Conditions: Fallopian Tube Clear Cell Adenocarcinoma Fallopian Tube Endometrioid Adenocarcinoma Fallopian Tube High Grade Serous Adenocarcinoma FIGO Stage III Ovarian Cancer 2014 FIGO Stage IIIA Ovarian Cancer 2014 FIGO Stage IIIA1 Ovarian Cancer FIGO Stage IIIA2 Ovarian Cancer FIGO Stage IIIB Ovarian Cancer 2014 FIGO Stage IIIC Ovarian Cancer 2014 FIGO Stage IVA Ovarian Cancer 2014 FIGO Stage IVB Ovarian Cancer 2014 Ovarian Clear Cell Adenocarcinoma Ovarian Endometrioid Adenocarcinoma Ovarian High Grade Serous Adenocarcinoma Primary Peritoneal Endometrioid Adenocarcinoma Primary Peritoneal High Grade Serous Adenocarcinoma Stage III Fallopian Tube Cancer AJCC v7 Stage III Primary Peritoneal Cancer AJCC v7 Stage IIIA Fallopian Tube Cancer AJCC v7 Stage IIIA Primary Peritoneal Cancer AJCC v7 Stage IIIB Fallopian Tube Cancer AJCC v7 Stage IIIB Primary Peritoneal Cancer AJCC v7 Stage IIIC Fallopian Tube Cancer AJCC v7 Stage IIIC Primary Peritoneal Cancer AJCC v7 Stage IV Fallopian Tube Cancer AJCC v6 and v7 Stage IV Primary Peritoneal Cancer AJCC v7
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 147
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and the best dose of ruxolitinib phosphate when given together with paclitaxel and carboplatin and to see how well they work in treating patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate together with paclitaxel and carboplatin may be a better treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel and carboplatin alone.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine whether treatment with ruxolitinib phosphate (ruxolitinib) in combination with conventional neoadjuvant and post-surgical chemotherapy is safe and tolerable in the primary therapy for epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. (Phase I) II. Demonstrate whether treatment with ruxolitinib in combination with conventional neoadjuvant and post-surgical chemotherapy results in a prolonged progression-free survival when compared to chemotherapy alone, in primary therapy for epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. Determine frequency of patients who do not receive surgery within 6 weeks of completing cycle 3 therapy for reasons other than non-response, disease progression, or medical contraindications. (Phase I) II. Determine if continuation of ruxolitinib as maintenance therapy in participants who complete 6 cycles of standard chemotherapy in combination with ruxolitinib and have not experienced unacceptable toxicity or disease progression is safe and tolerable. (Phase I) III. Determine the impact of ruxolitinib in combination with chemotherapy on progression-free survival as a function of proposed exploratory biomarkers - ALDH+ CD133+ (possibly also CD24+ CK19+) co-staining by AQUA immunofluorescence (IF); ratio of tumor expression of CD8:FOXP3 by immunohistochemistry (IHC); and tumor CD3, CD4, TAI-1, HLA class I and II, CD68 expression by IHC in archived tumor tissue, BRCA status, and serum C-reactive protein (CRP) and IL-6 levels in pre-treatment serum. (Phase II) IV. Investigate the prognostic significance of exploratory laboratory parameters in terms of both progression-free survival and overall survival in women receiving conventional chemotherapy alone. (Phase II) V. Determine whether treatment with ruxolitinib in combination with conventional chemotherapy is associated with total gross resection rate at time of interval cytoreductive surgery. (Phase II) VI. Determine whether treatment with ruxolitinib in combination with conventional chemotherapy is associated with complete pathologic response defined at interval cytoreductive surgery. (Phase II) VII. Demonstrate whether treatment with ruxolitinib in combination with conventional chemotherapy results in an improvement in overall survival in primary management of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of ruxolitinib phosphate, followed by a phase II study.

PHASE I PORTION OF STUDY IS COMPLETE (04/06/2018)

PHASE I (CYCLES 1-3): Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on days 1-21, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 6 weeks after completion of cycle 3, patients undergo tumor reductive surgery (TRS).

PHASE I (CYCLES 4-6): Within 6 weeks of TRS, patients receive ruxolitinib phosphate PO BID on days 1-21, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. If TRS is not performed due to non-response or medical contraindications and criteria for discontinuation of protocol therapy have not been met, patients should resume ruxolitinib phosphate, paclitaxel, and carboplatin within 6 weeks of completing cycle 3 of therapy.

MAINTENANCE THERAPY: Within 3 weeks after completion of cycle 6, patients receive ruxolitinib phosphate PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I (CYCLES 1-3): Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 6 weeks after completion of cycle 3, patients undergo TRS.

ARM I (CYCLES 4-6): Within 4 weeks of surgery (or within 6 weeks of completion of cycle 3 in patients who do not undergo TRS), patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

ARM II (CYCLES 1-3): Patients receive ruxolitinib phosphate PO BID on days 1-21 and paclitaxel and carboplatin as in arm I. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 6 weeks after completion of cycle 3, patients undergo TRS.

ARM II (CYCLES 4-6): Within 4 weeks of surgery (or within 6 weeks of completion of cycle 3 in patients who do not undergo TRS), patients receive ruxolitinib phosphate PO BID on days 1-21 and paclitaxel and carboplatin as in arm I. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients in phase I are followed up until resolution of adverse events, and patients in phase II are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms:
arm 1: See Detailed Description. arm 2: See Detailed Description.

Interventions: intervention 1: Carboplatin intervention 2: Paclitaxel intervention 3: Ruxolitinib Phosphate intervention 4: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO intervention 4: Undergo TRS

Protocol document:
Prot_SAP_000.pdf: 
NRG-GY007 
NCI Version Date: February 28, 2020 
i 
SUMMARY OF CHANGES 
For Protocol Amendment #8 to: NRG-GY007 
 
NCI Protocol #: NRG-GY007 
Local Protocol #: NRG-GY007 
 
NCI Version Date:  February 28, 2020 
 
Summary of Changes 
# 
Section 
Comments 
1. 
Title Pages 
• NCI Version Date is now February 28, 2020. 
• The Study Chair is now Charles Landen, M.D. 
• Wenxin Zheng’s address was updated. 
• Hee Sun Kim-Suh is no longer the study Research Nurse, and this 
position will not be replaced at this time. 
2. 
6.6 
In the last sentence, “using D2R and T forms” was changed to “via Rave.” 
3. 
ICDs 
The only change made to the Phase I and II ICDs was the NCI Version Date. 
 


NRG-GY007 
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NRG-GY007 
(ClinicalTrials.gov NCT #02713386) 
 
A PHASE I/II STUDY OF RUXOLITINIB WITH FRONT-LINE NEOADJUVANT AND 
POST-SURGICAL THERAPY IN PATIENTS WITH ADVANCED EPITHELIAL 
OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER 
 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI).  
 
Lead Organization: NRG / NRG Oncology 
This study is limited to NRG Oncology participation 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center, 1600 JFK Blvd., Suite 1020 
Philadelphia, PA 19103 
 
Study Team (28-FEB-2020) 
Study Chair (28-FEB-2020) 
Charles N. Landen, Jr., M.D. 
University of Virginia 
81 Hospital Drive 
Private Clinic Third Floor 
PO Box 800712 
Charlottesville, VA 22908 
434-243-6131 
Cl3nj@hscmail.mcc.virginia.edu  
 
 
Study Co-Chair (04/06/2018) 
Statistician (04/06/2018) 
Ronald J. Buckanovich, M.D. 
Michael Sill, Ph.D. 
University of Pittsburgh, Magee Women’s Research 
Institute 
NRG Oncology SDMC-Buffalo 
Department of Internal Medicine 
Elm and Carlton Streets 
204 Craft Ave Rm B333 
Buffalo, NY 14263 
Pittsburgh, PA 15213 
716-854-5702/FAX: 716-845-8393 
412-641-4721/FAX: 412-641-8605 
sillm@nrgoncology.org   
buckanovichrj@mwri.magee.edu     
 


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Protocol Agents 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Ruxolitinib 
Incyte 
752295 
129988 
NRG Oncology 
Carboplatin 
Commercial 
241240 
N/A 
N/A 
Paclitaxel 
Commercial 
673089 
N/A 
N/A 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Study Pathologist (28-FEB-2020) 
Translational Scientist (10/09/2017) 
(04/05/2019) 
Wenxin Zheng, M.D. 
Heather A Lankes, PhD, MPH 
Department of Gynecologic Pathology 
NRG Oncology 
UT Southwestern/Simmons Cancer Center-Dallas Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
6000 Harry Hines Blvd., NB6.408 
Philadelphia, PA 19103 
Dallas, TX 75390-9072 
lankesh@nrgoncology.org 
214-648-1190 
 
Wenxin.Zheng@UTSouthwestern.edu  
 
 
 
Correlative Scientist 
Data Coordinator (04/06/2018) 
Daniel J. Powell, PhD 
Izabela Frak, MA 
University of Pennsylvania 
NRG SDMC-Pittsburgh Office 
3200 Civic Center Blvd 
201 N. Craig St., Suite 500 
Smilow CTR, Rm 08-103 
Pittsburgh, PA 15213 
Philadelphia, PA 19104 
412-383-4913/FAX: 412-624-1082 
215-573-4783 
fraki@nrgoncology.org  
poda@mail.med.upenn.edu  
 
 
 
 
Protocol Coordinator (03/20/2017) 
 
Meg Colahan, M.A. 
 
NRG Oncology 
 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
 
Philadelphia, PA 19103 
 
215-854-0770/FAX: 215-854-0716 
 
colahanm@nrgoncology.org  
 
 
 
  
Disease Site Chair (10/09/2017) (04/06/2018) 
 
Carol Aghajanian, M.D. 
 


NRG-GY007 
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Document History 
 
Version/Update Date 
Amendment 8 
February 28, 2020 
Amendment 7 
04/05/2019 
Amendment 6 
07/30/2018 
Amendment 5 
04/06/2018 
Amendment 4 
08/16/2017 
Amendment 3 
02/22/2017 
Amendment 2 
12/06/2016 
Amendment 1 
09/20/2016 
Activation 
04/21/2016 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 


NRG-GY007 
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TABLE OF CONTENTS 
 
 
1. 
OBJECTIVES ................................................................................................................. - 8 - 
 
Primary Objective ............................................................................................... - 9 - 
 
Secondary Objectives.......................................................................................... - 9 - 
2. 
BACKGROUND .......................................................................................................... - 10 - 
 
Rationale for selected approach and trial design .............................................. - 10 - 
 
Ruxolitinib (10/10/2016) .................................................................................. - 16 - 
 
Reference/backbone chemotherapy regimen .................................................... - 18 - 
 
Evaluation of safety (10/10/2016) NOTE:  The Phase I portion of the 
study is complete.  (04/06/2018) ....................................................................... - 19 - 
 
Treatment modification rules (04/06/2018) ...................................................... - 24 - 
 
Safety evaluation of maintenance ruxolitinib in Phase I (03/20/2017) 
(04/06/2018) ...................................................................................................... - 24 - 
 
Other design considerations (04/06/2018) ........................................................ - 25 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA ............ - 26 - 
 
Patient Selection Guidelines ............................................................................. - 26 - 
 
Eligibility Criteria (10/10/2016) ....................................................................... - 26 - 
 
Ineligibility Criteria (10/10/2016)..................................................................... - 28 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 31 - 
4.1 
PRE-TREATMENT ASSESSMENTS ............................................................. - 31 - 
4.2 
ASSESSMENTS DURING TREATMENT ..................................................... - 32 - 
4.3 
ASSESSMENTS IN FOLLOW UP .................................................................. - 35 - 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION..................................................... - 36 - 
 
Treatment Regimens ......................................................................................... - 36 - 
 
Radiation Therapy ............................................................................................. - 43 - 
 
Tumor Reductive Surgery (TRS) ...................................................................... - 43 - 
 
Device ............................................................................................................... - 44 - 
 
Imaging (for imaging-focused study) ............................................................... - 44 - 
 
Integral Assay/Biomarker ................................................................................. - 44 - 
 
Intervention Not Otherwise Categorized .......................................................... - 44 - 
 
General Concomitant Medication and Supportive Care Guidelines ................. - 44 - 
 
Duration of Therapy (04/06/2018) .................................................................... - 45 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT (04/06/2018) .......................... - 46 - 
6.1 
Treatment modifications based on hematologic toxicity .................................. - 48 - 
6.2 
Modifications for Hematologic Toxicity (Nadirs) (10/10/2016) 
(04/06/2018) ...................................................................................................... - 49 - 
6.3 
Modifications for Non-Hematologic Toxicity (10/10/2016) (04/06/2018) ...... - 51 - 
6.4 
Criteria for Discontinuation of Ruxolitinib Maintenance Therapy (Phase I 
Component Only) (10/10/2016) ........................................................................ - 52 - 


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6.5 
Interruption and Restart of Ruxolitinib for Other Reasons ............................... - 52 - 
6.6 
Guidelines for Use of Cytotoxic Therapy, After Discontinuation of 
Protocol Directed Cytotoxic Therapy and Prior to Disease Progression In 
Phase II Component .......................................................................................... - 53 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 53 - 
7.1 
Protocol Agents ................................................................................................. - 53 - 
7.2 
Adverse Events and Serious Adverse Events ................................................... - 53 - 
7.3 
Adverse Events for Investigational Study Agents Not Provided by CTEP ...... - 54 - 
7.4 
Adverse Events for Commercial Study Agents ................................................ - 54 - 
7.5 
Expedited Reporting of Adverse Events ........................................................... - 54 - 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (04/06/2018) .................. - 58 - 
8.1 
CTEP Registration Procedures (04/06/2018).................................................... - 58 - 
8.2 
Patient Enrollment (04/06/2018)....................................................................... - 61 - 
8.3 
Data Submission / Data Reporting (04/06/2018) .............................................. - 62 - 
9. 
DRUG INFORMATION .............................................................................................. - 63 - 
9.1 
Ruxolitinib Phosphate, IND# 129988 ............................................................... - 63 - 
9.2 
Commercial Agents .......................................................................................... - 64 - 
10. 
PATHOLOGY/BIOSPECIMEN .................................................................................. - 65 - 
10.1 
Central Pathology Review Guidelines .............................................................. - 65 - 
10.2 
Tissue Selection for Integral Marker Testing ................................................... - 65 - 
10.3 
Tissue Selection for Integrated marker testing ................................................. - 65 - 
10.4 
Biospecimen Submission Tables (04/06/2018) (07/30/2018) (04/05/2019) ..... - 65 - 
10.5 
Laboratory Testing ............................................................................................ - 67 - 
11. 
SPECIAL STUDIES (NON-TISSUE) .......................................................................... - 68 - 
12. 
MODALITY REVIEWS .............................................................................................. - 68 - 
13. 
ASSESSMENT OF EFFECT ....................................................................................... - 68 - 
13.1 
Definition of Disease Assessments ................................................................... - 68 - 
14. 
DATA AND RECORDS .............................................................................................. - 72 - 
14.1 
Data Management/Collection ........................................................................... - 72 - 
14.2 
NRG Data Management Forms (10/10/2016) (04/06/2018) (07/30/2018) 
(04/05/2019) ...................................................................................................... - 73 - 
14.3 
Summary of Data Submission .......................................................................... - 76 - 
14.4 
Global Reporting/Monitoring ........................................................................... - 76 - 
15. 
STATISTICAL CONSIDERATIONS.......................................................................... - 76 - 
15.1 
Study Design (04/06/2018) (04/05/2019) ......................................................... - 76 - 
15.2 
Study Endpoints ................................................................................................ - 77 - 
15.3 
Primary Objectives Study Design ..................................................................... - 78 - 
15.4 
Sample Size and Power Calculations: (10/10/2016) ......................................... - 80 - 
15.5 
Study Monitoring of Primary Objectives .......................................................... - 82 - 


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15.6 
Accrual/Study Duration Considerations ........................................................... - 82 - 
15.7 
Dose Level Guidelines ...................................................................................... - 82 - 
15.8 
Secondary or Exploratory Endpoints (10/10/2016) .......................................... - 82 - 
15.9 
Exploratory Hypothesis and Endpoints ............................................................ - 86 - 
15.10 Gender/Ethnicity/Race Distribution  (04/06/2018) ........................................... - 86 - 
16. 
REFERENCES ............................................................................................................. - 87 - 
APPENDIX I - FIGO OVARIAN CANCER STAGING 2014................................................ - 91 - 
APPENDIX II - 
GUIDELINES for PATHOLOGIC CLASSIFICATION of TUMOR 
CELL TYPE - 93 - 
APPENDIX III - PERFORMANCE STATUS CRITERIA ..................................................... - 94 - 
APPENDIX IV - GENERAL CHEMOTHERAPY GUIDELINES ......................................... - 95 - 
APPENDIX V - CARBOPLATIN DOSE CALCULATION INSTRUCTIONS ..................... - 96 - 
APPENDIX VI - PATIENT PILL CALENDAR- RUXOLITINIB (03/20/2017) ................... - 98 - 
APPENDIX  VII - INHIBITORS and INDUCERS of CYP3A4 (10/10/2016) ..................... - 100 - 
APPENDIX  VIII– INTERVAL TUMOR REDUCTIVE SURGERY(TRS) (04/06/2018) .. - 101 - 
APPENDIX IX – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES 
(01/09/2017) (04/06/2018) (07/30/2018) (04/05/2019) .............................................. - 103 - 
APPENDIX X - PATIENT DRUG INFORMATION HANDOUT and WALLET CARD 
(10/10/2016) ................................................................................................................ - 115 - 
APPENDIX XI - 
CANCER THERAPY EVALUATION PROGRAM INTELLECTUAL 
PROPERTY OPTION TO COLLABORATORS ...................................................... - 117 - 
APPENDIX XII – PATHOLOGY VERIFICATION FORM (04/06/2018) (04/05/2019) ..... - 120 - 
APPENDIX XIII – PARTICIPATING INSTITUTIONS FOR PHASE I SAFETY LEAD-IN 
(04/06/2018) ................................................................................................................ - 121 - 
 
 
 


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NRG-GY007 
SCHEMA 
 
Phase I Component (01/09/2017) (04/06/2018)  
NOTE:  The Phase I Component is Complete 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
A Cycle is 21 days in length 
 
*NACT = Neoadjuvant chemotherapy 
† TRS = Tumor Reductive Surgery (See Section 5.1.1.2 and Appendix VIII) 
‡ Maintenance ruxolitinib will be evaluated only in participants who complete all 6 cycles of 
chemotherapy with RUX, until disease progression, unacceptable toxicity, or voluntary 
withdrawal. (See Section 5.1.1.4) 
 
Primary Endpoint: Safety/tolerability of RUX combined with chemotherapy: N = 12 to 42 
patients (10/10/2016) 
 
 
 
 
Candidate 
for NACT* 
Histologic 
diagnosis and 
Imaging guided 
core or 
laparoscopic 
biopsies 
Pathology 
consistent with 
epithelial 
OV/FT/PP 
Cancer 
(See Appendix 
II) 
 
RUX 
‡ 
3 Cycles Experimental regimen: 
Paclitaxel 70 mg/m2 or 80 mg/m2 IV 
D1,8,15 (P) 
Carboplatin AUC 5 or 6 IV D1 (C) 
Ruxolitinib (RUX) at 10 or 15 mg PO 
BID 12 hours apart Days 1-21.  The 
first dose must be at least 1 hour prior to 
the Paclitaxel.
3 Cycles 
Experimental 
regimen: 
P + C + RUX 
See Section 
5.1.1.3 
T
R
S 
† 


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Phase II Component (01/09/2017) (04/06/2018) (07/30/2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
A Cycle is 21 days in length 
 
*NACT = Neoadjuvant chemotherapy 
† TRS = Tumor Reductive Surgery 
 
Primary Endpoint: Progression-Free Survival 
N = Maximum 87 patients  enrolled to experimental regimen, 43 enrolled to reference regimen 
(10/10/2016) 
† Interval tumor reductive surgery; or core biopsies in case of progression, failure to respond to 
first 3 cycles or tumor reductive surgery medically contraindicated (See Section 5.1.2.2) 
 
 
1. 
OBJECTIVES 
 
Candidate for 
NACT* 
Histologic diagnosis 
and  
 Imaging guided 
core or 
laparoscopic 
biopsies 
Pathology consistent 
with epithelial 
OV/FT/PP 
Cancer 
(See Appendix II) 
 
 
Randomize 
Treatment Arm 2 
3 Cycles Experimental regimen: 
Paclitaxel 70 mg/m2 IV D1,8,15 
(P) 
Carboplatin AUC 5 IV D1 (C) 
Ruxolitinib (RUX) 15 mg PO 
BID 12 hours apart Days 1-21.  
The first dose must be at least 1 
hour prior to the Paclitaxel. 
See Section 5.1.2.1.2 
3 Cycles 
Experimental 
regimen: 
P + C + RUX 
 
See Section 
5.1.2.3.2 
T
R
S 
† 
Treatment Arm 1 
3 Cycles Reference regimen: 
Paclitaxel 80 mg/m2 IV D1, 8, 15 
(P) 
Carboplatin AUC 6 IV D1 (C) 
See Section 5.1.2.1.1 
3 Cycles 
Reference 
regimen: 
P + C 
 
See Section 
5.1.2.3.1  
T
R
S
† 


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Primary Objective 
 
1.1.1 Phase I – Determine whether treatment with ruxolitinib in combination with conventional 
neoadjuvant and post-surgical chemotherapy is safe and tolerable in the primary therapy 
for epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. 
 
1.1.2 Phase II – Demonstrate whether treatment with ruxolitinib in combination with 
conventional neoadjuvant and post-surgical chemotherapy results in a prolonged 
progression-free survival when compared to chemotherapy alone, in primary therapy for 
epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. 
 
 
Secondary Objectives 
 
 Phase I:  
• Determine frequency of patients who do not receive surgery within 6 weeks of 
completing cycle 3 therapy for reasons other than non-response, disease 
progression, or medical contraindications. (03/20/2017)  
 
• Determine if continuation of ruxolitinib as maintenance therapy in participants 
who complete 6 cycles of standard chemotherapy in combination with ruxolitinib 
and have not experienced unacceptable toxicity or disease progression is safe and 
tolerable. 
 
 Phase II: 
• Determine the impact of ruxolitinib in combination with chemotherapy on 
progression-free survival as a function of proposed exploratory biomarkers - 
ALDH+CD133+ (possibly also CD24+CK19+) co-staining by AQUA 
immunofluorescence (IF); ratio of tumor expression of CD8:FOXP3 by 
immunohistochemistry (IHC); and tumor CD3, CD4, TAI-1, HLA class I and II, 
CD68 expression by IHC in archived tumor tissue, BRCA status, and serum C-
reactive protein (CRP) and IL-6 levels in pre-treatment serum. (04/05/2019) 
 
Note: Testing of banked biospecimens will not occur until an amendment to this 
treatment protocol (or separate correlative science protocol) is reviewed and 
improved in accordance with Clinical Trials Network (NCTN) policies. 
 
• Investigate the prognostic significance of exploratory biomarkers (see above) in 
terms of both progression-free survival and overall survival in women receiving 
conventional chemotherapy alone. 
 
• Determine whether treatment with ruxolitinib in combination with conventional 
chemotherapy is associated with total gross resection rate at time of interval 
cytoreductive surgery. 
 


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• Determine whether treatment with ruxolitinib in combination with conventional 
chemotherapy is associated with complete pathologic response defined at interval 
cytoreductive surgery. 
 
• Demonstrate whether treatment with ruxolitinib in combination with conventional 
chemotherapy results in an improvement in overall survival in primary 
management of epithelial ovarian, fallopian tube, or primary peritoneal 
carcinoma. 
 
2. 
BACKGROUND 
 
 
Rationale for selected approach and trial design 
The constellation of diseases commonly referred to as “ovarian cancer,” includes 
epithelial ovarian, primary peritoneal and fallopian tube carcinomas, and is diagnosed in 
approximately 22,000 women in the United States annually. More sobering is the 
projection that annually approximately 14,000 will die of disease.1 Based on this high 
relative mortality to incidence rate, ovarian cancer ranks as the third most lethal 
malignancy affecting women. Its lethality has been attributed largely to advanced stage at 
diagnosis (and absence of effective screening for potentially early stage disease). In 
addition, after standard management of newly diagnosed advanced disease including 
surgical cytoreduction and platinum/taxane chemotherapy, the vast majority of patients 
will recur and die of disease. The benefits of “standard” front-line therapy are limited by 
both intrinsic and acquired drug resistance and the lack of specificity for mechanisms of 
disease progression. Thus, there is a need for the development of new agents with activity 
against ovarian cancer, primarily those specifically targeting such mechanisms. 
 
Although in clinical practice, based on selection factors, these patients are at higher risk 
for disease progression over time compared with patients selected for primary debulking 
surgery,  whether or not there are fundamental differences in tumor biology that would 
affect the application of novel approaches remains to be determined. In the absence of 
data to the contrary, it remains reasonable to consider the population receiving 
neoadjuvant chemotherapy with interval tumor reductive surgery to be representative of 
all women with stage III and IV epithelial ovarian cancer.  Furthermore, patients treated 
with neoadjuvant chemotherapy and interval tumor reductive surgery represent the ideal 
population for the study of targeted agents. In this circumstance, tumor tissue is obtained 
as part of standard care prior to and at a standard interval after treatment exposure, 
thereby allowing a pharmaco-dynamic evaluation of tumor based correlative laboratory 
parameters for their ability to predict therapeutic efficacy and assessment of surgically 
defined intermediate surrogate endpoints. In addition, with progression free survival as 
the goal standard primary outcome measure for efficacy, the event rate for this population 
allows relatively rapid screening of novel agents. 
 
Biologic agents directed against specific therapeutic targets are postulated to be more 
likely to be effective in patients with overexpression or activation of the intended target. 
Such is the promise of personalized medicine. However, the ability to demonstrate this 
principle conclusively within a clinical trial has been difficult. Neoadjuvant 


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chemotherapy with interval tumor reductive surgery has become a progressively 
pervasive approach to primary treatment in the U.S. and abroad. This trend has been 
bolstered by two randomized phase III trials comparing neoadjuvant chemotherapy 
followed by interval tumor reductive surgery to primary debulking surgery followed by 
post-operative chemotherapy.2,3 These trials demonstrated no survival advantage for 
primary debulking surgery; however, primary debulking surgery was associated with 
slightly greater perioperative major morbidity and mortality. The incorporation of 
neoadjuvant chemotherapy with interval surgery into clinical practice is likely to increase 
over time, given the randomized trial results and lack of well-defined selection criteria for 
primary debulking surgery. The proposed study reflects emerging clinical practice, and 
we anticipate rapid accrual of patients who meet all eligibility criteria, without excessive 
comorbidities or poor performance status that might compromise the outcome measures. 
 
