Clinical trial NCT02657928
Conditions: Estrogen Receptor Positive Postmenopausal Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Recurrent Uterine Corpus Carcinoma
Sponsor: Mayo Clinic
Start date: 2016-07-08; Completion date: 2020-10-07
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ribociclib and letrozole work in treating patients with estrogen receptor (ER) positive ovarian, fallopian tube, primary peritoneal, or endometrial cancer that has returned (come back) after a period of improvement. Ribociclib may stop the growth of tumor cells by blocking some enzymes needed for cell growth. Cancer cells that are estrogen receptor positive may need estrogen to grow. Letrozole lowers the amount of estrogen made by the body and this may stop the growth of tumor cells that need estrogen to grow. Giving ribociclib together with letrozole may be an effective treatment in patients with ovarian, fallopian tube, primary peritoneal, or endometrial cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a higher percentage of patients who are progression free at 12 weeks (PFS 12) as compared with that observed in prior studies with single agent letrozole.

SECONDARY OBJECTIVES:

I. Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a higher cancer antigen 125 (CA-125) response rate in patients with relapsed ER positive ovarian cancers and endometrial cancers as compared to that observed in previously reported single agent letrozole studies.

II. Median progression-free survival (PFS), overall survival (OS), the confirmed response rate, and adverse events.

TERTIARY OBJECTIVES:

I. Identify molecular biomarkers associated with a response to treatment with letrozole and ribociclib (LEE011) (in patients with relapsed ovarian carcinomas and endometrial cancers).

II. Develop patient derived xenograft (PDX) avatars on tumors from participants for possible future translational study evaluating a potential correlation between responses in the PDX model to patients' responses.

OUTLINE:

Patients receive ribociclib orally (PO) daily and letrozole PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 2 years.

Arms: arm 1: Patients receive ribociclib PO daily and letrozole PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Letrozole intervention 3: Ribociclib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 


 
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MC1561 
 
Table of Contents 
Phase 2 Trial of Ribociclib (LEE011) and Letrozole in ER Positive Relapsed Ovarian Cancer, Fallopian 
Tube Cancer, Primary Peritoneal Carcinomas and Endometrial Cancers .....................................................1 
Table of Contents ..........................................................................................................................................2 
Schema ..........................................................................................................................................................3 
1.0 
Background ...................................................................................................................................4 
2.0 
Goals ..............................................................................................................................................7 
3.0 
Patient Eligibility ...........................................................................................................................9 
4.0 
Test Schedule ..............................................................................................................................12 
5.0 
Grouping Factors .........................................................................................................................13 
6.0 
Registration Procedures ...............................................................................................................13 
7.0 
Protocol Treatment ......................................................................................................................15 
8.0 
Dosage Modification Based on Adverse Events .........................................................................17 
9.0 
Ancillary Treatment/Supportive Care .........................................................................................30 
10.0 
Adverse Event (AE) Reporting and Monitoring ..........................................................................32 
11.0 
Treatment Evaluation Using RECIST Guideline ........................................................................38 
12.0 
Descriptive Factors ......................................................................................................................44 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .............................................................44 
14.0 
Body Fluid Biospecimens - None ................................................................................................45 
15.0 
Drug Information .........................................................................................................................45 
16.0 
Statistical Considerations and Methodolology ............................................................................51 
17.0 
Pathology Considerations/Tissue Biospecimens .........................................................................56 
18.0 
Records and Data Collection Procedures ....................................................................................58 
19.0 
Budget .........................................................................................................................................59 
20.0 
Key References:...........................................................................................................................60 
Appendix I 
ECOG PERFORMANCE STATUS .................................................................................62 
Appendix II  
MEDICATION DIARY ....................................................................................................63 
Appendix III  
CONCOMITANT MEDICATIONS .................................................................................64 
 
 
 


 
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Schema 
 
Pre-Registration 
For determination of ER and RB 
 
 
↓ 
 
 
Registration 
 
 
 
 
 
Cohort A: Ovarian, primary 
peritoneal, fallopian tube ACA 
 
Cohort B: Endometrial cancer 
 
 
 
 
Treatment1 
Letrozole PO daily and  
Ribociclib (LEE011) PO Days 1-28 
 
 
↓ 
 
 
Event monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length=28 days ±3 days 
 
 
Generic name: Letrozole 
Mayo abbreviation: LETROZ 
Availability: Novartis 
Generic name: Ribociclib 
Mayo abbreviation: LEE011 
Availability: Novartis 
 
 
 
PD* at any time 
Unacceptable adverse  
 
Event 
events    
 
Monitoring 
Patient refusal 
*unless otherwise specified 


 
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1.0 
Background 
1.1 
There is a need for additional effective treatment of relapsed ovarian, fallopian 
tube, primary peritoneal carcinomas and endometrial cancers. These tumors are 
collectively the third most common cause of all cancer deaths in women. 
 
1.2 
Estrogen receptor (ER) positivity has been observed in 38-60% of all ovarian 
cancers (1,2). Ninety percent of all borderline ovarian tumors express ER (3). 
Aromatase is expressed by 33-81% of ovarian cancers (6). Estrogen receptor 
positivity is seen in 80 % of all endometrial cancers, more commonly in the low 
grade endometrioid tumors (23). Expression of aromatase has been observed in 
67% of all endometrial cancers (15,16). 
 
1.3 
At least three phase 2 trials of aromatase inhibitors in metastatic endometrial 
cancer have been reported in the literature (13, 14, 26). In a GOG trial of 
anastrozole reported by Rose et al, a 9% response rate was observed (2 PR and 2 
stable disease) in 23 patients with recurrent/metastatic endometrial cancer not 
exposed to cytotoxic chemotherapy (13). The 2 responses lasted 13 and 18 
months and both patients responding had grade 2 tumors. In this trial, the median 
progression free survival was 1 month and the median duration of anastrozole 
treatment was 4 weeks. In the second trial reported by Ma et al for the NCIC, 
letrozole was given to 32 postmenopausal women with recurrent endometrial 
cancers who had received at the most one prior progestational agent and no prior 
chemotherapy for metastatic disease. A 9.4% response rate and 39% stable 
disease was observed. A median progression -free survival of 6.7 months was 
observed in the subset with stable disease (13). Among 19 patients with available 
tissue in the second trial, ER positivity and PR positivity was seen in 86% of the 
cases. Only 2 of these 19 patients had a response, both having a partial response 
and both been ER and PR positive tumors. Seventy percent of the patients treated 
in the trial of Ma et al had not received prior hormonal treatment. The response 
rates seen in this trial were similar to the response rate seen with single agent 
tamoxifen or single agent progestational agents in recurrent endometrial cancers 
(13).The third trial was reported by Lindemann et al for the Nordic Society of 
Gynecologic Oncology on the use of exemestane in patients with advanced, 
persistent or recurrent endometrial cancer (26). In this trial, 51 patients with 
advanced or recurrent endometrial cancer with measurable disease were treated 
with exemestane 25 mg daily. Estrogen receptor positivity was defined as 2+ 
staining in 10% or more of the cancer cells. There were no responses noted in 11 
evaluable patients with ER negative disease. Among 40 patients with ER positive 
disease, responses were seen in 4 patients (10% response rate) with 2 patients 
achieveing a complete response.. An additional 25% of patients (10/40 patients) 
had stable disease after 6 months of treatment, for a 35% benefit ratio after 6 
months of treatment. All patients who responded to treatment had long lasting 
remissions (over 55 months and 23 months for the 2 patients who achieved a CR 
and 25.6 and 26.6 months among the patients who achieved PR).  
 


 
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1.4 
At least eight phase 2 clinical trials evaluating aromatase inhibitors have been 
completed on relapsed ovarian cancer. These studies showed a variable level of 
activity with a response rate ranging from 0-35% and stable disease noted in 20-
42%. (4-6).  
 
1.5 
Bowman et al reported in 2002 the largest phase 2 trial of letrozole in relapsed 
ovarian cancer. A total of 60 patients were treated. The authors observed a 
significant correlation between ER and PR expression in the tumors and benefit 
from treatment (prolongation of time to progression, CA-125 responses) (7). CA-
125 responses (greater than 50% decreases in baseline levels) were noted in 8% of 
the patients. Median time to progression was 12 weeks for the whole group. 
Stable disease at 12 weeks was noted in 17% of the patients with a median time to 
progression of 35 weeks for this subset (7). The authors concluded that there 
seems to be a subset of ovarian cancers that may benefit from letrozole therapy 
and that this subset is characterized by higher expression of estrogen and 
progesterone receptors.  
 
1.6 
Clinical data from Dr. Colon-Otero’s practice is also consistent with the presence 
of a subset of relapsed ovarian cancer patients who may obtain long term benefits 
from aromatase inhibitor therapy. Six patients with relapsed ovarian cancer cared 
for by Dr. Colon-Otero had responses to aromatase inhibitors lasting for 1 year to 
over 13 years after progressing on multiple chemotherapy regimens. Two of the 
patients had a grade 1 papillary serous carcinoma, 2 patients had high grade 
endometrioid carcinomas and 2 had high grade papillary serous carcinomas. ER 
and PR data was available in 2/6 patients and was positive on both of them. 
 
1.7 
Additional data also suggest that response rates to aromatase inhibitors are higher 
in patients with borderline ovarian tumors, which have a higher level of 
expression of estrogen receptors (8-9). 
 
1.8 
A trial of everolimus and letrozole in endometrial cancer demonstrated significant 
activity of this combination (27). All patients had received up to 2 prior 
chemotherapy regimens. A 32% response rate (11/35 evaluable patients) was 
observed including a 25% CR rate (9 patients). Forty percent of the evaluable 
patients experienced clinical benefit at 16 weeks (CR, PR or stable disease; CBR). 
Sixty five percent of the ER positive endometrioid tumors had clinical benefit 
(13/20 patients). All 7 cases with serous histology had progressive disease but 
only 2 of these tumors were ER positive.  
 
1.9 
In post-menopausal women with metastatic breast cancer, resistance to aromatase 
inhibitor therapy is associated with activation of the cyclin kinase pathway. The 
addition of a cyclin kinase inhibitor (palbociclib, PD0332991) to letrozole in a 
randomized phase 2 trial for patients with previously untreated ER positive 
metastatic breast cancer was associated with a significant prolongation of disease 
free survival (11). A total of 165 patients were studied with an increase in PFS 


 
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MC1561 
from 7.5 months to 26 months noted in the group treated with the combination of 
palbociclib (PD0332991) and letrozole (11).  
 
1.10 
Ribociclib (LEE011) is an oral inhibitor of CDK 4/6 that induces 
dephosphorylation of Rb and G1 cell cycle arrest in cancer cells. First in human 
trials showed a tolerable dose of 600 mg PO daily or 900 mg PO daily for 3 of 4 
weeks as well as a dose of 400 mg daily (12, 19). Multiple phase 1 studies of 
ribociclib as a single agent or in combination with multiple other agents including 
letrozole have been completed and/or are ongoing. For example, Study 
CLEE011A2115C is an ongoing, Phase 1B dose-escalation study, followed by a 
Phase 2 single-arm study of the combination of ribociclib and letrozole in 
poetmenopausal women with ER positive, HER2 negative metastatic breast 
cancer. As of August 6, 2015, 12 patients were treated with 400 mg ribociclib and 
letrozole as proposed in this study, with 9 patients completing Cycle 1. At the 
time of data cut-off dat, 2 SAEs have been reported including 1 case of hepatic 
function abnormalities and 1 case of elevated serum creatinine.We will use the 
400 mg PO daily dose for this proposed trial. 
 
1.11 
The p16-CDK4/6-Rb pathway regulates cell cycle progression from G1-S. Given 
the mechanism of action of ribociclib ( LEE011), RB expression is a pre-requisite 
for ribociclib anti-neoplastic effects. Lack of expression of p16 and expression of 
RB correlate with response to cyclin kinase inhibitors in general although no 
correlation between biomarker expression and response was noted by Lin et al in 
the postmenopausal breast cancer trial of letrozole and palbociclib 
(PD0332991)(18). In a xenotropic model of glioblastoma multiforme, Ling et al 
describes that response to cyclin kinase inhibitor (PD0332991) correlated with the 
presence of wild type RB, the lack of amplification of CDK4 and the lack of p16-
INK4a expression (17).  
 
1.12 
In ovarian cancer, Dong et al found that 71% of the tumors expressed pRb (20). In 
endometrial cancer, loss of Rb expression is a rare event, present in only 4 out of 
70 cases studied by Niemann et al (21,22, 24). Deletion of p16 with associated 
expression of Rb is not present in endometrial hyperplasia but has been seen in 
26% of cases of endometrial cancers evaluated by Koh et al and this phenotype 
correlates with higher grade tumors (25). 
 
