of 26 patients responding (complete or partial response) and 
medical judgment indicates, accrual to the second stage of the trial will be initiated. Otherwise, the 
study will be stopped and the treatment regimen will be classified as clinically uninteresting. If the 
study advances to the second stage, then an overall study accrual of 48 eligible and evaluable patients 
will be targeted, but permitted to range from 44 to 51 patients for administrative reasons. If more than 
6 out of 44-45 patients respond or 7 out of 46-51 patients respond then the regimen will be considered 
worthy for additional investigation. 
Under the assumed accrual ranges of 19 to 26 (stage 1) and 44 to 51 (cumulatively after stage 2), if the true 
probability of response is 10% (H0), then this study has a 64% probability of early termination and a 
probability of 10% of incorrectly declaring the study regimen interesting; if the true probability of tumor 
response is 25%, then the study has a 90% chance of correctly classifying the study regimen as being 
interesting.  
                   The following table summarizes the accrual and decision guideline.          
Stage of 
Accrual 
Targeted 
Cumulative Accrual 
Limits of Actual 
Accrual 
Max Number of Responses to 
Reject Study Regimen 
1 
23 
19-26 
2/(19-25), 3/26 
2 
48 
44-51 
6/(44-45), 7/(46-51) 
 
11.4 Secondary and exploratory analyses 
 
Secondary analyses 
The proportion of patients who have clinical benefit will be calculated and an estimate of 90% 
confidence interval will be provided. 
 
The frequency and maximum severity of acute adverse events will be tabulated graded by CTCAE 
v5.0.  
 
Kaplan-Meier median estimates and graphs will be used to describe PFS and OS survival functions. 
 
Exploratory analyses 
Summary statistics (and graphs where it is appropriate) will be done for exploratory biomarker 
endpoints.  
 
Appropriate methods will be implemented to explore the associations of biomarkers with the 
response and clinical benefit, e.g., Spearman’s correlation coefficient for interval/ordinal type of 

Page 66 of 80 
biomarker measurements with response or clinical benefit, chis-squared test for nominal type of 
biomarker measurements with response or clinical benefit. 
 
The purpose of exploratory objective is to explore and possibly generate hypotheses for future 
study. Therefore there will be no adjustment for multiple tests.  
 
11.5  Only those patients who are deemed "ineligible" or who receive no therapy will be eliminated from 
the analysis. All patients who receive any therapy will be evaluated for both treatment efficacy and 
toxicity. While on occasion, circumstances may prevent the determination of treatment efficacy, 
such patients will be included in the analysis and labeled as "unknown". This category will be listed 
and be reflected in the calculation of the response rate.  
12.0  
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APPENDIX A: PERFORMANCE STATUS SCALES 
 
 
 
As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5:649-655. The Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair.  
 
 

Page 70 of 80 
APPENDIX B: NYHA CLASSIFICATION OF HEART DISEASE 
 
New York Heart Association (NYHA) classification of heart disease 
Table 1: NYHA Classification of Heart Disease 
NYHA Class 
Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, e.g. shortness 
of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
 
 
 

Page 71 of 80 
APPENDIX C: PROHIBITED MEDICATIONS DURING STUDY DRUG TREATMENT 
Table 1.  List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors 
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, 
idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), 
posaconazole, ritonavir,  saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycinvoriconazole 
Strong CYP3A4/5 inducers 
Apalutamide, carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's wort 
(hypericum perforatum)2,3 
CYP3A4/5 substrates with 
NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine (dihydroergotamine), 
ergotamine, fentanyl,  pimozide, quinidine,  sirolimus, tacrolimus 
Medications with a known risk 
for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, chloroquine,  
chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, fluconazole, gatifloxacine, grepafloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomepromazine, levosulpiride, 
methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-
coronary), pentamidine, pimozide,  procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol,  sulpiride, sultopride, terlipressin, terodiline,  
thioridazine, vandetanib 
Herbal preparations/ 
medications 
Herbal preparations/medications or dietary supplements known as strong inducers 
or inhibitors of CYP3A4/5 or those with a known risk of QT prolongation are 
prohibited throughout the study. These herbal medications include, but are not 
limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients 
should stop using these herbal medications or dietary supplements 7 days prior to 
first dose of study drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on the study. 
Anticancer therapy (chemotherapy, all SERMS (including raloxifene), biologic or 
radiation therapy, and surgery) other than the study treatments must not be given 
to patients while the patient is on the study medication. If such agents are required 
for a patient then the patient must be discontinued study drug. 
 