Interleukin-6 (IL-6)-Janus Kinase (JAK)-STAT3 signaling axis. There is increasing 
evidence that the Interleukin-6 (IL-6)-Janus Kinase (JAK)-STAT3 signaling axis is 
fundamental to disease progression in ovarian cancer and JAK mediated activation of 
STAT3 in ovarian cancer and that members of this pathway may serve as rational 
therapeutic targets.  STAT3 is constitutively active in the majority of epithelial ovarian 
cancers.4 JAK mediated activation of STAT3 in ovarian cancer cells was reported as a 
therapeutic target of ovarian cancer cells over 10 years ago. Burke and colleagues 
demonstrated that the JAK2 inhibitor AG490 restricted cancer cell growth via the 
induction of apoptosis.4 There are likely multiple mechanisms by which JAK1/2 
signaling can act as a driver of tumor progression. Recently, Gritsina et al. noted, 
“persistent activation of signal transducer and activator of transcription (STAT3) is 
frequently detected in ovarian carcinoma. STAT3 is activated by Janus family kinases 
(JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor 
tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, 
motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 
activation suppresses anti-tumor immune responses and supports tumor-promoting 
inflammation.”5  
 
JAKs are known to upregulate inflammation in the tumor microenvironment, and the 
degree of chronic inflammation/desmoplasia has been associated with poor prognosis and 
may play a critical role in tumor progression and chemotherapeutic drug resistance for 
epithelial ovarian cancer. It has been shown that JAKs can mediate pro-inflammatory 
cytokine signaling through activation of STAT transcription factors.6 Systemic 
inflammation and tumor desmoplasia are known features of advanced solid tumors, and 
the degree of chronic inflammation and tumor desmoplasia have been considered poor 
prognostic factors.7,8 Furthermore, inflammatory signaling has been shown to mediate 
several metabolic features of advanced malignancy such as cachexia.9 Elevated serum 
levels of C-reactive protein (CRP), a well-established peripheral marker of systemic 
inflammation, have been associated with poor prognosis for a variety of solid tumors.10-23 
In a clinical trial of patients with metastatic pancreatic cancer, the median survival for 
those with baseline CRP level greater than 10 mg/L (median value) was 3.8 months, 
compared with 9.7 months for those with levels less than or equal 10 mg/L (hazard ratio 
2.3, 95% confidence interval 1.6 – 3.1).12  Chronic inflammation may also play a critical 


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role in tumor progression and chemotherapeutic drug resistance for epithelial ovarian 
cancer.24-26 The NFΚB pathway has been found to be a major source of pro-inflammatory 
cytokines. Furthermore, a major characteristic of CD44+ ovarian cancer stem cells is 
constitutive activation of the NFΚB pathway, and inhibition of this pathway has been 
shown to induce cell death in ovarian cancer stem cells.27 Consistent with the literature 
for pancreatic cancer, the degree of systemic inflammation appears to be a negative 
prognostic factor in patients with advanced ovarian cancer. Hefler et al. showed in a 
multi-institution study of 623 women with epithelial ovarian cancer that serum CRP was 
associated with platinum resistance and poor overall, independent of other established 
prognostic factors.20 Similarly, Sharma et al. showed that the Glasgow Prognostic 
Score,28 an index of systemic inflammatory response based on serum CRP level > 10 
mg/L and hypoalbuminemia (albumin < 3.5 g/dL) independently predicted poor overall 
survival in a multivariate analysis.29 IL-6, a pro-inflammatory cytokine synthesized and 
secreted in both tumor cells and stroma in the tumor microenvironment, is a) a key 
upstream promoter JAK/STAT3 signaling,30 b) typically present at high levels in the 
serum and ascites of women with advanced epithelial ovarian cancer,31 and c) a negative 
prognostic factor.31  
 
Emerging data suggest that the IL-6/JAK/STAT3 pathway is important in the regulation 
of growth and differentiation of tumor cells with stem cell properties. Though the 
definition of tumor cells with stem cell properties has been debated, several studies have 
identified aldehyde dehydrogenase (ALDH) enzymatic activity as a marker for cancer 
stem cells (CSCs). In a study of breast cancer, ALDH(+) cells were present in a majority 
of tumors and capable of directly generating tumors in vivo.32 Independent studies in 
colon cancer suggested that ALDH identifies colon CSCs; as few as 25 ALDH(+) cells 
could generate tumors whereas ALDH(-) cells could not. 33,34 33,3433,34   Based on the 
evidence for ALDH as a stem cell marker in solid tumors, we showed that ALDH(+) cells 
isolated from both ovarian cancer cell lines and primary debulking specimens were 
chemo-resistant and preferentially grew tumors, compared with ALDH(-) cells, 
validating ALDH as a marker of ovarian CSCs.35 Using ALDH in combination with 
CD133 (another marker identified in association with CSCs in many solid tumors), we 
observed even greater growth in the ALDH(+)CD133(+) cells compared with 
ALDH(+)CD133(-) cells from primary ovarian cancer samples, suggesting a further 
enrichment of ovarian CSCs in the ALDH(+)CD133(+) population. Finally, the presence 
of ALDH(+)CD133(+) cells in debulked primary tumor specimens correlated with 
reduced disease-free and overall survival in ovarian cancer patients. Taken together, our 
findings defined ALDH and CD133 as a functionally significant set of markers to 
identify ovarian CSCs. 
 
STAT3 is preferentially phosphorylated in CSCs from breast and colon cancers. 36,37 
36,3736,37  IL-6 has been shown to be a primary activator of STAT3 in breast CSCs leading 
to increased tumor growth and resistance to therapy.38 Importantly, JAK2 or STAT3 
inhibition decreased CSC number and blocked the growth of tumor xenografts. 36,39 
36,3936,39  
 
We also previously reported the presence of large numbers of carcinoma associated 


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mesenchymal stem cells (CA-MSCs) in ovarian cancer.40 CA-MSCs significantly 
promoted ovarian cancer growth via their actions on ovarian CSCs—increasing 
‘stemness’.  Importantly, we have found that compared to mesenchymal stem cells, CA- 
MSCs secrete large amounts of IL-6 and the hematopoietic stem cell regulatory factor 
leukemia inhibitory factor (LIF). As shown in Figure 1, we investigated whether IL-6 and 
LIF could impact ovarian CSCs. We found that while neither protein alone had 
significant impact, the combination of both IL-6 and LIF dramatically promoted the 
growth of ALDH+ CSCs (Figure 1A).  Both IL-6 and LIF signal via the GP130/JAK2 
receptor complex to activate STAT3 signaling.  We therefore evaluated the impact of 
CA-MSC on tumor cell STAT3 activation.  Consistent with increased IL-6 and LIF 
expression, we observed that CA-MSC conditioned media significantly increases STAT3 
phosphorylation (Figure 1Bi).  We next tested the impact of a STAT3 inhibitor (Stattic) 
and a JAK2 inhibitor (TG101209) on ovarian carcinoma CSC STAT3 phosphorylation. 
Similar to that observed for breast and colon cancers,36,37 we noted preferential 
phosphorylation of STAT3 in ovarian CSCs versus non-CSCs (sorted based upon ALDH, 
CD133, or CD24 depending on the cell line) (Figure 1Bii). Interestingly, in unsorted cells 
we observed that JAK2 inhibition was more effective at inhibiting STAT3 
phosphorylation than was the STAT3 inhibitor (Figure 1Bii).   We next performed 
cytotoxicity assays with the JAK2 inhibitor. In both human and murine cell lines we 
observed significant toxicity, with an average IC50 of ~750nM (Figure 1C).  We also 
tested the JAK2 inhibitor in a tumor sphere assay with cell lines and cells derived from 
primary tumors. As expected, isolated ovarian carcinoma CSCs demonstrated far greater 
The image part with relationship ID rId18 was not found in the file.


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tumor sphere forming capacity than unsorted controls and non-CSCs (Figure 1D). While 
JAK2 inhibition had minimal impact on primary tumor sphere growth for non-CSCs, 
treatment resulted in a 28-fold reduction in primary tumor sphere formation from ovarian 
carcinoma CSCs. In addition, secondary sphere formation was similarly blocked. 
 
Using a p53-/-,PTEN-/-,APC-/- murine orthotopic model of epithelial ovarian cancer 
(Wu, 2007), we have performed survival studies to evaluate the impact of JAK2 
inhibition on ovarian cancer growth. 
 
Tumors were initiated via intrabursal injection of CRE recombinase expressing 
adenovirus (AdCre) and monitored until tumors reached ~500 mm3.  Tumors were paired 
based on size and then randomized to cisplatin vs. cisplatin plus TG101209 for 21 days. 
Combinatory treatment of cisplatin plus TG101209 improved survival of mice compared 
with mice treated with cisplatin only (Fig 2A). 
 
We next treated ‘early stage’ ovarian cancers with TG101209. AdCre was injected into 
the ovarian bursa to initiate tumors and then treatment with TG101209 or vehicle was 
initiated one week after injection and maintained for 21 days.  Mice were monitored until 
they became ill or primary tumor volumes reached humane endpoints for euthanasia per 
institutional guidelines (~1000 mm3). TG101209-treated mice demonstrated significantly 
increased survival (Fig. 2B). In addition, at the time of sacrifice control mice were ill 
appearing, with evidence of ascites and bowel obstructions.  In contrast, TG101209 
treated mice were well at the time of euthanasia but were sacrificed because of primary 
tumor volumes met euthanasia criteria.  At necropsy, vehicle treated mice had widespread 
metastatic disease with metastatic nodules in the intestine, liver, peritoneum, adipose and 
bladder (Fig. 2C).  In contrast, only 1 of 14 mice treated with TG101209 had 
demonstrable metastases (Fig 2C).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The image part with relationship ID rId18 was not found in the file.


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Consistent with our work, Abubaker and colleagues reported that JAK2 inhibition, with a 
different small molecular JAK2 inhibitor, resulted in loss of stem-like cells and 
suppression of tumor growth in combination with paclitaxel.41 
 
The above data suggest that JAK2 targeting might be therapeutically beneficial in 
advanced epithelial ovarian and related malignancies, by selectively eliminating the CSC 
fraction of tumors in vivo and thereby reducing metastasis. 
 
Recent data suggest that IL-6/JAK/STAT3 signaling may impede intrinsic cell mediated 
anti-tumor immunity. The paradigm of Treg-mediated immunosuppression in human 
cancer was originally defined in epithelial ovarian cancer.42  In a detailed analysis of Treg 
cells in 104 ovarian carcinoma cases, it was shown that human tumor-infiltrating Treg 
cells suppressed tumor-specific T-cell immunity and contributed to growth of human 
tumors in vivo. At all stages of disease, increased accumulation of Treg cells in tumor 
was associated with poor OS. In addition, a high CD8+/Treg ratio has been associated 
with favorable prognosis in epithelial ovarian cancer,43 suggesting that an abundance of 
CD8 effector cells may overcome Treg-mediated suppression. We therefore hypothesize 
that those immune therapies that enhance CD8+ T-cell accumulation and activity while 
reducing the population of Treg cells will demonstrate anti-tumor activity. Experimental 
depletion of Treg cells in tumor-bearing mice has been shown to improve immune-
mediated tumor clearance, indicating that strong anti-tumor immunity may require 
breaking Treg-mediated tolerance to tumor antigens. 44,45 44,4544,45  Activation of the 
JAK/STAT pathway has been shown to stimulate the recruitment and expansion of 
negative regulatory cells including myeloid derived suppressor cells and regulatory T-
cells. Gritsina et al. showed that the JAK inhibitor AZD1480 significantly reduced tumor 
growth rate, volume and ascites production in a murine model of human ovarian cancer 
while decreasing the concentration of suppressor T cells in the peritoneal tumor 
microenvironment of tumor-bearing mice compared with control mice.5 A similar finding 
was recently reported in an immunocompetent pancreatic cancer in vivo model, with 
enhanced efficacy in combination with checkpoint inhibitors.46  
 
Finally, the IL-6/JAK/STAT3 pathway has been implicated in promotion of tumor 
invasion and metastasis. Silver et al demonstrated that inhibition of STAT3 (a down-
stream effect of JAK inhibition), reduced the motility of ovarian cancer cells in vitro. 
Activated STAT3 co-localized to focal adhesions in these cells, suggesting that 
JAK/STAT signaling may contribute to ovarian cancer cell invasiveness.47 Gritsina et al. 
demonstrated a reduction in tumor-associated matrix metalloproteinase (MMP) activity in 
an in vivo murine model of human ovarian cancer.5  
 
The above pre-clinical data provide compelling rationale for targeting the IL-
6/JAK/STAT3 signaling pathway in ovarian cancer. For this proposal, we have chosen to 
implement ruxolitinib; an FDA approved inhibitor of JAK1/2 with preliminary evidence 
of efficacy and tolerability when used in combination with chemotherapy in other solid 
tumors. The detailed rationale for this agent is detailed below (section 2.2). 
 
 
 


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This trial will not only examine the clinical and biologic effectiveness of an agent 
hypothesized to target key processes hypothesized to drive tumor progression in ovarian 
cancer, but will also serve as a model by which future biologic agents can be tested. In 
particular, it will allow determination of 1) whether or not the presumed target is indeed 
affected by the biologic agent through comparison of pre- and post-treatment tumor 
specimens; 2) whether efficacy is relatively enhanced in patients with hypothetically 
predictive biologic features; and 3) whether the biologic therapy adds additional clinical 
benefit to conventional chemotherapy. The unique features of the phase II randomized 
design would offer an efficient, resourceful mechanism to transition promising agents to 
phase III development with a higher likelihood of efficacy in patient populations selected 
based on predictive tools generated with phase II scientific data.  
 
 
Ruxolitinib (10/10/2016) 
 
Ruxolitinib is an oral JAK inhibitor with selectivity for JAK1 and JAK2. It is indicated 
for the treatment of intermediate or high-risk myelofibrosis. FDA approval for ruxolitinib 
was based largely on results of a phase III, randomized, placebo-controlled trial 
(COMFORT-I, NCT00952289) in 304 patients with intermediate to high risk 
myelofibrosis.48 The investigators demonstrated a reduction in spleen size by at least 35% 
by 24 weeks (primary endpoint) of 41.9% in the ruxolitinib group versus 0.7% for the 
placebo group, a significant improvement in symptom score and a 50% improvement in 
survival over the study period. The rate of discontinuation of the study drug because of 
adverse events was 11.0% in the treatment group versus 10.6% in the placebo group. 
Anemia and thrombocytopenia were the most common adverse effects related to 
ruxolitinib.  However these patients have hematopoietic compromise at baseline, and 
these events rarely led to discontinuation of study drug (one patient for each event). The 
starting dose of ruxolitinib depended on the baseline platelet count: 15 mg twice daily for 
a platelet count of 100,000/mcl to 200,000/mcl and 20 mg twice daily for a platelet count 
that exceeded 200,000/mcl. 
 
Although ruxolitinib has yet to be evaluated in patients with epithelial ovarian cancer, 
there is a clear mechanistic rationale as detailed above, and the combination of ruxolitinib 
with a variety of cytotoxic chemotherapy regimens has been under investigation in a 
number of ongoing clinical trials for multiple other solid tumors. Hurwitz et al. recently 
presented data from a randomized double-blind phase II study of ruxolitinib or placebo 
with capecitabine as second-line therapy (all had failed gemcitabine) in patients with 
metastatic pancreatic cancer.49 Ruxolitinib or placebo was administered at 15 mg twice 
daily, days 1 – 21 with capecitabine at 1000 mg/m2 twice daily, days 1 – 14. The primary 
outcome measure was overall survival. For the 127 enrolled, the 12-month survival was 
22% for the ruxolitinib group and 11% for the placebo group (hazard ratio 0.79, 95% CI 
0.53 – 1.18).  Interestingly, a pre-planned Cox regression analysis, adjusting for all other 
potential prognostic factors, demonstrated that for patients with a high baseline CRP level 
(> 13 mg/L, n = 60), treatment including ruxolitinib was associated with a statistically 
significant improvement in overall survival (hazard ratio 0.50, 95% confidence interval 
0.26 – 0.96). A preferential clinical benefit was also observed in this subgroup of 60 
patients with respect to clinical response, pain control, change in performance status, and 


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nutritional status. 
 
Adverse effects of ruxolitinib are detailed in section 7.3. 
 
Other trials exploring the combination of ruxolitinib with cytotoxic chemotherapy were 
initiated. These include: phase I trial of gemcitabine and ruxolitinib with or without nAb 
paclitaxel in advanced pancreatic cancer (NCT01822756); randomized phase II trial of 
capecitabine with or without ruxolitinib in breast cancer (NCT02120417); and phase II 
randomized trial of pemetrexed and cisplatin with or without ruxolitinib in non-small cell 
lung cancer (NCT02119650). There have been to date no studies evaluating the safety 
and/or efficacy of ruxolitinib in combination with platinum-taxane combination 
chemotherapy.  
 
For the ruxolitinib solid tumor clinical development program, Incyte terminated the sub-
study of the Phase 2 study, INCB 18424-267, of ruxolitinib or placebo in combination 
with regorafenib in patients with relapsed or refractory metastatic colorectal cancer 
(CRC) and high C-reactive protein (CRP) and the Phase 3 study, INCB 18424-362, of 
ruxolitinib or placebo in combination with capecitabine for the second-line treatment of 
patients with advanced or metastatic pancreatic cancer. These decisions were taken after 
planned interim analyses demonstrated that there was an insufficient level of efficacy to 
warrant continuation.  There were no obvious safety issues noted in either study.  These 
decisions were based on recommendations from independent, unblinded Data Monitoring 
Committees.  In addition to these studies, Incyte also took the decision to terminate other 
ongoing solid tumor studies of ruxolitinib in combination with chemotherapy relying pre-
selecting for patients with high CRP levels. These studies included Phase 2 studies in 
lung and breast cancer, INCB 18424-266 and INCB 18424-268, the other sub-study of 
INCB 18424-267, and a second Phase 3 study in pancreatic cancer, INCB 18424-363.    
Incyte is working to close-out these studies, unblind all patients, and further evaluate all 
available data. 
 
In summary, outcomes for patients with advanced epithelial ovarian, primary peritoneal 
and fallopian tube cancers treated with standard therapy have been historically poor. 
Preliminary data indicate the potential of JAK inhibition to decrease pro-inflammatory 
cytokine mediated signaling, directly target CSC, decrease the infiltration of tumor with 
negative regulatory T cells and reduce invasive and metastatic potential. We hypothesize 
that the implementation of a JAK inhibitor in combination with standard chemotherapy 
may translate into improved disease-related outcomes in women with epithelial ovarian 
cancer and related malignancies and that subsets of patients may experience enhanced 
benefit based on biologic characteristics of tumors and their microenvironments. Safety 
and efficacy of ruxolitinib have been demonstrated in a phase III cancer trial, leading to 
FDA approval in an oncology indication. Recent results of a phase II trial preliminarily 
suggested an overall survival advantage for ruxolitinib in combination with second line 
chemotherapy compared with chemotherapy alone for patients with metastatic pancreatic 
cancer, with a statistically significant effect in those with evidence of up-regulated pro-
inflammatory signaling; treatment in combination with single agent chemotherapy was 
relatively tolerable with no major safety signals. We therefore propose a phase II 


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randomized trial to evaluate the efficacy of ruxolitinib in patients with newly diagnosed 
advanced disease in the context of and following standard cytotoxic therapy and surgery 
with exploration of biologic characteristics hypothetically predictive of efficacy. 
(04/06/2018) 
 
 
Reference/backbone chemotherapy regimen 
A consideration of relative efficacy and safety was made in the determination of the 
reference/backbone chemotherapy regimen for this trial. Results of two phase III 
randomized trials, JGOG 301650 and GOG-026251suggests that intravenous carboplatin 
with dose-dense weekly paclitaxel would be the most reasonable choice.  Long-term 
outcomes data demonstrated significant improvement in progression-free and overall 
survival (OS) in JGOG 3016 and in progression-free survival (PFS) in the non-
bevacizumab subset within GOG-0262. Furthermore, long-term outcome data from 
JGOG 3016 demonstrated maximal benefit of weekly dose-dense therapy in patients with 
more advanced suboptimal disease, reflecting the population to be evaluated in NRG-
GY007. From the safety standpoint, due to the concern for possible additive 
myelosuppression with the addition of ruxolitinib to a platinum-taxane regimen, data 
related to differential hematologic toxicity of the every three week versus dose-dense 
regimen in the front-line setting were reviewed. As summarized in Table 1 and Table 2, 
results from both JGOG 3016 and GOG-0262 demonstrated that though actual 
percentages in types of clinically significant toxicities differed (most likely due to 
differences in grading systems), the only grade 3 or greater hematologic toxicity 
significantly worse for the dose-dense paclitaxel group was anemia. Of note, although 
clinically impactful myelosuppression was no different between regimens for JGOG 
3016, for GOG-0262, grade ≥3 neutropenia was significantly greater in the every 3 week 
paclitaxel cohort (83.1%), than in the weekly dose-dense group (72.0%). In both trials, 
there was no difference in the rates of febrile neutropenia or in grade ≥ 3 
thrombocytopenia. 
 
Table 1. JGOG 3016: Hematologic Toxicity (N = 626) 
 
Type 
 
Q3W 
Weekly 
P value 
Anemia (Grade ≥ 3) 
 44% 
69% 
< 0.0001 
Neutropenia (Grade ≥ 3) 
 88% 
92% 
0.15 
Febrile Neutropenia 
(Grade ≥ 3) 
 9% 
 9% 
1.00 
Thrombocytopenia (Grade 
≥ 3) 
 38% 
 44% 
0.19 
 
Table 2. GOG-0262: Hematologic Toxicity (N = 683) 
 
Type 
 
Q3W  
Weekly 
Relative Risk 
95% CI 
Anemia (CTC Grade ≥ 3) 
15.7% 
36.5% 
0.33 – 0.57 
Neutropenia (CTC Grade ≥ 3) 
83.1% 
72.0% 
1.06 – 1.25 


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Febrile Neutropenia (CTC 
Grade ≥ 3) 
4.7% 
3.8% 
0.60 – 2.50 
Thrombocytopenia (CTC Grade 
≥ 3) 
15.7% 
19.7% 
0.58 – 1.11 
 
Another advantage of the carboplatin with dose-dense paclitaxel regimen is three times 
more frequent opportunities for patient safety assessment. From the feasibility standpoint, 
the dose-dense weekly regimen has become a community standard and is listed in the 
National Comprehensive Cancer Network (NCCN) guidelines as standard (category 1). 
In order to control for the potential influence on efficacy outcomes as they related to 
variations in cytotoxic regimens, the chemotherapy regimen in NRG-GY007 will be held 
consistent across the study population. 
 
 
Evaluation of safety (10/10/2016) NOTE:  The Phase I portion of the study is 
complete.  (04/06/2018)   
However, because there are no studies yet demonstrating the safety of combining 
ruxolitinib with platinum-taxane combination chemotherapy, this trial will initially 
employ a formal phase I component primarily designed to evaluate the safety of 
ruxolitinib in combination with standard platinum-taxane chemotherapy.   Our proposed 
phase I design is informed by data related to myelosuppression from the two front-line 
randomized phase III trials examining carboplatin and dose-dense paclitaxel (JGOG 3016 
and GOG-0262). The dose-dense regimens in these trials initiated carboplatin at an AUC 
of 6 IV q 3 weeks with paclitaxel initiated at 80 mg/m2 IV weekly.  The protocols for 
these trials utilized systematic dose modification rules for carboplatin (and paclitaxel for 
GOG-0262) related to neutropenia and for carboplatin related to thrombocytopenia. For 
GOG-0262, the required dose modification for the first instance of dose-limiting 
neutropenia and/or thrombocytopenia was a reduction in carboplatin AUC.  
 
Eligibility for both JGOG 3016 and GOG-0262 included a minimum absolute neutrophil 
count (ANC) of 1.5 x 109/L and a minimum platelet count of 100 x 109/L. In addition, 
patients were required to have both a minimum ANC of 1.0 x 109/L and a minimum 
platelet count of 75 x 109/L to receive treatment on cycle day 1 in subsequent cycles (C2 
– C6), and both a minimum ANC of 0.5 x 109 /L and a minimum platelet count of 50 x 
109/L to receive paclitaxel on days 8 and 15 during any cycle. 
 
As stated above, for JGOG 3016 and GOG-0262, indications for carboplatin dose 
reduction based on neutropenia were: febrile neutropenia, absolute neutrophil count 
(ANC) < 0.5 x 109/L persisting ≥ 7 days, or treatment delay > 7 days. Granulocyte-
colony stimulating factor (G-CSF) was implemented for complicated neutropenia or 
treatment delay based on neutropenia. Rules for holding day 15 of weekly paclitaxel for 
dose limiting neutropenia were also included. The indications for carboplatin dose 
reduction based on thrombocytopenia differed slightly between the two trials. For JGOG 
3016, carboplatin was dose reduced for a platelet count < 10 x 109/L or for bleeding 
associated with a platelet count between 10 x 109 /L and 50 x 109/L. In GOG-0262, 
carboplatin was dose reduced for a platelet count < 25 x 109/L (CTC grade 4) or for 
bleeding associated with a platelet count between 25 x 109/L and 50 x 109/L (CTC grade 


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3). 
 
Data related to dose modification and dose intensity for the dose-dense regimen in JGOG 
3016 led to the following observations: 
 
- 
Fewer than 50% of patients completed the regimen without dose modifications, and 
most dose modifications were made due to neutropenia.  
 
- 
The frequency of cycle delay (> 7 days) was 76% (compared with 67% in the q 3 
week paclitaxel cohort). The vast majority of delays were due to neutropenia. 
 
- 
Mean dose intensity for carboplatin in AUC (mg/mL per min) in the dose-dense 
weekly paclitaxel cohort was 4.62 (compared with 5.13 in the q 3 week paclitaxel 
cohort).  
 
- 
The mean dose intensities relative to those predicted by initial dose levels for both 
carboplatin and paclitaxel were 77% and 79%, respectively (compared with 85% and 
86%, respectively, for the q 3 week paclitaxel cohort).  
 
- 
Despite lower overall dose intensity for both standard agents in the dose-dense 
cohort, the dose-dense regimen was associated with a significant advantage in terms 
of both PFS and OS. 
 
Data related to dose modification and dose intensity for the 288 women assigned to the 
dose-dense regimen in GOG-0262 led to the following observations: 
 
- 
83% received carboplatin in all 6 cycles (compared with 91% of 314 in the q 3 week 
paclitaxel cohort). 
 
- 
76% received paclitaxel in all 6 cycles (compared with 87% in the q 3 week 
paclitaxel cohort). 
 
- 
The cumulative incidence of patients requiring carboplatin dose reduction for dose-
limiting neutropenia and/or thrombocytopenia was 24.0% by C3 (based on C1 and C2 
hematologic DLT events), with an additional 18% requiring dose reduction by C6. 
See section 15.3.2 for details.   
 
Given the concern for possible additive myelosuppression with the addition of ruxolitinib 
to the dose-dense paclitaxel regimen, we have integrated the following elements in the 
design of the phase I portion of NRG-GY007, in order to provide a rigorous evaluation of 
safety and toxicity and to maximize protection of trial participants: 
 
- 
Evaluation of dose-limiting toxicity (DLT) over longer interval. The phase I portion 
evaluates dose level safety as a function of DLT for more than one cycle, specifically 
in cycle (C) 1(C1) and C2. No patient may be enrolled at the next higher dose level, 
until all patients at the previous dose level have been followed through the end of C2. 


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Patients who do not experience DLT and who do not complete 2 cycles of therapy 
will be replaced.  By including two cycles rather than one, we will improve the 
resolution in capturing early, potentially cumulative serious impact on DLT related to 
myelosuppression.  
 
- 
Dose escalation design, with provision for initial de-escalation of ruxolitinib dose. 
The standard single agent dose for ruxolitinib as chronic therapy for moderate to 
severe myelofibrosis (a condition associated with extremely poor marrow reserve and 
chronic thrombocytopenia) is 25 mg PO bid. Lower doses ranging from 5 mg PO 
daily to 15 mg PO bid are known to be biologically active (see Investigator 
Brochure). The dose/schedule incorporated in the majority of completed and ongoing 
phase I, II and III trials with cytotoxic chemotherapy combined with ruxolitinib is 15 
mg/PO bid; this is the target dose/schedule. In the original version of the concept we 
proposed a dose de-escalation design. We have revised this to primarily a dose 
escalation design with exception of an initial de-escalation of ruxolitinib dose to 
account for the possibility that the starting ruxolitinib dose could be too high.  In that 
case, we would re-escalate if a safe ruxolitinib dose is identified, to take into account 
the possibility that patients could tolerate increase in carboplatin AUC and/or increase 
in weekly paclitaxel dose with a lowered ruxoliltinib dose.  The minimum cycle 1 
dose for ruxolitinib would be 5 mg PO bid even though a dose as low as 5 mg PO qd 
is known to be biologically active. In addition, the dose of ruxolitinib is de-escalated 
at each escalation of carboplatin or paclitaxel is two-fold, given the potential for 
overlapping myelotoxicity and the potential to compromise the efficacy of the 
standard agents. For example, if the dose of paclitaxel is escalated from 70 mg/m2 to 
80 mg/m2 with dose of ruxolitinib fixed and that dose level is found to be 
unacceptable, then we would be missing the opportunity to test whether paclitaxel at 
80 mg/m2 would be safe with a reduced dose of ruxolitinib. Overall, this approach 
provides an obvious safety benefit while maintaining at least standard of care 
treatment; the main potential disadvantages would be inefficiency and cost. In order 
to maximize the effectiveness of the standard regimen, we have maintained what 
would be considered standard initiating dose levels for both carboplatin and 
paclitaxel. The dose levels are shown in section 5.1.1.1. 
 
Dose levels 2 through 1, with carboplatin at AUC 5, can be justified by data from 
JGOG 3016 related to neutropenia and/or thrombocytopenia-triggered dose 
reductions of carboplatin in the dose-dense cohort and resultant carboplatin dose 
intensity. As detailed earlier, these data indicate an intrinsically high rate of 
neutropenia and thrombocytopenia for carboplatin initiated at AUC 6 that would have 
equated to a hematologic DLT on NRG-GY007, hence requiring dose reduction.  The 
single most important observation was that mean dose intensity for carboplatin in 
AUC (mg/mL per min) in the dose-dense weekly paclitaxel cohort was 4.62 
(compared with 5.13 in the q 3 week paclitaxel cohort), yet the dose-dense regimen 
was associated with a significant advantage in terms of both PFS and OS.  
 
Dose levels -2 through 3, with paclitaxel at 70 mg/m2, can be justified based on 
cumulative dose of 210 mg/m2 over a three-week period, greater than 175 mg/m2 


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administered in the every-three-week regimen, and in increased likelihood that the 
vast majority of patients will be able to receive all three weekly doses.  This would in 
most cases actually increase the cumulative dose delivered per cycle compared to a 
circumstance in which a weekly dose is omitted, an all too common problem 
observed in JGOG 3016 and GOG-0262. 
 