1.13 
In view of the above findings, it is conceivable that inhibition of the cyclin kinase 
pathway in ER positive ovarian cancers and endometrial cancers may lead to 
synergism when administered concomitantly with aromatase inhibitors. The 
proposed pilot study will evaluate the response rate and progression free survival 
of patients with relapsed estrogen receptor positive ovarian cancer and relapsed 
estrogen receptor positive endometrial cancers treated with letrozole and 
ribociclib (LEE011).  
 
1.14 
A phase 2 trial of everolimus and letrozole in relapsed ER positive ovarian cancer 
by Colon-Otero et al just completed acrual. Primary endpoint of this trial was the 


 
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MC1561 
demonstration that mTOR inhibition with everolimus given together with 
letrozole will significantly prolong the time to progression and lead to an increase 
in the percentage of patients without progressive disease at 12 weeks of treatment 
(PFS12) (a PFS12 greater than 45%) compared to historical controls of letrozole 
alone (which had shown a PFS12 of 20%). Preliminary analysis of the first 16 
patients enrolled in the trial showed that the primary endpoint was met with 69% 
percent of the patients not progressing at 12 weeks. This study also demonstrated 
the feasibility of developing PDX models from CT guided biopsy specimens on 
these patients as planned on this proposed study. These results support the 
concept that some of the proven effective interventions to circumvent resistance 
to aromatase inhibitor therapy in ER positive breast cancer, like mTOR inhibition 
and cyclin kinase inhibition, may also be effective in other ER positive tumors 
like ovarian cancer. 
 
2.0 
Goals 
2.1 
Primary objective: 
Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a 
higher percentage of patients who are progression free at 12 weeks (PFS 12) as 
compared with that observed in prior studies with single agent letrozole.  
2.2 
Secondary objectives 
2.21 
Demonstrate if the combination of letrozole and ribociclib (LEE011) leads 
to a higher CA-125 response rate in patients with relapsed ER positive 
ovarian cancers and endometrial cancers as compared to that observed in 
previously reported single agent letrozole studies.  
2.22 
Other secondary endpoints will consist of median progression-free 
survival (PFS), overall survival (OS), the confirmed response rate, and 
adverse events. 
2.3 
Correlative Research 
2.31  Identify molecular biomarkers associated with a response to treatment 
with letrozole and ribociclib (LEE011) ( in patients with relapsed ovarian 
carcinomas and endometrial cancers). 
2.32 
Develop PDX avatars on tumors from participants for possible future 
translational study evaluating a potential correlation between responses in 
the PDX model to patients’ responses.  
2.321 For proposed future patient derived xenograft experiments, 
response to therapy is tumor volumes measured by ultrasound; this 
measurement exhibit a standard deviation in the range of 10 to 
25% of the tumor volume. Taking the high end of the standard 
deviation, for each model we anticipate 5 animals per group 
(control or letrozole + ribociclib) will give us approximately 80% 
power to determine a 50% difference in tumor volume (57% 
difference for 4 animals). Thus, 10 animals/model will be adequate 
for this comparison. To explore whether the responsiveness of 


 
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MC1561 
tumors to letrozole + ribociclib is not due to either agent alone, 
additional cohorts of 5 animals treated with letrozole and 5 animals 
treated with riboccilcib, will also be treated for a total of 20 
animals/model. However, formal comparisons will only be made 
between control and combination therapy, and thus no penalties for 
multiple comparisons will be assessed. The study endpoint is 28 
days following treatment initiation. “Response” will be defined as 
tumors with at least a 50% reduction in tumor volume at study end. 
“Unresponsive” will be defined as tumors with less than 10% 
tumor volume reduction at study end. Intermediate values will be 
defined as “Stable”. Tumor growth curves will be plotted 
graphically and notated to indicate the outcome status of the 
originating patients. End of study tumor volumes will be correlated 
with outcome status of the originating patient in an exploratory 
fashion. 
The preclinical combinatorial data will be compared to patient 
clinical trial outcome data to determine if the avatar models match 
clinical findings related to tumor responsiveness to therapy. If so, 
numerous directions may be taken that could include profiling 
tumor tissues to identify biomarkers for responsiveness or utilizing 
the avatar models to explore other therapeutic alternatives to 
nonresponders. 
2.322 Should these exploratory studies demonstrate a correlation of 
benefit on protocol therapy to a specific “ribociclib/letrozole DNA 
response signature”, after discussions with the Sponsor and co-
investigators, the study will be amended to enroll an additional 
cohort of patients that are screened and demonstrated to be 
‘positive’ for the putative response signature to validate these 
findings. 
 


 
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3.0 
Patient Eligibility 
3.1 
Pre-Registration- Inclusion Criteria 
3.11 
Ability to understand and the willingness to sign a written informed consent 
document. 
3.12 
Age ≥18 years and post-menopausal. 
3.13 
Histologically confirmed recurrent ovarian, fallopian tube or primary peritoneal 
carcinoma or endometrial cancer in post-menopausal women. 
NOTE: Pure clear cell and pure mucinous carcinomas are ineligible. Platinum 
sensitive, platinum resistant and platinum refractory disease are eligible. No 
limitations in the number of prior regimens. 
3.14 
Patient has disease amenable to biopsy and is agreeable to undergo a biopsy. 
NOTE: Under unusual circumstances, submission of ascites material may be 
acceptable if a biopsy is not possible. This exception will require approval by one 
of the study Principal Investigators. 
3.15 
Willing to provide tissue samples for ER and RB staining (see Sections 6.2 and 
17.1). 
3.2 
Registration – Inclusion Criteria 
3.21 
Measurable disease by RECIST criteria as defined in Section 11.0.  
3.22 
Tumors must stain positive for estrogen receptor positive (≥10%) by IHC. 
3.23 
ECOG Performance Status (PS) 0, 1, or 2 (Appendix I) 
3.24 
The following laboratory values obtained ≤21 days prior to registration.  
• 
Absolute neutrophil count (ANC) ≥1000/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤1 x ULN; or total bilirubin ≤3.0 x ULN with direct bilirubin 
≤1.5 x ULN in patients with well-documented Gilbert’s Syndrome. 
• 
Aspartate transaminase (AST) ≤2.5 x ULN (≤5x ULN in patients with liver 
metastasis) 
• 
INR ≤2 
• 
Creatinine ≤1.5 mg/dL  
• 
Potassium, total calcium (corrected for serum albumin), magnesium, sodium 
and phosphorus ≤ULN (or corrected to ≤ULN with supplements prior to 
registration) 
3.25 
Ability to swallow study medication  
3.26 
Provide informed written consent. 
3.27 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study).  
3.28 
Willing to provide tissue samples for correlative research purposes (see Sections 
6.0 and 17.0).  
 
 


 
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3.3 
Registration – Exclusion Criteria  
3.31 
Patients who have central nervous system (CNS) involvement unless they meet 
ALL of the following criteria: 
• 
≥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. 
3.32 
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.). 
3.33 
Clinically significant, uncontrolled heart disease or cardiac repolarization 
abnormalities and/or recent events 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) at screening 
• 
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), long QT syndrome or 
family history of long QT syndrome  
• 
Idiopathic sudden death or congenital long QT syndrome  
•  Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia 
or hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia. 
•  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 
•  Inability to determine the QT interval on screening (QTcF, using Fridericia’s 
correction) 
NOTE: QTcF, using Fridericia’s correction, is QT/RR^0.33 where 
RR=60/Heart Rate. 
• 
Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening 
• 
Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening 
• 
Tachycardia (heart rate >110 at rest), by ECG or pulse at screening 
3.34 
Inability to determine the QTcF interval on the ECG (i.e.: unreadable or not 
interpretable) or QTcF >450 msec (using Fridericia’s correction). 
NOTE: All as determined by screening ECG.  
3.35 
Patient is currently receiving any of the following medications and cannot be 
discontinued ≤7 days prior to starting study drug (see Appendix III, as well as 
Section 7.6 and Table 5-7 of Ribociclib Investigator’s Brochure for details): 


 
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known strong inducers or inhibitors of CYP3A4/5 including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville oranges or that have a narrow 
therapeutic window and are predominantly metabolized through CYP3A4/5 or 
herbal preparations/medications or dietary supplements 
3.36 
Patient is currently receiving or has received systemic corticosteroids within 
≤2 weeks prior to starting study drug, or who have not fully recovered from side 
effects of such treatment.  
NOTE: The following uses of corticosteroids are permitted: single doses, topical 
applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways 
diseases), eye drops or local injections (e.g., intra-articular) 
3.37 
Patient has received radiotherapy ≤4 weeks or limited field radiation for 
palliation ≤2weeks 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 ≥30% of the bone marrow was irradiated. 
3.38 
Patient has had major surgery ≤14 days prior to registration or has not recovered 
from major side effects (tumor biopsy is not considered as major surgery). 
3.39a 
Known to be HIV positive (testing not mandatory).  
3.39b Patient has a known hypersensitivity to any of the excipients of ribociclib 
including peanut and soy. 
3.39c 
Patient is currently receiving warfarin or other coumarin-derived anticoagulant 
for treatment, prophylaxis or otherwise. NOTE: Therapy with dabigatran, 
heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. 
3.39d Participation in a prior investigational study within 30 days prior to enrollment or 
≤5 half-lives of the investigational product, whichever is longer 
3.39e 
Patient has not recovered from all toxicities related to prior anticancer therapies 
to NCI-CTCAE version 4.0 Grade <3  
(Exception to this criterion: patients with any grade of alopecia or neuropathy are 
allowed to enter the study). 
3.39f 
Patient with a Child-Pugh score B or C. 
3.39g 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 significant 
small bowel resection).  
3.39h  Prior therapy for ovarian or uterine cancer with ribociclib or an aromatase 
inhibitor (letrozole, anastrozole or exemestane). 
3.39i 
Patient has received systemic chemotherapy ≤3 weeks prior to registration. 
 


 
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4.0 
Test Schedule 
Tests and procedures 
 
Active Monitoring Phase 
Pre-
Registration 
≤21 days 
prior to 
registration 
During Cycle 1-
2 
(every 14 days) 
±3 days 
Prior to Cycle 3 and 
beyond 
(every 28 days ±3 
days)8 
(Prior to Cycle 4 for 
tumor measurements 
and CA-125) 
End of 
Treatment 
History and exam,Wt, PS 
 
X 
X 
X 
X 
Adverse event assessment* 
 
X 
X 
X 
X 
Patient Medication Diary 
(Appendix II)2 collected at 
the end of each cycle 
 
 
X 
X 
X 
Hematology group 
(HgB, WBC, PLT, ANC) 
 
X 
X5 
X5 
X 
Chemistry group 
(creatinine, Na, K, P, Total 
bili, alk phos, AST, ALT) 
 
X 
X6 
X6 
X 
Serum Magnesium 
 
X 
X6 
X6 
 
PT/INR 
 
X 
 
 
 
Lipid panel 
 
X 
 
X1 
X 
Urinalysis 
 
X 
 
 
 
Chest x-ray (in addition to 
CT chest) 
 
X 
 
 
 
ECG7,R  
 
X 
X7 
X 
X 
ECHOR 
 
X 
As clinically indicated 
CA-1251 
 
X 
 
X1 
X 
Tumor Measurements: CT 
or MRI of the chest, 
abdomen and pelvis1 
 
X 
 
X1 
X3 
Tumor biopsies 4,R 
 
X 
 
 
 
ER/PR/RB status from 
archived tissue if available  
(If archived not readily 
available, status must be 
collected off fresh tissue 
biopsy) 
X 
 
 
 
 
1. As assessed by examination or imaging studies (CT scans and/or MRI as indicated). Use same imaging 
throughout the study. Tumor measurements by imaging studies and serum CA-125 levels (if abnormal 
at baseline) to be performed every 12 weeks (at baseline, at 12 weeks, at 24 weeks, etc). No need to 
obtain imaging studies or CA-125 levels before Cycle 4 (12 weeks). Lipid panel every 12 weeks. 
2. The diary must begin the day the patient starts taking the medications and must be completed per 
protocol and returned to the treating institution OR compliance must be documented in the medical 
record by any member of the care team. 
3. Except in case of discontinuation from treatment due to progression, tumor assessment at EOT is not 
necessary if the previous evaluation was done within 6 weeks of EOT. 
4. Tumor biopsies must be collected after registration and confirmation of ER and RB positive status and 
prior to starting treatment, unless a fresh biopsy is needed for determination of ER and RB positive 
status. Patients should only have one biopsy procedure for this study. If patient receives fresh biopsy 


 
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MC1561 
procedure to determine ERand RB status, then tissue for correlative studies should be obtained at that 
time. 
5. Check weekly per protocol if toxicity until toxicity resolves or as clinically indicated. 
6. Obtain also potassium, calcium, phosphorus and magnesium levels in the event of prolongation of QT 
interval of any level and in the event of toxicities that can be associated with electrolyte imbalance 
(diarrhea, nausea, other cardiac toxicities). Levels will need to be checked regularly until they 
normalize. See Section 8.0. 
7. A standard 12-Lead ECG is recommended at baseline, Cycle 1 Day 1 if ≥7 days from baseline and at 
Cycle 1 Day 15 and Cycle 2 Day 1and 15. Cycle 3-6 the ECG will be obtained on Day 1. For patients 
with QTcF ≥481 ms at any time, follow the procedures described in the “Ribociclib Dose Modification 
section”, Section 8.0. After 2 years of treatment, ECGs will be done every 3 cycles. 
8. After 2 years of treatment, Clinical evaluations/test and blood tests can be obtained locally by an 
oncologist and mailed/faxed to Mayo Clinic. Patients must return to every 3 cycles for follow-up at 
Mayo Clinic. 
 