 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes) or drugs 
which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the 
blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of December 2019.Check https www crediblemeds.org/healthcare-providers/drug-list for 
the most updated list.  
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to increase 
the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of ribociclib or the 
exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk, or conditional risk of 
QT prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 
 

Page 72 of 80 
Table 2.  List of medications to be used with caution during study drug treatment 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, crizotinib, 
diltiazem, faldaprevir,  imatinib,  isavuconazole, netupitant, nilotinib, tofisopam, 
Schisandra sphenanthera (nan wu wei zi), verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, dabrafenib, efavirenz, etravirine, genistein,lopinavir5, modafinil, 
nafcillin,telotristat 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine,  aprepitant,  atorvastatin, avanafil, bosutinib,brotizolam, 
budesonide, buspirone,  cannabinoids6, cannabidiol6, cobimetinib,   darifenacin, 
dasatininb, ebastine, eletriptan, eplerenone, everolimus, felodipine, fluticasone, 
grazoprevir, ibrutnib, isavuconazole, ivabradine, ivacaftor, , levomethadyl (LAAM), 
lomitapide, lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, 
naloxegol, neratinib, nisoldipine, perospirone, quetiapine, ridaforolimus, sildenafil, 
simeprevir, simvastatin, ticagrelor, tilidine,  tolvaptan, triazolam, ulipristal, vardenafil, 
venetoclax, vicriviroc, voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin,  bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine,rifamycin, simeprevir, telmisartan,timcodar, 
troglitazone, valinomycin, velpatasvir 
Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine, 
atomoxetine,  bedaquiline, bendamustine, bortezomib, bosutinib, buprenorphine, 
cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib,clozapine, 
cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid, 
desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, epirubicin, eribulin 
mesylate, ezogabine(retigabine), famotidine, felbamate, fingolimod, flupentixol,  
gemifloxacin, granisetron, hydrocodone-ER, iloperidone, imipramine (melipramine), 
isradipine, ketanserin, lapatinib, lenvatinib, leuprolide, lithium, melperone, 
midostaurin, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, 
nicardipine, nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, osimertinib,  
oxytocin, paliperidone, palonosetron,  panabinostat, pasireotide, pazopanib, 
perflutren lipid microspheres, perphenazine, pilsicainide, pimavanserin, 
pipamperone, promethazine, prothipendyl,  rilpivirine, risperidone, romidepsin, 
sertindole, sorafenib, sunitinib, tamoxifen, tipiracil/trifluridine, tizanidine, tolterodine, 
toremifene,trimipramine, tropisetron, vardenafil, vemurafenib, venlafaxine, 
vorinostat, ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
 Amantadine,  6-beta-hydroxycortisol, carboplatin, cisplatin, cephalexin, cephradine,   
ipratropium,  lamivudine, linagliptin, metformin, oxali 
platin, oxybutynin, phenformin, picoplatin, pilsicainide, pindolol, , ranitidine, 
sorafenib,  tropisetron, trospium, umeclidinium,, , and zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, methotrexate, 
mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, 
sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered 
with a potent inhibitor.2  The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-
providers/drug-list for the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity.  
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir and atazanavir is prohibited when combined with ritonavir (see Table 14-1) 
6 Based data that, exposure of cannabidiol (CBD), tetrahydrocannabinol (THC), 11-hydroxy THC, increased by ~2-3 
folds when co-administered with ketoconazole (CYP3A4 inhibitor); Stott et al, Springerplus. 2013; 2: 236 

Page 73 of 80 
 
 
 
 
Category 
Drug Name 
 
 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 

Page 74 of 80 
APPENDIX D- PATIENT PILL CALENDAR:  
Patient Name: ________________________Date of first dose on calendar: _______________         
Patient Study ID: ____________________Cycle #:__________________________________ 
 
 
 
 
• Complete one form for each cycle of treatment 
• You will take Ribociclib once a day for 21 days followed by 7 days off.  You will take 
Letrozole once a day every day.   
• Please bring this form and your bottles of Letrozole and Ribociclib each time you return for 
an appointment 
Day 
Date 
Time of Ribociclib 
Dose 
Dose 
taken 
Time of 
Letrozole Dose 
Dose  
taken 
 
Comments 
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Page 75 of 80 
APPENDIX E - DIGITAL PATHOLOGY SCREENING FORM 
 
 
BIOPATHOLOGY CENTER 
DIGITAL PATHOLOGY SCREENING FORM 
 
One H&E stained slide from the recurrent tumor (obtained at secondary surgery, prior biopsy, or SOC image-
guided fine needle/core biopsy) or from the original diagnostic specimen documenting low-grade serous 
carcinoma must be sent for determination of eligibility by digital pathology review. 
 