- 
Eight participants per cohort as opposed to standard 3 + 3 design (see sections 15.1 
and 15.4). The intrinsic rate of hematologic toxicity requiring dose modifications for 
the standard regimen required a greater number of participants per dose level than 
that evaluated using a standard 3 + 3 design, in order to increase the confidence in 
assessing the likelihood of DLT.  
 
- 
Hard stop. The protocol requires a hard stop (suspension of accrual) and central (NCI) 
safety review of all available safety data from the phase I portion, including that 
related to all chemotherapy cycles and interval tumor reductive surgery, prior to 
commencing onto the randomized phase II portion of the trial. 
 
- 
Limited access for phase I portion. The phase I evaluation will be conducted only in a 
limited number of phase I NRG sites, to assure timely assessment and weekly 
reporting. 
 
Studies thus far have demonstrated no concern for interactions between ruxolitinib and 
either carboplatin or paclitaxel.52 In vitro, ruxolitinib and its M18 metabolite do not 
inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. 
Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant 
concentrations. In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, 
BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems at 
clinically relevant concentrations. Ruxolitinib is not a substrate for the P-gp transporter. 
The major route of elimination of carboplatin is renal excretion. Thus the primary 
determinant of carboplatin clearance is glomerular filtration rate (GFR). Ruxolitinib has 
no effect on GFR based on data from the phase III studies. So it is highly unlikely 
ruxolitinib will affect carboplatin clearance or plasma levels. The metabolism of 
paclitaxel is catalyzed by CYP2C8 and CYP3A4. Ruxolitinib does not inhibit any of 
these enzymes, so there is little chance of an interaction with paclitaxel.  Ruxolitinib is 
metabolized by CYP3A4 and somewhat by CYP2C19.  Neither carboplatin nor paclitaxel 
are inhibitors of either of those enzymes. This information would suggest limited value of 
a formal pharmacokinetic analysis a priori. 
 
Assuming a safe dose level for ruxolitinib is defined in the phase I portion, the trial also 
includes two predetermined comparative interim analyses within the randomized phase II 
portion, evaluating early and intermediate events.  The goal of these interim analyses will 
be to review adverse events in the randomized phase II portion of the study comparing 
the experimental and reference regimens. Both of these will be conducted by the NRG 
DSMB. In NRG-GY007, ruxolitinib in cycle 3 is continued only for (not beyond) the 21 
days of the cycle. As for GOG-0262, in NRG-GY007, barring evidence of non-response, 
disease progression or development of medical co-morbidities posing an unacceptable 


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surgical risk, interval surgery must be performed following cycle 3, as soon as nadir 
counts permit, but within 6 weeks after the completion of cycle 3. This time window is 
considered standard. While the likelihood of surgical delay given a 6 week window is 
extremely low, the interim analyses of safety in the phase II randomized component of 
the trial will evaluate differences in delay (beyond this window) of interval surgery. In 
the event that grade 3 or greater hematologic/non-hematologic toxicity or delay of 
interval tumor reductive surgery for more than 6 weeks after completion of C3 is 
significantly higher among patients on the ruxolitinib arm, the NRG DSMB may 
recommend further dose modification or study termination. The first analysis will be 
conducted after the first 10 patients in each treatment group have completed study 
therapy. There is a precedent for such an approach in NCI sponsored trials, for example 
GOG-0219. The second analysis will be conducted at the time of the interim futility 
analysis related to PFS, the primary endpoint of the trial. 
 
For both the phase I and phase II portions of this trial, given the concern for possible 
additive myelosuppression with the addition of ruxolitinib to the carboplatin with dose-
dense paclitaxel regimen and the notion that the known therapeutic benefit of standard 
primary platinum-taxane chemotherapy can in no way be compromised at the expense of 
evaluating the potential for JAK1/2 inhibition to improve long term outcome in trial 
participants, dose modifications for ruxolitinib based on clinically significant neutropenia 
and/or thrombocytopenia will be instituted prior to or concurrently with (as would be 
indicated with standard therapy) dose modifications of the standard therapeutic agents 
that could adversely affect the efficacy of the standard regimen. 
 
Summary of findings from phase I dose escalation (04/06/2018) 
 
The phase I portion of the study enrolled 17 patients in total, 7 to dose-level 1 
(carboplatin AUC 5, paclitaxel 70 mg/m2/week, ruxolitinib 15 mg twice daily) and 10 to 
dose-level 2 (carboplatin AUC 6, paclitaxel 70 mg/m2/week, ruxolitinib 10 mg twice 
daily). Neither of the dose levels was associated with dose-limiting non-hematologic 
toxicity or unexpected toxicities in this patient population.  As anticipated from historical 
data with carboplatin and weekly dose-dense paclitaxel, dose-limiting events were 
hematologic. A summary of cumulative data from each dose level is included in Table 
2.4.1. Based on the pre-defined protocol criteria, dose level 1 was felt to be safe and 
tolerable, with expected hematologic toxicity, and was selected as the starting dose for 
the randomized phase II component of the trial. The dose levels for carboplatin (AUC=5) 
and paclitaxel (70 mg/m2 per week) safely achieve generally-accepted dose levels that are 
appropriate for this high-risk patient population with advanced-stage disease.   
 
Table 2.4.1 DLT summary  
 
Dose 
Level 
Patients 
Treated 
Evaluable 
for DLT 
Assessment 
Inevaluable 
for DLT 
Assessment 
DLT 
Decision 
1 
7 
7 
0 
Febrile neutropenia 
(1 patient) 
Safe 


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Grade 4 neutropenia 
> 7 days (1 patient) 
2 
10 
7 
3 
Omission day 15 
paclitaxel due to 
neutropenia (2 
patients) 
Unsafe 
Grade 4 
thrombocytopenia 
and delay of cycle 2 
therapy due to 
neutropenia (1 
patient) 
 
Of 11 evaluable patients, all underwent surgery within 6 weeks of completing cycle 3.   
 
 
Treatment modification rules (04/06/2018) 
As was the case for the phase I portion of the trial, treatment modification rules for the 
phase II portion will be as utilized in GOG-0262. The exception to this would be in the 
case of dose-limiting neutropenia and thrombocytopenia (C3 through C6 for phase I and 
C1 through C6 for phase II), where modifications of ruxolitinib dose are interdigitated. 
Please see section 6.2 for details.  
 
While there is evidence of long-term safety with ruxolitinib monotherapy in other 
populations and while there is a rationale for both ruxolitinib combined with platinum-
based chemotherapy and maintenance ruxolitinib in patients with advanced ovarian 
cancer, the data supporting the implementation of maintenance ruxolitinib in NRG-
GY007 is indirect. Single agent anti-tumor activity for a less effective analog of 
ruxolitinib in pre-clinical in vivo models of human ovarian cancer was associated with 
improved outcome and prevention of metastasis (providing rationale for a maintenance 
phase to maximize likelihood of overall clinical benefit).  In addition, reduction in 
inflammation as a major mechanism for JAK inhibition suggests that long term treatment 
may result in enhanced efficacy. There is indirect evidence of safety for long term 
treatment with ruxolitinib at 25 mg PO bid in patients with bone marrow disease. Despite 
the fact that these patients have ‘sick marrow’ they tolerate months of therapy with 
ruxolitinib with minimal side-effects. Nevertheless, there is no preliminary direct 
evidence of long term safety of maintenance ruxolitinib in humans with 
advanced/metastatic solid tumors. 
 
 
Safety evaluation of maintenance ruxolitinib in Phase I (03/20/2017) (04/06/2018) 
Given the above considerations, in the interest of beginning to examine the safety of 
maintenance therapy in advance of potential future efficacy evaluations, in NRG-GY007 
we proposed to examine safety and tolerability of maintenance therapy within only the 
phase I cohort(s). Specifically, participants who completed all 6 cycles of chemotherapy 
with ruxolitinib will continue ruxolitinib maintenance at the C6 dose/schedule (see 
sections 5.1.1.4) until disease progression, unacceptable toxicity (see section 6.4), or 
voluntary withdrawal.  Unacceptable toxicity is defined in section 6.4. The primary 


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endpoint of this maintenance evaluation was safety/tolerability. By focusing on the exact 
population within the phase I cohort(s) that would theoretically be eligible for 
maintenance therapy on higher order trials, we will maximize our ability to acquire 
unique information in an efficient manner. 
 
Safety and tolerability of maintenance ruxolitinib beyond chemotherapy has been 
demonstrated in 5 of the 17 patients enrolled to the phase I portion of the study who thus 
far have completed 6 cycles of combination treatment. Based on guidelines in Section 6.2 
of the protocol, the starting dose in maintenance was 5 mg BID in 2 patients, 10 mg BID 
in 2 patients, and 15 mg BID in 1 patient.  There were no dose reductions during 
maintenance. For the 16 cycles of single agent maintenance ruxolitinib administered to 
these 5 patients, there have been no grade 3 or greater adverse events and no worsening 
of adverse events after cycle 6. Anemia decreased in severity from grade 2 to grade 1 or 0 
for three patients. Alopecia decreased in severity from grade 2 to grade 1 in one patient. 
 
 
Other design considerations (04/06/2018) 
The phase II portion will be initiated without maintenance ruxolitinib with the objectives 
of examining relative efficacy and safety with the combination of ruxolitinib and standard 
chemotherapy versus chemotherapy alone; exploring key mechanistic translational 
questions; and providing a framework for expanded clinical research, which if successful 
could potentially lead to examination of the maintenance question. 
 
Based on an FDA approval in December 2018,53 patients enrolled on this trial who have 
deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutations 
and who are in complete or partial response to carboplatin and paclitaxel with or without 
ruxolitinib will be permitted to receive olaparib maintenance after completing the study 
regimen. Given that the use of olaparib in such patients could affect PFS (the primary 
endpoint of this trial), PFS will be adjusted statistically (see section 15.) based on BRCA 
mutation status. BRCA mutation testing has been considered within standard care for 
women with epithelial ovarian, tubal and peritoneal cancer since at least 2014.54 
Therefore, BRCA mutation status (i.e., comprehensive BRCA1 and BRCA2 sequencing, 
including assessment of gene rearrangements) will be a required on-study data element 
for participation on this trial (see also section 3.2.14).  (04/05/2019) 
 
With regard to the evaluation of PFS, the primary efficacy endpoint for the phase II 
randomized component, an active futility rule has been implemented, examining outcome 
when the study reaches approximately 50% of the planned information-time. 
 
With the understanding that epithelial ovarian cancer and related malignancies are 
diverse histologically and may reflect key differences in tumor biology, a strong 
consideration was given to eligibility as it relates specifically to histology. NRG-GY007 
includes of all histologic Mullerian duct adenocarcinoma subtypes except for mucinous 
adenocarcinomas, grade 1 endometrioid adenocarcinomas and low grade serous 
carcinomas, as women with stage III and IV cancers of these histologic subtypes would 
be unlikely to benefit from standard platinum-taxane combination chemotherapy or 
benefit from JAK1/2 inhibition based on the available knowledge, and would be better 


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suited for rare tumor trials, reflecting the molecular and clinical features of these rare 
histologic types. Because these cases are rare, exclusion would not jeopardize feasibility 
of this study.  There are supportive preclinical data for JAK inhibition in high grade 
serous and endometrioid tumors, and IL-6 may be an important driver of tumor 
progression in clear cell adenocarcinomas. In order to avoid an imbalanced distribution, 
for the phase II portion of the trial, the population is stratified by clear cell versus the 
high grade serous/endometrioid prior to randomization. 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the NRG Statistical and 
Data Management Center-Pittsburgh Office: 412-624-2666. (04/06/2018) 
 
 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
 
 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
 
 Women of childbearing potential should be willing and able to use medically acceptable 
forms of contraception during the trial. 
 
3.1.3 Submission of tumor tissue is required for all patients.  Investigators should check with 
their site pathology department regarding release of tissue before approaching patients 
about participation in the trial.  (See Section 10.4 for details.) (07/30/2018) 
 
 
Eligibility Criteria (10/10/2016) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
 Patients must have clinically and radiographically suspected and previously untreated 
FIGO stage (Appendix I) III or IV epithelial ovarian, primary peritoneal or fallopian tube 
cancer, high grade, for whom the plan of management will include neoadjuvant 
chemotherapy (NACT) with interval tumor reductive surgery (TRS) who have undergone 
biopsies for histologic confirmation. See Appendix II for Guidelines to Aid in 
Classification of Tumor Cell Type. 
 


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3.2.2 Institutional confirmation of Müllerian epithelial adenocarcinoma on core biopsy (not 
cytology or fine needle aspiration) or laparoscopic biopsy. (For Phase II of the study 
FFPE tissue should be available for laboratory analysis.) Patients with the following 
histologic epithelial cell types are eligible: high grade serous carcinoma, high grade 
endometrioid carcinoma, clear cell carcinoma, or a combination of these. 
 
 All patients must have measurable disease as defined by RECIST 1.1.  Measurable 
disease is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded).  Each lesion must be ≥ 10 mm when 
measured by CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when 
measured by chest x-ray.  Lymph nodes must be ≥ 15 mm in short axis when measured 
by CT or MRI. 
 
3.2.4 Appropriate stage for study entry based on the following diagnostic workup: 
• History/physical examination within 28 days prior to registration; 
• Radiographic imaging of the chest, abdomen and pelvis within 28 days prior to 
registration documenting disease consistent with FIGO stage III or IV disease; 
• Further protocol-specific assessments as detailed in section 4.1. 
 
3.2.5 Age ≥ 18 
 
3.2.6 The trial is open to females only. 
 
3.2.7 ECOG/Karnofsky Performance Status of 0, 1, or 2 (see Appendix III) within 28 days 
prior to registration. 
 
3.2.8 Adequate hematologic function within 14 days prior to registration defined as follows: 
• ANC greater than or equal to 1,500/mcl. This ANC cannot have been induced by 
granulocyte colony stimulating factors.  
• Platelets greater than or equal to 100,000/mcl 
• Hemoglobin greater than 9.0 mg/dl (transfusions are permitted to achieve baseline 
hemoglobin level)  
 
3.2.9 Adequate renal function within 14 days prior to registration defined as follows: 
• Estimated CrCl ≥ 50 mL/min according to the Cockcroft-Gault formula. 
(07/30/2018) 
 
3.2.10 Adequate hepatic function within 14 days prior to registration defined as follows: 
• 
Bilirubin ≤ 1.5 x ULN 
• 
ALT and AST ≤ 3 x ULN 
• 
Alkaline phosphatase ≤ 2.5 x ULN 
 


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3.2.11 Neurologic function: Neuropathy (sensory and motor) less than or equal to CTCAE 
Grade 1. 
 
 
3.2.12 Ability to swallow and retain oral medication. 
  
3.2.13 The patient must provide study-specific informed consent prior to study entry. 
 
3.2.14 BRCA testing results (i.e., comprehensive BRCA1 and BRCA2 sequencing, including 
assessment of gene rearrangements) must be submitted for all patients enrolled to 
Amendment 7 and subsequent amendments. BRCA testing results are optional for all 
patients enrolled prior to Amendment 7. Please refer to Section 4.2.2 for details. Due to 
the long acceptance of germline BRCA testing through Myriad, Myriad testing reports 
will be accepted without additional documentation. If testing for germline BRCA is done 
by other organizations, in addition to the testing report, documentation from a qualified 
medical professional (e.g., ovarian cancer specialty physician involved in the field, high 
risk genetics physician, genetics counselor) detailing the laboratory results is required. 
Please retain a copy of all reports (positive, VUS, or negative). (04/05/2019) 
 
 
Ineligibility Criteria (10/10/2016) 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.3.1 Patients with suspected non-gynecologic malignancy, such as gastrointestinal. 
 
3.3.2 Patients with a history of other invasive malignancies, with the exception of non-
melanoma skin cancer and other specific malignancies as noted in Section 3.33 and 
Section 3.3.7 are excluded if there is any evidence of other malignancy being present 
within the last three years (2 years for breast cancer, see Section 3.33). Patients are also 
excluded if their previous cancer treatment contraindicates this protocol therapy. 
 
3.3.3 Patients who have received prior chemotherapy for any abdominal or pelvic tumor within 
the last three years are excluded. Patients may have received prior adjuvant 
chemotherapy and radiotherapy for localized breast cancer, provided that it was 
completed more than 2 years prior to registration, the patient remains free of recurrent or 
metastatic disease and hormonal therapy has been discontinued. 
 
3.3.4 Patients who have received prior radiotherapy to any portion of the abdominal cavity or 
pelvis or thoracic cavity within the last three years are excluded. Prior radiation for 
localized cancer of the head and neck or skin is permitted, provided that it was completed 
more than three years prior to registration, and the patient remains free of recurrent or 
metastatic disease. 
 
3.3.5 Patients who have received any targeted therapy (including but not limited to vaccines, 
antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their 
epithelial ovarian, fallopian tube or peritoneal primary cancer. 
 


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3.3.6 Patients with mucinous carcinoma, low grade endometrioid carcinoma, low grade serous 
carcinoma or carcinosarcoma. 
 
3.3.7 Patients with synchronous primary endometrial cancer, or a past history of primary 
endometrial cancer, unless all of the following conditions are met: Stage not greater than 
I-A, grade 1 or 2, no more than superficial myometrial invasion, without vascular or 
lymphatic invasion; no poorly differentiated subtypes, including serous, clear cell or 
other FIGO grade 3 lesions. 
 
3.3.8 Severe, active co-morbidity defined as follows: 
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal 
or antiviral treatment 
• Known brain or central nervous system metastases or history of uncontrolled seizures 
• Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within 6 months from enrollment, New York Heart Association Class III or 
IV congestive heart failure, and serious arrhythmia requiring medication (this does 
not include asymptomatic atrial fibrillation with controlled ventricular rate). 
• Partial or complete gastrointestinal obstruction  
 
3.3.9 Patients who are not candidates for major abdominal surgery due to known medical 
comorbidities.  
 
3.3.10 Patients with any condition that in the judgment of the investigator would jeopardize 
safety or patient compliance with the protocol. 
 
3.3.11 Patients who are unwilling to be transfused with blood components. 
 
3.3.12 Concurrent anticancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy, 
immunotherapy, hormonal therapy, investigational therapy). 
 
3.3.13 Receipt of an investigational study drug for any indication within 30 days or 5 half-lives 
(whichever is longer) prior to Day 1 of protocol therapy. 
 
3.3.14 Patients who, in the opinion of the investigator, are unable or unlikely to comply with the 
dosing schedule and study evaluations. 
 
3.3.15 Patients who are pregnant or nursing.  The effects of ruxolitinib on the developing human 
fetus are unknown.  For this reason, women of child-bearing potential (WOCBP) must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  WOCBP must 
have a screening negative serum or urine pregnancy test within 14 days of registration.  A 
second pregnancy test must be done within 24 hours prior to the start of the first cycle of 
study treatment.  Women must not be breastfeeding. (01/09/2017) 
 
Women who are not of childbearing potential (i.e., who are postmenopausal or surgically 
sterile) do not require contraception. 


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Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy 
and/or bilateral oophorectomy) or who is not postmenopausal.  Menopause is defined 
clinically as 12 month amenorrhea in a woman over 45 in the absence of other biological 
or physiological causes.  In addition, women under the age of 55 must have a 
documented serum follicle stimulating hormone (FSH) level greater than 40mIU/mL. 
 
3.3.16 Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C 
infection or known history of tuberculosis.  
(This exclusion criterion is necessary because the treatments involved in this protocol 
may be immunosuppressive.) 
 
 


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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
PRE-TREATMENT ASSESSMENTS 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(Cycle 1) 
(calendar days) 
(03/20/2017) 
History and Physical 
≤ 28 days 
≤ 28 days 
Vital Signs (Blood Pressure, 
Heart Rate, Temperature) 
≤ 28 days 
≤ 28 days 
Performance Status 
≤ 28 days 
≤ 28 days 
Toxicity Assessment 
≤ 14 days 
≤ 14 days 
Concurrent Medications 
≤ 14 days 
≤ 14 days 
CBC/Differential/Platelets 
≤ 14 days 
≤ 14 days 
Electrolytes, including BUN, 
creatinine, Ca, and 
magnesium 
≤ 14 days 
≤ 14 days 
CrCl by the Cockcroft-Gault 
Formula 
≤ 14 days 
≤ 14 days 
Bilirubin, ALT, AST, 
Alkaline Phosphatase, 
Albumin 
≤ 14 days 
≤ 14 days 
Pregnancy Test (if 
childbearing potential exists) 
≤ 14 days 
≤ 24 hours1 (01/09/2017) 
EKG 
≤ 28 days 
≤ 28 days 
FSH 
X5 
 
Audiogram2 
≤ 28 days 
≤ 28 days 
CA-125 
 
≤ 28 days 
Radiographic Tumor 
Measurement3 
≤ 28 days 
≤ 28 days 
Biopsy for Histologic 
Diagnosis4 
 
 
 
1  The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of hCG. 
2 
Although not required, should be considered at baseline and repeated as clinically necessary 
during the treatment period with carboplatin for patients with a history of hearing loss. 
3 
Radiographic tumor measurements should be obtained via imaging of the chest, abdomen 
and pelvis to establish the location and extent of disease. See RECIST 1.1 for allowable 
imaging modalities used to assess disease at baseline (and subsequent assessments). Contrast 
CT is the preferred modality. 
4 
Core biopsy (not cytology or fine needle aspiration) or laparoscopic biopsy must have been 
performed (within standard clinical care) prior to enrollment to confirm diagnosis (see 
section 3.2.2). (10/10/2016) 
5 
FSH if needed to determine menopausal status per 3.3.16


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4.2 
ASSESSMENTS DURING TREATMENT 
4.2.1  ASSESSMENTS DURING TREATMENT – PHASE I  NOTE: The Phase I portion of the study is complete. (04/06/2018) 
 
 
Assessments 
 
 
Prior to Cycles 2-6   
(03/20/2017)  
During Cycles 1 – 6 of 
Carboplatin/Paclitaxel/ 
Ruxolitinib 
During Maintenance Ruxolitinib 
Days 8 & 15 
TRS1 
Prior to Each Cycle 
(Cycles 7- 12) 
Prior to Every 
Other Cycle 
(Cycles ≥ 13) 
Timed (Treatment 
Cycle Independent) 
History and Physical 
≤ 1 day of treatment 
 
Prior to TRS4 
≤ 1 day of treatment 
≤ 1 day of treatment 
 
Vital Signs  
(Blood Pressure, Heart Rate, 
Temperature) 
Day of treatment 
Day of treatment 
Prior to TRS4 
Day of treatment 
Day of treatment 
 
Performance Status 
≤ 1 day of treatment 
 
Prior to TRS4 
≤ 1 day of treatment 
≤ 1 day of treatment 
 
Toxicity Assessment  
≤ 1 day of treatment1 
≤ 1 day of treatment2 
Prior to TRS4 
≤ 1 day of treatment 
≤ 1 day of treatment 
 
Concurrent Medications 
≤ 1 day of treatment 
 
 
≤ 1 day of treatment 
≤ 1 day of treatment 
 
CBC/Differential/ 
Platelets 
≤ 3 days of treatment 
≤ 1 day of treatment  
Prior to TRS4 
≤ 3 days of treatment 
≤ 3 days of treatment 
 
Electrolytes, including, BUN, 
creatinine, Ca, and magnesium  
≤ 3 days of treatment 
 
Prior to TRS4 
≤ 3 days of treatment 
≤ 3 days of treatment 
 
CrCl by the Cockcroft-Gault 
Formula (10/10/2016) 
≤ 3 days of treatment 
 
 
≤ 3 days of treatment 
≤ 3 days of treatment 
 
Bilirubin, ALT, AST, Alkaline 
Phosphatase, Albumin 
≤ 3 days of treatment 
 
Prior to TRS4 
≤ 3 days of treatment 
≤ 3 days of treatment 
 
CA-125 
≤ 3 days of treatment 
 
Prior to TRS4 
≤ 3 days of treatment 
≤ 3 days of treatment 
 
Radiographic Tumor 
Measurement3 
 
 
Prior to TRS6 
 
 
X6 
Documentation of Gross 
Residual Disease 
 
 
At time of 
TRS 
 
 
 
Patient Pill Calendar5 
≤ 1 day of treatment 
 
Prior to TRS4 
≤ 1 day of treatment 
≤ 1 day of treatment 
 
1 
TRS = Tumor Reductive Surgery. See section 5.3 and Appendix VIII for guidelines.   
2 
Toxicity assessment should occur weekly during Cycles 1 and 2. Beginning in Cycle 3, toxicity assessments will occur prior to each cycle for Cycles 3-6. 
3 
Radiographic tumor measurements should be obtained via imaging of the chest, abdomen and pelvis to re-assess disease using the same modality as for pre-
treatment baseline imaging (see section 4.1), until disease progression is confirmed according to guidelines in section 13.1.3; at the investigator’s discretion, 
they can be repeated any other time if clinically indicated based on symptoms, physical signs or rising CA-125 levels suggestive of new or progressive 
disease. A tool is provided to calculate dates of re-imaging. 
4  
Within 3 weeks after completing cycle 3. Prior to TRS.  
5 
See Appendix VI. 
6 
Within 3 weeks of completing Cycle 6, prior to initiating Cycle 7 (maintenance ruxolitinib); then every 12 weeks (+/- 7 days) following cycle 7, day 1 
(regardless of delays and/or changes in treatment schedule) for the first 2 years; then every 24 weeks for the next 3 years; then annually.  
 


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4.2.2  
ASSESSMENTS DURING TREATMENT – PHASE II (04/06/2018) 
 
Assessments 
Prior to Cycles 2-6   (03/20/2017) 
During Cycles 1 – 6 of 
Carboplatin/Paclitaxel/ +/- Ruxolitinib 
Post-Treatment Visit7 
Days 8 & 15 
TRS1 
 
History and Physical 
≤ 1 day of treatment 
 
 
Day of visit 
Vital Signs  
(Blood Pressure, Heart Rate, Temperature) 
Day of treatment 
Day of treatment 
Prior to TRS4 
Day of visit 
Performance Status 
≤ 1 day of treatment 
 
Prior to TRS4 
Day of visit 
Toxicity Assessment  
≤ 1 day of treatment2 
≤ 1 day of 
treatment2 
Prior to TRS4 
Day of visit 
Concurrent Medications 
≤ 1 day of treatment 
 
 
 
CBC/Differential/ 
Platelets 
≤ 3 days of treatment 
≤ 1 day of treatment 
Prior to TRS4 
≤ 3 days of visit 
Electrolytes, including, BUN, creatinine, Ca, and 
magnesium  
≤ 3 days of treatment 
 
Prior to TRS4 
≤ 3 days of visit 
CrCl by the Cockcroft-Gault Formula (10/10/2016) 
≤ 3 days of treatment 
 
 
 
Bilirubin, ALT, AST, Alkaline Phosphatase, Albumin 
≤ 3 days of treatment 
 
Prior to TRS4 
≤ 3 days of visit 
CA-125 
≤ 3 days of treatment 
 
Prior to TRS4 
≤ 3 days of visit 
Radiographic Tumor Measurement3 
 
 
Prior to TRS 
≤ 7 days of visit 
Documentation of Gross Residual Disease 
 
 
At time of TRS 
 
Patient Pill Calendar (for patients receiving 
Ruxolitinib)5 
≤ 1 day of treatment 
 
Prior to TRS4 
Day of visit 
Tissue Samples for Histologic Diagnosis6 
 
 
At time of 
TRS6 
 
BRCA1/2 Testing8 (04/05/2019) 
 
 
 
 
 
1 
TRS = Tumor Reductive Surgery. See section 5.3 and Appendix VIII for guidelines. 
2 
Toxicity assessment should occur weekly during Cycles 1 and 2. Beginning in Cycle 3, toxicity assessments will occur prior to each cycle for Cycles 3-6. 
3 
Radiographic tumor measurements should be obtained via imaging of the chest, abdomen and pelvis to re-assess disease using the same modality as for pre-
treatment baseline imaging (see section 4.1), until disease progression is confirmed according to guidelines in section 13.1.3; at the investigator’s discretion, 
they can be repeated any other time if clinically indicated based on symptoms, physical signs or rising CA-125 levels suggestive of new or progressive 
disease. A tool is provided to calculate dates of re-imaging. 
 