*After 2 years of treatment, adverse events will also be assessed every 3 cycles during the patients 
follow-up at Mayo Clinic. 
R Biopsies and Creation of Avatar will be Research funded.  
5.0 
Grouping Factors 
Tumor Type (Cohort): 
Cohort A: Ovarian, primary peritoneal, fallopian tube ACA vs. Cohort B: Endometrial 
cancer 
NOTE: Collected at Registration (Step 2) Only 
6.0 
Registration Procedures 
6.1 
Pre-Registation (Step 1) 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration application. The registration application is available 24 
hours a day, 7 days a week. Back up and/or system support contact information is 
available on the Web site. If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
The instructions for the registration application are available on the MCCC web 
page (http://hsrwww.mayo.edu/ccs/training) and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions. It is the responsibility of 
the individual registering the patient to confirm that the process has been 
successfully completed prior to release of the study agent. Patient registration via 
the registration application can be confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office (507) 284-2753. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Prior to accepting the pre-registration, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient pre-registration eligibility  


 
14 
MC1561 
• 
Existence of a signed consent form   
• 
Existence of a signed authorization for use and disclosure of protected health 
information. 
6.13 
Pre-registration tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.2 
Registration (Step 2) 
6.21 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application.  The registration/ 
randomization application is available 24 hours a day, 7 days a week. Back up 
and/or system support contact information is available on the website. If unable 
to access the website, call the MCCC Registration Office at (507) 284-2753 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page 
 and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and an MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office 
. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.22 
Correlative Research 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19c and 17.1). 
6.23 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
6.24 
Prior to accepting the registration, registration application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
6.25 
Treatment cannot begin prior to registration and must begin ≤7 days after 
registration. 




 
16 
MC1561 
Ribociclib will be administered as a flat-fixed dose (e.g. 400 mg daily), and not 
by body weight or body surface area. Letrozole will also be administered as a 
fixed dose. 
 
 
 


 
17 
MC1561 
8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. NOTE: There are no specific dose modifications for 
letrozole unless indicated in the tables below.  
 
ALERT: ADR reporting may be required for some adverse events (See Section 10). 
Table 8.1  
Dose Levels  
(Based on Adverse Events in Tables 8.2-8.3) 
Dose 
Level 
RIBOCICLIB 
LETROZOLE 
0* 
400 MG PO DAILY 
2.5 MG PO DAILY 
-1 
400 MG PO DAILY (Days 1-21 Q 28 days) 
2.5 MG PO QOD 
-2 
200 MG PO DAILY (Days 1-21 Q 28 days) 
N/A 
*Dose level 0 refers to the starting dose. N/A=not applicable 
 
Table 8.2 
Dose Modifications  
NOTE: Cycles will be 28 (±3) days in length. Day 1 of each cycle will begin 
with the administration of letrozole regardless of the ribociclib dosing based on 
adverse event. Omitted doses will not be made up. This table will be used for 
both Day 1 (retreatment AEs) and Days 2-28 (interval AEs) for Ribociclib. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
GRADE 
ADVERSE EVENT 
AGENT 
ACTION** 
INVESTIGATIONS 
Grade 2  
Platelet count decreased  
<75,000 - 50,000/mm3; 
<75.0 - 
50.0 x 109/L) 
RIBOCICLIB 
Omit until recovery to 
Grade ≤1 
Re-initiate ribociclib at the 
same dose 


 
18 
MC1561 
CTCAE 
System/Organ/Class 
(SOC) 
GRADE 
ADVERSE EVENT 
AGENT 
ACTION** 
INVESTIGATIONS 
Grade 3  
Platelet count decreased 
(<50,000 - 25,000/mm3; 
<50.0 - 
25.0 x 10e9 /L) 
RIBOCICLIB 
Omit until recovery to 
Grade ≤1 
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 
Platelet count decreased 
(<25,000/mm3; <25.0 x 
10e9 /L) 
RIBOCICLIB 
Omit until recovery to 
Grade ≤1 
Re-initiate ribociclib at the 
next lower dose level 
•If toxicity recurs at Grade 
4: discontinue ribociclib 
 
Grade 3 
Neutrophil count 
decreased 
(≥0.5 - <1.0 x 109/L) 
RIBOCICLIB 
Omit 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, 
reduce ribociclib dose to 
the next lower dose level. 
If resolved in ≤7 days, 
resume ribociclib at same 
dose level 
 
Grade 4 
Neutrophil count 
decrease 
(<0.5 x 109/L) 
RIBOCICLIB 
Omit 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 


 
19 
MC1561 
CTCAE 
System/Organ/Class 
(SOC) 
GRADE 
ADVERSE EVENT 
AGENT 
ACTION** 
BLOOD AND 
LYMPHATIC 
SYSTEM 
DISORDERS 
Grade 3 
Febrile neutropenia 
ANC <1.0 x 109/L with 
[a single temperature of 
>38.3°C (101°F) or a 
sustained temperature of 
≥38°C (100.4°F) for 
more than one hour] 
RIBOCICLIB 
Omit 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 
Febrile neutropenia 
Life-threatening 
consequences; urgent 
intervention indicated 
RIBOCICLIB Discontinue 
BLOOD AND 
LYMPHATIC 
SYSTEM 
DISORDERS 
Grade 3 
Anemia 
Hgb <8.0 g/dL; 
<4.9 mmol/L; 
<80 g/L; transfusion 
indicated 
RIBOCICLIB 
Omit until recovery to 
Grade ≤2 
Re-initiate ribociclib at the 
same dose 
Grade 4 
Anemia 
Life-threatening 
consequences; urgent 
intervention indicated 
RIBOCICLIB Discontinue 
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at 
the start of the next cycle, then the dose will remain lowered for that entire subsequent 
cycle. If that cycle is completed with no further adverse events >Grade 2, then the dose may 
be increased, at the investigator’s discretion, one level at a time, in the following cycles. 
This applies to both ribociclib and letrozole.  
 
NOTE: At the investigator discretion ribociclib or letrozole may be continued if one agent 
is discontinued due to adverse events. 
 


 
20 
MC1561 
8.3 
Recommendations for ribociclib and letrozole dose modifications in case of 
hepatic toxicities 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0* unless otherwise specified   
8.31 
Blood Bilirubin Increased 
CTCAE 
System/Organ/Class 
(SOC) 
Grade 
ADVERSE 
EVENT 
AGENT 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
INVESTIGATIONS 
Grade 1 (>ULN – 
1.5 x ULN) 
(confirmed 48 to 
72hrs later) 
BLOOD 
BILIRUBIN 
INCREASED 
RIBOCICLIB 
and 
LETROZOLE 
Maintain dose level with 
LFTs monitored bi-weekly 
Grade 2 (>1.5 – 3.0 x 
ULN) 
Omit ribociclib and 
letrozole 
If resolved to ≤Grade 1 in 
≤28 days, then maintain 
dose level 
If resolved to ≤Grade 1 
in >28 days or toxicity 
recurs, then reduce 1 
dose level 
If toxicity recurs after two 
dose reductions,discontinue 
ribociclib and letrozole and 
go to event monitoring 
Grade 3 (>3.0 – 10.0 
x ULN) 
Omit ribociclib and 
letrozole 
If resolved to ≤Grade 1 
in ≤28 days, lower 1 dose 
level of ribociclib 
If resolved to ≤Grade 1 in 
>28 days or toxicity recurs, 
discontinue ribociclib and 
letrozole 
Grade 4 (>10.0 x 
ULN) 
Discontinue ribociclib and 
letrozole 
AT TIME OF RETREATMENT 
INVESTIGATIONS 
Grade 1 (>ULN – 
1.5 x ULN) 
(confirmed 48 to 
72hrs later) 
BLOOD 
BILIRUBIN 
INCREASED 
RIBOCICLIB 
and 
LETROZOLE 
Maintain dose level with 
LFTs monitored bi-weekly 


 
21 
MC1561 
CTCAE 
System/Organ/Class 
(SOC) 
Grade 
ADVERSE 
EVENT 
AGENT 
ACTION** 
INVESTIGATIONS Grade 2 (>1.5 – 3.0 x 
ULN) 
BLOOD 
BILIRUBIN 
INCREASED 
RIBOCICLIB 
and 
LETROZOLE 
Hold ribocicliband 
letrozole 
If resolved to ≤Grade 1 in 
≤28 days, then maintain 
dose level 
If resolved to ≤Grade 1 
in >28 days or toxicity 
recurs, then reduce 1 
dose level 
If toxicity recurs after two 
dose reductions,discontinue 
Ribociclib and letrozole and 
go to event monitoring 
 
Grade 3 (> 3.0 – 10.0 
x ULN) 
 
 
Hold ribocicliband letrozole 
If resolved to ≤ grade 1 in 
≤ 28 days, lower 1 dose 
level of ribociclib 
If resolved to ≤ grade 1 in > 
28 days or toxicity recurs, 
discontinue ribociclib and 
letrozole 
 
Grade 4 (> 10.0 x 
ULN) 
 
 
Discontinue ribociclib and 
letrozole 
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. 
 
8.32 
Alanine Aminotransferase or Aspartate Aminotransferase Increased 
CTCAE 
System/Organ/Class 
(SOC) 
Grade 
ADVERSE EVENT 
AGENT 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
INVESTIGATIONS 
Same grade as baseline 
or increase from 
baseline Grade 0 to 
Grade 1 
(confirmed 48 to72 hrs 
later) 
ALANINE 
AMINOTRANSFER
ASE INCREASED  
 
AND  
 
RIBOCICLIB 
and 
LETROZOLE 
Maintain dose level with 
LFTs monitored bi-weekly 


 
22 
MC1561 
CTCAE 
System/Organ/Class 
(SOC) 
Grade 
ADVERSE EVENT 
AGENT 
ACTION** 
INVESTIGATIONS 
Increase from baseline 
to Grade 2 (>3.0 
– 5.0 x ULN) 
ASPARTATE 
AMINOTRANSFER
ASE INCREASED  
Omit ribociclib and 
letrozole 
If resolved to ≤Grade 1 in 
≤28 days, then maintain 
dose 
level 
If resolved to ≤Grade 1 in 
>28 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 and letrozole 
and go to event 
monitoring 
 
Increase from baseline 
to Grade 3 (>5.0 
– 20.0 x ULN) 
Omit ribociclib and 
letrozole 
If resolved to ≤Grade 1 in 
≤28 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 
>28 days or toxicity 
recurs, discontinue 
ribociclib and letrozole 
 
Grade 4 (>20.0 x ULN) 
Discontinue ribociclib and 
letrozole 
AT TIME OF RETREATMENT 
INVESTIGATIONS 
Same grade as baseline 
or increase from 
baseline Grade 0 to 
Grade 1 
(confirmed 48 to72 hrs 
later) 
ALANINE 
AMINOTRANSFE
RASE 
INCREASED  
 
AND  
RIBOCICLIB 
and 
LETROZOLE 
Maintain dose level with 
LFTs monitored bi-weekly 


 
23 
MC1561 
CTCAE 
System/Organ/Class 
(SOC) 
Grade 
ADVERSE EVENT 
AGENT 
ACTION** 
Increase from baseline 
grade 0 or 1 to Grade 2 
(>3.0 – 5.0 x ULN) 
or 
from baseline Grade 2 
to Grade 3 (>5.0 – 20.0 
x ULN) 
 
ASPARTATE 
AMINOTRANSFE
RASE 
INCREASED  
Hold ribociclib and 
letrozole 
If resolved to ≤Grade 1 in 
≤28 days, then maintain 
dose 
level 
If resolved to ≤Grade 1 in 
>28 days or toxicity recurs, 
then reduce 1 dose level 
If toxicity recurs after two 
dose 
reductions,discontinue 
Ribociclib and letrozole 
and go to event monitoring 
Increase from baseline 
Grade 0 or 1 to Grade 3 
(>5.0 – 20.0 x ULN) 
Hold ribociclib and 
letrozole 
If resolved to ≤Grade 1 in 
≤28 days, lower 1 dose 
level of ribociclib 
If resolved to ≤Grade 1 in 
>28 days or toxicity recurs, 
discontinue ribociclib and 
letrozole 
Grade 4 (>20.0 x ULN) 
Discontinue ribociclib and 
letrozole 
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 (>3 x ULN) 
in patients with normal values at baseline and total bilirubin 
>2 x ULN without evidence of cholestasis 
or 
AST or ALT ≥Grade 3 (>5 x ULN) in patients with Grade 1 
or 2 at baseline, and total bilirubin >2 x ULN  
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 and letrozole 
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. 
8.4 
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. 