The H&E, along with a completed copy of this form, corresponding pathology report, and printout of the IRT 
Screening Confirmation must be shipped by overnight courier at the institution’s expense to: 
 
GOG 3026 Pathology Review 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
 
 
Protocol 
GOG 3026 
 
 
PATIENT INFORMATION 
Screening ID 
 
Patient Initials 
 
SPID 
 
Block # 
 
Date Collected 
 
 
 
REQUESTING SITE 
Institution Name 
 
Contact for Questions Regarding Submission 
Name 
 
Phone 
 
Email 
 
 
 
 

Page 76 of 80 
APPENDIX F - TRANSLATIONAL RESEARCH BIOSPECIMEN PROCEDURES 
 
I. Requesting Translational Research Biospecimen Kits 
One single chamber kit will be provided per patient for the collection and shipment of frozen whole blood. 
 
Sites can order kits online via the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). Each site may order two kits per protocol per day 
(daily max = 6 kits).  
 
 
Please contact the Biopathology Center if you need assistance (Email: BopPhone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should arrive within 
3-5 business days. 
 
Note: Unused materials and kits should be returned to the Biopathology Center. A pre-paid shipping label for 
the return of unused supplies and kits may be obtained via the Kit Management system. Select “Empty Kit” for 
package contents when returning unused kits. 
 
II. Archival FFPE Tissue Shipped to the Biopathology Center 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the specimen type (e.g., 
recurrent, primary, metastatic). Only one block may be submitted per tissue type. 
• Recurrent tumor should be collected prior to the patient receiving any study treatment. Recurrent tumor 
collected from the site of primary disease should be labeled recurrent primary (FRP01). Recurrent tumor 
collected from a site other than the site of primary disease (e.g., lymph node) should be labeled recurrent 
metastatic (FRM01). 
• Archival primary (FP01) and metastatic (FM01) tumor should be collected prior to the patient receiving any 
treatment. 
 
Mandatory FFPE Biospecimen Requirement 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided on a 
permanent basis, then 20 unstained slides (10 charged, 5µm & 10 uncharged, 10µm) must be submitted. All 
tissue sections must be cut sequentially from one block. 
 
Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational research tissue 
biospecimen with: 
 
patient ID (XXXX-3026-YYYY) 
patient ID (XXXX-3026-YYYY) 
specimen code (see above) 
collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on the back of the 
slide or over the tissue. The label must fit on the slide and should not be wrapped around the slide or hang 
over the edge. 

Page 77 of 80 
 
Required Documentation 
All FFPE tissue should be submitted with the following documentation: 
• Corresponding pathology report or Pathology Verification Form (Appendix H) 
• FFPE Materials Verification Form (Appendix G) 
• Translational Research – FFPE Submission Form (printout of form completed in Rave) 
 
III. Whole Blood Shipped to the Biopathology Center 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described below. Multiple tubes may be used to 
collect the required amount. Do not use glass blood collection tubes. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is needed for 
processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Immediately freeze the whole blood in an upright position in a -70oC to -80oC freezer or by direct exposure 
with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for storage, store and ship on dry 
ice within 24 hours of collection. 
 
Labeling Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational research whole 
blood biospecimen with: 
 
patient ID (XXXX-3026-YYYY) 
specimen code (WB01) 
collection date (mm/dd/yyyy) 
 
Required Documentation 
All whole blood should be submitted with the following documentation: 
• Translational Research – Whole Blood Submission Form (printout of form completed in Rave) 
 
IV. Shipping Translational Research Biospecimens 
• Translational research biospecimens must not be shipped until after patient registration. 
• The required documentation must be included for each translational research biospecimen.  
• All translational research biospecimens should be shipped to: 
 
Biopathology Center / Protocol GOG-3026 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
A. FFPE Tissue Shipped to the Biopathology Center 
FFPE tissue and all required documentation should be shipped using your own container at your own expense 
to the Biopathology Center (address above). Do not ship FFPE tissue for Saturday delivery. 
 