Radiographic tumor measurement should be obtained at the following time points: prior to TRS at 11 weeks (+/- 14 days) following cycle 1, day 1; and at 26 
weeks (+/- 14 days) following cycle 1, day 1 [at 20 weeks (+/- 14 days) for patients who do not undergo TRS due to evidence of non-response or medical 
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4 
Within 3 weeks after completing cycle 3. Prior to TRS. 
5 
See Appendix VI.  
6 
See section 5.3 for guidelines related to TRS. Gross tumor tissue should be analyzed histologically per standard anatomic pathology procedures. In the 
absence of gross tumor tissue, tissue from the required specimens removed surgically in accordance with section 5.3 guidelines should be assessed 
histologically. There must be sufficient FFPE tissue representative of microscopic tumor available for laboratory analysis (see section 10 for requirements); 
the only exception to this requirement would be evidence of pathologic complete response. For patients that do not undergo TRS (in the case of disease 
progression, failure to respond to first 3 cycles of protocol therapy or TRS medically contraindicated), imaging guided core biopsies should be obtained 
which fulfill basic requirements for tissue studies as detailed in Section 10. 
7 
3 weeks +/- 7 days following Cycle 6, Day 1 treatment. 
8 
Comprehensive BRCA1/2 testing results (i.e., comprehensive BRCA1 and BRCA2 sequencing including assessment of gene rearrangements) must be 
submitted for all patients enrolled to Amendment 7 and subsequent amendments. BRCA testing results are optional for all patients enrolled prior to 
Amendment 7. Patients with prior BRCA1/2 testing should provide a formal copy of BRCA1/2 testing results, consisting of both the official BRCA1/2 
testing report and, if appropriate, per Section 3.2.14, documentation by an appropriate qualified medical professional. The BRCA Status Form must also be 
completed in Rave. (04/05/2019) 
 
 


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4.3 
ASSESSMENTS IN FOLLOW UP 
 
4.3.1 ASSESSMENTS IN FOLLOW UP – PHASE I (04/06/2018)  NOTE: The Phase I 
portion of the study is complete. 
 
Assessments 
Schedule 
Toxicity Assessment 
X1 
Radiographic tumor measurement 
X2 
 
1 
Patients who discontinue treatment for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. For reporting of delayed toxicity, 
see Section 7. 
 
2 
In the case that protocol directed therapy is discontinued for reasons other than 
disease progression, follow radiographic tumor measurement schedule as defined 
under section 4.2.1, until disease progression documented by RECIST 1.1 (see 
section 13.1.3) or until patient initiates a subsequent cancer therapy. 
 
4.3.2 ASSESSMENTS IN FOLLOW UP – PHASE II (04/06/2018)   
 
Assessments 
Schedule 
History and Physical 
X1 
Serum CA-125 Level 
X1 
Vital Status 
X2 
Toxicity Assessment 
X3 
Radiographic tumor measurement4 
X1 
 
1 
Every 12 weeks (+/- 7 days) for the first 2 years; then every 24 weeks (+/- 7 days) 
for the next 3 years until disease progression or patient initiates a subsequent 
cancer therapy except for olaparib maintenance therapy as indicated in women 
with deleterious or suspected deleterious BRCA1 or BRCA2 mutations who are in 
complete or partial response to carboplatin and paclitaxel with or without 
ruxolitinib. (04/05/2019) 
 
2 
Vital Status should be reported every 3 months for 2 years and then every 6 
months for 3 years. Follow-up forms are collected for the 5-year follow-up period 
or until study termination. 
 
3 
Patients who discontinue treatment for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. For reporting of 
delayed toxicity, see Section 7. 
 
4 
Radiographic tumor measurements should be obtained via imaging of the chest, 
abdomen and pelvis to re-assess disease using the same modality as for pre-
treatment baseline imaging (see section 4.1), until disease progression is 
confirmed according to guidelines in section 13.1.3; at the investigator’s 


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discretion, they can be repeated any other time if clinically indicated based on 
symptoms, physical signs or rising CA-125 levels suggestive of new or 
progressive disease. A tool is provided to calculate dates of re-imaging. 
 
 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION 
 
Study sites must follow General Chemotherapy Guidelines in Appendix IV. Note 
that the maximum dose of carboplatin will be 750 mg at an AUC of 5 and 900 mg at an 
AUC of 6. 
 
Protocol treatment must begin within 7 days after registration. 
 
Cycles are 21 days in duration. 
 
Treatment will be given in the outpatient setting. (10/10/2016) 
 
 
Treatment Regimens 
 
5.1.1 Phase I Component  (04/06/2018)   
 
NOTE:  The Phase I portion of this study is complete.  Please 
proceed to Section 5.1.2 for the Phase II Component. 
 
Limited access for phase I component. The phase I component will be conducted only in 
a limited number of phase I NRG sites, to assure timely assessment and weekly reporting. 
 
5.1.1.1 Chemotherapy - Cycles 1-3: (10/10/2016) 
 
Ruxolitinib (see dose levels Table below) orally (PO) twice daily (BID), continuously on 
Days 1 – 21. The first dose of ruxolitinib will be taken at least 1 hour prior to the first 
dose of paclitaxel on Cycle 1, Day 1. The dose of ruxolitinib will be assigned according 
to the dose escalation Table below at the time of patient enrollment. 
 
 
 


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Ruxolitinib will be self-administered by the study patient orally (PO) without regard to 
food in an outpatient setting twice daily (BID) approximately 12 hours apart, generally 
after the morning and evening meal.  If the patient is more than 4 hours late in taking a 
dose, the dose should be skipped. 
 
Ruxolitinib dose should not be replaced in the event of emesis. (03/20/2017) 
 
Paclitaxel 70 mg/m2 or 80 mg/m2 IV (see Table below) over 1 hour on Days 1, 8 and 15 
 
Carboplatin AUC 5 or 6 (see Table below) IV over 30 min on Day 1.  
 
Phase I Dose Levels 
 
Dose Level 
 
Agent 
Patients 
(range) 
Carboplatin 
(AUC) 
Paclitaxel 
mg/m2/wk 
Ruxolitinib 
(mg) 
-2 
4-7 
5 
70* 
5 bid 
-1 
4-7 
5 
70* 
10 bid 
1 (Starting Dose 
Level) 
4-7 
5 
70* 
15 bid 
2 
4-7 
6 
70* 
**RD5.70 -1 
3 
4-7 
6 
70* 
**RD5.70 
4 
4-7 
6 
80 
***RD6.70 -1 
5 
4-7 
6 
80 
***RD6.70 
 
* If no DLT is encountered through the first 2 cycles of therapy, the dose of paclitaxel 
may be escalated to 80 mg/m2 per discretion of the site investigator. 
**RD5.70 = Recommended dose of ruxolitinib with carboplatin AUC=5 and paclitaxel 
70 mg/m2/wk 
***RD6.70 = Recommended dose of ruxolitinib with carboplatin AUC=6 and paclitaxel 
70 mg/m2/wk 
 
In general, once RD5.70 is established, carboplatin and paclitaxel will be escalated 
sequentially, in an attempt to define RD6.70 and RD6.80, de-escalating ruxolitinib at 
each escalation of carboplatin or paclitaxel, unless ruxolitinib is already at the minimum 
dose of 5 bid, in which case that dose will be maintained.  The rationale for this design is 
detailed in section 2.4. 
 
The starting dose level (Dose Level 1) will consist of carboplatin AUC 5, paclitaxel 70 
mg/m2/wk and ruxolitinib at 15 mg bid.  
 
If Dose Level 1 is considered safe, then will escalate in a linear fashion to Dose Level 2 
(in this case carboplatin AUC 6, paclitaxel 70 mg/m2/wk, ruxolitinib 10 mg bid), then 
Dose Level 3 (in this case carboplatin AUC 6, paclitaxel 70 mg/m2/wk, ruxolitinib 15 mg 
bid), then Dose Level 4 (in this case carboplatin AUC 6, paclitaxel 80 mg/m2/wk, 
ruxolitinib 10 mg bid), then Dose Level 5 (in this case carboplatin AUC 6, paclitaxel 80 
mg/m2/wk, ruxolitinib 15 mg bid). If Dose Level 5 is considered safe, then Dose Level 5 


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will be considered the phase II regimen. If any dose level beyond Dose Level 1 is deemed 
too toxic, then the previous dose level will be declared the phase II regimen. 
 
If Dose level 1 is deemed too toxic, then this could be secondary to ruxolitinib dose. In 
that case, will dose de-escalate to Dose Level -1.  
 
If Dose Level -1 is deemed too toxic, this could be secondary to ruxolitinib dose. In that 
case, will Dose de-escalate to Dose Level -2.  
 
• Arrows indicate re-escalation to levels with higher Carboplatin AUC and/or 
higher weekly paclitaxel dose, but with lower ruxolitinib dose, in order to 
control for the possibility that dose limiting toxicity had been dependent on 
ruxolitinib dose (however, the dose level of ruxolitinib will not be de-escalated 
below 5 bid): 
 
o If Dose Level -1 is considered safe, then will escalate to Dose 
Level 2 (in this case carboplatin AUC 6, paclitaxel 70 mg/m2/wk, 
ruxolitinib 5 mg bid). In that case, if Dose Level 2 is considered 
safe, then will escalate to Dose Level 3 (in this case carboplatin 
AUC 6, paclitaxel 70 mg/m2/wk, ruxolitinib 10 mg bid). If Dose 
Level 3 is considered safe, then will escalate to Dose Level 4 (in 
this case carboplatin AUC 6, paclitaxel 80 mg/m2/wk, ruxolitinib 5 
mg bid). If Dose Level 4 is considered safe, then will escalate to 
Dose Level 5 (in this case carboplatin AUC 6, paclitaxel 80 
mg/m2/wk, ruxolitinib 10 mg bid). If Dose Level 5 is considered 
safe, then Dose Level 5 will be considered the phase II regimen. If 
any dose level beyond Dose Level -1is deemed too toxic, then the 
previous dose level will be declared the phase II regimen.  
o If Dose Level -1 is deemed too toxic but Dose Level -2 is 
considered safe, then will escalate to Dose Level 3 (in this case 
carboplatin AUC 6, paclitaxel 70 mg/m2/wk, ruxolitinib 5 mg bid). 
If Dose Level 3 is considered safe, then will escalate to Dose Level 
4 (in this case carboplatin AUC 6, paclitaxel 80 mg/m2/wk, 
ruxolitinib 5 mg bid). If Dose Level 4 is considered safe, then Dose 
Level 4 will be considered the phase II regimen, since the 
ruxolitinib dose will not be re-escalated above 5 mg bid in this 
scenario.  If any dose level beyond Dose Level -2 is deemed too 
toxic, then the previous dose level will be declared the phase II 
regimen. 
o If Dose Level -2 is deemed too toxic, it will be considered unsafe 
to proceed to phase II. 
  
During the Phase I portion, in which the dose limiting toxicities of the study agents will 
be assessed over cycles 1 and 2, enrollment to a dose level will be staggered so that no 
more than 4 participants will be at risk at any given time. All enrolling sites will be 
required to participate in a regularly scheduled teleconference with the Study Chair and 


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Phase I Subcommittee Chair, and their assigned delegates. 
 
5.1.1.1.1 
Pre-Medication: 
 
Paclitaxel 
 
Due to the risk of immediate hypersensitivity reaction, paclitaxel should always 
be infused before carboplatin. 
 
For all courses where paclitaxel is to be administered, it is recommended that a 
preparative regimen be employed prior to the treatment regimen, to reduce the 
risk associated with hypersensitivity reactions to this drug.  
 
This regimen should include standard dose(s) of dexamethasone (either IV or 
PO), an anti-histamine H1 (diphenhydramine 25-50 mg IV or orally, or an 
equivalent dose of an alternate H1 blocker such as loratadine or fexofenadine), 
and a standard dose of anti-histamine H2 IV (such as cimetidine, ranitidine, or 
famotidine). 
 
5.1.1.1.2 
Dosing of Carboplatin 
 
See Appendix V for current dosing instructions.  
 
Note that carboplatin dose will be recalculated if patient has weight change ≥ 10% 
from baseline. 
 
5.1.1.1.3 
Assessment of Compliance with Ruxolitinib 
 
Patients will be required to maintain a pill calendar (see Appendix VI) to be 
reviewed by the investigator or designee at study visits according to section 4.2. 
Patients will also be instructed to bring their ruxolitinib bottles with them to each 
study visit.  Pill counts will be conducted to assess medication compliance. 
 
Compliance with ruxolitinib will be calculated, by SDMC, based on the drug 
accountability documented by the investigator or designee and monitored by 
SDMC by review of pill calendars.  
 
5.1.1.2 Interval Tumor Reductive Surgery 
 
Barring evidence of non-response, disease progression or medical contraindication, the 3 
cycles of chemotherapy will be followed by interval tumor reductive surgery (TRS) 
within 6 weeks after completion of cycle 3, as soon as nadir counts permit and surgery 
deemed safe by investigator. Disease progression by RECIST (see section 13.1) is an 
absolute contraindication to proceeding with TRS. Relative contraindications to 
proceeding with TRS would include either stable disease or development of medical 
comorbidities that would put a patient at high surgical risk. Relative contraindications to 


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proceeding with TRS require discussion with the Study Chair or Study Co-Chair prior to 
omitting TRS.  See section 5.3 and Appendix VIII for details regarding TRS. 
 
5.1.1.3 Chemotherapy Cycles 4-6 
 
Barring disease progression or unacceptable toxicity, resume treatment with Paclitaxel, 
Carboplatin and Ruxolitinib (same dose level as for cycles 1-3) as soon as investigator 
deems safe, within 6 weeks of surgery.  
 
If TRS is not performed due to non-response or medical contraindications (see section 
5.1.1.2) and criteria for discontinuation of protocol therapy have not been met, Cycle 4 of 
protocol therapy should be initiated with no treatment break. 
 
5.1.1.4 Chemotherapy - Maintenance Ruxolitinib (Phase I portion Only) (10/09/2017) 
 
Patients who complete all cycles of chemotherapy will continue Ruxolitinib alone at 
the C6 dose/schedule until disease progression, unacceptable toxicity or voluntary 
withdrawal. Maintenance therapy will be initiated after completing C6.  Day 1 
treatment during maintenance therapy will not be given until the ANC is ≥ 1,000 
cells/mcl and the platelet count is ≥ 75,000/mcl. Treatment with ruxolitinib will be 
delayed for a maximum of 3 weeks beyond completion of C6 (6 weeks from day 1 of C6) 
until these values are achieved. Patients who fail to recover adequate counts within this 
time frame will no longer receive any protocol-directed therapy.  
 
During the maintenance phase of therapy with ruxolitinib, the dose of ruxolitinib should 
be initiated based on platelet count at the conclusion of cycle 6 of chemotherapy after 
recovery of platelet count to ≥75,000/mcl, as follows: For platelet count  ≥100,000/mcl, 
initiate at dose level as administered during cycle 6 with chemotherapy. For platelet count 
of 75,000/mcl to less than 100,000/mcl, reduce one dose level (see Table A).  
 
Following subsequent hematologic evaluations specified in section 4.2, the dose of 
ruxolitinib should be modified according to the following rules, using dose levels 
specified in Section 6 Table A and the following platelet count ranges:  
• ≥100,000/mcl 
• 75,000/mcl to less than 100,000/mcl 
• 50,000/mcl to less than 75,000/mcl.  
 
If subsequent platelet count decreases into the next lower range, reduce one dose level.  
No dose level re-escalation is permitted.  Discontinue study therapy for platelet count < 
50,000/mcl.   
 
5.1.1.5 Definition of Dose-Limiting Toxicity (DLT) (10/10/2016) 
 
DLT is defined as either hematologic or non-hematologic toxicity (assessed in 
accordance with the CTEP CTCAE Version 4.0), which cause any of the following: 
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• Dose delay > 7 days related to any toxicity (treatment related adverse event). 
 
• Omission of day 8 or day 15 paclitaxel 
 
• Any treatment related death. 
 
Hematologic Toxicity:  
 
• Study treatment-related febrile neutropenia. 
 
• Grade 4 neutropenia lasting > 7 days. 
 
• Study treatment-related Grade 4 thrombocytopenia or bleeding associated with 
Grade 3 thrombocytopenia. 
 
Non-Hematologic Toxicity: 
 
• Study treatment-related Grade 3 or Grade 4 non-hematological toxicity (excluding 
alopecia, paclitaxel hypersensitivity reaction; and excluding fatigue, other 
hypersensitivity reaction, pain, depression, dyspepsia, nausea, vomiting, 
dehydration, hypotension, constipation, diarrhea, dizziness, extremity edema, 
peripheral ischemia,  hypokalemia, hyperkalemia, hypomagnesemia, 
hypocalcemia, and hypophosphatemia, and infusion reaction responsive to 
medical management and supportive care).   
 
5.1.1.6 Dose Escalation Design (10/10/2016) (03/20/2017) 
 
At each dose level, DLT will be based on cycle 1 and 2 of therapy, though the phase II 
dose could be modified after evaluation of cumulative data. Patients who experience DLT 
will be treated as per standard care based on the judgment of the investigator, without 
ruxolitinib, but will continue on study to evaluate whether or not such patients undergo 
interval tumor reductive surgery within 6 weeks of completing cycle 3 therapy for 
reasons other than non-response, disease progression, or medical contraindications. 
Patients who do not experience DLT and who do not complete 2 cycles of therapy will be 
replaced. Patients who miss more than 25% of ruxolitinib doses in the first two cycles of 
therapy (based on pill diary review) without medical justification would also be replaced. 
 
For all dose levels, 4 participants will be enrolled initially, per cohort. If no DLTs are 
observed through 2 cycles of therapy in these 4 participants, then the dose level would be 
considered safe and escalation to the next higher dose level. Otherwise, the dose level 
will be expanded to up to 3 additional participants. Out of 7 participants, a dose level 
with 2 or fewer participants experiencing DLT events over the first 2 cycles of therapy 
would be considered safe. As indicated previously, enrollment to a dose level will be 
staggered so that no more than 4 participants are at risk at any given time. There are two 
dose de-escalation levels for ruxolitinib (see table in section 5.1.1.1) should the starting 


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dose level (1) be considered too toxic (≥3 participants experiencing a DLT).  If one of 
these dose levels is considered safe, then re-escalation to successive levels is permitted, 
increasing first carboplatin AUC, then weekly paclitaxel dose. 
 
No intra-patient dose escalations will be allowed.  
 
No patient may be enrolled at the next higher dose level until all patients at the previous 
dose level have been followed through the end of the second cycle.  
 
As the initial treatment of ovarian cancer and related malignancies with paclitaxel and 
carboplatin is known to require treatment modifications to maintain dose-intensity and 
cumulative dose-delivery, treatment modification will be allowed as specified in Section 
6. 
 
5.1.2 PHASE II Component  
 
5.1.2.1 Chemotherapy Cycles 1-3 
 
 
 
Pre-Medication: 
 
Paclitaxel 
 
Due to the risk of immediate hypersensitivity reaction, paclitaxel should always be 
infused before carboplatin. 
 
For all courses where paclitaxel is to be administered, it is recommended that a 
preparative regimen be employed prior to the treatment regimen, to reduce the risk 
associated with hypersensitivity reactions to this drug.  
 
This regimen should include standard dose(s) of dexamethasone (either IV or PO), an 
anti-histamine H1 (diphenhydramine 25-50 mg IV or orally, or an equivalent dose of an 
alternate H1 blocker such as loratadine or fexofenadine), and a standard dose of anti-
histamine H2 IV (such as cimetidine, ranitidine, or famotidine). 
 
5.1.2.1.1 
Reference Regimen - Treatment Arm 1 (07/30/2018) 
Paclitaxel 80 mg/m2 IV over 1 hour on Days 1, 8 and 15.  
Carboplatin AUC 6 IV over 30 min on Day 1. 
 
5.1.2.1.2 Experimental/Ruxolitinib Regimen - Treatment Arm 2 (04/06/2018) (07/30/2018)   
 
Ruxolitinib 15 mg PO BID, continuously on Days 1 – 21. The first dose of 
ruxolitinib will be taken at least 1 hour prior to the first dose of paclitaxel on 
Cycle 1, Day 1.  If the patient is more than 4 hours late in taking a dose, the dose 
should be skipped. 
 
Paclitaxel 70 mg/m2 IV over 1 hour on Days 1, 8 and 15.  


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Carboplatin AUC 5  IV over 30 min on Day 1. 
 
5.1.2.2 Interval Tumor Reductive Surgery (TRS) 
 
Barring evidence of non-response, disease progression or medical contraindication, the 3 
cycles of chemotherapy will be followed by interval tumor reductive surgery (TRS) 
within 6 weeks after completion of cycle 3, as soon as nadir counts permit and surgery 
deemed safe by investigator. Disease progression by RECIST (see section 13.1) is an 
absolute contraindication to proceeding with TRS. Relative contraindications to 
proceeding with TRS would include either stable disease or development of medical 
comorbidities that would put a patient at high surgical risk. Relative contraindications to 
proceeding with TRS require discussion with the Study Chair or Study Co-Chair prior to 
omitting TRS. See section 5.3 and Appendix VIII for details regarding TRS. 
 
5.1.2.3 Chemotherapy Cycles 4-6 (04/06/2018)   
 
Barring disease progression or unacceptable toxicity, resume protocol therapy as soon as 
investigator deems safe but within 4 weeks of surgery. 
 
If TRS is not performed due to non-response or medical contraindications (see section 
5.1.2.2) and criteria for discontinuation of protocol therapy have not been met, Cycle 4 of 
protocol therapy should be initiated with no treatment break.  As noted in Section 5.9, 
inability to resume protocol therapy within 3 weeks after the completion of Cycle 3 for 
patients who do not undergo TRS due to non-response or medical contraindications 
would require discontinuation of protocol therapy. 
 
5.1.2.3.1 Reference Regimen 
 
Paclitaxel and Carboplatin as in section 5.1.2.1.1 
 
5.1.2.3.2 Experimental/Ruxolitinib Regimen (04/06/2018)   
 
Paclitaxel, Carboplatin and Ruxolitinib as in Section 5.1.2.1.2 
 
 
Radiation Therapy 
 
Not Applicable 
 
 
Tumor Reductive Surgery (TRS)  
 
Barring evidence of non-response, disease progression or medical contraindication, tumor 
reductive surgery (TRS) will be performed within 6 weeks after the completion of Cycle 
3 of protocol therapy. The goals of surgery are documentation of the extent of disease at 
exploration and total resection of all macroscopic and palpable tumor. The purpose and 
details of the procedure are described in Appendix VIII 


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Device  
 
Not Applicable. 
 
 
Imaging (for imaging-focused study) 
 
Not Applicable. 
 
 
Integral Assay/Biomarker  
 
Not Applicable. 
 
 
Intervention Not Otherwise Categorized 
 
Not Applicable. 
 
 
General Concomitant Medication and Supportive Care Guidelines 
 
5.8.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the investigator within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
 
5.8.1.1 Antiemetics (10/10/2016)  
It is anticipated that nausea and vomiting may be a significant side effect of each 
regimen. Follow institution, ASCO or NCCN guidelines for high emetic risk intravenous 
chemotherapy (acute and delayed emesis prevention). NOTE: as moderate inhibitors of 
CYP3A4, aprepitant and other neurokinin 1 (NK1) receptor antagonists can increase 
plasma concentrations of ruxolitinib, NK1 receptor antagonists should be avoided if 
possible. If use of NK1 receptor antagonists is unavoidable, follow section 5.8.2 for 
guidance.  
 
5.8.1.2 Anticoagulants - Use at discretion of investigator. No specific contraindication. 
 
5.8.1.3 Blood products – Use at discretion of investigator. No specific contraindication. 
 
5.8.1.4 Antidiarrheals - Use at discretion of investigator. No specific contraindication. 
 
5.8.1.5 Analgesics - Use at discretion of investigator. No specific contraindication. 
 
5.8.1.6 Hematopoietic Growth Factors – see section 6.1 
 
5.8.1.7 Nutritional supplementation - Use at discretion of investigator. No specific 
contraindication. 
 


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5.8.2 Prohibited Therapies 
 
 Amifostine 
 Inducers of CYP3A4 (Appendix VII) may be used with caution, and investigators 
should seek other options if available.  
 Use of potent inhibitors of CYP3A4 (ketoconazole, clarithromycin, itraconazole, 
nefazodone or telithromycin, voriconazole or posaconazole, see Appendix VII) and 
use of fluconazole should be avoided; any intended use should be discussed with the 
Study Chair or Study Co-Chair prior to co-administration. If approved by the Study 
Chair or Study Co-Chair, dose modifications of ruxolitinib will be made according to 
section 2.3 of the Jakafi (ruxolitinib) Prescribing Information 
(https://www.jakafi.com/pdf/prescribing-information.pdf), with frequent complete 
blood count monitoring during the period of co-administration.  Based on the low 
overall bioavailability of topical ketoconazole, there are no restrictions on topical 
ketoconazole in the study. (10/10/2016) 
 Moderate CYP3A4 inhibitors (Appendix VII) may be used with caution. Differences 
in individual sensitivity and variation in potency of inhibition of various CYP 
enzymes may result in the need for a reduced dose of ruxolitinib during a period of 
concomitant medication use. Any intended use should be discussed with the Study 
Chair or Study Co-Chair prior to co-administration. If used, the ruxolitinib dose may 
be reduced from BID to QD with frequent complete blood count monitoring during 
the period of co-administration.  
 Use of any concurrent anticancer therapy (eg, chemotherapy, radiation therapy, 
surgery, immunotherapy, biologic therapy, hormonal therapy, or tumor embolization) 
other than those specified in the Protocol.  
 Concomitant use of a JAK inhibitor.  
 Use of any investigational medication within 30 days or 5 half-lives, whichever is 
longer, prior to Cycle 1, Day 1 of study treatment is prohibited.  
 St John’s wort and rifampin are not permitted at any time during participation in the 
study.  
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements can be found in Appendix X. 
 
5.8.3 Participation in Other Trials  
 
Not applicable. 
 
 
Duration of Therapy (04/06/2018) 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 
Disease progression 
 
Intercurrent illness that prevents further administration of protocol therapy 
 
Unacceptable adverse event(s), as described in Section 6 
 
Inability to resume protocol therapy within 6 weeks following TRS or within 3 weeks 


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after the completion of Cycle 3 for patients who do not undergo TRS due to non-
response or medical contraindications (see sections 5.1.1.2 and 5.1.2.2). (10/09/2017) 
 
Dose-limiting toxicity (Section 5.1.1.5) during Cycle 1 or Cycle 2 of the Phase I 
component. 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
Phase I Only: Patients who discontinue protocol therapy during Cycle 1 through 
Cycle 6 for reasons other than disease progression will be treated as per standard care 
based on the judgment of the investigator, without ruxolitinib, but will continue on 
study to evaluate whether or not such patients undergo interval tumor reductive 
surgery within 6 weeks of completing cycle 3 therapy for reasons other than non-
response, disease progression, or medical contraindications. (03/20/2017)  
 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT (04/06/2018)   
 
This section specifies treatment modifications/management in patients enrolled in 
the phase I component of the trial.  
In order to maintain dose-intensity and cumulative dose-delivery on this study, 
reasonable efforts will be made to minimize dose reduction and treatment delays as 
specified. Any patient whose treatment is delayed must be evaluated on a weekly basis 
until adequate hematologic and non-hematologic parameters have been met. No dose 
escalation is planned for this study. 
 
Table A defines Phase I dose reduction increments for each agent as specified in sections 
6.2 and 6.3.  
 
NOTE: The Phase I portion of the study is complete.  
 
USE TABLE B for Phase II Dosing Instructions. 
 
Table B defines Phase II dose reduction increments for each agent as specified in sections 
6.2 and 6.3. 
 
Table A:  
Intra-patient Dose Reduction Increments for Toxicity in Patients 
Receiving Experimental Regimen (for Phase I portion Only) 
 
 
Drug 
Maximum 
Starting 
Dose 
First 
Incremental 
Reduction 
Second 
Incremental 
Reduction 
Third 
Incremental 
Reduction 
Fourth 
Incremental 
Reduction 
Carboplatin 
(AUC, 
mg/mL/min) 
6 
5* 
4 
Discontinue 
study therapy 
 
Paclitaxel 
80* 
70 
60 
Discontinue 
 


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(mg/m2) 
study therapy 
Ruxolitinib 
(mg AM/mg 
PM) 
15/15 
10/10* 
5/5 
5/0 
Discontinue 
study therapy 
 
*Starting doses in dose level 1 of phase I portion  
 
For the Phase I component, protocol therapy will be discontinued for development of a 
DLT (as defined in Section 5.1.1.5) during Cycle 1 or Cycle 2. The definition of DLT as 
defined in Section 5.1.1.5 and as it relates to the Phase I component should be 
distinguished from references to and definitions of DLT-ANC and DLT-PLT in Section 
6.2. 
 
Table B:  Intra-Patient Dose Reduction Increments for Toxicity for Phase II portion 
 
Drug 
Starting 
Dose 
First 
Incremental 
Reduction 
Second 
Incremental 
Reduction 
Third 
Incremental 
Reduction 
Reference Regimen 
 
 
 
 
Carboplatin (AUC, mg/mL/min) 
6 
5 
4 
Discontinue 
carboplatin 
Paclitaxel (mg/m2) 
80 
70 
60 
Discontinue 
paclitaxel 
Experimental/Ruxolitinib Regimen 
 
 
 
 
Carboplatin (AUC, mg/mL/min) 
5 
4 
Discontinue 
carboplatin 
 
Paclitaxel (mg/m2) 
70 
60 
Discontinue 
paclitaxel 
 
Ruxolitinib (mg AM/mg PM) 
15/15 
10/10 
5/5 
Discontinue 
ruxolitinib 
 
 
 


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6.1 
Treatment modifications based on hematologic toxicity 
Treatment decisions will be based on the absolute neutrophil count (ANC) rather than the 
total white cell count (WBC). 
 