 
24 
MC1561 
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 
• 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, (fractionated if total bilirubin >2 x ULN), 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 re-testing 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 pre-existing 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. 


 
25 
MC1561 
• Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction. 
• 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 8.2.17.02), and reported 
as SAE using the term “potential drug-induced liver injury”. All events should be 
followed up with the outcome clearly documented. 
8.5 
Dose modification guidance for ribociclib in case of QTcF prolongation 
Grade 
Dose Modification 
For all 
grades 
1. Check quality of the ECG and the QTcF value and 
repeat if needed 
2. Perform an analysis of serum electrolytes (K+, Ca++, 
Phos, Mg++). If below the lower limit of normal, 
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 inhibitCYP3A4 and/or to prolong the QTcF-interval. 
4. Check compliance with correct dose and administration 
of ribociclib 
1 
QTcF 450-480 ms 
Perform steps 1-4 as directed in “For All Grades.” No dose 
adjustment required. 
2 
QTcF 481-500 ms 
Omit ribociclib. Perform steps 1-4 as directed in the “For All 
Grades” section above. 
Perform a repeat ECG one hour after the first QTcF of ≥481ms. 
Repeat ECG as clinically indicated until the QTcF returns to < 
481 ms. Restart ribociclib with dose reduced by 1 dose level.  
 
• If QTcF ≥481 ms recurs, ribociclib should be reduced 
again by 1 dose level (please refer to the dosing 
schedule table)  
• Repeat ECGs 7 days and 14 days after dose 
resumption (then as clinically indicated) for any 
patient who has therapy interrupted due to QTcF 
≥481 ms 


 
26 
MC1561 
3 
QTcF ≥501 ms on at 
least two separate ECGs 
Omit ribociclib. Perform steps 1-4 as directed in the “For All 
Grades” section above. 
• 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 
clinically indicated until the QTcF returns to <481 ms. 
• If QTcF returns to <481 ms, ribociclib should be reduced by 
1 dose level. (Please refer to the dosing schedule table) 
• If QTcF remains  ≥ 481 ms after performing steps 1-4 as 
directed in the “For All Grades” section above, discontinue 
ribociclib. 
 
Repeat ECGs 7 days and 14 days after dose resumption for 
any patient who has therapy interrupted due to QTcF 
≥501 ms 
• If QTcF of ≥501 ms recurs, discontinue ribociclib 
4 
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 the “For 
All Grades” section above. 
• Obtain local cardiologist or qualified specialist consultation 
and repeat cardiac monitoring as indicated until the QtcF 
returns to <481 ms 
Additional follow-up for QTcF prolongation 
In case of QTcF prolongation regardless of the grade: 
• 
Perform an analysis of serum potassium, calcium, phosphorus, and magnesium, and if 
below lower limit of normal, correct with supplements to within normal limits. 
• 
Review concomitant medication usage for the potential to inhibit CYP3A4 and/or to 
prolong the QT-interval. 
• 
Check compliance with correct dose and administration of ribociclib. 
8.6 
Ribociclib and letrozole dose adjustment and management recommendation 
for all other adverse reactions 
Grade Dose Adjustment and Management Recommendations 
1 
No dose adjustment required. Initiate appropriate medical therapy and monitor. 
2 
Dose interruption until recovery to Grade ≤1. Initiate appropriate medical therapy 
and monitor. 


 
27 
MC1561 
Re-initiate ribociclib and letrozole at the same dose. 
If the same toxicity recurs at Grade 2, interrupt ribociclib and letrozole until 
recovery to Grade ≤1. Re-initiate ribociclib at the next lower dose level. 
3 
Dose interruption until recovery to Grade ≤1. Initiate appropriate medical therapy 
and monitor. 
Re-initiate ribociclib and letrozole at the next lower dose level 
If toxicity recurs at Grade 2: temporary dose interruption until recovery to Grade 
≤1 and reduce ribociclib and letrozole dose to the next lower dose level 
If toxicity recurs at Grade 3, discontinue ribociclib and letrozole 
4 
Discontinue ribociclib and letrozole and treat with appropriate medical therapy. 
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. 
8.7 
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. 
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. 
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 non-drug therapies section of the patient record. 
Bisphosphonates and denosumab 
Bisphosphonates and denosumab are allowed as indicated.  
Hematopoietic growth factors 
Hematopoietic growth factors may be used according to ASCO guidelines. 


 
28 
MC1561 
Palliative radiotherapy 
Palliative radiation is permitted if done solely for bone pain relief. It should not be 
delivered to a target lesion and it should not encompass more than 25% of 
irradiated bone marrow. No dose modification of study treatment is needed during 
palliative radiotherapy. 
Permitted concomitant therapy requiring caution 
Refer to the ribociclib (LEE011) Investigator’s Brochure, Section 7.6 and Table 
5-7, as well as Appendix III of protocol for information on possible interactions 
with other drugs. 
Medications to be used with caution during ribociclib and letrozole in this study 
are listed below (see Appendix III). 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 (see Appendix III): 
• 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 or conditional risk for QT prolongation 
Prohibited concomitant therapy 
The following medications are prohibited during study treatment in the study (see Section 
7.6 and Table 5-7 of ribociclib IB and Appendix III). 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 
• 
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. 
• 
Other investigational and antineoplastic therapies not part of the study 
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. 
 


 
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30 
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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (ASCO) 
Update of Recommendation for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. J Clin Oncol 2006; 24:3187-3205, 2006. 
9.3 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.4 
Diarrhea: This could be managed conservatively with loperamide (for grade 1-2 
diarrhea). The recommended dose of loperamide is 4 mg at first onset, followed by 2 mg 
every 2-4 hours until diarrhea free (maximum 16 mg/day). 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
9.5 
Concomitant medications: Patients must be instructed not to take any medications (over-
the-counter or other products) during the protocol treatment period without prior 
consultation with the investigator. The investigator should instruct the patient to notify 
the study site about any new medications he/she takes after the start of study drug. All 
medications (other than study drug) and significant non-drug therapies (including 
physical therapy and blood transfusions) taken within 28 days of starting study 
treatment through the 30-day safety follow up visit should be reported on the 
CRF. 
9.51 
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 lists in Appendix III 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 Database (v05,release 
date: 29 Oct 2015)2), 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


 
31 
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/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 
(https://crediblemeds.org/www.qtdrugs.org).). Please contact the medical monitor 
with any questions. 
 


 
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10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)  
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3). With this information, determine whether the event must be 
reported as an expedited report (see Section 10.). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT). Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
10.2  Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific consent 
form. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.0 of the protocol and the study specific consent form. 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  


 
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10.31  AEs Experienced Utilizing Investigational Agents and Commercial 
Agent(s) on the SAME Arm 
NOTE: When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
Routine Reporting 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol. See Section 10.6. 
• Routine AE reporting for Phase 3 clinical studies using an investigational 
agent/intervention and a commercial agent in combination must be 
reported as defined by the general guidelines provided by sponsors, 
Groups, Cancer Centers, or Principal Investigators. See Section 10.6. 
 
Expedited Reporting 
• An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
• An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible 
attribution to the commercial agent require an expedited report. Refer to 
Section 10.4 for specific AE reporting requirements or exceptions. 
• Commercial agent expedited reports must be submitted to the FDA via 
MedWatch. 
• An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent. Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited reporting 
is required. The clinical investigator must determine severity. 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  






 
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MC1561 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE 
term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of 
the onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benigh, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.52 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.53 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting. 
 
 


 
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10.6 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
System Organ Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Gastrointestinal 
Disorders 
Diarrhea 
X 
X 
Mucositis oral 
X 
X 
Investigations 
Alanine aminotransferase 
increased 
X 
X 
Aspartate aminotransferase 
increased 
X 
X 
Blood bilirubin increased 
X 
X 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
Investigations 
Electrocardiogram QT 
corrected interval 
prolonged 
X 
X 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or 
electronic, as applicable) the following AEs experienced by a patient and 
not specified in Section 10.6: 
10.611 Grade 1 and 2 AEs deemed possibly, probably, or definitely 
related to the study treatment or procedure. 
10.612 Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
10.613 Grade 5 AEs (Deaths) 
10.6131  Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
10.6132 
Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.62 Refer to the instructions in the Forms Packet (or electronic data entry 
screens, as applicable) regarding the submission of late occurring AEs 
following completion of the Active Monitoring Phase (i.e., compliance 
with Test Schedule in Section 4.0). 
 
 
 


 
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11.0 
Treatment Evaluation Using RECIST Guideline 
Eligible patients for this trial have to have measurable diseasebasedon RECIST v1.1 
criteria 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the 
footnote for the table regarding measureable disease in Section 11.44, as it pertains to 
data collection and analysis. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1) . Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the short axis measurements in the case of lymph nodes are used 
in the RECIST guideline. 
11.1 
Schedule of Evaluations:  
For the purposes of this study, patients should be reevaluated every 12 weeks.  
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21  Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest 
diameter can be accurately measured as ≥2.0 cm with chest x-
ray, or as ≥1.0 cm with CT scan, CT component of a PET/CT, or 
MRI.  
11.212 A superficial non-nodal lesion is measurable if its longest 
diameter is ≥1.0 cm in diameter as assessed using calipers (e.g. 
skin nodules) or imaging. In the case of skin lesions, 
documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
11.213 A malignant lymph node is considered measurable if its short 
axis is >1.5 cm when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  
NOTE: Tumor lesions in a previously irradiated area are considered 
measurable disease. 
11.22 Non-Measurable Disease 
11.221 All other lesions (or sites of disease) are considered non-
measurable disease, including pathological nodes (those with a 
short axis ≥1.0 to <1.5 cm). Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present 
in the same patient, these are preferred for selection as target lesions. In 


 
39 
MC1561 
addition, lymph nodes that have a short axis <1.0 cm are considered non- 
pathological (i.e., normal) and should not be recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods:  
• All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• The same method of assessment and the same technique must be used 
to characterize each identified and reported lesion at baseline and 
during follow-up. For patients having only lesions measuring at least 1 
cm to less than 2 cm must use CT or MRI imaging for both pre- and 
post-treatment tumor assessments.  
• Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used at the same evaluation 
to assess the antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:  
• 
Conventional CT and MRI: This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness 
is 5 mm or less. If CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice 
thickness.  
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the 
type and site of disease. The lesions should be measured on the same 
pulse sequence. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-
hold scanning techniques, if possible. 
• PET-CT: If the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  
• Physical Examination: For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be 
done. In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
11.33 Measurement at Follow-up Evaluation:  
• 
In the case of stable disease (SD), follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum 
interval of 12 weeks (see Section 11.44). 


 
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MC1561 
• 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a 
side effect of the treatment) and progressive disease. 
• Cytologic and histologic techniques can be used to differentiate 
between PR and CR in rare cases (e.g., residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can 
remain.) 
 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• Measurable lesions (as defined in Section 11.21) up to a maximum of 
5 lesions, representative of all involved organs, should be identified as 
“Target Lesions” and recorded and measured at baseline. These lesions 
can be non-nodal or nodal (as defined in 11.21), where no more than 2 
lesions are from the same organ and no more than 2 malignant nodal 
lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified 
(as there often will be), there is no reason to perform additional studies 
beyond those specified in the protocol to discover new lesions.  
• Target lesions and target lymph nodes should be selected on the basis 
of their size, be representative of all involved sites of disease, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
(or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be 
selected.  
• Baseline Sum of Dimensions (BSD): A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the baseline sum of 
dimensions (BSD). The BSD will be used as reference to further 
characterize any objective tumor response in the measurable 
dimension of the disease.  
• Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the 
target lymph nodes will be calculated and reported as the post-baseline 
sum of dimensions (PBSD). If the radiologist is able to provide an 
actual measure for the target lesion (or target lymph node), that should 
be recorded, even if it is below 0.5 cm. If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small 
to measure, a default value of 0.5 cm should be assigned. If it is the 


 
41 
MC1561 
opinion of the radiologist that the target lesion or target lymph node 
has likely disappeared, the measurement should be recorded as 0 cm. 
• The minimum sum of the dimensions (MSD) is the minimum of the 
BSD and the PBSD. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- 
target lesions or non-target lymph nodes and should also be recorded at 
baseline. These lesions and lymph nodes should be followed in accord with 
11.433. 
 