B. Whole Blood Shipped to the Biopathology Center 

Page 78 of 80 
Frozen whole blood should be shipped using the biospecimen kit provided to the Biopathology Center 
(address above). If including frozen whole blood from more than one patient in a kit, each whole blood 
specimen should be placed in a separate zip-lock bag. 
 
Frozen biospecimens should be shipped Monday through Thursday for Tuesday through Friday delivery. Do 
not ship frozen biospecimens on Friday or the day before a holiday. Note: Saturday delivery is not available for 
frozen biospecimens.  
 
Frozen biospecimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-70oC freezer, 
liquid nitrogen, or direct exposure with dry ice) until the biospecimens can be shipped. 
 
Shipping Frozen Translational Research Biospecimens in a Single Chamber Kit   
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen biospecimens from patient in a separate zip-lock bag. 
3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Put the secondary 
envelope into a Tyvek envelope. Expel as much air as possible before sealing both envelopes. 
4. Place the Tyvek envelope containing the frozen biospecimens into the kit and fill the chamber to the top with 
dry ice. 
5. Insert a printout of the Rave-completed Translational Research – Whole Blood Submission Form for each 
whole blood biospecimen.  
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other durable sealing 
tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement/). Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 

Page 79 of 80 
APPENDIX G – BIOPATHOLOGY CENTER FFPE MATERIALS VERIFICATION FORM 
  
 
This form should be completed by the person in the pathology department who provides the FFPE materials to 
the requestor. Please return this form, along with the FFPE materials, to the requestor. The requestor must 
include this completed form with the shipment of FFPE materials. 
REQUIRED FFPE MATERIALS 
• One of the following tumor types must be submitted: 
• Archival recurrent primary (FRP01) or recurrent metastatic (FRM01) tumor – i.e., collected prior to 
study treatment. 
• Archival primary (FP01) or metastatic (FM01) tumor – i.e., collected prior to any treatment. 
• Every attempt should be made to provide an FFPE block; however, if a block cannot be provided on a 
permanent basis, then 20 unstained slides (10 charged [5µm] and 10 uncharged [10µm]) must be submitted. 
• All tissue sections must be cut sequentially from one block.  
 
PATIENT INFORMATION (to be completed by person requesting FFPE materials) 
 
Study ID: ________________________________ 
 
FFPE MATERIALS (to be completed by person preparing FFPE materials) 
Surgical Pathology #: ____________      Block #: __________      Date Collected: __ __ / __ __ / __ __ __ _ 
 
Tissue Type: □ Recurrent Primary (FRP01) 
□ Recurrent Metastatic (FRM01) 
□ Primary (FP01) 
 
 
□ Metastatic (FM01) 
Site:  
□ Ovary 
□ Fallopian Tube 
□ Peritoneum  
 
□ Other, specify __________________________________ 
Materials Prepared  
Count 
 
Thickness (μm) 
Block 
 
 
Not Applicable 
Charged slides 
 
 
 
Uncharged slides 
 
 
 
 
__________________________________________ 
 
 
______________________________ 
Name of person preparing materials  
 
 
 
 
Date 

Page 80 of 80 
  
APPENDIX H - BIOPATHOLOGY PATHOLOGY VERIFICATION FORM 
 
  
 
A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the 
Biopathology Center. 
If a pathology report is not available, a copy of the radiology report or operative report from the tissue 
collection procedure in addition to a completed copy of this appendix (i.e., Pathology Verification from) must 
also be submitted to the Biopathology Center. 
Note: If this information is not provided with the tissue biospecimen, then the tissue will not be accepted by 
the Biopathology Center. 
 
 
Please have the Pathologist responsible for signing out this patient’s case complete the following: 
Study ID: __________________________________ 
Date of Procedure (mm/dd/yyyy): _________________________________________ 
Tissue Type (circle one): 
Recurrent Primary 
 
Recurrent Metastatic 
 
 
 
 
Primary 
 
 
Metastatic 
 Site Tissue Taken From: ________________________________________________ 
Diagnosis: ___________________________________________________________ 
 Recurrent disease documented by: ________________________________________ 
 
I agree that this tissue may be released for research purposes only and that the release of this tissue will not 
have any impact on the patient’s care. 
 
 
___________________________________  
 
_____________________ 
Pathologist’s Signature 
 
 
 
 
Date 
___________________________________ 
Pathologist’s Printed Name