Lower Limits for ANC and Platelet Count 
• Subsequent cycles of treatment for Cycles 2 - 6 will not be initiated until the 
ANC is ≥ 1,000 cells/mcl and the platelet count is ≥ 75,000/mcl. Patients who fail 
to recover adequate counts within a 3-week delay will no longer receive protocol-
directed therapy. 
•  The Day 8 and 15 paclitaxel dose will not be administered unless the ANC is ≥ 
500 cells/mcl and the platelet count is ≥ 50,000/mcl. If not given, these doses are 
omitted and not made up.  
• For patients receiving the experimental regimen, ruxolitinib will be held until 
ANC and platelets recover to allow administration of chemotherapy (paclitaxel 
and/or carboplatin) as specified by the protocol.  
 
During ruxolitinib maintenance (Phase I component only), Day 1 treatment 
will not be given until the ANC is ≥ 1,000 cells/mcl and the platelet count is ≥ 
75,000/mcl. Treatment with ruxolitinib will be delayed for a maximum of 3 
weeks beyond completion of C6 (6 weeks from day 1 of C6) until these values 
are achieved. Patients who fail to recover adequate counts within this time frame 
will no longer receive any protocol-directed therapy. See also Section 5.1.1.4. 
(10/09/2017) 
 
Use of Hematopoietic Cytokines and Protective Agents: 
 
Myeloid growth factor support. It is anticipated that myelosuppression may be a 
significant adverse effect of protocol therapy. In general, patients will NOT receive 
prophylactic myeloid growth factors unless they experience complicated neutropenia, 
treatment delays due to neutropenia, or dose omissions due to neutropenia. In particular, 
myeloid growth factors should not be used to avoid initial chemotherapy dose 
modifications as stipulated in the protocol. Granulocyte-colony stimulating factor (G-
CSF) support with filgrastim will be implemented for febrile neutropenia and for dose-
limiting neutropenia as specified in section 6.2. When G-CSF is used prophylactically in 
subsequent chemotherapy cycles after dose-limiting neutropenia has been documented, it 
is recommended that filgrastim (dose according to institutional standard) will be 
administered daily subcutaneously starting 24-72 hours after the last dose of 
chemotherapy and continuing through hematopoietic recovery. Administration of growth 
factors on the same day as chemotherapy is not recommended. Pegfilgrastim is not 
recommended for chemotherapy regimens given less than every 2 weeks. 
 
Note: JAK inhibition by ruxolitinib may reduce the effectiveness of growth factor 
support. Ruxolitinib will be held when chemotherapy is also held for low ANC (see 
above); this will coincide with situations where filgrastim is used for the active 
management of complicated neutropenia. However, ruxolitinib may be administered 


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concomitantly with prophylactic filgrastim during subsequent chemotherapy cycles after 
dose-limiting neutropenia has been documented in a prior cycle(s). Filgrastim will not be 
administered prophylactically during cycles of ruxolitinib maintenance therapy (applies 
to phase I component only). 
 
Patients will NOT receive prophylactic thrombopoietic agents. 
 
Given the mechanism of action of ruxolitinib, which may inhibit or diminish the efficacy 
of erythropoiesis-stimulating agents (ESAs), and the thromboembolic risk associated with 
ovarian cancer and related malignancies, the use of ESAs is not permitted. Patients 
may receive iron supplements, vitamin B supplementation and/or transfusions as 
clinically indicated for management of anemia.  
 
Patients may NOT receive amifostine or other protective reagents. 
 
6.2 
Modifications for Hematologic Toxicity (Nadirs) (10/10/2016) (04/06/2018)   
Dose-limiting neutropenia (DLT-ANC, defined in section 6.2) or dose limiting 
thrombocytopenia (DLT-PLT, defined in section 6.2) will be handled according to 
Tables B and C.  
 
DLT-ANC is defined by the occurrence of febrile neutropenia, Grade 4 neutropenia 
lasting > 7 days, delay of treatment for more than 7 days because of neutropenia, ANC < 
1000 cells/mcl on Day 1, or omission of day 8 or day 15 paclitaxel because of 
neutropenia.  
 
Febrile neutropenia is defined within the CTCAE as a disorder characterized by an ANC 
<1000/mcl and a single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than one hour. 
 
DLT-PLT is defined as a platelet count < 25,000/mcl (CTC grade 4), bleeding associated 
with a platelet count between 25,000/mcl and 50,000/mcl (CTC grade 3), delay of 
treatment on Day 1 of a cycle > 7 days because of thrombocytopenia, platelet count < 
75,000/mcl on Day 1, or inability to administer day 8 or day 15 paclitaxel due to 
thrombocytopenia.  
 
Anemia: No dose modifications will be made for anemia. Patients may receive red blood 
cell transfusions, and/or iron and vitamin B supplementation using standard supportive 
care guidelines. 
 
Tables B and C delineate the dose-modification rules based on the occurrence of DLT-
ANC and/or DLT-PLT.  Refer to Table B for dose reduction increments. Study therapy 
will be discontinued in the event that any agent is discontinued based on an incremental 
dose reduction.  
 
 
 


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Table C:  
Dose Modification Rules for Dose-Limiting Hematologic Toxicity, 
 
DLT 
ANC 
DLT 
PLT 
1st 
Occurrence 
2nd  
Occurrence 
3rd  
Occurrence 
Yes 
No 
Reduce ruxolitinib (if 
on experimental 
regimen) one dose 
increment. 
Administer GCSF 
starting after day 8 
paclitaxel 
Reduce ruxolitinib (if 
on experimental 
regimen) one dose 
increment. Reduce 
carboplatin 
one dose increment, 
discontinue day 15 
paclitaxel dose,  
and 
administer GCSF 
starting after day 8 
paclitaxel 
Discontinue 
study therapy  
Yes 
Yes 
Reduce ruxolitinib (if 
on experimental 
regimen). 
Reducecarboplatin one 
dose increment and 
administer GCSF 
starting after day 8 
paclitaxel 
Discontinue study 
therapy  
 
No  
Yes 
Reduce ruxolitinib (if 
on experimental 
regimen). Reduce 
carboplatin one dose 
increment 
Discontinue study 
therapy 
 
 
 
During the maintenance phase of therapy with ruxolitinib (Phase I Component only), the dose 
of ruxolitinib should be initiated based on platelet count at the conclusion of cycle 6 of 
chemotherapy and following recovery of platelet count to ≥75 x 109/L with maximum delay of 3 
weeks, as follows: For platelet count > 100 x 109/L, initiate at dose level as administered during 
cycle 6 with chemotherapy. For platelet count of 75 x 109/L to less than 100 x 109/L, reduce one 
dose level (see Table A). Following subsequent hematologic evaluations specified in section 4.2, 
the dose of ruxolitinib should be modified according to the following rules, using dose levels 
specified in Table A and the following platelet count ranges: > 100 x 109/L, 75 x 109/L to less 
than 100 x 109/L, 50 x 109/L to less than 75 x 109/L. This includes the provision to re-escalate 
ruxolitinib dose with recovery of platelet counts. If subsequent platelet count decreases into the 
next lower range, reduce one dose level; conversely, if subsequent platelet count increases into 
the next higher range, increase one dose level. In any case, discontinue study therapy for platelet 
count < 50 x 109/L. (03/20/2017)  
 


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6.3 
Modifications for Non-Hematologic Toxicity (10/10/2016) (04/06/2018)   
Table B above should be used for dose level modifications for non-hematologic toxicity 
only as indicated specifically in the sections below. In general, dose modifications are to 
be made only after maximal medical management has been implemented. 
 
Peripheral Neuropathy. Grade 2 (or greater) peripheral neuropathy requires reduction 
of one dose level in paclitaxel and delay in all subsequent protocol-directed therapy for a 
maximum of three weeks until recovered to Grade 1. If peripheral neuropathy fails to 
recover to Grade 1 by a maximum delay of three weeks from time therapy is due, or 
recurs, then paclitaxel should be withheld from all subsequent chemotherapy cycles. 
 
Renal toxicity (associated with reduction in GFR) is not expected as a direct 
complication of chemotherapy or ruxolitinib in this untreated patient population using the 
prescribed dose and schedule of each regimen. As such, there are no specific dose 
modifications for renal toxicity. However, the target AUC dose of carboplatin must be 
recalculated each cycle in any patient who develops renal insufficiency, defined by serum 
creatinine greater than 1.5 x institutional upper limit normal (ULN). In addition, 
ruxolitinib should be reduced one dose level for estimated CrCl (see section 4.2.1) of 
between 30 and 49 and two dose levels for CrCl between 15 and 29. Ruxolitinib should 
be discontinued for CrCl below 15. Should there be a concomitant indication for dose 
level reduction of ruxolitinib due to a drop in CrCl and hematologic toxicity, only one 
dose level decrease would apply at that time.  
 
Hepatic toxicity is not expected as a direct complication of chemotherapy in this 
untreated patient population using the prescribed dose and schedule for each regimen. 
However, the development of Grade 3 (or greater) elevations in SGOT (AST), SGPT 
(ALT), alkaline phosphatase or bilirubin requires reduction of one dose level in paclitaxel 
and delay in subsequent therapy for a maximum of three weeks until recovered to Grade 
1. 
 
There will be no dose modifications for alopecia, nausea, constipation, hypokalemia, 
hypocalcemia, or hypomagnesemia. It is recommended that routine medical measures 
be employed to manage these adverse events. Grade 3 diarrhea on day of planned 
treatment will require holding of paclitaxel in patients on weekly paclitaxel. Any grade 3 
diarrhea will mandate a one dose level reduction of paclitaxel in future cycles.  In 
addition, since ruxolitinib has been associated with diarrhea, though usually grade 1 to 2, 
ruxolitinib should be held for grade 3 diarrhea until resolution to grade 2 or less. If the 
diarrhea is clearly infectious and has resolved, the above mandated dose reductions do 
not apply. 
 


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In general, the occurrence of a hypersensitivity reaction to paclitaxel is not considered a 
dose-limiting toxicity. Patients may be retreated at full doses after administration of 
medication to prevent hypersensitivity reactions, and adjustments in infusion rates should 
be made. However, if despite these safety measures repeat attempt at infusion of the 
inciting drug results in a recurrent hypersensitivity reaction, the inciting drug should be 
discontinued for the remainder of the study. 
 
Potential modifications for other non-hematologic toxicities with an impact on organ 
function of Grade 2 (or greater) require discussion with one of the study co-chairs except 
where noted below. 
 
Special Modifications of Study Treatment 
 
For any CTCAE Grade 3 non-hematologic adverse event (except controllable 
nausea/emesis) considered to be at least possibly related to study treatment, protocol 
directed treatment should be held until symptoms resolve to ≤ CTCAE Grade 1. If a 
CTCAE Grade 3 adverse event persists for > three weeks or recurs after resumption of 
therapy, the patient may be taken off protocol directed treatment after consulting with the 
Study Chair. 
 
For any CTCAE Grade 4 non-hematologic adverse event (except controllable 
nausea/emesis), the patient may be taken off protocol directed treatment therapy after 
consulting with the Study Chair. 
 
6.4 
Criteria for Discontinuation of Ruxolitinib Maintenance Therapy (Phase I 
Component Only) (10/10/2016) 
 
During the maintenance phase of the phase I component, ruxolitinib will be discontinued 
for unacceptable toxicity defined as grade 3 or greater toxicity; for symptomatic grade 2 
toxicity requiring continuous medical management for 2 weeks; or for asymptomatic 
grade 2 toxicity persisting for two consecutive 3-week cycles. 
 
6.5 
Interruption and Restart of Ruxolitinib for Other Reasons  
 
Except for the hematologic criteria specified in Section 6.2 (and in the case of DLT in 
Cycle 1 or Cycle 2 of the Phase I component, defined in Section 5.1.1.5), interruption of 
ruxolitinib for safety reasons is at the discretion of the investigator. In some 
circumstances, it may be necessary to temporarily interrupt treatment as a result of 
adverse experiences that may have an unclear relationship to study drug. Except for cases 
otherwise specified, restart of ruxolitinib should occur at the most recently administered 
dose. If the same AE recurs following restart of study drug the investigator should 
consider reducing the study drug dose for any subsequent restart after recovery and after 
discussing with Study Chair or Study Co-Chair. 
 
Procedures for Interruption of Ruxolitinib 
 


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In the case of ruxolitinib interruption, the patient should be provided written instructions 
at the study visit, or should be notified by phone with written follow-up as soon as 
possible. Dose modification, interruption, and restart should be recorded by the 
investigator or designee in the patient’s medical record and recorded in the CRF. 
 
6.6 
Guidelines for Use of Cytotoxic Therapy, After Discontinuation of Protocol Directed 
Cytotoxic Therapy and Prior to Disease Progression In Phase II Component (28-
FEB-2020) 
In the absence of disease progression, in the Phase II component of the trial, if treatment 
is delayed more than 21 days for adverse events (as directed specifically in section 6.), 
protocol-directed therapy is discontinued. In that case, a patient may, at discretion of the 
investigator, continue non-protocol directed carboplatin and/or paclitaxel therapy 
(including dose reductions and growth factor support) for up to 6 total cycles of cytotoxic 
therapy, according to best clinical practice standards. There are no specific guidelines in 
this situation for dose modifications, laboratory testing, or use of growth factor support. 
In such situations, treatment data should still be submitted via Rave. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1 
Protocol Agents 
 
Investigational Agents 
The investigational agent administered in NRG-GY007 is ruxolitinib, which is being 
made available under an IND sponsored by NRG Oncology.  For patients receiving 
ruxolitinib, determination of whether an adverse event meets expedited reporting criteria, 
see the reporting table in section 7.52 of the protocol. 
Ruxolitinib:  IND #129988; IND Sponsor: NRG Oncology 
 
Commercial Agents 
The commercial agents in NRG-GY007 are carboplatin and paclitaxel.  For patients 
receiving carboplatin and paclitaxel, determination of whether an adverse event meets 
expedited reporting criteria, see the reporting table in Section 7.52 of the protocol 
 
7.2 
Adverse Events and Serious Adverse Events 
 
 The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 
for AE reporting.  CTCAE version 5.0 will be utilized  for AE reporting beginning April 
1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
(04/06/2018)   
 
 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 


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associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Adverse Events for Investigational Study Agents Not Provided by CTEP 
 
The primary clinical risks with ruxolitinib treatment are the potential sequelae of 
decreased hematopoietic proliferation attributable to the inhibition of growth factor 
pathways associated with JAK inhibition. Dose-dependent, reversible thrombocytopenia, 
anemia, and neutropenia were the most frequent treatment-emergent AEs (TEAEs) 
observed during the Phase 3 clinical studies of ruxolitinib in patients with myelofibrosis. 
Increased rates of infection and anemia are potential risks of myelosuppression. In 
healthy volunteers, patients with rheumatoid arthritis, and patients with pancreatic cancer 
or hormone-refractory prostate cancer, the effects on hematopoietic proliferation have 
been less pronounced, presumably because of greater bone marrow reserve. The most 
frequent non-hematologic AEs in clinical trials have been mild, reversible increases in 
ALT and AST, bruising, hypercholesterolemia, dizziness, headache, and urinary tract 
infections.  
 
For a thorough assessment of the risks of ruxolitinib, see the IB.52 
 
7.4 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information 
 
7.5 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Regulatory Affairs by phone at 215-854-0770. An electronic report 
must be submitted immediately upon re-establishment of the Internet connection. 
 


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 Expedited Reporting Methods 
• CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification 
is electronically submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS24-hour notification must be followed by a complete report within 3 
days.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review.  When submitting supporting source documentation, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each 
page, and fax supporting documentation to the NRG Regulatory Affairs at 215-854-
0716. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
 Expedited Reporting Requirements for Adverse Events  
 
 
7.5.2.1 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 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) 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.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 


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Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
Effective Date:  May 5, 2011 
 
7.5.2.2 Phase 1, 2 and 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a non-IND/IDE within 30 Days of the Last 
Administration of the Commercial Agent/Intervention 1, 2  (10/09/2017) 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the commercial agent(s)/intervention  
An adverse event is considered serious if it results in ANY of the following outcomes:   
7) Death 
8) A life-threatening adverse event  
9) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
10) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
11) A congenital anomaly/birth defect.  
12) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to NRG via 
CTEP-AERS within 24 hours of learning of the AE, followed by a complete report within 3 calendar days of 
the initial 24-hour report. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
24-Hour 3 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 


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Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 3 calendar days of 
the initial 24-hour report. 
 
1Serious adverse events that occur more than 30 days after the last administration of commercial 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
• 
Grade 1 and 2 AEs resulting in hospitalization or prolongation of hospitalization 
    2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half 
lives,   rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
 
 
  
 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
 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.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
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.  
 
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 via CDUS unless otherwise specified. 
 
 Reporting to the Pharmaceutical Company:  The CTEP-AERS report will be sent 
directly to Incyte via the CTEP-AERS system upon submission to NCI.  (10/10/2016) 
 


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 Reporting to the FDA:  The NRG Oncology Regulatory Department will submit an IND 
safety report to the FDA and all participating investigators no later than 15 calendar days 
after determining that the suspected adverse reaction or other information qualifies for 
reporting (21 CFR 312.32(c)(1)).  Any unexpected fatal or life-threatening suspected 
adverse reaction will be reported to the FDA no later than 7 calendar days after initial 
receipt of the information by GOG (21 CFR 312.32(c)(2).  Each report will be submitted 
on FDA Form 3500A (21 CFR 320.31(d) (3)). 
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES (04/06/2018)   
 
8.1 
CTEP Registration Procedures (04/06/2018)   
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
Documentation requirements per registration type are outlined in the table below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
• Added to a site roster 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 


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• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please 
contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov>. 
 
8.1.1 Requirements for NRG-GY007 Site Registration (01/09/2017) (03/20/2017) 
(04/06/2018)    
Before patient enrollment, submit the following documents to the NRG Oncology 
Regulatory Department (See Section 8.1.2.2): 
• 
IRB approval letter (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or a combination is accepted) 
• 
IRB-approved informed consent 
• 
IRB Membership list or IRB assurance number 
• 
FDA Form 1572 for institution PI (study-specific) 
• 
Current CV (signed and dated within 2 years) for institution PI and all sub-
investigators listed on FDA Form 1572 
• 
Medical License for institution PI and sub-investigators listed on FDA Form 1572 
• 
Lab license, certificates, and Normal Lab Values (NLV) for labs listed on FDA Form 
1572 
• 
Signed Investigator Signature Page  
• 
Signed financial Disclosure Form for all investigators listed on FDA Form 1572 
• 
Pharmacy Information Form 
• 
Signed Trial and Toxicity Management Training Certificate of Review* 
 
*Trial and Toxicity Management Training 
 
All institutions participating in this trial will be required to participate in a Trial and 
Toxicity Management Training.  This training will focus on the toxicities and the toxicity 
management around ruxolitinib.  The institution PI and one study coordinator/nurse from 
each site must review the Trial and Toxicity Management slides and submit a signed 
Certificate of Review to satisfy this regulatory requirement.  This is an institution-
specific requirement to participate in this trial.  Training slides will be provided by NRG 
and details for participation are on the NRG-GY007 NRG Oncology web site.  NRG 
Oncology will notify CTSU when an institution has satisfied this requirement. 
 
The NRG Oncology Regulatory Department Administrative Office will receive, review, 
and approve all regulatory documents. Please allow 7-10 days for review and approval 
of all documents prior to screening first patient. 
 
8.1.2 IRB Approval (01/09/2017) (04/06/2018)   
 


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Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support system (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
•  A valid IRB approval 
• Compliance with all protocol specific requirements.  
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this 
study are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office.  For sites using the CIRB, IRB approval information is received from 
the CIRB and applied to the RSS in an automated process.  Signatory Institutions must 
submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via 
IRBManager to indicate their intent to open the study locally.  The CIRB’s approval of 
the SSW is then communicated to the CTSU Regulatory Office.  In order for the SSW 
approval to be processed, the Signatory Institution must inform the CTSU which CIRB-
approved institutions aligned with the Signatory Institution are participating in the study.  
 
8.1.2.2 Submitting Regulatory Documents:  
The required regulatory documents can be submitted electronically or via mail to the 
NRG Oncology Regulatory Department.   
 
NRG Oncology Regulatory Department 
ATTN: NRG-GY007 
1600 JFK Blvd., Suite 1020 
Philadelphia, PA 19103 
E-mail: NRG-GY-Regulatory@NRGOncology.org    
 
8.1.2.3 Checking Your Site’s Registration Status: (01/09/2017) (03/20/2017) 
You can verify your site registration status on the members’ section of the CTSU 
website.  
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• Click on the Regulatory tab 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status given only reflects compliance with IRB documentation and 


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institutional compliance with protocol-specific requirements outlined by the Lead 
Network.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their 
affiliated networks. 
8.2 
Patient Enrollment (04/06/2018)   
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
 
NOTE:  The Phase I portion is complete. 
For the Phase I portion, the SDMC-Buffalo Office web-based patient reservation system 
will be used, in which slots for particular patients are reserved.  Reservations are not 
transferrable to other patients, and if the patient is not enrolled within the required 
timeframe, the reservation is cancelled and the slot is then made available to other 
patients and sites.  If all slots are reserved, patients can be added to a waiting list. 
(10/10/2016) 
 
The URL for the Phase I reservation system can be found at 
https://nrg42.nrgoncology.org/phaseireservations. (03/20/2017) 
 
 Oncology Patient Enrollment Network (OPEN) (04/06/2018)   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. . To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam ) and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient position in the Rave database. OPEN can be accessed at https://open.ctsu.org or 
from the OPEN tab on the CTSU members’ web site https://www.ctsu.org.  To assign an 
IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval.   
 
Prior to accessing OPEN site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your records.  
 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 


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additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
  
8.3 
Data Submission / Data Reporting (04/06/2018)   
 
Data collection for this study will be done exclusively through the Medidata Rave clinical 
data management system.  Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS).  To access Rave via iMedidata, the site user must have an active CTEP-
IAM account (check at < https://ctepcore.nci.nih.gov/iam/index.jsp  >) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site 
Investigator) on either the LPO or participating organization roster at the enrolling site. 
To hold the Rave CRA role or CRA Lab Admin role, the user must hold a minimum of 
an AP registration type.  To hold the Rave Site Investigator role, the individual must be 
registered as an NPIVR or IVR.  Associates can hold read-only roles in Rave.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.  To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page.  Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account.  Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave 
is available on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com.   
 
 


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9. DRUG INFORMATION  
 
9.1 
Ruxolitinib Phosphate, IND# 129988 
 
 Chemical Name:  1H-Pyrazole-1-propanenitrile, β-cyclopentyl-4-(7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-, (βR)-, phosphate (1:1) 
 
 Molecular Formula: C17H18N6.H3PO4 
 
 M.W.:  404.36 
 
9.1.4 Mode of Action: Ruxolitinib is an oral JAK inhibitor with selectivity for JAK1 and 
JAK2. 
 
9.1.5 Formulation:  Round curved white to almost white 5 mg tablets  
 
9.1.6 Route of Administration:  Oral 
 
9.1.7 How Supplied: Ruxolitinib will be supplied in HDPE bottles containing 60 tablets. 
(10/10/2016) 
 
9.1.8 Ordering/Accountability:  
 
 
Initial Supply: Following submission and approval of all required regulatory documents 
(as stated in section 8.1.2), an initial supply may be requested by emailing the drug 
request form to NRG-GY-Regulatory@NRGOncology.org .   
 
 
Subsequent Supply: If additional drug is needed, please email the drug request form to 
NRG-GY-Regulatory@NRGOncology.org  
 
 
Drug Accountability:  All study drug must be accounted for during the course of this 
study.  Site must maintain an NCI Drug Accountability Record Form (DARF).   
 
 
Drug Destruction:  At the conclusion of the study, remaining inventory is documented on 
the DARF and unused drug is to be destroyed as per institution policy and recorded on 
the DARF.  The final DARF must be forwarded to the NRG Oncology Regulatory 
Department via email to NRG-GY-Regulatory@NRGOncology.org   
 
9.1.9 Drug Distribution: All drug orders are shipped via FedEx Priority Overnight delivery for 
shipments to US sites by Incyte.  Each shipment will contain 3 cycles worth of drug.  
 
9.1.10 Stability/Storage:  Ruxolitinib has been shown to be stable for up to 6 months at 40°C 
and up to 24 months when stored at 25°C. 
 


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9.1.11 Concomitant dosing with CYP3A4 substrates52  
Co-administration of ruxolitinib with midazolam increased midazolam Cmax by 14% 
while minimally increasing overall exposure AUC by 9% suggesting that co-
administration of midazolam with ruxolitinib does not lead to clinically meaningful 
increases in the peak known to undergo extensive hepatic as well as intestinal 
metabolism. Thus it was concluded that ruxolitinib did not show any potential to inhibit 
CYP3A4 enzymes and hence no dose adjustment is necessary when ruxolitinib is co-
administered with CYP3A4 substrates. 
 
9.1.12 Interactions Between Ruxolitinib and Either Carboplatin or Paclitaxel52  
Studies thus far have demonstrated no concern for interactions between ruxolitinib and 
either carboplatin or paclitaxel.52 In vitro, ruxolitinib and its M18 metabolite do not 
inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. 
Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant 
concentrations. In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, 
BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems at 
clinically relevant concentrations. Ruxolitinib is not a substrate for the P-gp transporter. 
The major route of elimination of carboplatin is renal excretion. Thus the primary 
determinant of carboplatin clearance is glomerular filtration rate (GFR). Ruxolitinib has 
no effect on GFR based on data from the phase III studies. So it is highly unlikely 
ruxolitinib will affect carboplatin clearance or plasma levels. The metabolism of 
paclitaxel is catalyzed by CYP2C8 and CYP3A4. Ruxolitinib does not inhibit any of 
these enzymes, so there is little chance of an interaction with paclitaxel.  Ruxolitinib is 
metabolized by CYP3A4 and somewhat by CYP2C19.  Neither carboplatin nor paclitaxel 
are inhibitors of either of those enzymes.  
 
9.1.13 Adverse Effects Please refer to the Ruxolitinib IB for complete AE information. 
 
9.1.14 Investigator Brochure52: 
 
To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the investigator brochure for comprehensive pharmacologic 
and safety information. The IB can be requested by sending a request to NRG-GY-
Regulatory@NRGOncology.org  .  In the subject line of the request, please state, “NRG-
GY007 IB Request”.  The following information must be stated in the request: 
 
Institution Name 
CTEP Institution Code 
Principal Investigator 
 
9.2 
Commercial Agents 
Carboplatin (NSC #241240) 
Paclitaxel (NSC #673089) 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
 


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 Adverse Events 
 
Please refer to the package insert for complete discussion of adverse events. 
 
 Administration: 
 
 
 
Please see Sections 5.1.1.1 and 5.1.2.1.2 for administration instructions. Please refer to 
the current FDA-approved package insert provided with each drug and the site-specific 
pharmacy for toxicity information and instructions for drug preparation, handling, and 
storage. 
 
10. 
PATHOLOGY/BIOSPECIMEN 
 
10.1 
Central Pathology Review Guidelines 
 
Not Applicable.  
 
10.2 
Tissue Selection for Integral Marker Testing 
 
Not Applicable. 
 
10.3 
Tissue Selection for Integrated marker testing 
 
Not Applicable. 
 
10.4 
Biospecimen Submission Tables (04/06/2018) (07/30/2018) (04/05/2019) 
 
Biospecimens listed below should not be submitted until after patient registration and 
Bank ID assignment. (10/10/2016) 
 
A detailed description of the biospecimen procedures can be found in Appendix IX. 
 
If biospecimen availability is limited, the mandatory biospecimens listed in section 
10.4.1 should be submitted before the optional biospecimens listed in section 10.4.2. 
 
 Mandatory Biospecimen Submissions (Phase II only) (01/09/2017) (04/06/2018) 
(07/30/2018) (04/05/2019) 
 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s biospecimens as outlined below. 
 