11.43 Response Criteria 
11.431 All target lesions and target lymph nodes followed by 
CT/MRI/PET-CT/Chest X-ray/physical examination must be 
measured on re-evaluation at evaluation times specified in Section 
11.1. Specifically, a change in objective status to either a PR or CR 
cannot be done without re-measuring target lesions and target 
lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first 
response or confirmation of response. In selected circumstances, 
certain non-target organs may be evaluated less frequently. For 
example, bone scans may need to be repeated only when complete 
response is identified in target disease or when progression in bone 
is suspected. 
 
11.432 Evaluation of Target Lesions 
• Complete Response (CR):All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
c. Normalization of tumor 
biomarkers. 
• Partial Response (PR): 
At least a 30% decrease in PBSD 
(sum of the longest diameter for all 
target lesions plus the sum of the 
short axis of all the target lymph 
nodes at current evaluation) taking as 
reference the BSD (see Section 
11.41). 
• Progression (PD): 
At least one of the following must be 
true: 
a. At least one new malignant lesion, 
which also includes any lymph 


 
42 
MC1561 
node that was normal at baseline 
(<1.0 cm short axis) and increased 
to ≥1.0 cm short axis during 
follow-up.  
b. At least a 20% increase in PBSD 
(sum of the longest diameter for 
all target lesions plus the sum of 
the short axis of all the target 
lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41). In addition, 
the PBSD must also demonstrate 
an absolute increase of at least 0.5 
cm from the MSD.  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify 
for PR, nor sufficient increase to 
qualify for PD taking as reference the 
MSD. 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
• Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target 
lesions.  
b. Each non-target lymph node must 
have a reduction in short axis to 
<1.0 cm. 
c. Normalization of tumor 
biomarkers 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes 
and/or maintenance of tumor marker 
level above the normal limits. 
• Progression (PD): 
At least one of the following must be 
true: 
a. 
At least one new malignant 
lesion, which also includes any 
lymph node that was normal at 
baseline (<1.0 cm short axis) and 
increased to ≥1.0 cm short axis 
during follow-up.  
b. Unequivocal progression of 
existing non-target lesions and 
non-target lymph nodes. (NOTE: 
Unequivocal progression should 
not normally trump target lesion 




 
44 
MC1561 
symptomatic deterioration. A patient is classified as having PD due to 
“symptomatic deterioration” if any of the following occur that are not 
either related to study treatment or other medical conditions: 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors  
Platinum Type: Refractory (PD while on initial platinum based therapy) vs. Resistant (PD 
within 6 months of completion of platinum based therapy) vs. Sensitive (PD beyond 6 
months of platinum based therapy) 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Patients who develop PD while receiving therapy will go off treatment and be 
followed for survival in the event monitoring phase (see Section 18.0). 
13.2 
Patients who go off protocol treatment for reasons other than PD will go off 
treatment and be followed per Section 18.0 in the event monitoring phase. 
13.3 
Patients who are in CR, PR or SD will continue on therapy until progression, 
toxicity or until the treating physician and the patient decide to stop treatment. 
After they go off treatment, they will be followed in event monitoring per section 
18.0. 
13.4 
Patients who develop non-CNS PD at any time should go off treatment and be 
followed in event monitoring (see section 18.0). These patients should be treated 
with alternative chemotherapy if their clinical status is good enough to allow 
further therapy.  
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time 
of registration, the patient did not satisfy each and every eligibility criteria for 
study entry. The patient may continue treatment off-protocol at the discretion of 
the physician as long as there are no safety concerns, and the patient was properly 
registered. The patient will go directly to the event-monitoring phase of the study 
(or off study, if applicable).  
• If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 
18.0 of the protocol.  
• If the patient never received treatment, on-study material must be submitted. 
Event monitoring will be required per Section 18.0 of the protocol.  
13.6 
A patient is deemed a major violation, if protocol requirements regarding 
treatment in cycle 1 of the initial therapy are severely violated that evaluability for 
primary end point is questionable. All data up until the point of confirmation of a 
major violation must be submitted. The patient will go directly to the event-
monitoring phase of the study. The patient may continue treatment off-protocol at 
the discretion of the physician as long as there are no safety concerns, and the 


 
45 
MC1561 
patient was properly registered. Event monitoring will be required per Section 
18.0 of the protocol. 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason 
before any study treatment is given. On-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data 
submission is necessary. 
 
14.0 
Body Fluid Biospecimens - None 
15.0 
Drug Information 
15.1 
Investigational Study Treatment (Ribociclib) 
15.11 Background: Ribociclib is an orally bioavailable, highly selective small 
molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that 
induces G1 arrest at sub-micromolar concentrations in a variety of 
retinoblastoma protein (pRb)-positive cancer cells in vitro. 
15.12 Formulation: The ribociclib drug product is planned for oral 
administration. The available clinical forms are hard gelatin capsules (10 
mg, 50 mg and 200 mg), film-coated tablets (50 mg and 200 mg) and an 
oral solution (30 mg/mL). The capsules only contain the drug substance; 
there are no excipients. The film-coated tablets consist of drug substance 
and compendial quality microcrystalline cellulose, 
hydroxypropylcellulose, crospovidone, colloidal silicon dioxide and 
magnesium stearate. The film-coating is a mix of compendial quality 
polyvinyl alcohol, titanium dioxide, iron oxides, talc, lecithin and xanthan 
gum. The oral solution consists of ribociclib succinate in water with an 
orange flavoring agent and the compendial excepients citric acid, 
methylparaben, potassium sorbate, and sodium saccharin. 
15.13 Preparation and storage: The shelf life of the drug product is established 
based on ongoing stability studies and may be extended during the clinical 
study. The capsules and film-coated tablets are packaged in HDPE bottles. 
The oral solution is provided as 100 mL in 180 mL brown glass bottles. A 
press-in bottle adapter and oral dosing syringe are also provided in the 
administration kit. Refer to the clinical labels for current shelf-life, in-use 
and storage conditions for the capsules, film-coated tablets and oral 
solution.  
15.14 Administration: Ribociclib should be taken with a large glass of water 
(~250 mL) at the same time each day. Ribociclib can be taken without 
regard to meals. Swallow the capsules or film-coated tablets whole, and do 
not chew, crush, or open them. Avoid consumption of grapefruit, Seville 
oranges or products containing the juice of each. Orange juice is allowed.  
15.15 Pharmacokinetic information: 
Absorption – Rapidly absorbed with median Tmax ranging from 1 to 4 
hours. 


 
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MC1561 
Distribution – Steady state was generally reached by Day 8 and mean half-
life ranged from 15.9 to 32.6 hours. 
Metabolism – Ribociclib underwent extensive hepatic metabolism 
via CYP3A4 in humans based on in vitro and in vivo studies. 
Following oral administration of a single 600 mg dose of 
ribociclib in humans (CLEE011A20102), the primary metabolic 
pathways for ribociclib involved (dealkylation, C and/or N-
oxygenation, oxidation (-2H)) and combinations thereof. Phase 
II conjugates of ribociclib involved N-acetylation, sulfation, 
cysteine conjugation, glycosylation and glucuronidation. 
Ribociclib was the major circulating drug-derived entity in 
plasma. No major unique human metabolites were found in 
plasma. 
Excretion – The half-life for ribociclib is 32 hours. Ribociclib is 
mainly eliminated via hepatic clearance, with renal clearance 
playing a lesser role. 
15.16 Potential Drug Interactions: Based on in vitro data, ribociclib is 
primarily metabolized by CYP3A4. Based on clinical data, ritonavir (a 
strong CYP3A4 inhibitor) and rifampicin (a strong CYP3A4 inducer) 
markedly increased and decreased ribociclib exposure, respectively. 
Therefore, drugs that are strong inhibitors or inducers of CYP3A4 should 
not be co-administered with ribociclib. Patients who receive medications 
that are moderate inhibitors or inducers of CYP3A4/5 should be observed 
for signs of overexposure or potential reduced efficacy of ribociclib, 
respectively. 
Examples of strong CYP3A4 inhibitors include: boceprevir, 
clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, 
ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, 
and voriconazole. 
Examples of strong CYP3A4 inducers include: avasimibe, carbamazepine, 
mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), and 
St. John's wort.  
Based on clinical data, ribociclib is a moderate inhibitor of CYP3A4 
activity. Therefore, drugs with narrow therapeutic windows that are 
CYP3A4/5 substrates should not be coadministered with ribociclib. 
Patients taking drugs that are sensitive substrates of CYP3A4/5 that do not 
have a narrow therapeutic index should be observed for signs of 
overexposure of the concurrent medication. 
Examples of CYP3A4/5 substrates with narrow therapeutic windows 
include: alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, and terfenadine. 


 
47 
MC1561 
Co-administration of ribociclib with other drugs that inhibit BSEP may 
result in intrahepatic cholestasis and hepatic toxicity. Therefore known 
BSEP inhibitors should be used with caution during treatment with 
ribociclib. Additionally, caution is recommended with co-administration 
of sensitive substrates of the renal transporters, MATE1 and OCT2, and 
with sensitive substrates of BCRP. Examples of BSEP inhibitors: 
bosentan, fusidate, glibenclamide, lovastatin, sulindac, troglitazone (TGZ-
sulfate). Examples of MATE1 and OCT2 substrates: acyclovir, 
amantadine, amiloride, cephalexin, cephradine, cimetidine, famotidine, 
fexofenadine, memantine, metformin (also a substrate for OCT1, MATE1, 
and MATE2K), pindolol, procainamide, ranitidine, and varencicline. 
Examples of BCRP substrates: rosuvastatin and sulfasalazine. 
Prolongation of the QT interval has been observed with ribociclib. Caution 
should be exercised with all medications that are known to produce this 
effect. Those known to have a strong signal will be prohibited and others 
are to be used with caution. Particular attention should be paid to drugs 
with a possible risk of QT prolongation that are also CYP3A4 substrates. 
Concurrent administration of these medications with ribociclib may lead 
to additive QT effects due to CYP3A4 inhibition ribociclib.  
 
15.17 Known potential toxicities:  
Common known potential toxicities, ≥10%: 
Central Nervous System: Headache, isomnia 
Dermatologic: Rash, maculopapular rash, alopecia, pruritus 
Gastrointestinal: Nausea, vomiting, diarrhea, stomatitis, constipation, 
abdominal pain, decreased appetite 
General Disorders: Asthenia, fatigue, peripheral edema, pyrexia 
Hematologic: Anemia, leukopenia, lymphopenia, neutropenia 
Hepatic: AST/ALT increased, blood bilirubin increased 
Infections: Urinary tract infection 
Musculoskeletal: Back Pain 
Respiratory: Dyspnea 
Less common known potential toxicities, 1% - <10%: 
Cardiovascular:  Electrocardiogram QT prolongation, syncope 
Dermatologic:  Erythema 
Eye:  Lacrimation increased, dry eye 
Gastrointestinal: Dysgeusia, dyspepsia, weight decreased 
Hematologic:  Thrombocytopenia, febrile neutropenia 
Hepatic: Drug induced liver injury, hepatocellular injury, hepatotoxicity, 
hepatic failure 
Metabolic: Hypocalcemia, hypokalemia, hypophosphatemia 
Renal:  Blood creatinine increased 
Respiratory, Thoracic, Mediastinal:  Epistaxis 


 
48 
MC1561 
15.18 Drug procurement: Novartis will provide ribociclib free of charge to 
study participants for use in this trial. Each participating site will 
order/monitor drug supply. 
Outdated or remaining drug is to be destroyed on-site as per procedures in 
place at each institution. 
 
15.19 Nursing Guidelines 
1. There are numerous drug to drug interactions with this agent. Assess 
patient’s medication list including over the counter agents and refer to 
section 15.16 for a list of classes of drugs to avoid or use with caution 
while patient is receiving ribociclib. 
2. Monitor ECG per protocol. Agent is known to cause QT prolongation. Use 
with caution with other agents know to prolong the QT interval. 
3. Rash is a known side effect. Instruct patient to report any rash or pruritis to 
the study team.  
4. Gastrointestinal side effects are common, including nausea, vomiting, 
diarrhea, and stomatitis/mucositis. Manage symptomatically and monitor 
for effectiveness. 
5. Monitor CBC w/differential. Cytopenias have been commonly seen. 
6. Monitor renal function and encourage hydration.  
7. Rarely patients may experience elevated LFTs. Monitor liver function and 
report any increased LFT’s to the treating physician. 
8. Agent may cause headaches and insomnia. Manage symptomatically and 
monitor for effectiveness. 
9. Pyrexia, asthenia may be seen. Manage symptomatically and as necessary 
with dose reductions/holds per protocol guidelines. 
 