MANDATORY BIOSPECIMENS 
Required Biospecimen (Biospecimen 
Code) 
Collection Time Point 
Sites Ship Biospecimens To 
PRE-TREATMENT 
Pre-treatment Serum (SB01) 
prepared from 7-10mL of blood drawn into 
plain red top tube(s) 
Prior to study treatment 
NRG BB-Columbus within 16 
weeks of registration3 
FFPE Primary Tumor (FP01)1 
Prior to all treatment 
NRG BB-Columbus within 8 


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1st Choice: block 
2nd Choice: 35 unstained slides (30 charged, 
5µm & 5uncharged, 10µm)2 
weeks of registration3 
FFPE Metastatic Tumor (FM01) 1 
1st Choice: block 
2nd Choice: 35 unstained slides (30 charged, 
5µm & 5 uncharged, 10µm) 
Prior to all treatment (Optional if 
FP01 is submitted) 
TUMOR REDUCTIVE SURGERY 
FFPE Interval Primary Tumor (FP02) 1 
1st Choice: block 
2nd Choice: 35 unstained slides (30 charged, 
5µm & 5 uncharged, 10µm)2 
During interval Tumor Reductive 
Surgery (TRS) or image-guided 
biopsy 
NRG BB-Columbus within 16 
weeks of registration23 
FFPE Interval Metastatic Tumor (FM02) 1 
1st Choice: block 
2nd Choice: 35 unstained slides (30 charged, 
5µm & 5 uncharged, 10µm)2 
During interval Tumor Reductive 
Surgery (TRS) or image-guided 
biopsy (Optional if FP02 is 
submitted) 
1 
A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the 
NRG BB-Columbus 
2 
If tumor tissue is limited, priority should be given to the 30 charged, 5µm sections. If less than the 
requested number of slides are available, contact the NRG BB-Columbus 
(BPCBank@nationwidechildrens.org). 
3 
NRG BB-Columbus / Protocol NRG GY007, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org 
 
 Optional Biospecimens (04/06/2018) (07/30/2018) (04/05/2019)   
 
If the patient gives permission to participate in this optional study component, then 
participating sites are required to submit the patient’s biospecimens as outlined below. 
 
Note: Collection materials and shipping labels are not provided for some optional 
biospecimens. Refer to Appendix IX for details. 
 
OPTIONAL BIOSPECIMENS 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
PRE-TREATMENT 
Snap Frozen Primary (RP01) or 
Metastatic (RM01) Tumor1,2 
≥0.2g total weight in cryovials3 
At the time of biopsy for histologic 
confirmation. Tumor tissue should be 
processed in the following order of 
priority: 
1. Snap Frozen (1-5 segments) 
2. Cryopreserved (one segment) 
3. OCT Frozen (two segments) 
 
Submit one of each type - Primary 
preferred; submit metastatic if 
primary not available. If tissue is 
limited, submit at least one segment 
processed in order of priority (above). 
NRG BB-Columbus within 
16 weeks of registration4 
 
Snap Frozen Adjacent Normal (RN01) 
Tissue1,2 
≥0.05g total weight in cryovials3 
Cryopreserved Primary (RP02) or 
Metastatic (RM02) Tumor1,2 
≥0.2g total weight in cryopreservation 
media3 
OCT Frozen Primary (RP03) or 
Metastatic (RM03) Tumor1,2 
≥0.2g total weight in OCT3 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) 
tube(s) 
Prior to receiving any study treatment. 


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Whole Blood for Cell-Free DNA (WB02) 
10mL drawn into a Streck (cell-free 
DNA) tube 
NRG BB-Columbus the day 
the specimen is collected4 
TUMOR REDUCTIVE SURGERY 
Snap Frozen Primary (RP04) or 
Metastatic (RM04) Tumor1,2 
≥0.2g total weight in cryovials3 
During interval Tumor Reductive 
Surgery (TRS) or image-guided 
biopsy. Tumor tissue should be 
processed in the following order of 
priority: 
1. Snap Frozen (1-5 segments) 
2. Cryopreserved (one segment) 
3. OCT Frozen (two segments) 
 
Submit one of each type - Primary 
preferred; submit metastatic if 
primary not available. If tissue is 
limited, submit at least one segment 
processed in order of priority (above). 
NRG BB-Columbus within 
16 weeks of registration4 
 
Cryopreserved Primary (RP05) or 
Metastatic (RM05) Tumor1,2 
≥0.2g total weight in cryopreservation 
media3 
OCT Frozen Primary (RP06) or 
Metastatic (RM06) Tumor1,2 
≥0.2g total weight in OCT3 
Whole Blood (WB03) 
7-10mL drawn into purple top (EDTA) 
tube(s) 
After receiving the first three cycles of 
study treatment; at the time of interval 
Tumor Reductive Surgery (TRS) or 
image-guided biopsy. 
Whole Blood for Cell-Free DNA (WB04) 
10mL drawn into a Streck (cell-free 
DNA) tube 
NRG BB-Columbus the day 
the specimen is collected4 
1 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the 
NRG BB-Columbus. 
2 
If a pathology report is not available for frozen tissue, a copy of the radiology report or operative 
report from the tissue removal procedure must be sent to the NRG BB-Columbus, along with a 
completed copy of the Pathology Verification (Appendix XII). 
3 
Total dimension of each segment should not exceed 1.0x1.0x0.5cm. Each segment should be frozen in 
a separate cryovial. 
4 
NRG BB-Columbus / Protocol NRG GY007, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org 
 
10.5 
Laboratory Testing 
 
Note: Testing of banked biospecimens will not occur until an amendment to this 
treatment protocol (or separate correlative science protocol) is reviewed and approved 
in accordance with National Clinical Trials Network (NCTN) policies.  
 
 Cancer Stem Cells (Exploratory Biomarker) 
 
Pending review and approval in accordance with NCTN policies, unstained sections of 
FFPE will be batch shipped to Drs. Buckanovich and Powell for exploratory biomarker 
analysis including (1) CD8:FOXP3 immunohistochemistry (IHC), (2) tumor CD3, CD4, 
TAI-1, HLA class I and II, and CD68 IHC, and (3) AQUA immunofluorescence and 
quantitative PCR analysis of ALDH, CD133, CD24, and CK19. 
 
 C-Reactive Protein and IL-6 (Exploratory Biomarker) 
 
Pending review and approval in accordance with NCTN policies, aliquots of frozen 


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serum will be batch shipped to Drs. Buckanovich and Powell for analysis of C-reactive 
protein and IL-6. 
 
10.5.3 Optional Biospecimens (04/06/2018) (07/30/2018) (04/05/2019) 
 
 
The purpose of the optional biospecimen collection is to support CPTAC efforts. 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
 
Not applicable. 
 
12. 
MODALITY REVIEWS 
 
Not Applicable. 
 
13. 
ASSESSMENT OF EFFECT  
 
13.1 
Definition of Disease Assessments  
 
Disease progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).53 Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria. 
 
13.1.1  Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT 
scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters.  
 
Note: Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is obtained to 
confirm persistence at least 90 days following completion of radiation therapy.  
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease. Leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal/pelvic masses (identified by physical exam and not CT or MRI), are 


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considered as non-measurable. 
 
Notes: 
Bone lesions:  Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described 
above.  Blastic bone lesions are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non- measurable) since they 
are, by definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion that can be 
reproducibly measured should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
13.1.2 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 


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Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans), but NOT lung. 
  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline, and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible. If possible, body 
scans should be performed with breath-hold scanning techniques. 
 
NRG will not allow PET-CT use for RECIST 1.1 response criteria.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.  
 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): CA-125 alone 
cannot be used to determine progression in this study.  
 


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13.1.3 Criteria for Determining Disease Progression 
 
Determination of disease progression should take into consideration all target (see 
Section 13.1.4) and non-target lesions (see section 13.1.5). 
 
13.1.4 Evaluation of Target Lesions 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
13.1.5 Evaluation of Non-Target Lesions 
 
Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
 
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular 
time point. 
  
Although a clear progression of only “non-target” lesions is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Study Chair or Study Co-
Chair). 
 
13.1.6 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression or death, whichever occurs first. 
 
13.1.7 Survival 
 
Survival is defined as the duration of time from study entry to time of death or the date of 
last contact. 
 
13.1.8 Total Gross Resection 
 
At the time of TRS, total gross resection is defined as no visible or palpable tumor 
remaining after completion of surgery and no evidence of disease on radiographic 
imaging outside of the surgical field at the time of radiographic tumor measurement just 
prior to TRS (see section 4.2). 


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13.1.9 Complete Pathologic Response 
 
At the time of TRS, complete pathologic response is defined as no evidence of disease on 
radiographic imaging at the time of radiographic tumor measurement just prior to TRS 
(see section 4.2), no visible or palpable tumor at the time of surgical exploration, and no 
pathologic evidence of disease in tissue specimens obtained at TRS (see section 5.3 for 
details regarding TRS). 
 
14. 
DATA AND RECORDS 
 
14.1 
Data Management/Collection 
 
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). To access iMedidata/Rave, the 
site user must have an active CTEP-IAM account and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization 
rosters at the enrolling site.  Each person responsible for data management must be on the 
NRG roster in order to receive access to Medidata Rave®. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata 
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings) and will be listed in the 
upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave accounts also will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
 


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14.2 
NRG Data Management Forms (10/10/2016) (04/06/2018) (07/30/2018) (04/05/2019) 
The following forms must be completed for all patients registered and submitted to the 
NRG Oncology Statistics and Data Management Center (SDMC) in Buffalo, NY 
according to the schedule below.  Electronic case report forms must be submitted through 
the Medidata Rave Electronic Data Entry System (www.imedidata.com).    All 
amendments to forms must also be submitted through Medidata Rave.   The operative 
report, discharge summary and pathology reports can be sent to the NRG Oncology 
SDMC in Buffalo, NY via postal mail or uploaded in Medidata Rave. The upload option 
is an alternative method for submitting paper reports. 
 
Form 
Comments 
Baseline Folder  
(Forms due within 2 weeks of registration) 
Baseline/History Forms: 
- 
Visit Information – Baseline Form 
- 
Registration Form 
- 
Pre-Treatment Summary Form 
- 
On Study History Surgery Form 
- 
Pre-Study History Chemotherapy Information 
Form 
- 
Pre-Study Radiation Therapy Information Form 
- 
Concomitant Medications Form 
- 
Vitals Form 
- 
Specimen Consent* 
- 
Vitals Form 
- 
ECG Information Form 
- 
Medical History Form  
- 
Bio-Marker Information Form 
- 
BRCA Status Form**  
 
Baseline Adverse Event Reporting 
- 
Baseline Adverse Event-Terms 
- 
Baseline Adverse Event AE Grades 
 
The appropriate forms will load in the 
Baseline Folder based on the answers 
reported on the corresponding Baseline 
Visit Information form. 
*Phase II only 
 
 
**Required for patients enrolled to  
Amendment 7 and subsequent 
amendments.  Requested, but not 
required, for patients entered before 
Amendment 7. 
Visit Folder 
(Forms due within 2 weeks of the completion of each cycle*) 
Cycle Information and Treatment Forms: 
- 
Visit Information Form 
- 
Post-Treatment Weekly Lab loader** 
- 
Cycle Drug Information Form  
- 
Labs and Chemistries Form 
- 
Lab Loader 
- 
Dose Limiting Toxicity Form 
- 
Vitals Form 
- 
Physical Exam 
The appropriate forms will load in the 
Visit Folder based on the answers 
reported on the corresponding Visit 
Information forms. 
 
*Patients on the Phase 1 portion – the 
forms will be due within 72hrs from the 
start of the subsequent cycle. 
 
 


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- 
 
- 
ECG Information Form 
- 
Biomarker Information 
 
Toxicity Forms: 
- 
Toxicity Report-Section 1 Form 
- 
Toxicity Report – AEs Toxicity Report -AE 
Grades 
 
**Labs and Chemistries Forms will be 
collected prior to each dose of study 
drug. 
 
Solid Tumor Evaluation Folder  
(Forms due within 2 weeks of disease evaluation) 
 
Solid Tumor Evaluation Forms: 
 -     Target Lesions Form 
 -     No Target Lesions Form 
 -     Non-Target Lesions Form 
 -     New Target Lesions Form 
 -     Status and Response Form 
 
 
This protocol uses the STE loader. 
Please report STE forms at specified 
time points as required per protocol.  
A tool is provided to calculate dates of 
re-imaging.  
Pathology Folder 
(Reports and slides due within 6 weeks of registration) 
 
Primary disease: 
- 
Pathology Report (initial core biopsy report) 
- 
Tumor Reductive Surgery Report 
- 
Image guided core biopsy report (submit if 
TRS is not performed) 
 
 
Submit one copy of the pathology 
reports to SDMC in Buffalo, NY via 
postal mail or upload the pathology 
report online via RAVE. 
Surgery Folder 
(forms due within 8 weeks of Surgery) 
This folder will load only for patients who have undergone surgery 
 
- 
Surgery Visit Information Form 
- 
Operative Report 
- 
Pathology Report 
- 
Discharge Summary Report 
- 
Surgical Reporting Form 
- 
Summary of Operative Findings-Bowel 
- 
Summary of Operative Findings-Mesentery 
- 
Summary of Operative Findings Abdominal 
Organs Form 
- 
Summary of Operative Findings Pelvis Form 
- 
Summary of Operative Findings Peritoneum 
Submit one copy of the Pathology, 
Operative, and Discharge Summary 
reports to SDC via postal mail or 
upload the pathology report online via 
RAVE. 
 
♦ Appropriate forms will load based 
on the answers reported on the 
corresponding Surgery Visit 
Information form. 
 


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- 
Summary of Operative Findings Nodes 
Primary Disease Description Form♦ 
- 
Post-Operative Complications Form♦ 
Translational Research Folder 
(Phase II only)  
TR Forms: 
Pre-Treatment - Mandatory 
- 
Pre-Treatment Serum (SB01) 
- 
FFPE Primary Tumor (FP01) 
- 
FFPE Metastatic Tumor (FM01) optional 
Tumor Reductive Surgery - Mandatory 
- 
FFPE Interval Primary Tumor (FP02) 
- 
FFPE Interval Metastatic Tumor (FM02) 
optional 
Pre-Treatment - Optional 
- 
Snap Frozen Primary (RP01) 
- 
Snap Frozen Metastatic (RM01) optional 
- 
Snap Frozen Adjacent Normal (RN01) 
- 
Cryopreserved Primary (RP02) 
- 
Cryopreserved Metastatic (RM02) optional 
- 
OCT Frozen Primary (RP03) 
- 
OCT Frozen Metastatic (RM03) optional 
- 
Whole Blood (WB01) 
- 
Whole Blood for Cell-Free DNA (WB02) 
Tumor Reductive Surgery - Optional 
- 
Snap Frozen Primary (RP04) 
- 
Snap Frozen Metastatic (RM04) optional 
- 
Cryopreserved Primary (RP05) 
- 
Cryopreserved Metastatic (RM05) optional 
- 
OCT Frozen Primary (RP06) 
- 
OCT Frozen Metastatic (RM06) optional 
- 
Whole Blood (WB03) 
- 
Whole Blood for Cell-Free DNA (WB04) 
The appropriate forms will load in the 
Translational Research Folder based on 
the answers reported on the Specimen 
Consent form. 
 
An electronically completed copy of 
Form TR must accompany each 
biospecimen shipped to the NRG BB-
Columbus. Handwritten forms will not 
be accepted. (01/09/2017) 
 
SB01, RP01-03, RM01-03, RN01, and 
WB01-02 is due one week from 
registration 
 
FP01 or FM01 are due 8 weeks from 
registration. 
 
FP02 or FM02, RP04-06, and WB03-04  
are due 16 weeks from registration. 
Treatment Completion Folder 
(Forms due within 2 weeks of treatment completion) 
Treatment Completion Form 
 
Follow-up Visit Folder 
(Forms due within 2 weeks of follow-up visits, disease progression or death) 
Visit Information Follow-Up Form 
 
Follow-Up Form 
 
Follow-Up Period Adverse Event: 
 
 
Follow-up visits should be scheduled 
every 3 months for 2 years, and then 
every 6 months for 3 years for a total of 


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- Follow-Up Adverse Event – Part 1 
- Follow-Up Adverse Event –Terms 
- Follow-Up Adverse Event – AE Grades 
Solid Tumor Evaluation: 
- Target Lesions Form 
- Non-Target Form 
- New Target Lesions Form 
- Status and Response Form 
5 years or until study terminations. 
 
The appropriate forms will load in the 
Follow-up Visit Folder based on the 
answers reported on the corresponding 
Follow-up Visit Information forms. 
 
 
 
14.3 
Summary of Data Submission 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7.5 for information about expedited and routine 
reporting.   
 
For reporting of second primary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is 
required. 
 
14.4 
Global Reporting/Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for 
submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html) 
 
15. 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Design (04/06/2018) (04/05/2019) 
 
Phase I Study: 
The phase I study will escalate dose-levels until an MTD is estimated or the maximum 
dose-level is determined to be safe. The selected dose-level for the phase II study will be 
the dose-level that estimates the MTD or the maximum dose-level in the study 
(whichever is lower). The selected dose will be called “the recommended phase II dose.” 
All patients on this part of the study will receive the experimental regimen. The minimum 
number of patients studied in this part of the study will be 8 (perhaps 4 if the accrual is 
unusually slow). The maximum number of patients studied in the phase I study is not 
expected to exceed 32 patients. Safety will be evaluated by dose-limiting toxicities in 
cycles 1 and 2. 


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Phase II Study: 
The study will prospectively stratify patients before randomization by initial performance 
status (0 or 1 versus 2) and cell type (clear cell versus the high grade 
serous/Endometrioid). Randomization will be 2:1 with approximately twice as many 
patients randomized to the experimental regimen as to the reference regimen. Patients 
with BRCA mutation are anticipated to receive further therapy to delay disease 
progression. The primary analysis will include BRCA status as a post-randomization 
stratification factor. BRCA strata will be BRCA mutated versus not BRCA mutated or 
BRCA status unknown. The total number of patients randomized is expected to be about 
130 in a single stage of accrual. An interim futility analysis will be conducted at 
approximately 1/2 the information time. If the interim futility analysis does not 
recommend further accrual, the study will suspend accrual after consultation with the 
DMC. An analysis of toxicity will be conducted as well. The study will use PFS as the 
primary endpoint to compare the experimental regimen to the reference regimen using a 
log-rank test stratified by performance status, cell type, and BRCA status. 
 
15.2 
Study Endpoints 
 
 Primary Endpoints:  
 
Phase I Endpoint: Whether or not a patient experiences a dose-limiting toxicity (DLT) in 
cycles 1 or 2 (see section 5.1.1.5). 
Phase II Endpoint: Progression-free survival (PFS). 
 
 Secondary Endpoints: 
 
Phase I Secondary Endpoint:  
• The frequency and severity of adverse events for all cycles of therapy, including 
those for maintenance ruxolitinib. 
• The frequency of patients who could not receive surgery within the defined 
timeframe for reasons other than non-response, disease progression, or medical 
contraindications will be given by the dose-level administered. 
• The number of patients who discontinue ruxolitinib in the first 3 months of 
maintenance therapy. (10/10/2016) 
 
Phase II Secondary Endpoints: 
• Subset analyses within categorized, important exploratory laboratory parameters 
that examine the treatment effect on PFS.  
• A log-rank test utilizing the categorized values of the exploratory laboratory 
parameters or a Cox proportional hazards (PH) model to estimate of the hazard 
ratio for progression or death in PFS and overall survival (OS). If feasible, the PH 
model will examine the effect of continuous measures. 
• Patients will be dichotomized by total gross resection. Differences in the 
proportion who have total gross resection by treatment arm will be examined with 
Fisher’s Exact Test. Multivariate logistic modeling will be conducted if feasible. 
• Patients will be dichotomized by complete pathologic response. Differences in the 
proportion who have complete pathologic response by treatment arm will be 
examined with Fisher’s Exact Test. Multivariate logistic modeling will be 


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conducted if feasible. 
• Overall survival (OS) by treatment arm. Log-rank test and Cox PH estimate of the 
HR. 
 
15.3 
Primary Objectives Study Design 
 
 Primary Hypothesis and Endpoints 
 
Phase I Study Primary Endpoint: Whether or not a patient experiences a dose-limiting 
toxicity (DLT) in cycles 1 or 2. 
 
Phase I Primary Hypotheses: The regimen is considered safe if the probability of a patient 
experiencing a DLT in cycles 1 or 2 is 35% or less for the experimental regimens 
examined on this study. The regimen is considered too toxic if the probability of a patient 
experiencing a DLT in cycles 1 or 2 is 55% or more. (10/10/2016)  
 
Phase II Primary Endpoint: Progression-free survival (PFS). 
 
Phase II Primary Hypotheses: The null hypothesis is that 𝑆𝑆0(𝑡𝑡) ≥𝑆𝑆1(𝑡𝑡) for all t where 
𝑆𝑆0(𝑡𝑡) is the survival function of PFS for the reference arm and 𝑆𝑆1(𝑡𝑡) is the survival 
function of PFS for the experimental regimen. The alternative hypothesis is that 𝑆𝑆0(𝑡𝑡) <
𝑆𝑆1(𝑡𝑡) for some t.  
 
 How Primary Endpoints Will Be Analyzed (10/10/2016) 
 
Phase I Historical Data Analysis: 
An analysis of GOG 262 toxicity data showed that approximately 13 of patients on the 
weekly regimen experienced treatment related non-hematological toxicities in cycles 1 or 
2. The original study did not include paclitaxel dose omissions and required a delay of 
greater than 14 days. The current study includes dose omissions and delays of greater 
than 7 days to declare DLT events. Approximately 20% had dose reductions in cycles 1 
or 2 due to hematological toxicities or infections, and about 7% had delays of 
administering the regimen for cycle 2 or 3 due to protocol adverse events for more than 7 
days. About 19% had an omission of paclitaxel on either day 8 or day 15 of cycles 1 or 2. 
Overall, the estimated probability of a patient experiencing a DLT in cycles 1 or 2 is 
about 34% to 37%, depending in part on the proportion of patients who have grade 4 
neutropenia lasting longer than 7 days and those with the excluded adverse events that 
cannot be controlled with maximal medical management. The 95% CI for the probability 
of a patient experiencing a DLT is approximately 29.7 ~ 41.8%. Therefore, the null 
hypothesis for tolerable regimens based on the historical data and definitions of DLT will 
be Ho: p = 0.35 where p is the probability of a DLT. The alternative hypothesis is Ha: p = 
0.60. 
 
Phase I Study Design 
The study will accrue patients to each dose-level in cohorts of size 4-7. Enrollment to a 
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time. Patients must be considered evaluable for toxicity in cycles 1 and 2 to be included 
in the analysis. The regimen will be evaluated for safety in cycles 1 and 2 (noting delays 
in starting cycle 3). Patients who do not experience DLT and who do not complete 2 
cycles of therapy will be replaced. Patients who miss more than 25% of ruxolitinib doses 
in the first two cycles of therapy (based on pill diary review) without medical justification 
would also be replaced. Patients will be classified as having no DLTs in cycles 1 and 2 
(i.e. not experiencing a DLT) or having at least 1 DLT in either cycle 1 or cycle 2. If no 
more than 2 patients experience at least 1 DLT out of 7 evaluable patients, then the 
current dose-level will be deemed safe and the study will escalate up to the next dose-
level. If 3 or more patients out of 7 experience DLTs, then the current dose-level will be 
considered too toxic, and a lower dose-level may be considered for the recommended 
phase II study. Escalation/de-escalation will continue until a dose-level is considered too 
toxic/safe, the highest dose-level is evaluated and deemed safe, or the lowest level is 
deemed too toxic. 
 
To increase the efficiency of the study, patients will be entered in two cohorts per dose-
level. Instead of the typical 3+3 design, we will enter patients onto the study in a 4+3 
manner. If 0 patients have DLTs in the first set of 4, then escalation will proceed 
immediately. If 1 or 2 patients have DLTs in the first set of 4, then the dose-level will be 
expanded to 7 in total. If the total number of patients experiencing DLTs is 2 or less, then 
escalation will continue. If 3 or more patients are observed to have DLTs at a particular 
dose-level, then that dose-level will be deemed too toxic, and consideration will be given 
to a lower dose-level. 
 
Before beginning the phase II study, the number of patients who could not receive their 
tumor reductive surgery within the specified timeframe for reasons other than non-
response, disease progression, or medical contraindications will be examined.  
 
Phase II Analysis (04/05/2019) 
Approximately 130 patients will enroll onto the study in a single stage. The analysis will 
be an intent to treat analysis of all enrolled patients. Patients will be randomized in a 2:1 
fashion to the experimental to reference regimen. Treatment randomization will be 
balanced on cell type (clear cell versus high grade serous/Endometrioid) and performance 
status (0 or 1 versus 2). The analysis will also include BRCA status as a post-
randomization, stratification factor. An interim safety analysis will be conducted once 
there are 10 participants enrolled and treated on the experimental arm. Tabulations of 
toxicities will be reviewed by the study chair and phase I chair. Patients will be 
monitored for disease progression or death (PFS endpoint). Time at risk will be assessed 
from the date of randomization. Patients who start another therapy prior to progression 
will continue to be followed for PFS. The data will be frozen approximately at one-half 
the information time for futility (after 46 PFS events) and a toxicity assessment. If there 
are still patients entering the study, and if the log-rank statistic for the hazard of 
progression or death favors the reference arm (i.e. indicates a higher hazard of 
progressing or dying on the experimental arm), then the study will recommend study 
suspension. Otherwise, the study will recommend continued accrual based on efficacy 
interim results. A final analysis will be conducted after 93 PFS events. 


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15.4 
Sample Size and Power Calculations: (10/10/2016) 
 
 
Phase I Study (10/10/2016) 
Up to seven patients will be evaluated at each dose level. Patients will be enrolled to each 
dose-level in two cohorts. The probability mass function for the number of DLTs is 
provided below: 
 
𝑝𝑝(𝑥𝑥𝑖𝑖= 𝑗𝑗) = ቀ𝑛𝑛𝑖𝑖
𝑗𝑗ቁ𝜋𝜋𝑗𝑗(1 −𝜋𝜋)𝑛𝑛𝑖𝑖−𝑗𝑗 
 
where 𝑛𝑛1 = 4, 𝑛𝑛2 = 3, 𝑖𝑖= 1, 2 for first and second cohort respectively, and 𝜋𝜋 is the 
probability of DLT. 
 
In order to proceed to a higher dose-level, it is necessary that: 
 
𝑃𝑃(𝑋𝑋1 = 0) + 𝑃𝑃(𝑋𝑋1 = 1)𝑃𝑃(𝑋𝑋2 ≤1) + 𝑃𝑃(𝑋𝑋1 = 2)𝑃𝑃(𝑋𝑋2 ≤0) 
  
The chances of escalating after examining only 4 patients is 17.9% and 4.1% when the 
true DLT is 35% and 55%, respectively. 
 
The dose-level will be considered too toxic (that is, to have exceeded the maximum 
tolerated dose (MTD)) if 𝑥𝑥1 + 𝑥𝑥2 ≥3. Otherwise, it will be considered safe. The goal of 
the study will be to identify doses that do not exceed the MTD for administration in the 
phase II study. The dose-level operating characteristics for this decision rule is a 46.0% 
probability of declaring a safe regimen as being too toxic when the probability of a DLT 
is 35% (𝜋𝜋= 0.35).  If the probability of a DLT is 55% (𝜋𝜋= 0.55), then the chances of 
declaring the regimen safe is 16%. 
 
For comparison purposes, the 3+3 design has about a 34.5% probability of declaring a 
safe regimen (cycle 1 p=0.20) as being too toxic and a 23.3% probability of declaring a 
toxic regimen (cycle 1 p=0.40) as being safe when 6 patients are evaluated at that dose-
level. Many dose escalating designs contain a (-1) and (-2) dose-level.  
 
Table of the distribution of the recommended phase II dose (RP2D) for various 
probabilities of DLT across different dose-levels is not provided because of complex 
escalation rules. 
 
Phase II Study 
The number of PFS events required to achieve the desired operating characteristics can 
be approximated with Schoenfeld’s equation: 
 
𝐷𝐷= ൫𝑍𝑍𝛼𝛼+ 𝑍𝑍𝛽𝛽൯
2
𝜋𝜋(1 −𝜋𝜋)𝜃𝜃2 
Where 𝛼𝛼= 𝛽𝛽= 0.15 are the type I and type II errors, respectively, 𝜋𝜋 (not to be confused 
with the same character in the phase I study) is the probability of being randomized to the 


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experimental treatment (𝜋𝜋= 2/3), and 𝜃𝜃= 𝑙𝑙𝑙𝑙(𝐻𝐻𝐻𝐻) = 𝑙𝑙𝑛𝑛(0.625) = −0.47. 𝑍𝑍𝛼𝛼= 𝑍𝑍𝛽𝛽=
1.0364, so under the alternative hypothesis where the HR=0.625, the total number of 
required events is 87.52 or 88. However, an interim futility analysis is to be performed at 
one-half the information time (about 47 PFS events), so a correction to the distribution of 
the final test statistic is used. Note from Jennison and Turnbull (p49, eq. 3.1) that we will 
use the standardized test statistics, related to the log-rank test statistics (before squaring in 
the common Chi-square test) at the interim and final analyses, which will be designated 
by Z1 and Z2, respectively. According to Jennison and Turnbull, the standardized statistics 
for the log-rank test will be distributed as a multivariate normal distribution with the 
following parameters: 
 
൬𝑍𝑍1
𝑍𝑍2൰~𝑀𝑀𝑀𝑀𝑀𝑀ቌቆ𝜃𝜃ඥ𝐼𝐼1
𝜃𝜃ඥ𝐼𝐼2
ቇ, Σ = ቆ
1
ඥ𝐼𝐼1/𝐼𝐼2
ඥ𝐼𝐼1/𝐼𝐼2
1
ቇቍ 
 
where Ik is the information obtained at the kth stage of the design with 𝐼𝐼𝑘𝑘= 2𝑑𝑑𝑘𝑘/9 and dk 
being the total number of observed events at that time. 𝐼𝐼𝑘𝑘= 2𝑑𝑑𝑘𝑘/9 (instead of 𝐼𝐼𝑘𝑘= 𝑑𝑑𝑘𝑘/4 
in this case because the randomization is 2:1).  Since the use of Weiand et al. plans on 
observing Z1 at 50% information time, the covariance between Z1 and Z2 is about 0.707.  
The cumulative distribution function of Z1 and Z2 is provided below by F(.): 
 
𝑃𝑃(𝑍𝑍1 ≤𝑧𝑧1, 𝑍𝑍2 ≤𝑧𝑧2) = 𝐹𝐹(𝑧𝑧1, 𝑧𝑧2|𝜃𝜃, 𝐼𝐼1, 𝐼𝐼2) 
 
The design will reject the null hypothesis Ho:𝜃𝜃≥0 only if 𝑍𝑍1 < 0 and 𝑍𝑍2 < 𝑐𝑐2. Since 
𝛼𝛼= 0.15, we wish to find 𝑐𝑐2 so that 𝐹𝐹(0, 𝑐𝑐2|𝜃𝜃= 0, 𝐼𝐼1, 𝐼𝐼2) = 0.15. Searching algorithms 
can quickly find the value of 𝑐𝑐2 = −0.9805 which deviates slightly from the usual value 
of -1.036 obtained with a single stage test. 
 
The required number of events to obtain 85% power is 93 PFS events with the interim 
analysis.  That is to say: 
 
𝐹𝐹(0, −0.9805|𝜃𝜃= −0.47, 𝐼𝐼1 = 10.3, 𝐼𝐼2 = 20.7) = 0.85 
 
It is unlikely that the interim analysis will be conducted at precisely 50% of the 
information time.  The realized information at the interim and final analyses will be used 
to determine the critical value of 
2c  under the null hypothesis so that the probability of a 
type I error does not exceed 15%. The probability of early termination under the 
alternative hypothesis is 6.5%. The probability of early termination under the null 
hypothesis is 50%. 
 
GOG protocol data 0262 was used to estimate the median time of PFS and to project the 
times of analysis for the interim and final analysis. 
 
In order to obtain the required number of events in a suitable timeframe, we will accrue 
130 patients. We anticipate an accrual rate of 5 patients per month. The period of active 


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accrual is expected to be 26 months. We expect an interim analysis about 24 months after 
trial activation and a final analysis 40 months after trial activation (assuming a 14 month 
median PFS time with an exponential survival distribution). Using GOG-0262 survival 
distribution data did not significantly impact these estimates. 
15.5 
Study Monitoring of Primary Objectives 
 
During the phase I portion of the study, all enrolling sites will be required to participate 
in a regularly scheduled teleconference including the Study Chair, and Phase I 
Subcommittee Chair and his/her assigned delegates. 
 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  
 
15.6 
Accrual/Study Duration Considerations 
As stated above, we anticipate an accrual rate of 5 patients per month. The period of 
active accrual is expected to be 26 months. We expect an interim analysis about 24 
months after trial activation and a final analysis 40 months after trial activation (assuming 
a 14 month median PFS time with an exponential survival distribution). 
 
15.7 
Dose Level Guidelines 
An escalation/de-escalation design enrolling single cohorts of 8 patients will be used for 
regimens on this study.  See above for further design details. 
 
See section 5.1.1.1 for the dose-levels and section 5.1.1.5 for the definition of DLTs. 
 
15.8 
Secondary or Exploratory Endpoints (10/10/2016) 
 
15.8.1 Secondary Hypotheses and Endpoints for the Phase I Study (10/10/2016) 
 
 
1. 
There is no hypothesis to be tested for the frequency and severity of adverse 
events in the phase I study. They will be collected mostly for descriptive 
purposes. Tables of the maximum grade by patient and organ (or organ system) 
will be made. 
 
2. 
The null hypothesis relating the probability of a patient failing to undergo interval 
tumor reductive surgery is 15% or less, i.e. H0: p ≤ 0.15. The alternative 
hypothesis is that the probability is 40% or more, i.e. H1: p ≥ 0.40. 
 
3. 
The null hypothesis relating the probability of a patient discontinuing ruxolitinib 
in the first 3 months of maintenance therapy for toxicity is 10% or less, i.e. H0: p 
≤ 0.10. The alternative hypothesis is that the probability is 30% or more, i.e. H1: p 
≥ 0.30. 
 


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15.8.2 Secondary Hypotheses and Endpoints:  
1. 
Subset analyses within categorized, important exploratory laboratory parameters 
that examine the treatment effect on PFS. The null hypothesis is that the survival 
functions by treatment are the same against the alternative hypothesis that says the 
survival functions are different. 
 
2 
A log-rank test utilizing the categorized values of the exploratory laboratory 
parameters or a Cox proportional hazards (PH) model to estimate of the hazard 
ratio for progression or death in PFS and overall survival (OS). If feasible, the PH 
model will examine the effect of continuous measures. One set of null hypotheses 
is that the survival functions by the lab parameters are the same. Another set of 
null hypotheses is that the hazard ratio (HR) is equal to 1.0. The alternative 
hypotheses are that the survival functions are different or that the HR ≠1.0, 
respectively. 
 
3 
Patients will be dichotomized by total gross resection (Yes/No). Differences in the 
proportion who have total gross resection by treatment arm will be examined with 
Fisher’s Exact Test. Multivariate logistic modeling will be conducted if feasible. 
 
4 
Patients will be dichotomized by complete pathologic response. Differences in the 
proportion who have complete pathologic response by treatment arm will be 
examined with Fisher’s Exact Test. Multivariate logistic modeling will be 
conducted if feasible. 
 
5 
Overall survival (OS) by treatment arm. Log-rank test and Cox PH 
 
15.8.3 Definitions of Secondary Endpoints and How These Will Be Analyzed in the Phase I 
Study (10/10/2016) 
 
1.  
Adverse event described by severity (grade) and organ (or organ system) effected. 
 
2. 
Whether or not a patient fails to undergo interval tumor reductive surgery. We 
expect about 85% of patients to undergo cytoreductive surgery in the prescribed 
timeframe in the absence of progressive disease and comorbidities. Historical data 
are limited, but in the 44 patients from GOG-0262 who underwent neoadjuvant 
chemotherapy with carboplatin plus dose-dense weekly paclitaxel (as proposed 
for NRG-GY007), only 4 patients did not undergo interval surgery. On the other 
hand, within the context of a dose-escalating phase I cohort that could include 
between 8 and 32 patients, it would be challenging to determine, with precision, 
the true rate of proceeding to interval cytoreductive surgery in NRG-GY007. 
Therefore, we would propose to set the lower bar at less than or equal to 60% as 
unacceptable (during the phase I dose-escalating component), and we would not 
proceed to the phase II component until a more tolerable regimen was defined.  In 
addition, the proportion of patients eligible for interval cytoreduction would be 
monitored as a secondary endpoint in the randomized phase II portion, with an 
increased number of patients treated in a more uniform manner. 


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Let X = The number of patients who fail to undergo interval tumor reductive 
surgery. The study will be stopped if X is equal to or exceeds a threshold, x. 
 
Sample Size 
x 𝑃𝑃(𝑋𝑋≥𝑥𝑥|𝑝𝑝= 0.15) 𝑃𝑃(𝑋𝑋≥𝑥𝑥|𝑝𝑝= 0.4) 
8 
4 
2.1% 
40.6% 
16 
6 
2.4% 
67.1% 
24 
8 
2.0% 
80.8% 
32 
8 
4.1% 
94.3% 
 
A final dose-level with 4 or more patients failing to receive reductive tumor 
surgery in the appropriate timeframe will be examined more closely by the DMC 
for consideration of not proceeding with the phase II portion of the study. 
 
3. 
Let X = The number of patients who discontinue ruxolitinib due to toxicity in the 
first 3 months in of the maintenance phase. Maintenance ruxolitinib will not be 
included in the phase II portion of the study if X is equal to or exceeds a 
threshold, x. 
 
Sample Size x 𝑃𝑃(𝑋𝑋≥𝑥𝑥|𝑝𝑝= 0.10) 𝑃𝑃(𝑋𝑋≥𝑥𝑥|𝑝𝑝= 0.3) 
8 
3 
3.8% 
44.8% 
16 
5 
1.7% 
55.0% 
24 
6 
2.8% 
77.1% 
32 
7 
3.6% 
88.7% 
 
A final dose-level with 3 or more patients out of 8 requiring discontinuation of 
ruxolitinib due to toxicity in the first 3 months of the maintenance phase will be 
examined more closely by the DMC for consideration of eliminating ruxolitinib 
maintenance in the phase II study. Furthermore, if the study proceeds into the 
phase II study with maintenance ruxolitinib, then the first 32 evaluable patients 
randomized to the ruxolitinib arm will be examined. If 7 or more of the first 32 
patients experience DLTs in maintenance, then the regimen will be examined 
again by the DMC for modification. 
 
15.8.4 Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
1. 
Often continuous laboratory biomarkers are dichotomized at the median. If many 
values are below the threshold of detection, they may be dichotomized as being 
positive (i.e. > 0) or negative (less than the threshold of detection). Sometimes 
they are inherently ordered (e.g. cell staining intensity). Ordinal categorical data 
may be dichotomized in a manner that splits the number of observations into two 
equally sized groups. Alternatively, the analysis may be done directly to look for 
evidence of trends in the hazard of PFS. More generally, the effect of treatment on 
PFS will be examined within each of these subsets using a log-rank test or a Cox 
PH model. Since treatment assignment is random, it is anticipated that about two 
thirds of the patients will belong to the experimental therapy. Interest will center 


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on whether the hazard of PFS changes from one group to another. Inferences may 
be feasible with as little as 10 events within each treatment group. If the hazards 
of PFS depend on the group examined, then the variable may be predictive of 
treatment effect, or to put it another way, an interaction term may be significant in 
a larger study. 
 
2. 
These analyses will be done strictly with patients assigned to the reference arm 
(they can also be done in the experimental arm as well). The biomarkers will be 
categorized using the same techniques as discussed above. The impact of the 
biomarkers on PFS or OS will be assessed using log-rank tests or Cox PH models. 
In some instances, Cox modelling will be conducted on the continuous measure 
and checked for model adequacy.  
 
3. 
The total gross tumor resection is defined as the removal of all visible tumor at 
the time of surgery. The simplest analysis to examine whether or not treatment 
has an impact of total resection will be Fisher’s Exact Test. The results of this 
analysis will be presented in terms of the odds ratio (MLEs and CIs). If there are a 
sufficient number with responses in each group to allow for asymptotic analyses, 
then the analysis may be adjusted for prognostic factors using logistic models. 
 
The total gross tumor resection at the time of surgery is a continuous variable, and 
the sample sizes are expected to be sufficiently large to assure that the central 
limit theorem applies to sample means of each arm.  Therefore, simple Z tests 
should be adequate for testing the equivalencies of tumor mass resected between 
the experimental and reference arms.  Differences in treatment arms are expected 
to be characterized using normal distribution theory.  More complex linear models 
may be used if the data warrant. 
 
4. 
This analysis will use the same techniques as the one used to analyze patients with 
total gross resection. 
 
5. 
Overall survival is defined as the time from randomization until death or date last 
seen. The endpoint for OS is death. The effect of treatment on OS will be 
conducted with the log-rank statistic and characterized with a Cox PH model. If 
there are significant prognostic factors, then the analysis may be stratified on 
them or explicitly included in the model. 
 
15.8.5 Interim Analysis for All Other Endpoints (Goals):  
The analysis of the severity of toxicity by treatment arm (dichotomized into severe versus 
not severe) will be presented to the DMC at the time of the interim futility analysis. 
 
15.8.6 Power Calculations:  
If the median overall survival (not PFS) is 28 months, then we anticipate 70 deaths in 45 
months of study accrual and monitoring.  This gives about 79% power of detecting a 
37.5% reduction in the hazard of death when testing at the 15% level of significance.  
Power drops to 58.3% when testing at the 5% level of significance.  The probability of 


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detecting a 30% reduction in the hazard of death is only 41% (alpha=5%). 
 
15.9 
Exploratory Hypothesis and Endpoints 
Toxicity will be characterized by the frequency and severity of adverse events in the 
phase I study for the experimental regimen. Toxicity will be characterized by the 
frequency and severity of adverse events according to treatment arm in the phase II study.  
They will be dichotomized as severe or not severe for each category of toxicity, and the 
hypothesis of equal proportions of severe toxicities to the reference arm will be assessed 
using an exact Chi-square test (or Fisher’s Exact Test).  If a 95% CI for the risk ratio or 
odds ratio is strictly greater than 1.5, then the study will highlight such a category as 
being potentially problematic. 
 
Effects of Treatment on Stemness and C-reactive protein (CRP): 
 
A multivariate linear model will be used to determine the effect of treatment on the 
number of cancer stem cells (CSCs) observed in tissue obtained from the patient after 3 
cycles of therapy.  The model will be adjusted with the patients’ pre-treatment count of 
CSC, which will be log transformed to reduce the amount of right skewness.  Treatment 
with ruxolitinib is expected to reduce the amplification of CSC during therapy. 
 
The prognostic value of CSC will be assessed with the pre-therapy values.  Landmark 
analyses will be conducted to see if changes in CSC are associated with PFS.  The 
predictive value of CSC will be formally examined with a Cox model using an interaction 
term with treatment.  Subset analyses will be conducted as well in the event that a formal 
analysis fails to reject the null hypothesis. 
 
Similar analyses can be conducted on the measurements taken for serum C-reactive 
protein (CRP).  Linear models can examine the effect of therapy on CRP values, 
adjusting for baseline levels.  The impact of baseline values on PFS and OS can be 
assessed for prognostic and predictive significance with log-rank statistics and Cox 
models.  Finally, the impact of changes in CRP values on PFS and OS can be examined 
with landmark analyses or as time dependent covariates. 
 
15.10 Gender/Ethnicity/Race Distribution  (04/06/2018) 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
2 
0 
0 
0 
2 
Asian 
2 
0 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
1 
0 
0 
0 
1 
Black or African 
American 
7 
0 
0 
0 
7 
White 
128 
0 
7 
0 
135 
More Than One Race 
0 
0 
0 
0 
0 
Total 
140 
0 
7 
0 
147 


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APPENDIX I - FIGO OVARIAN CANCER STAGING 2014  
 
STAGE I: Tumor confined to ovaries  
 
IA Tumor limited to 1 ovary, capsule intact, no rumor on surface, negative washings. 
 
IB Tumor involves both ovaries otherwise like 1A. 
 
IC Tumor limited to 1 or both ovaries 
 
IC1 
Surgical spill 
IC2 
Capsule rupture before surgery or tumor on ovarian surface 
IC3 
Malignant cells in the ascites or peritoneal washings 
 
STAGE II: 
Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim) 
 
or primary peritoneal cancer  
 
IIA Extension and/or implant on uterus and/or Fallopian tubes 
 
IIB Extension to other pelvic intraperitoneal tissues 
 
STAGE III: 
Tumor involves 1 or both ovaries with cytologically or histologically 
 
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the 
 
retroperitoneal lymph nodes  
 
IIIA Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the pelvis 
 
 
IIIA1 Positive retroperitoneal lymph nodes only 
IIIA1(i)  
Metastasis ≤ 10 mm 
IIIA1(ii) 
Metastasis > 10mm 
 
 
IIIA2 
Microscopic, extrapelvic (above the brim) peritoneal involvement ± 
positive retroperitoneal lymph nodes 
 
IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
IIIC Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
STAGE IV: Distant metastasis excluding peritoneal metastasis 
 
IVA 
Pleural effusion with positive cytology 
 


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IVB 
Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal 
organs (including inguinal lymph nodes and lymph nodes outside of the abdominal 
cavity). 
 
Other major recommendations are as follows: 
• Histologic type including grading should be designated at staging 
• Primary site (ovary, Fallopian tube or peritoneum) should be designated where possible 
• Tumors that may otherwise qualify for stage I but involved with dense adhesions justify 
upgrading to stage II if tumor cells are histologically proven to be present in the adhesions 
 
 
 
 


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APPENDIX II - GUIDELINES FOR PATHOLOGIC CLASSIFICATION OF TUMOR CELL 
TYPE 
 
Histologic features for determination of Tumor Cell Type and Tissue of Origin are imperfect and 
subject to lack of specificity, resulting in significant lack of agreement by expert pathologists.  This 
lack of agreement is most problematic when small biopsy material is evaluated in the clinical context 
of advanced stage cancer or with tumor recurrence.  Nevertheless, a consensus is developing that 
immunohistologic phenotypes are associated with common genetic features of tumors and thus form a 
rational basis for meaningful classification of cell type (Soslow, Kobel).  These features are mutational 
pattern of expression of p53 antigen and diffuse nuclear WT-1 antigen expression in high grade serous 
mullerian adenocarcinoma, lack of diffuse nuclear estrogen receptor (ER) expression in clear cell 
carcinomas, and the expression of ER and lack of significant WT-1 expression in endometrioid 
carcinomas.  These immunohistologic features do not define cell type but are useful criteria to 
consider when attempting to classify tumors--especially for poorly differentiated tumors.  For 
example, a tumor with a solid growth pattern (lacking histologically evident glandular differentiation) 
that shows a mutational pattern of p53 staining by immunohistochemistry (diffuse strong nuclear p53 
expression or complete lack of p53 expression in tumor cells) should be classified as a high grade 
serous cancer (diffuse nuclear WT-1 expression will also likely be present).  Conversely, lack of 
mutational p53 pattern by immunohistochemistry would most consistent with high grade endometrioid 
adenocarcinoma, including carcinosarcoma (malignant mixed mullerian tumor).  Diffuse nuclear ER 
expression is uncommon in clear cell carcinoma and thus is useful for distinguishing poorly 
differentiated endometrioid carcinoma (with areas of “clear’ cells) from clear cell carcinoma.  These 
features are summarized in the following table: 
 
Immunophenotypes of Common Epithelial Ovarian Carcinoma Cell Types – GY007 
 
High Grade Serous Adenocarcinoma 
p53mut 
WT-1nuclear 
ERvariable 
Endometroid Adenocarcinoma  
p53wt 
WT-1negative 
ERpositive 
Clear Cell Adenocarcinoma 
 
p53wt 
WT-1negative 
ERnegative 
 
P53mut: diffuse strong nuclear immunoreactivity or complete lack of nuclear immunoreactivity 
in tumor cells  
 
P53wt: 
Wild type p53 expression.  Variable nuclear immunoreactivity of tumor cells, often 
expressed with the same tissue distribution (similar pattern) as Ki-67 antigen expression 
(because both p53 and Ki-67 antigen are expressed in normal dividing cells).  In poorly 
differentiated rapidly dividing tumors p53 antigen is commonly prominent and strong 
but lacks the constitutive (every tumor cell) pattern of expression associated with 
mutation. 
 
WT-1nuclear:  nuclear expression of WT-1 
 
ERnuclear:  nuclear expression of Estrogen Receptor 
 
Refs:  Soslow RA, Int J Gynecol Pathol. 2008, 27:161-74. 
Kobel, M et al . American Journal of Surgical Pathology, 2009, 33:14-21 


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APPENDIX III - PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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APPENDIX IV - GENERAL CHEMOTHERAPY GUIDELINES  
 
 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of 
chemotherapy delayed up to 7 days (without this being considered to be a protocol 
violation) for major life events (e.g., serious illness in a family member, major holiday, 
vacation which is unable to be re-scheduled).  Documentation to justify this decision 
should be provided. 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-
hour window before and after the protocol-defined date” for “Day 1” treatment of 21 or 
28 day cycles.  If the treatment due date is a Friday, and the patient cannot be treated on 
that Friday, then the window for treatment would include the Thursday (1 day earlier 
than due) through the Monday (day 3 past due). 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 
14, Day 15, or Day 16. 
• Chemotherapy doses can be “rounded” according to institutional standards without 
being considered a protocol violation (most institutions use a rule of approximately +/- 
5% of the calculated dose). 
• Chemotherapy doses are required to be recalculated if the patient has a weight change 
of greater than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for < 10% weight changes. 
 
 


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APPENDIX V - CARBOPLATIN DOSE CALCULATION INSTRUCTIONS  
 
1) The Cockcroft-Gault formula will be used in NRG trials 
2) Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted.  
3) A carboplatin calculation tool is available on the GOG website (Web Menu, Tools). 
 
Dosing of Carboplatin: 
 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) according to 
the Calvert formula using an estimated glomerular filtration rate (GFR) from the Cockcroft-Gault 
formula. 
2) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring dose 
modification, the dose of carboplatin will not need to be recalculated for subsequent cycles, but 
will be subject to dose modification for toxicity as noted in the protocol. 
3) Carboplatin doses should be recalculated if the patient has a weight change of greater than or equal 
to 10%. 
4) At the time of dose modification, if the patient’s age has changed (the patient has had a birthday), 
the site can use the current age. 
5) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine clearance 
should be estimated using a minimum value of 0.7 mg/dl.  
6) For trials where patients enter and are treated within less than or equal to 12 weeks of surgery:  If a 
more appropriate (higher) baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the initial estimation of GFR. 
 
CALVERT FORMULA: 
 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 


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AUC 4 = 600 mg 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated creatinine 
clearance. The estimated creatinine clearance (ml/min) is calculated by the method of Cockcroft-
Gault using the following formula: 
Creatinine Clearance (mL/min) =    [140-Age (years)] x Weight (kg) x 0.85  
                                                             
72 x serum creatinine (mg/dl)  
Notes: 
 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient.  A BMI calculator is available 
at the following link:  http://www.nhlbisupport.com/bmi/ 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25.   
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater than 
or equal to 25. 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
2) The Cockcroft-Gault formula above is specifically for women (it includes the 0.85 factor). 
At the time of a dose modification for toxicity:  
If the serum creatinine at the time of a dose modification is lower than the creatinine used 
to calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the 
time of a dose modification is higher than the creatinine used to calculate the previous 
dose, use the current (higher) creatinine.  This will ensure that the patient is actually 
receiving a dose reduction.  
 
 


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APPENDIX VI - PATIENT PILL CALENDAR- RUXOLITINIB (03/20/2017) 
 
NRG-GY007 – A PHASE I/II STUDY OF RUXOLITINIB WITH FRONT-LINE NEOADJUVANT 
AND POST-SURGICAL THERAPY IN PATIENTS WITH ADVANCED EPITHELIAL OVARIAN, 
FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER  
 
Today’s date ________________________________ 
 
Patient Name____________________________ Patient Study ID _____________________  
(initials acceptable for patient’s name) 
 
Cycle #__________      
 
INSTRUCTIONS TO THE PATIENT: 
 
This is a calendar on which you are to record the number of pills you take each day. 
1. Complete one form for each cycle (21 days). 
2. Unless otherwise instructed, you will take ___ tablets of Ruxolitinib each morning (AM Dose) and ___ 
tablets of Ruxolitinib each evening (PM Dose), about 12 hours apart. Tablets may be taken with or without 
food. It is generally best to take the tablets after the morning and evening meal. 
3. Record the date, the number of tablets you took, and when you took the.   
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your tablet bottle and this form to your physician when you go for your next appointment. 
6.   If you miss a dose of Ruxolitinib, take it as soon as you remember. If you are more than 4 hours late in 
taking a dose, the dose should be skipped.  Please call your doctor’s office for instruction if you skip or 
miss a dose or at any other time if you have questions. 
7.   Do NOT take another dose of ruxolitinib beyond what is instructed for any reason, even including 
vomiting any time after a dose. 
Date 
Day 
AM Dose 
PM Dose 
 
# Tablets 
Time 
Taken 
# Tablets 
Time 
Taken 
Comments 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 


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10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
Patient’s Signature: ________________________________  Date: ________________ 
 
 
 
 


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APPENDIX  VII - INHIBITORS AND INDUCERS OF CYP3A4 (10/10/2016) 
 
A list of CYP3A4 inhibitors and inducers 
This list is not comprehensive. Please refer to a frequently-updated drug information reference for 
strong CYP3A4 inducers and inhibitors:   
http://www.uptodate.com/contents/image?imageKey=CARD/76992&topicKey=HEME%2F1370&sou
rce=outline_link&utdPopup=true 
 
Strong Inhibitors 
Moderate 
Inhibitors 
Strong Inducers 
Moderate Inducers 
Atazanavir 
Amiodarone¶ 
Carbamazepine 
Bexarotene 
Boceprevir 
Aprepitant 
Enzalutamide 
Bosentan 
Ceritinib 
Cimetidine¶ 
Fosphenytoin 
Dabrafenib 
Clarithromycin 
Conivaptan 
Lumacaftor  
Dexamethasone¶ 
Cobicistat and cobicistat 
containing coformulations 
Crizotinib 
Mitotane 
Efavirenz 
Darunavir 
Cyclosporine¶ 
Phenobarbital 
Eslicarbazepine 
Idelalisib 
Diltiazem 
Phenytoin 
Etravirine 
Indinavir 
Dronedarone 
Primidone 
Modafinil 
Itraconazole 
Erythromycin 
Rifabutin 
Nafcillin 
Ketoconazole 
Fluconazole 
Rifampin 
(rifampicin) 
St. John's wort 
Lopinavir 
Fosamprenavir 
Rifapentine 
 
Nefazodone 
Fosaprepitant¶ 
 
 
Nelfinavir 
Grapefruit juice 
 
 
Ombitasvir-paritaprevir-
ritonavir 
Imatinib 
 
 
Ombitasvir-paritaprevir-
ritonavir plus dasabuvir 
Isavuconazole 
(isavuconazonium 
sulfate) 
 
 
Posaconazole 
Mifepristone 
 
 
Ritonavir and ritonavir 
containing coformulations 
Netupitant 
 
 
Saquinavir 
Nilotinib 
 
 
Telaprevir 
Tibolone 
 
 
Telithromycin 
Verapamil 
 
 
Voriconazole 
 
 
 


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APPENDIX  VIII– INTERVAL TUMOR REDUCTIVE SURGERY(TRS) (04/06/2018)   
 
The guidelines for TRS are adapted in part from the Gynecologic Oncology Group Surgical Procedures Manual 
(2010 revision).  
 
Note: These guidelines for surgery are within standard care. The components of the surgical procedure outlined 
below should be performed only when benefits outweigh risks. 
 
Purpose 1) Documentation of the extent of disease at exploration 
 
 
2) Maximal resection of all gross (macroscopic and palpable) tumor 
 
 
3) Documentation of the extent of disease at completion of surgery 
 
Content of Procedure 
 
1) Exposure must be adequate to explore the entire abdominal cavity and allow safe cytoreductive surgery.  
The surgical approach for this procedure is at the discretion of the treating surgeon and can be either via 
laparotomy or minimally invasive techniques.  If a primarily minimally invasive technique is utilized, 
conversion to laparotomy should be performed if the minimally invasive surgical techniques do not 
allow for adequate exposure, are contraindicated for reasons related to patient safety or are limited in 
their ability to access known disease sites for maximal tumor resection.     On the other hand, for a 
patient initially explored via a minimally invasive approach, if in the opinion of the surgeon total gross 
tumor resection would be technically impossible regardless of approach, conversion to  laparotomy 
could be avoided. 
 
2) If free peritoneal fluid is identified it should be aspirated for cytology. If no free peritoneal fluid is 
present and if no macroscopic or palpable tumor is identified, peritoneal washings should be obtained.  
Every effort should be made to lavage the peritoneal cavity in its entirety. .  
3) Exploration to document the extent of gross disease by palpation and inspection (when applicable), 
including evaluation of the ovaries, fallopian tubes, uterus, all abdominal and pelvic peritoneal surfaces 
(including the under surface of the diaphragms, and the serosa and mesentery of the entire 
gastrointestinal tract), and omentum. 
 
a. If gross evidence of tumor is identified, then a maximal attempt to resect all gross tumor should be 
made, with surgical procedures that may include but are not limited to: 
 
i. Bilateral salpingo-oophorectomy 
ii. Hysterectomy (extrafascial or modified radical) 
iii. Omentectomy 
iv. Removal of tumor implants along visceral and parietal peritoneal surfaces 
v. Retroperitoneal lymphadenectomy 
vi. Bowel resection 
vii. Other (e.g. splenectomy, partial hepatic resection, diaphragmatic resection), as clinically 
indicated  
 
b. If no gross evidence of tumor is identified, then the minimum procedure should be: 
i. Bilateral salpingo-oophorectomy 
ii. Hysterectomy (total or supracervical) 
iii. Omentectomy 
iv. Peritoneal biopsies 


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1. Right and left pelvic wall 
2. Cul-de-sac 
3. Bladder 
4. Right and left paracolic 
5. Right diaphragm (scraping of surface for cytology may substitute for biopsy) 
v. Biopsies of adhesive bands and abnormally scarred areas 
vi. One sample of cytologic washings in the absence of ascites 
vii. Removal of any suspicious lymph nodes 
 
 


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APPENDIX IX – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES 
(01/09/2017) (04/06/2018) (07/30/2018) (04/05/2019) 
 
1. Obtaining a Bank ID for Translational Science Biospecimens 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
biospecimens and accompanying paperwork must be labeled with this coded patient number. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that a 
patient has agreed to participate in the translational science component. If a patient has previously 
been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the same as the previously 
assigned Bank ID. 
 