 


 
49 
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15.2  Letrozole for Oral Administration (Femara®) 
15.21 Background: Letrozole is a nonsteroidal, competitive inhibitor of the 
aromatase enzyme system which binds to the heme group of aromatase, a 
cytochrome P450 enzyme which catalyzes conversion of androgens to 
estrogens. This leads to inhibition of the enzyme and a significant 
reduction in plasma estrogen levels. Letrozole does not affect synthesis of 
adrenal or thyroid hormones, aldosterone, or androgens. Patients treated 
with letrozole do not require glucocorticoid or mineralocorticoid 
replacement therapy. 
15.22 Formulation: Letrozole is available for oral administration as 2.5 mg tablets. 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store letrozole at room 
temperature of 77°F (25°C); excursions permitted to 59°F to 86°F (15°C 
to 30°C).  
15.24 Administration: Refer to the treatment section for specific administration 
instructions. Administer orally with or without food.  
15.25 Pharmacokinetic information: 
Distribution: Vd: ~1.9 L/kg 
Protein binding: weak 
Metabolism: Hepatic via CYP3A4 and CYP2A6 into an inactive carbinol 
metabolite 
Half-life elimination: Terminal: ~ 2 days 
Excretion: Urine (90%; 6% as unchanged drug, 75% as glucuronide 
carbinol metabolite, 9% as unidentified metabolites) 
15.26 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CY2A6 (minor) CYP3A4 
(minor). Inhibitor of CYP2A6 (strong), CYP2C19 (weak) 
Increased Effect/Toxicity: CYP2A6 substrates, methadone, vitamin K 
antagonists (eg, warfarin) 
Decreased Effect: digoxin, tegafur, vitamin K antagonists (eg, warfarin) 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
Common known potential toxicities, >10%:  
Cardiovascular: Edema 
Central nervous system: Headache, dizziness, fatigue 
Endocrine & metabolic: Hypercholesterolemia, hot flashes 
Gastrointestinal: Nausea, weight gain, constipation 
Neuromuscular & skeletal: Weakness, arthralgia, arthritis, bone pain, back 
pain, bone mineral density decreased/osteoporosis, bone fracture 
Respiratory: Dyspnea, cough 
Miscellaneous: Diaphoresis, night sweats 
 
 


 
50 
MC1561 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Chest pain, hypertension, chest wall pain, peripheral 
edema, cerebrovascular accident including hemorrhagic stroke, thrombotic 
stroke, thromboembolic event including venous thrombosis, 
thrombophlebitis, MI, angina, transient ischemic attack 
Central nervous system: Insomnia, pain, anxiety, depression, vertigo, 
somnolence 
Dermatologic: Rash, alopecia, pruritis 
Endocrine & metabolic: Breast pain, hypercalcemia 
Gastrointestinal: Diarrhea, vomiting, weight loss, abdominal pain, 
anorexia, dyspepsia 
Genitourinary: Urinary tract infection, vaginal bleeding, vaginal dryness, 
vaginal hemorrhage, vaginal irritation 
Neuromuscular & skeletal: Limb pain, myalgia 
Ocular: Cataract 
Renal: Renal disorder 
Respiratory: Pleural effusion 
Miscellaneous: Infection, influenza, viral infection, secondary malignancy 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anaphylactic reaction, angioedema, arterial thrombosis, cardiac failure, 
carpal tunnel syndrome, endometrial cancer, endometrial hyperplasia, 
endometrial proliferation, erythema multiforme, hepatitis, leukopenia, 
memory impairment, stomatitis, tachycardia, thrombocytopenia, toxic 
epidermal necrolysis, trigger finger 
15.28 Drug procurement: Novartis will provide letrozole free of charge to study 
participants for use in this trial. Each participating site will order/monitor drug 
supply. 
15.29  Nursing guidelines 
15.291 Manage hot flashes with non-hormonal interventions (ie: 
venlafaxine XR 75 mg daily). 
15.292 Manage pain (arthralgias). Instruct patient to report unrelieved 
pain. 
15.293 May take with food if needed for nausea. Instruct patient to report 
unrelieved nausea or vomiting. 
15.294 Assess for changes in bowel patterns. Manage diarrhea or 
constipation with non-prescription drugs. Tell patients to report 
unrelieved diarrhea or constipation. 
15.295 If patient experiences difficulty breathing or sudden onset chest 
pain, instruct them to seek emergency medical attention 
immediately. 
15.296 Monitor for signs of edema, instruct patient to report any swelling 
in legs, feet, or hands. 
15.297 Drug procurement: Commercially available. 
 
 


 
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16.0 
Statistical Considerations and Methodolology 
16.1 
Overview 
This study will be a single-arm phase II study to determine the initial clinical 
benefit of letrozole in combination with ribociclib in patients with ovarian cancer 
(Cohort A) or endometrial cancer (Cohort B).. The primary endpoint will be the 
percentage of patients alive and progression-free at the 12 week-timepoint 
(PFS12) assessed in each cohort separately. The null hypothesis will be set at a 20% 
for PFS12, the rate observed by Bowman et al in a phase 2 trial of letrozole in 
ovarian cancer (7). The treatment of letrozole and ribociclib will be deemed 
worthy of further investigation if 45% or more of patients are alive and 
progression-free at 12 weeks. Secondary endpoints will consist of CA-125 
response, progression-free survival (PFS), overall survival (OS), confirmed 
response rate, and adverse events. These endpoints will be assessed in each cohort 
separately. In addition, this study will also assess a couple translational endpoints 
as well.  
16.11 
Primary Endpoint:  
The primary endpoint of this trial is the proportion of patients alive and 
progression-free at 12 weeks (PFS12). All patients meeting the eligibility 
criteria who have signed a consent form and have begun treatment will be 
evaluable for PFS12. Patients who go off treatment early (prior to 12 
weeks) will be considered as failures.  
16.12 Sample Size:  
The one-stage study design is fully described in Section 16.2. 19 evaluable 
patients will be accrued to each of the 2 cohorts of this phase II study 
unless undue toxicity is encountered. We anticipate accruing an additional 
patient per arm to account for ineligibility, cancellation, major treatment 
violation, or other reasons. Therefore, maximum accrual is expected to be 
20 patients per cohort (40 patients total). To account for patients that are 
consented and do not meet full eligibility criteria, we anticipate having to 
consent and screen 80 patients to achieve the maximum accrual of 40 
patients. 
16.13 Accrual Time and Study Duration:  
The anticipated accrual rate is approximately3-4 patients per month. 
Therefore, the accrual period for this phase II study is expected to be 
approximately 12 months. The final analysis can begin approximately 20 
months after the trial begins, i.e. as soon as the last patient has been 
followed for 12 weeks plus time for data entry and clean-up. 
16.2 
Statistical Design 
16.21 Decision Rule: For each cohort separately, the largest PFS12 rate where 
the proposed treatment regimen would be considered ineffective in this 
population is 20% (7), and the smallest PFS12 rate that would warrant 
subsequent studies with the proposed regimen in this patient population is 


 
52 
MC1561 
45%. The following one-stage design uses 19 evaluable patients per arm to 
test the null hypothesis that the true PFS12 rate in this patient population 
is at most 20% (7).  
16.211 Final Analysis Decision Rule (full 19 eligible patients): Enter 19 
evaluable patients in each cohort. If 6 or fewer patients are alive 
and progression-free at 12 weeks, we will consider this regimen 
ineffective in this patient population. If 7 or more patients are 
alive and progression-free, we may recommend further testing of 
this regimen in subsequent studies in this patient population. 
16.212 Over Accrual: If more than the target number of patients are 
accrued, the additional patients will not be used to evaluate the 
stopping rule or used in any decision making process. Analyses 
involving over accrued patients is discussed in Section 16.35. 
16.213 Data and Safety Monitoring:  
The principal investigator(s) and the study statistician will 
review the study at least twice a year to identify accrual, adverse 
event, and any endpoint problems that might be developing. The 
trial is monitored continually by the study team who are notified 
of every grade 4 and 5 event in real time. The Mayo Clinic 
Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) 
is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC 
Statistical Office. Any safety issues requiring protocol changes 
are communicated through protocol amendments. 
Adverse Event Stopping Rule: Based on previous experience 
with this disease, we expect approximately 30% of patients to 
experience Grade 4+ adverse events. If at any time, 4 of the 
initial 10 patients or 40% of all patients (i.e., when accrual is 
greater than 10 patients), have experienced any Grade 4 or 5 
adverse event (at least possibly related to the study treatment), 
accrual to the study will be suspended to allow for a full review 
of the data. Each grade 5 event will be reviewed on a case by 
case basis in a real time fashion to determine whether study 
accrual should be suspended. After consideration by the study 
team [ie, Study Chair(s), Statistician, Operations Office, etc] and 
consultation with representatives at the primary Internal Review 
Board (IRB) affiliated with the Operations Office, a decision will 
be made as to whether and how the study will proceed.  
16.22 Power and Significance Level: Assuming that the number of PFS12 
successes is binomially distributed, the significance level is 7% when the 
true PFS12 rate is 20% and the power is 83% when the true PFS12 rate is 
45%.  


 
53 
MC1561 
16.23 Other Considerations: Toxicity, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries 
or changes in standard care will be taken into account in any decision to 
terminate the study. 
16.3 
Analysis Plan 
16.31 Primary Endpoint: The proportion of PFS12 successes will be estimated 
by the number of successes divided by the total number of evaluable 
patients. Ninety-five percent confidence intervals for the true success 
proportion will be calculated according to the exact binomial method.  
16.32 Definitions and Analyses of Secondary Endpoints (Note: These endpoints 
will be analyzed separately for each cohort).  
16.321 CA-125 response: The key secondary endpoint of the study will 
be a CA-125 response, defined as a 50% or greater reduction in 
baseline CA-125. The null hypothesis will be set at CA-125 
response rate of 8.3%, based on the response of single agent 
letrozole, as reported by Bowman et al (7). The treatment of 
letrozole and ribociclib will be considered promising, based on 
CA-125, if the observed CA-125 response rate is 30% or more. 
This will require at least 6 CA-125 responders in 19 evaluable 
patients.  
16.322 Progression-Free survival (PFS) is defined as the time from 
registration to the first of either disease progression or death 
from any cause. Patients who receive the study drug, but then 
never return for an evaluation will be censored on their last 
follow-up date. PFS will be estimated using the method of 
Kaplan-Meier. 
16.323 Overall survival (OS) is defined as the time from registration to 
death from any cause. OS will be estimated using the method of 
Kaplan-Meier. 
16.324 The confirmed response rate will be estimated using RECIST 1.1 
criteria. A confirmed tumor response is defined to be either a CR 
or PR.. All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be 
evaluable for response. Patients who go off study early before 
having a tumor assessment performed will be considered a 
failure.  
16.33 Adverse Events: All patients that have intitiated treatment will be 
considered evaluable for adverse event (AE) analyses. The maximum 
grade for each type of AE will be recorded for each patient, and frequency 
tables will be reviewed to determine AE patterns. AEs will be analyzed 
separately by cohort. 
16.34 Translational Endpoints for xenograft experiments: Xenograft will be 
created on each patient with plans for the following future translational 


 
54 
MC1561 
experiments.For patient derived xenograft experiments, response to 
therapy is based on tumor volumes measured by ultrasound; this 
measurement exhibits a standard deviation in the range of 10 to 25% of 
the tumor volume. Taking the high end of the standard deviation, for each 
model we anticipate 5 animals per group (control or letrozole + ribociclib) 
will give us approximately 80% power to determine a 50% difference in 
tumor volume (57% difference for 4 animals), with a 2-sided significance 
level of 0.05. Thus, 10 animals/model will be adequate for this comparison. 
To explore whether the responsiveness of tumors to letrozole + ribociclib 
is not due to either agent alone, additional cohorts of 5 animals treated 
with letrozole and 5 animals treated with ribociclib, will also be treated for 
a total of 20 animals/model. However, formal comparisons will only be 
made between control and combination therapy, and thus no penalties for 
multiple comparisons will be assessed. The study endpoint is 28 days 
following treatment initiation. “Response” will be defined as tumors with 
at least a 50% reduction in tumor volume at study end. “Unresponsive” 
will be defined as tumors with less than 10% tumor volume reduction at 
study end. Intermediate values will be defined as “Stable”. Tumor growth 
curves will be plotted graphically and notated to indicate the outcome 
status of the originating patients. End of study tumor volumes will be 
correlated with outcome status of the originating patient as well. In 
addition, this study will identify molecular biomarkers associated with a 
response to treatment with letrozole and ribociclib in patients with 
relapsed ovarian and endometrial carcinomas. Finally, we will determine 
if response rates to letrozole and ribociclib in PDX avatars correlate to 
responses noted in the patients. For these additional analyses, the Fisher’s 
Exact test will be used to measure the associations. All of these 
translational endpoints are considered exploratory and hypothesis 
generating due to the small proposed sample size for this study.  
16.35 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in 
any decision making processes; however, they will be included in final 
point estimates and confidence intervals as though they were accrued for 
the final analysis. 
16.4 
Inclusion of Women and Minorities 
16.41 This study will be available to all eligible women, regardless of race or 
ethnic origin. 
16.42 There is no information currently available regarding differential effects of 
this regimen in subsets defined by race or ethnicity, and there is no reason 
to expect such differences to exist. Therefore, although the planned 
analysis will, as always, look for differences in treatment effect based on 
racial groupings, the sample size is not increased in order to provide 
additional power for subset analyses. 


 
55 
MC1561 
16.43 Based on prior studies involving similar disease sites, we expect about 
20% of patients will be classified as minorities by race and all will be 
women. Expected sizes (per study design) of racial by gender subsets are 
shown in the following table: 
Accrual Estimates by Gender/Ethnicity/Race 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
4 
0 
4 
Not Hispanic or Latino 
36 
0 
36 
Ethnic Category: Total of all subjects 
40 
0 
40 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
4 
0 
4 
Black or African American 
4 
0 
4 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
White 
32 
0 
32 
Racial Category: Total of all subjects 
40 
0 
40 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 


 
56 
MC1561 
17.0 
Pathology Considerations/Tissue Biospecimens  
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Pathology Considerations/ 
Correlative Study  
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, Core, 
etc. (# of each to 
submit) 
Pre-
registration 
Registration 
(prior to start of 
treatment) 
Process at 
site? (Yes 
or No) 
Temperature 
Conditions for 
Storage /Shipping 
Immunohistochemistry for 
pathology review and ER, 
PR status  
if archival tissue is not 
available a new biopsy must 
be obtained 
Archived 
tissue for 
eligibility 
Paraffin 
embedded  
3 unbaked, unstained 
slides at 5 microns  
15 positively charged 
slides at 5 microns 
X 
 
Yes 
N/A. 
RB status must be obtained:  
if archival tissue is not 
available a new biopsy must 
be obtained 
(Section 17.2) 
Mandatory 
Paraffin 
embedded 
5 slides, 1 H&E, plus 
4 unstained slides @ 
5 microns 
X 
 
No 
Ambient using kit 
from Clarient 
Confirmation  
(will not change eligibility if 
different from archived) of 
IHC for ER, PR status for 
patients with archival tissue  
(Section 17.3) 
Mandatory 
Paraffin 
embedded 
1 core biopsy 
 
X 
Yes 
N/A. 
Fresh tumor biopsies for 
creation of Tumor Avatar 
(Section 17.4) 
Mandatory 
Fresh 
Specimen 
5 core specimens 
 
X 
Yes 
On ice cold McCoy 
medium transported 
on ice to 
 
Lab in Rochester 
MN 
NOTE: Each patient will have one (1) biopsy procedure for this study. If tissue is needed for pre-registration for ER/PR/RB confirmation, then all 
other biopsy tissue should be obtained at the same time. 




 
58 
MC1561 
o Samples procured in Rochester will be picked up in the Radiology suite by the 
 lab contact. 
o Upon receipt of samples from both locations, tumor cores will be minced, pooled and 
directly injected intraperitoneally into SCID mice in the 
 Laboratory, per the 
relevant IACUC protocol maintained by the 
 Lab. 
17.4 
Potential additional translational studies: 
 has approximately 300 Avatar models of ovarian cancer cases 
that could be tested for RB, P16 and ER, PR, and Cyclin D expression. Ten tumors that 
stain positive for RB and ER and negative for P16 could be tested for the efficacy of the 
combination of letrozole and ribociclib as well as 10 tumors that do not stain with those 
biomarker features. Genomic analysis for the identification of genetic changes associated 
with response in the Avatar tumors could be pursued. Analysis of the tumors once 
resistance occurs for identification of genomic changes associated with resistance to 
ribociclib (LEE011) could be pursued as well. 
 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
18.11 Pre-Registration Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Pre-Registration Screening Failure 
Complete only if patient is NOT registered after she is 
pre-registered 
Pathology materials  
See Section 17.0 (for central review, eligibility, etc. 
confirmation prior to Registration) 
 
18.12 Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study 
≤14 days after registration 
Adverse Event - Baseline 
RECIST Measurement - Baseline 
Research Tissue Submission - Baseline 
(see Section 17.0) 
End of Active Treatment/Cancel 
Notification 
Submit ≤14 days after registration if 
withdrawal/refusal occurs prior to beginning protocol 
therapy 
 
18.13 Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
At each evaluation 
during treatment 
At end of treatment 
Evaluation/Treatment  
X 
X 
Nadir/Adverse Event  
X 
X 


 
59 
MC1561 
CRF 
Active-Monitoring Phase 
At each evaluation 
during treatment 
At end of treatment 
RECIST Measurement 
X 
X 
End of Active Treatment/Cancel 
Notification  
 
X 
ADR/AER 
At each occurrence (see 
Section 10.0) 
 
 
18.14 Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
q.3 
months 
until PD 
At PD 
After PD 
q. 6 mos. 
Death 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
 
19.0 
Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded: ECGs, baseline ECHO and AVATAR studies and 
research biopsies. 
19.3 
Study drugs provided: Ribociclib and letrozole  
 
 
 


 
60 
MC1561 
20.0 
Key References: 
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immunohistochemical determination may lead to new aspects. Gynecol Oncol 1992;47:317–22. 
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2. Rao BR, Slotman BJ. Endocrine factors in common epithelial ovarian cancer. Endocr Rev 
1991;12:14–26. ExternalResolverBasic Bibliographic Links [Context Link] 
3. Abu-Jawdeh GM, Jacobs TW, Niloff J, Cannistra SA. Estrogen receptor expression is a common 
feature of ovarian borderline tumors. Gynecol Oncol 1996;60:301–7. [Context Link] 
4. Papadimitriou CA, Markaki S, Siapkaras J et al. Hormonal therapy with letrozole for relapsed 
epithelial ovarian cancer. Long-term results of a phase II study. Oncology 2004;66:112–7. 
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5. Bowman A, Gabra H, Langdon SP et al. CA125 response is associated with estrogen receptor 
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Link] 
6. Li YF, Hu W, Fu SQ, Li JD, Liu JH, Kavanagh JJ: Aromatase inhibitors in ovarian cancer: Is there a 
role? International Journal of Gynecological Cancer. 18 (4): 600-614, 2008. 
7. Bowman A, Gabra H, Langdon SP et al. CA125 response is associated with estrogen receptor 
expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive 
subgroup. Clin Cancer Res 2002;8:2233–9. ExternalResolverBasic Bibliographic Links [Context 
Link] 
8. Kavanagh JJ, Hu W, Fu SQ et al. Anti-tumor activity of letrozole in patients with recurrent advanced 
low malignant potential or low grade serous ovarian tumors. J Clin Oncol (2007 ASCO Annual 
Meeting Proceedings, Chicago, IL) 2007;25: No. 185 (Abstract 5582). [Context Link]  
9. Lee EJ, Deavers MT, Hughes JI, Lee JH, Kavanagh JJ. Metastasis to sigmoid colon mucosa and 
submucosa from serous borderline ovarian tumor: response to hormone therapy. Int J Gynecol Cancer 
2006;16(Suppl. 1):295–9. [Context Link] 
10. S. Mabuchi, D. A. Altomare, M. Cheung, et al., “RAD001 inhibits human ovarian cancer cell 
proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer 
model,” Clinical Cancer Research, vol. 13, no. 14, pp. 4261–4270, 2007. 
11. Finn et al: Abstract S1-6, SABCS 2012 
12. 17.Novartis, data on file. 
13. Rose PG, Brunetto VL, Vanle L, et al. A phase II trial of anastrozole in advanced recurrent or 
persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 
2000;78(2):212-216. 
14 Ma BB, Oza A, Eisenhauer E, et al. The activity of letrozole in patients with advanced or recurrent 
endometrial cancer and correlation with biological markers: a study of the National Cancer Institute 
of Canada Clinical Trials Group. Int J Gynecol Cancer. 2004;14(4):650-658. 
15. Bulun SE, Zeitoun K, Sasano H, Simpson ER. Aromatase in aging women. Semin Reprod Endocrinol 
1999;17:349—58 
16. Sasano H, Harada N. Intratumoral aromatase in human breast, endometrial, and ovarian malignancies. 
Endocr Rev 1998;19:593—607. 
17. Ling Cen, Brett L. Carlson, Mark A. Schroeder, Jamie L. Ostrem, Gaspar J. Kitange, Ann C. Mladek, 
Stephanie R. Fink, Paul A. Decker, Wenting Wu, Jung-Sik Kim, Todd Waldman, Robert B. Jenkins, 
and Jann N. Sarkaria : p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor 
PD0332991 in glioblastoma xenograft cells Neuro-Oncology 14(7):870–881, 2012.  
18. Dean et al. Cell Cycle 2012;11:2756-2761 
19. Infante JR, Shapiro GI, Witteveen PO, Gerecitano JF, Ribrag V, Chugh R, et al. Phase 1 multicenter, 
open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in 
patients with advanced solid tumors or lymphomas. Mol Cancer Ther 2013;12: A276. 


 
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20. Dong Y, Walsh MD, McGuckin MA, Cummings MC, Gabrielli BG, Wright GR et al. (1997). Int J 
Cancer 74: 407–415.  
21. Semczuk A, Schneider-Stock R, Miturski R, Skomra D, Tomaszewski J, Roessner A et al. (2000). 
Pathol Res Pract 196: 41–46.  
22. G Scambia1, S Lovergine2 and V Masciullo1,2: RB family members as predictive and prognostic 
factors in human cancer. Oncogene (2006) 25, 5302–5308. doi:10.1038/sj.onc.1209620 
23. Reid-Nicholson M, Iyengar P, Hummer AJ et al: Immunophenotypic diversity of endometrial 
adenocarcinomas: implications for differential diagnosis. Modern Pathology (2006) 19, 1091–1100. 
doi:10.1038/modpathol.3800620;  
24. Niemann TH1, Yilmaz AG, McGaughy VR, Vaccarello L.: Retinoblastoma protein expression in 
endometrial hyperplasia and carcinoma.. Gynecol Oncol. 1997 May;65(2):232-6. 
25. Koh VM1, Shi YX, Tang QH.: P16 and retinoblastoma protein expression in endometrial carcinoma 
and clinical significance. Eur J Gynaecol Oncol. 2011;32(3):309-15. 
26. Lindemann K, Malander S, Christensen RD et al: Examestane in advanced or recurrent endometrial 
carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO). 
BMC Cancer. 2014 Feb 5;14:68. doi: 10.1186/1471-2407-14-68. 
27. Slomovitz BM, Jiang Y, Yates MS et al: Phase 2 study of everolimus and letrozole in patients with 
recurrent endometrial cancer.  
 


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


 
63 
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Appendix II  MEDICATION DIARY 
Name ______________________ 
Study No.MC1561 
Patient No. ______________ 
Patient Instructions 
• Please indicate on the calendar below every day that you take your study medication by 
placing the dose taken on the line under the date.  
• If you miss a dose, place a check “0” under the date, but remember to take your prescribed 
dose at the next regularly scheduled time. 
• Bring all bottles and any unused study medication along with this diary when you return for 
your next appointment. 
• Ribociclib should be taken at the same time every day, either with or without food. The 
capusles or tablets should be swallowed whole with a glass of water. The capsules or tablets 
should not be chewed or crushed. If the pills are thrown up, this should be noted on your 
diary but you should not take another pill until your next scheduled dose.  
• You should avoid eating foods high in fat, avoid drinking grapefruit juice, and avoid eating 
Seville (sour) oranges and grapefruit while on this study.  
 
 
 
 
 
Date:__________________ Participant Signature___________________________________ 
 
Area Below To Be Completed only by Coordinator 
Number of pills returned
  
 
Study Coordinator Initials
 
Date______________________ 
 
Discrepancy Yes____ No_____ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Ribociclib 
 
 
 
 
 
 
 
Letrozole 
 
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Ribociclib 
 
 
 
 
 
 
 
Letrozole 
 
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Ribociclib 
 
 
 
 
 
 
 
Letrozole 
 
 
 
 
 
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Ribociclib 
 
 
 
 
 
 
 
Letrozole 
 
 
 
 
 
 
 


 
64 
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Appendix III  CONCOMITANT MEDICATIONS 
List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 
inhibitors 
Atazanavir/ritonavir 
Boceprevir (Victrelis) 
Clarithromycin (Biaxin) 
Cobicistat (Tybost) 
Conivaptan (Vaprisonl) 
Danoprevir/ritonavir  
Eltegravir/ritonavir 
Grapefruit juice 
Indinavir/ritonavir 
Itraconazole (Sporanox, Onmel) 
Ketoconazole (Nizoral, Xolegel, 
Extina) 
Lopinavir/ritonavir 
Mibefradil (Posicor) 
Nefazodone (Serzone)  
Nelfinavir (Viracept) 
Ombitasvir/paritaprevir/dasabuvir/ritonavir 
(VIEKIRA PAK)  
Posaconazole (Noxafil) 
Ritonavir (Norvir)  
Saquinavir (Invirase) 
Saquinavir/ritonavir 
Telaprevir (Incivek)  
Telithromycin (Ketek) 
Tipranavir/ritonavir  
Troleandomycin (Triocetin, Tekmisin) 
Voriconazole (Vfend) 
Strong CYP3A4/5 
inducers 
Carbamazepine (Tegretol, 
Carbatrol, Equetro, Epitol) 
Lumacaftor 
Mitotane (Lysodren)  
Phenobarbital (Luminol)  
Phenytoin (Dilantin, Dilantin-125, 
Phenytek, Cerebyx) 
Rifabutin (Mycobutin)  
Rifampin (or rifampicin; Rifadin)3 
St. John's wort (hypericum perforatum)3 
CYP3A4/5 
substrates with 
NTI1 
Alfentanil (Alfenta) 
 Astemizole (Hismanal)  
Cisapride (Prepulsid, Propulsid)  
Cyclosporine (Neoral, 
Sandimmune,    Restasis, 
Gengraf)  
Diergotamine  
Dihydroergotamine (DHE 45, 
Migranal)  
Ergotamine (Ergomar)  
Fentanyl (Duragesic, Abstral, 
Subsys, Ionsys, Sublimaze)  
 Pimozide (Orap)  
Quinidine (Quinaglute, Quinidex)  
 Sirolimus (Rapamune)  
Tacrolimus (Protopic, Prograf, Hecoria)  
  
Medications with a 
known risk for QT 
prolongation4 
Amiodarone (Cordarone, 
Nexterone, Pacerone) 
Anagrelide (Agrylin) 
Arsenic trioxide 
Astemizole (Hismanal) 
Azithromycin (Zithromax, AzaSite, 
Zmax) 
Ibutilide (Corvert)  
Levofloxacin (Levaquin, Quixin, Iquix)  
Levomethadyl (OrLAAM, LAAM)  
Ibutilide, 
Levofloxacin, 
Levomepromazine, 
Levosulpiride 


 
65 
MC1561 
Category 
Drug Name 
Chlorpromazine (Thorazine, 
Largactil) 
Cilostazol (Pletal)  
Ciprofloxacin (Cipro, Cetraxal, 
Ciloxan, Proquin)  
Cisapride (Prepulsid, Propulsid)  
Citalopram (Celexa)  
Clarithromycin (Biaxin) 
Disopyramide (Norpace)  
Dofetilide (Tikosyn)  
Domperidone (Motilium)  
Donepezil (Aricept)  
Dronedarone (Multaq)  
Droperidol (Inapsine)  
Erythromycin (Ilotycin, Staticin, 
Ery-tab, Ery-Ped, Pce, Erythra-
Derm, T-Stat, Ery, E.e.s., 
Erygel, Eryped, Eryc, Akne-
mycin)  
Escitalopram (Lexapro) 
Flecainide (Tambocor)  
Fluconazole (Diflucan)  
Halofantrine (Halfan)  
Haloperidol (Haldol)  
Methadone (Diskets, Methadose, 
Dolophine)  
Moxifloxacin (Avelox, Vigamox, Moxeza)  
Ondansetron (Zofran, Zuplenz)  
Papaverine HCl (intra-coronary) 
Pentamidine (NebuPent, Pentam)  
Pimozide (Orap)  
Procainamide (Pronestyl, Procan-SR, 
Procanbid)  
Propofol (Diprivan)  
Quinidine (Quinaglute, Quinidex)  
Sevoflurane (Ultane, Sojourn)  
Sotalol (Betapace, Sotylize, Sorine)  
Sparfloxacin (Spacin, Zagam, Zagam 
Respipac)  
Sulpiride (Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Prometar, 
Sulpor)Sultopride, 
Terlipressin, 
Terodiline 
Thioridazine (Mellaril, Melleril)  
Vandetanib (Caprelsa) 
 
Herbal 
preparations/ 
medications 
Herbal preparations/medications are prohibited throughout the study. These 
herbal medications include, but are not limited to:  
 
St. John’s wort 
Kava 
Ephedra (ma huang) 
Gingko biloba 
Dehydroepiandrosterone (DHEA) 
Yohimbe 
Saw palmetto 
Ginseng 
 
Patients should stop using these herbal medications 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, 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. 


 
66 
MC1561 
Category 
Drug Name 
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 January 2018.Check https www crediblemeds.org/healthcare-providers/drug-   
list for the most updated list. 
 
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. 
 
List of permitted medications requiring caution during study drug treatment 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant 
Amprenavir (Agenerase) 
Asafetida resin (Ferula asafetida) 
Cimetidine (Tagamet) 
Crizotinib  
Darunavir (Prezista)  
Diltiazem (Cardizem, Dilt-cd, Dilacor, 
Tiazac) 
Faldaprevir  
Imatinib 
Isavuconazole 
Netupitant (Akynzeo) 
Nilotinib 
Schisandra sphenanthera (na wu wei zi) 
Tofisopam (Emandaxin, Grandaxin, 
Sériel) 
Verapamil (Covera-HS, Calan, Verelan, 
Isoptin) 
Moderate CYP3A4/5 
inducers 
Bosentan (Tracleer) 
Dabrafenib 
Efavirenz (Sustiva, Atripla) 
Etravirine (Intelence) 
Genistein 
Lopinavir5 
Modafinil (Provigil) 
Nafcillin 
Telotristat 


 
67 
MC1561 
Category 
Drug Name 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine (Almirid, 
Cripar) 
Aprepitant 
Atorvastatin (Lipitor) 
Avanafil (Stendra, Spedra) 
Bosutinib (Bosulif) 
Brotizolam (Lendormin) 
Budesonide (Entocort, Pulmicort, 
Ucens) 
Buspirone (Buspar) 
Cobimetinib 
Darifenacin (Enablex) 
Dasatininb, 
Ebastine (Evastin, Kestine, Ebastel, 
Aleva, Ebatrol) 
Eletriptan (Relpax) 
Eplerenone (Inspra) 
Felodipine (Plendil) 
Fluticasone (Cutivate) 
Grazoprevir 
Ibrutinib 
Isavuconazole 
Ivabradine 
Ivacaftor (Kalydeco) 
Levomethadyl (LAAM) 
Lomitapide (Juxtapid) 
Lovastatin 
Lumefantrine (or benflumetol; Coartem) 
Lurasidone (Latuda) 
Maraviroc (Selzentry, Celsentri) 
Midazolam 
Midostaurin 
Naloxegol 
Neratinib 
Nisoldipine 
Perospirone (Lullan) 
Quetiapine (Seroquel) 
Ridaforolimus (Deforolimus) 
Sildenafil (Viagra, Revatio) 
Simeprevir 
Simavastatin 
Ticagrelor (Brilinta) 
Tilidine (Tilidin, Valoron, Valtran) 
Tolvaptan (Samsca) 
Triazolam (Halcion) 
Ulipristal 
Vardenafil (Levitra, Staxyn) 
Venetoclax 
Vicriviroc 
Voclosporin (Luveniq)  


 
68 
MC1561 
Category 
Drug Name 
Strong BSEP 
inhibitors 
Alectinib 
Atorvastatin 
Bromocriptine 
Candesartan 
Clobetasol 
Clofaziminie 
Dabigatran 
Dipyridamole 
Glyburide 
Grazoprevir 
Ledipasvir 
Mifepristone 
Pioglitazone 
Reserpine 
Rifamycin 
Simeprevir 
 
Telmisartan 
Timcodar 
Troglitazone (TGZ-sulfate, Rezulin, 
Resulin, Romozin, Noscal) 
Valinomycin 
Velpatasvir 
Medications that carry 
a possible risk for QT 
prolongation2 
Alfuzosin (Uroxatral) 
Apomorphine (Apokyn) 
Aripiprazole (Abilify) 
Artenimol+piperaquine 
Asenapine 
Atomoxetine (Strattera) 
Bedaquiline (Sirturo) 
Bendamustine 
Bortezomib 
Bosutinib 
Buprenorphine 
Cabozantinib 
Capecitabine 
Ceritinib 
Clomipramine 
Clozapine (Clozaril, FazaClo) 
Crizotinib 
Cyamemazine (cyamepromazine) 
Dabrafenib 
Dasatinib 
Degarilix 
Delamanid 
Desipramine 
Dexmedetomidine (Precedex) 
Dolasetron (Anzemet) 
Ketanserin 
Lapatinib 
Lenvatinib 
Leuprolide 
Lithium 
Melperone 
Midostaurin 
Mifepristone 
Mirabegron 
Mirtazapine 
Moexipril/HCTZ 
Necitumumab 
Nicardipine 
Nilotinib 
Norfloxacin 
Nortriptyline 
Nusinersen 
Ofloxacin (Floxin, Ocuflox) 
Osimertinib 
Oxytocin (Pitocin, Syntocinon) 
Paliperidone (Invega) 
Palonosetron 
Prothipendyl 
Rilpivirine (Edurant) 
Risperidone (Risperdal) 


 
69 
MC1561 
Category 
Drug Name 
Efavirenz 
Eliglustat 
Epirubicin 
Eribulin mesylate (Halaven) 
Ezogabine (retigabine) 
Famotidine (Pepcid, Fluxid, Select) 
Felbamate (Felbatol) 
Fingolimod (Gilenya) 
Flupentixol 
Gemifloxacin (Factive) 
Granisetron (Sancuso, Granisol) 
Hydrocodone-ER 
Iloperidone (Fanapt) 
Imipramine (melipramine) 
Isradipine (Dynacirc) 
Lithium (Lithobid, Lithane) 
Mirabegron (Myrbetriq, Betmiga) 
Mirtazapine (Remeron) 
Moexipril (Univasc) 
Norfloxacin (Noroxin) 
Panabinostat 
Pasireotide (Signifor) 
Pazopanib 
Perflutren lipid microspheres 
Perphenazine 
Pilsicainide 
Pimavanserin 
Pipamperone (Dipiperon, Dipiperal, 
Piperonil, Piperonyl, Propitan) 
Promethazine (Phenergan, Phenadoz, 
Promethegan) 
 
Romidepsin 
Sertindole (Serdolect, Serlect) 
Sorafenib 
Sunitinib 
Tamoxifen 
Tipiracil/Trifluridine 
Tizanidine (Zanaflex) 
Tolterodine (Detrol) 
Toremifene 
Trimipramine 
Tropisetron 
Vardenafil (Levitra, Staxyn) 
Vemurafenib 
Venlafaxine 
Vorinostat 
Ziprasidone (Geodon) 
MATE1/2 substrates3 
Acyclovir 
Cephalexin 
Cimetidine 
Fexofenadine 
Ganciclovir 
Glycopyrronium 
Metformin 
Pindolol 
Plisicainide 
Ranitidine 
Topotecan 
Varenicline 
 


 
70 
MC1561 
Category 
Drug Name 
MATE1 and OCT1/2 
substrates3 
 
Amantadine (Symmetrel) 
6-Beta-hydroxycortisol 
Carboplatin 
Cisplatin 
Cephalexin (Keflex) 
Cephradine (Cefradine) 
Lamivudine 
Linagliptin 
 
 
Memantine (Namenda) 
Metformin  
Oxyplatin 
Oxybutynin 
Phenformin 
Picoplatin 
Pilsicainide 
Pindolol (Visken) 
Ranitidine (Zantac, Select) 
Sorafenib 
Tropisetron 
Trospium 
Umeclidinium 
Zidovudine 
BCRP substrates 
Danunorubicin 
Dolutegravir 
Doxorubicin 
Hematoporphyrin 
Imatinib 
Methotrexate 
Mitoxanthrone 
Pitavastatin 
Rosuvastatin (Crestor) 
Sulfasalazine (Azulfidine) 
Irinotecan 
Ethinyl Estradiol 
Simvastatin 
Sulfasalazine 
Sofosbuvir 
Tenofovir 
Topotecan 
Venetoclax 


 
71 
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Category 
Drug Name 
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. 
3MATE1 and MATE2 share considerable substrate specificity. 
4OCT1 and OCT2 share considerable substrate specificity. 
5Lopinavir is prohibited when combined with ritonavir. 
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.