Please contact Support if you need assistance or have assigned more than one Bank ID to a patient 
(Email: support@nrgoncology.org). 
 
2. Requesting Translational Science Biospecimen Kits (03/20/2017) 
2.1 
Frozen Biospecimens 
One single chamber kit will be provided per patient for the shipment of frozen biospecimens. 
Collection supplies will only be provided for pre-treatment serum biospecimens. Sites must use their 
own supplies for the collection of frozen tissue and whole blood biospecimens. 
 
Sites can order kits online via the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). Each site may order two kits per protocol 
per day (daily max = 6 kits).  
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should 
arrive within 3-5 business days. 
 
Unused materials and kits should be returned to the NRG BB-Columbus. A pre-paid shipping label for 
the return of unused supplies and kits may be obtained via the Kit Management system. Select “Empty 
Kit” for package contents when returning unused kits. 
 
2.2 
Whole Blood for Cell-Free DNA (Collected in Streck Tubes) 
Collection materials and shipping labels are not provided for the optional whole blood for cell-free 
DNA biospecimens. Sites must utilize their own materials for collection and shipment of these 
biospecimens. Shipment will be at the site’s expense. 
 
3. Tissue Biospecimens Shipped to the NRG BB-Columbus 
3.1 
General Information for Tissue Biospecimens 
 
3.1.1 Collection of Surgical Suite Data 
The designated operating room staff should record the time the tissue is removed from the 
patient. For frozen tissue biospecimens, the time tissue is removed from the patient to the start 


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of freeze time must be documented on Form TR as Estimated Processing Time. 
 
3.1.2 Transport of Tissue from the Surgical Suite to the Gross Pathology Suite 
Tissue should be transported in a closed container (sterile container or tray covered in plastic 
wrap). Do not use ice or wrap tissue biospecimens in gauze. 
 
3.1.3 Receipt of Tissue in the Gross Pathology Suite 
All tissue must first undergo gross pathology evaluation and the collection of appropriate 
samples for patient diagnosis. Once the appropriate review and clinical sample collection has 
been completed, the residual tissue may be released for research purposes and should be 
processed in the following order: 
1. FFPE (mandatory - tumor: one segment; section 3.2 below), 
2. Snap Frozen (optional - tumor: 1-5 segments, adjacent normal [pre-treatment only]: 1-3 
segments; section 3.3 below), 
3. Cryopreserved (optional - tumor: one segment; section 3.4 below), and 
4. OCT Frozen (optional - tumor: two segments; section 3.5 below). 
 
If tissue is limited, submit at least one segment processed in the order of priority. 
 
3.2 
FFPE Tumor Tissue 
Only one block may be submitted per tissue type. All FFPE tissue must be submitted with the 
corresponding pathology report. 
 
3.2.1 Mandatory FFPE Biospecimen Requirement 
3.2.1.1 Tumor Tissue Type 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
required type: 
 
• Primary (FP01) and metastatic (FM01) tumor should be collected prior to all treatment. 
• Interval primary (FP02) and interval metastatic (FM02) tumor should be collected during 
the interval Tumor Reductive Surgery (TRS) or image-guided biopsy. 
 
FFPE Type 
Every attempt should be made to provide a FFPE block; however, if a block cannot be 
provided on a permanent basis, then 35 unstained slides (30 charged, 5µm, and 5 uncharged, 
10 µm) should be submitted.  All slides must be cut sequentially from one block. If tumor 
tissue is limited, priority should be given to the 30 charged, 5µm sections. If less than the 
requested number of slides are available, contact BPCBank@nationwidechildrens.org. 
 
3.2.2 Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational 
science tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY007) 
specimen code (see section 3.2.1.1 above) 


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collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be 
wrapped around the slide or hang over the edge. 
 
3.2.3 Completing Form TR for FFPE Biospecimens 
The type of biospecimen (block or slides) should be specified on Form TR. If submitting 
slides, the slide type, thickness, and count should also be specified. 
 
The time the tissue was in formalin (i.e., fixation time) should be entered as Estimated 
Processing Time. 
 
3.3 
Snap Frozen Tumor and Adjacent Normal Tissue 
Sites must use their own supplies for the collection of frozen tissue biospecimens. 
 
Note: This procedure requires access to a CryoCooler (Ops Diagnostics, CG 08-07) or 
equivalent. If your site does not have access to this equipment, frozen tissue biospecimens 
should not be collected. 
 
3.3.1 Optional Snap Frozen Biospecimen Requirements 
Note: To minimize the risk of cross-contamination, always use clean, disposable scalpels and 
forceps when cutting different types of tissue (i.e., tumor and normal) from the same patient 
and tissues from different patients. 
 
3.3.1.1 Tumor Tissue 
• Snap frozen tissue should be the most representative of the required type: 
• Pre-treatment snap frozen primary (RP01) or metastatic (RM01) tumor should be 
collected at the time of biopsy for histologic confirmation. 
• Interval snap frozen primary (RP04) or metastatic (RM04) tumor should be collected 
at the time of interval tumor reductive surgery (TRS). 
• The total time from surgical removal to start of freeze must be no more than 30 minutes (≤15 
minutes preferred). This total time must be entered on Form TR as Estimated Processing 
Time. 
• A minimum of one and a maximum of five segments of tumor should be submitted. Total 
tumor tissue volume should be ≤200mg. Each segment should measure no greater than 
1.0x1.0x0.5cm and frozen in a separate cryovial. 
• Tumor segments need not be contiguous, but must be collected from the same tumor nodule 
and be as close in proximity to each other as possible. 
 
3.3.1.2 Adjacent Normal Tissue 
• Snap frozen tissue should be the most representative of the required type: 
• 
Pre-treatment adjacent normal (RN01) tissue should be collected at the time of biopsy 
for histologic confirmation. 


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• The total time from surgical removal to start of freeze must be no more than 35 minutes 
(≤15 minutes preferred). This total time must be entered on Form TR as Estimated 
Processing Time. 
• A minimum of one and a maximum of three segments of adjacent normal tissue should be 
submitted. Total adjacent normal tissue volume should be ≤50mg (≤200mg preferred). Each 
segment should measure no greater than 1.0x1.0x0.5cm and be frozen in a separate cryovial. 
• In general, adjacent normal tissue should be collected from a perilesional, grossly 
uninvolved tissue adjacent to tumor. 
 
3.3.2 Processing Snap Frozen Tissue 
Note: To minimize tumor tissue ischemic time, process the tumor tissue prior to processing the 
adjacent normal tissue. 
 
1. At least 30 minutes prior to tissue procurement: 
a. Storage boxes should be pre-labeled and pre-chilled, either on dry ice or within a -80°C 
freezer. 
b. Prepare a commercially available CryoCooler (Ops Diagnostics, CG 08-07) or 
equivalent as per the manufacturer’s instructions. Warming of the cooler should be 
minimized by always keeping the lid closed and locked when not actively adding or 
removing biospecimens. 
c. Label cryovials as described below. Use 2mL cryovials as tissue biospecimens will be 
shipped to the NRG BB-Columbus. 
2. Using a clean Petri dish, weigh one tissue segment and record the weight on a cryovial. 
Place the tissue segment in the pre-chilled, pre-labeled cryovial. 
3. Freeze the tissue segment within the cryovial for 3 to 5 minutes. Record the start of freeze 
time. The time tissue is removed from the patient to the start of freeze time must be 
documented on Form TR as Estimated Processing Time. 
4. Repeat steps 2 and 3 for all tissue segments. 
5. Once all tumor and normal tissue segments have been frozen, place properly labelled 
cryovials in a pre-chilled storage box and transfer to a liquid nitrogen freezer until 
shipment. Ship frozen on dry ice. 
 
3.3.3 Labeling Snap Frozen Biospecimens 
A waterproof permanent marker or printed label should be used to label each translational 
science snap frozen tumor and normal tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY007) 
specimen code (see section 3.3.1.1 above) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (on corresponding pathology report for FFPE) 
tissue weight 
 
3.3.4 Completing Form TR for Snap Frozen Biospecimens 
The type of biospecimen (snap frozen) should be specified on Form TR. 
 


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The time tissue is removed from the patient to the start of freeze time must be documented on 
Form TR as Estimated Processing Time. 
 
3.4 
Cryopreserved Tumor Tissue 
Sites must use their own supplies for the collection of frozen tissue biospecimens. 
 
Note: This procedure requires access to a CoolCell LX freezing unit (Catalog # BCS-405, 
Biocon) or equivalent, as well as cryopreservation media. If your site does not have access to 
these supplies,  frozen tissue biospecimens should not be collected. 
 
3.4.1 Optional Cryopreserved Biospecimen Requirements 
3.4.1.1 Tumor Tissue Type 
Cryopreserved tissue should be the most representative of the required type (e.g., primary or 
metastatic tumor). 
• Pre-treatment cryopreserved primary (RP02) or metastatic (RM02) tumor should be 
collected at the time of biopsy for histologic confirmation. 
• Interval cryopreserved frozen primary (RP05) or metastatic (RM05) tumor should be 
collected at the time of interval tumor reductive surgery (TRS). 
 
3.4.2 Processing Cryopreserved Tumor 
1.Prior to tissue procurement: 
a. Label two cryovials as described below. 
b. Using sterile technique, fill the labeled cryovials with 1mL of cryopreservation media. 
c. The first time the CoolCell LX freezing unit (or equivalent) is used, fill additional 
unlabeled cryovials with 1mL of cryopreservation media. Unlabeled tubes with 
cryopreservation media are used to fill the empty slots of the unit that are not occupied by 
cryovials containing tissue in cryopreservation media. These “placeholders” may be saved 
and reused for each cryopreservation procedure. If the vials appear grossly contaminated, 
they should be replaced with fresh placeholder cryovials. 
2. Place the tumor tissue segment in the pre-labeled cryovial containing 1mL of ambient 
preservation media. 
3. Ensure each cryovial (actual tumor biospecimens and placeholders) is closed tightly and 
place into the CoolCell LX freezing unit (or equivalent). The unit and cryopreservation 
media in all cryovials should be at ambient temperature. Carefully close the lid to the unit. 
4. Place unit in a -80°C freezer for at least 18 hours. 
5. After at least 18 hours in a -80°C freezer, the cryovials containing tumor biospecimens 
may be transported to liquid nitrogen vapor storage or shipped immediately to the NRG 
BB-Columbus on dry ice. 
 
3.4.3 Labeling Cryopreserved Biospecimens 
A waterproof permanent marker or printed label should be used to label each translational 
science cryopreserved tumor tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY007) 
specimen code (see section 3.4.1.1 above) 


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collection date (mm/dd/yyyy) 
surgical pathology accession number (of corresponding pathology report) 
 
3.4.4 Completing Form TR for Cryopreserved Biospecimens 
The type of biospecimen (Other; specify, “Cryopreserved”) should be specified on Form TR. 
 
The time the tissue is removed from the patient to the start of freeze time must be documented 
on Form TR as Estimated Processing Time. 
 
3.5 
OCT Frozen Tumor Tissue 
Sites must use their own supplies for the collection of frozen tissue biospecimens. 
 
3.5.1 Optional OCT Biospecimen Requirements 
3.5.1.1 Tumor Tissue Type 
OCT tissue should be the most representative of the required type (e.g., primary or metastatic 
tumor). 
• Pre-treatment OCT primary (RP03) or metastatic (RM03) tumor should be collected at 
the time of biopsy for histologic confirmation. 
• Interval OCT frozen primary (RP06) or metastatic (RM06) tumor should be collected at 
the time of interval tumor reductive surgery (TRS). 
 
3.5.2 Processing OCT Frozen Tumor 
1.  At least 30 minutes prior to tissue procurement: 
a. Prepare for freezing tissue in an OCT mold: 
i. 
Ensure access to a freezing plate on a pathology cryostat, or 
ii. 
Ensure access to the flat surface of a dry ice block, or 
iii. 
Prepare a commercially available CryoCooler (Ops Diagnostics, CG 08-07) or 
equivalent. 
The objective of any appropriate method is to provide a flat surface colder than -30°C to 
rapidly freeze tissue embedded in OCT media. Do not freeze tissue in OCT media by 
placing warm tissue in a -70°C to -90°C freezer, dry ice ethanol bath, or submersion in an 
isopentane cryobath. 
b. Label one tissue cryomold and zip bag as described below. 
2.  Using a clean Petri dish, weigh one tissue segment and record the weight on the cryomold 
and zip bag. 
3. Place a thin layer of OCT in the mold to cover the bottom surface. 
4.  Working quickly, gently place (“float”) the tissue on the surface of the bottom layer of 
OCT. Ensure that the largest dimension of the tissue is facing upward. Lay needle core 
biopsy biospecimens length-wise in the mold. 
5. Working quickly, fill the remainder of the mold with approximately 4mL of OCT 
(completely cover the tissue). Carefully dispense the OCT to avoid generating bubbles in 
the media. Ensure the tissue is laying flat in the mold and the OCT completely covers the 
tissue in a level plane. 
6. Quickly place the cryomold on the level cold plate or flat, level surface of dry ice. Allow 
the tissue and OCT to freeze for 3 to 5 minutes. When the tissue and OCT are completely 
frozen, the block will turn white. 


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7. Once frozen, quickly wrap the mold in pre-chilled foil and place the block in the 
corresponding labeled zip bag. Maintain the tissue block buried in dry ice, in a -70°C to -
90°C freezer, or in liquid nitrogen vapor (not liquid phase) until shipment. Ship frozen on 
dry ice. 
 
3.5.3 Labeling OCT Frozen Biospecimens 
A waterproof permanent marker or printed label should be used to label each translational 
science OCT frozen tumor tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY007) 
specimen code (see section 3.5.1.1 above) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (of corresponding pathology report) 
tissue weight 
 
3.5.4 Completing Form TR for OCT Frozen Biospecimens 
The type of biospecimen (OCT) should be specified on Form TR. 
 
The time tissue is removed from the patient to the start of freeze time must be documented on 
Form TR as Estimated Processing Time. 
 
4.  
Serum Shipped to the NRG BB-Columbus 
4.1 
Mandatory Serum Biospecimen Requirements 
Serum should be collected pre-treatment (SB01). 
 
4.2 
Processing Serum Biospecimens 
1.  Label cryovials and a 15mL conical tube as described below. Use 2mL cryovials as serum 
will be shipped to the NRG BB-Columbus. 
 2.  Draw 7-10mL of blood into red top tube(s).  
3.  Allow the blood to clot at 4°C (or in a bucket with ice) for at least 30 minutes but no longer 
than 3 hours. 
4.  Centrifuge the blood at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the serum (top, straw-colored layer) from the red blood cells (bottom, red layer). 
5.  Transfer the serum into a 15mL conical tube and gently mix. 
6. Quickly, evenly dispense (aliquot) the serum into the pre-labeled cryovials and cap 
the tubes securely. Place at least 0.25mL into each cryovial. 
7.  Immediately freeze the serum in an upright position in a -70oC to -80oC freezer or by direct 
exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for 
storage, store and ship on dry ice within 24 hours of collection. 
 
4.3 
Labeling Serum Biospecimens 
A waterproof permanent marker or printed label should be used to label each translational 
science serum biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 


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protocol number (NRG-GY007) 
specimen code (SB##; see section 4.1 above) 
collection date (mm/dd/yyyy) 
 
5. 
Whole Blood (in EDTA) Shipped to the NRG BB-Columbus 
Sites must use their own supplies for the collection of frozen whole blood biospecimens. 
 
5.1 
Optional Whole Blood Biospecimen Requirements 
Whole blood should be collected prior to receiving study treatment (WB01) and after receiving 
the first three cycles of study treatment at the time of interval tumor reductive surgery (WB03). 
 
5.2 
Processing Whole Blood Biospecimens 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described below. Multiple 
tubes may be used to collect the required amount. Do not use glass blood collection tubes. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Immediately freeze the whole blood in an upright position in a -70oC to -80oC freezer or 
by direct exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not 
available for storage, store and ship on dry ice within 24 hours of collection at the 
institution’s expense. 
 
5.3 
Labeling Whole Blood 
A waterproof permanent marker or printed label must be used to label each translational 
science whole blood biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY007) 
specimen code (WB##; see section 5.1 above) 
collection date (mm/dd/yyyy) 
 
6. 
Whole Blood for Cell-Free DNA Shipped to the NRG BB-Columbus 
Sites must utilize their own materials for collection and shipment of whole blood for cell-free 
DNA biospecimens. Collection materials and shipping labels are not provided and shipment 
will be at the site’s expense. 
 
Note: This collection requires Streck (cell-free DNA) blood collection tubes and an ambient 
shipper. If your site does not have access to Streck tubes and ambient shippers, then this 
biospecimen should not be collected.   
 
6.1 
Optional Whole Blood for Cell-Free DNA Biospecimen Requirements 
Whole blood for cell-free DNA should be collected prior to receiving study treatment (WB02) 
and after receiving the first three cycles of study treatment at the time of interval tumor 
reductive surgery (WB04). 
 
6.2 
Special Notes Regarding the Collection of Blood in Streck (Cell-Free DNA) Tubes 


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• Heparin should be avoided in pre-collection flush procedures. 
• All other blood biospecimens should be drawn before the Streck (cell-free DNA) tube 
when multiple blood biospecimens are collected on the same day. 
• Over or under filling a Streck (cell-free DNA) tube will result in an incorrect blood-to-
additive ratio. 
• No other tube may be substituted for a Streck (cell-free DNA) tube. 
 
 
6.3 
Collecting Streck (Cell-Free DNA) Whole Blood 
1.  Label the Streck (cell-free DNA) collection tube as described below. 
2. Draw 10mL of blood into the labeled tube. 
3.  Immediately after collection, gently invert the tube 5-10 times. 
4. Ship whole blood to the NRG BB-Columbus the day the biospecimen is collected. If the 
whole blood absolutely cannot be shipped the day it is collected, the tube must remain at 
room temperature until shipment. 
 
6.4 
Labeling Cell-Free Streck Whole Blood 
A waterproof permanent marker or printed label must be used to label each translational 
science cell-free Streck whole blood biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY007) 
specimen code (WB##; see section 6.1 above) 
collection date (mm/dd/yyyy) 
 
7. 
Submitting Form TR 
A specimen transmittal form (i.e., Form TR) for each biospecimen will be available in the 
Translational Research Folder in Rave, once the Specimen Consent (located in the Baseline 
Folder) has been completed. 
 
An electronically (i.e., Rave) completed copy of Form TR must accompany each biospecimen 
shipped to the NRG BB-Columbus. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus if biospecimens are not 
collected. 
 
Form TR should be printed from the Translational Research Form screen in Rave using the 
“PDF File” link at the top of the form. Clicking this link will generate a single page PDF. Do 
not use the “Printable Version” or “View PDF” links at the bottom of the form or any other 
method to print the form, as these formats will not be accepted.  
  
Retain a printout of the completed form for your records. 
  
Please contact Support if you need assistance (Email: support@nrgoncology.org). 
 
8. 
Shipping Translational Science Biospecimens 
8.1 
General Information for Shipping Biospecimens to the NRG BB-Columbus 


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• Translational science biospecimens should not be shipped until after patient registration 
and Bank ID assignment. 
• An electronically completed copy of Form TR must be included for each translational 
science biospecimen.  
• All translational science biospecimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG-GY007 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
8.2 
FFPE Tissue Shipped to the NRG BB-Columbus 
FFPE tissue and a copy of the corresponding pathology report should be shipped using your 
own container at your own expense to the NRG BB-Columbus (address in section 8.1). 
 
Do not ship FFPE tissue for Saturday delivery. 
 
8.3 
Frozen Biospecimens Shipped to the NRG BB-Columbus 
All frozen biospecimens (i.e., serum, tissue, whole blood in EDTA) should be shipped using 
the one specimen kit provided to the NRG BB-Columbus (address in section 8.1). 
 
Note: All frozen biospecimens from a given patient must be shipped together in the one 
biospecimen kit provided. If all biospecimens from a given patient are not shipped together in 
one kit, then your instuitution must provide the additional shipping materials (e.g., kits, 
bioharzard bags, etc.) and ship at your institution’s expense.  
 
Frozen biospecimens should be shipped Monday through Thursday for Tuesday through 
Friday delivery. Do not ship frozen biospecimens on Friday or the day before a holiday. Note: 
Saturday delivery is not available for frozen biospecimens.  
 
Frozen biospecimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-
70oC freezer, liquid nitrogen, or direct exposure with dry ice) until the biospecimens can be 
shipped. 
 
8.3.1 Shipping Frozen Translational Science Biospecimens in a Single Chamber Kit 
 
Note: All frozen biospecimens from a given patient must be shipped together in the one 
biospecimen kit provided. If all biospecimens from a given patient are not shipped together in 
one kit, then your instuitution must provide the additional shipping materials (e.g., kits, 
bioharzard bags, etc.) and ship at your institution’s expense. 
 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen biospecimens from each time point in a separate zip-lock bag. 


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3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Put the 
secondary envelope into a Tyvek envelope. Expel as much air as possible before sealing both 
envelopes. 
4. Place the Tyvek envelope containing the frozen biospecimens into the kit and fill the 
chamber to the top with dry ice. 
5. Insert a copy of Form TR for each biospecimen.  
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other 
durable sealing tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). Attach the air bill. (03/20/2017) 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 
8.4 
Whole Blood in Streck Tubes Shipped to the NRG BB-Columbus 
Whole blood in Streck tubes must be kept at room temperature until processed at the NRG BB-
Columbus. An ambient shipper with a SAF-T-TEMP Gel Pak or an insulated shipper must be 
used when shipping whole blood in Streck tubes. These shippers are not provided. 
 
Whole blood in Streck tubes should be shipped Priority Overnight at the site’s expense to the 
NRG BB-Columbus (address in section 8.1). 
 
Whole blood in Streck tubes can be shipped to the NRG BB-Columbus Monday through 
Friday for Tuesday through Saturday delivery. Do not ship whole blood the day before a 
holiday. Use your own shipping container to ship specimens via FedEx priority overnight. 
 
When shipping whole blood in Streck tubes, your site must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the NRG BB-
Columbus at BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  
 
8.4.1 Shipping Whole Blood Using Your Own Shipping Container 
1. Place the whole blood biospecimen in a biohazard envelope containing absorbent material. 
2. Expel as much air as possible before sealing the bag. 
3. Wrap the biohazard envelope in bubble wrap or another padded material. 
4. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing 
the envelope. 
5. Place the Tyvek envelope in either an ambient shipper or an insulated shipping container.  
a. If using an ambient shipper, prepare the SAF-T-TEMP Gel Pak for shipment and place it in 
the bottom of the ambient shipper before adding the specimens. If contents of the Gel Pak 
are crunchy, place the Gel Pak in a warm water bath until the gel is smooth. Do not 
refrigerate, freeze, or microwave. 
6. Insert a copy of Form TR for each biospecimen.  
7. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
8. Attach a completed FedEx air bill. Shipping expenses are not covered. Shipping costs must 
be paid by your site. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 


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9. 
Banking Translational Science Biospecimens for Future Research 
Biospecimens will remain in the NRG BB-Columbus and made available for approved 
research projects if the patient has provided permission for the use of her biospecimens for 
future health research. 
 
Note: Testing of banked biospecimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in accordance 
with National Clinical Trials Network (NCTN) policies. 
 
The patient’s biospecimen consent choices will be recorded on the signed informed consent 
document and electronically via the Specimen Consent form. At the time of biospecimen 
selection for project distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her biospecimens at any 
time if the patient changes her mind. 
 
If the patient revokes permission to use her biospecimens, the NRG BB-Columbus will destroy 
or return any remaining biospecimens. The patient’s biospecimens will not be used for any 
further research; however, any biospecimens distributed for research prior to revoking consent 
cannot be returned or destroyed. In addition, the patient cannot be removed from any research 
that has been done with her biospecimens distributed prior to revoking consent. 
 
Note: If return of biospecimens is requested, shipping will be at the site’s expense. 
 
 
 


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APPENDIX X - PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
(10/10/2016) 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, Ruxolitinib.  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
 
The following concomitant medications, treatments or supplements are prohibited: 
  
 Amifostine 
 Inducers of CYP3A4 may be used with caution, and physicians should seek other options if 
available. Any intended use of a CYP3A4 inducer should be discussed with the study 
investigator in advance. 
 Use of potent inhibitors of CYP3A4 (ketoconazole, clarithromycin, itraconazole, 
nefazodone or telithromycin, voriconazole or posaconazole, and use of fluconazole should 
be avoided; any intended use should be discussed with the study investigator prior to co-
administration. Based on the low overall bioavailability of topical ketoconazole, there are 
no restrictions on topical ketoconazole in the study.  
 Moderate CYP3A4 inhibitors may be used with caution. Differences in individual 
sensitivity and variation in potency of inhibition of various CYP enzymes may result in the 
need for a reduced dose of ruxolitinib during a period of concomitant medication use. Any 
intended use should be discussed with the study investigator prior to co-administration.  
 Use of any concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, hormonal therapy, or tumor embolization) other than 
those specified in the research protocol.  
 Concomitant use of a JAK inhibitor.  
 Use of any investigational medication within 30 days or 5 half-lives, whichever is longer, 
prior to Cycle 1, Day 1 of study treatment is prohibited.  
 St John’s wort and rifampin are not permitted at any time during participation in the study. 
 
Please refer to a frequently-updated drug information reference for strong CYP3A4 inducers and 
inhibitors:   
http://www.uptodate.com/contents/image?imageKey=CARD/76992&topicKey=HEME%2F1370&sou
rce=outline_link&utdPopup=true 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Ruxolitinib may interact with other drugs which can cause side effects. Certain medications, 
supplements and food products are prohibited while on this study, including grapefruit juice and St. 
John’s Wort are not allowed on this study. 


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For this reason, it is very important to tell your study doctors of any medicines you are taking before 
you enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When you 
talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements.  It is helpful to bring your 
medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Ruxolitinib must be used very carefully with other medicines that use certain liver enzymes to be 
effective or to be cleared from your system.  Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to review any medicines and herbal supplements that 
are considered inducers/inhibitors of CYP isoenzymes. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine.  Your 
study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug_ 
Ruxolitinib_______________.  This clinical trial is sponsored by the 
NCI.  _Ruxolitinib_________________ may interact with drugs that 
are processed by your liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
 
_Ruxolitinib_________________ interacts with a specific liver 
enzyme called CYP3A4 and must be used very carefully with other 
medicines that interact with this enzyme.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered 
inducers/inhibitors of CYP3A4.  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


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APPENDIX XI - CANCER THERAPY EVALUATION PROGRAM INTELLECTUAL 
PROPERTY OPTION TO COLLABORATORS 
 
A.   The IP Option described in this Section A would apply to inventions that would be described 
in patent disclosures that claim the use and/or the composition of the Agent(s) and that are 
conceived or first actually reduced to practice pursuant to clinical or non-clinical studies 
utilizing the NCI CTEP provided Agent(s)("Section A Inventions"): 
     Institution agrees to grant to Collaborator(s): (i) a royalty-free, worldwide, non-exclusive license 
for commercial purposes with the right to sub license to affiliates or collaborators working on behalf 
of Collaborator for Collaborator’s development purposes; and (ii) a time limited first option to 
negotiate an exclusive, or co-exclusive, if applicable, world-wide, royalty bearing license for 
commercial purposes, including the right to grant sub licenses, subject to any rights of the Government 
of the United States of America, on terms to be negotiated in good faith by the Collaborator(s) and 
Institution. If Collaborator accepts the non-exclusive commercial license, the Collaborator agrees to 
pay all out of pocket patent prosecution and maintenance costs which will be pro-rated and divided 
equally among all licensees.  If Collaborator obtains an exclusive commercial license, in addition to 
any other agreed upon licensing arrangements such as royalties and due diligence requirements, the 
Collaborator agrees to pay all out of pocket patent prosecution and maintenance costs.  Collaborator(s) 
will notify Institution, in writing, if it is interested in obtaining a commercial license to any Section A 
Invention within three (3) months of Collaborator’s receipt of a patent application or six (6) months of 
receipt of an invention report notification of such a section A invention.  In the event that Collaborator 
fails to so notify Institution, or elects not to obtain an exclusive license, then Collaborator’s option 
expires with respect to that Section A Invention, and Institution will be free to dispose of its interests 
in accordance with its policies.  If Institution and Collaborator fail to reach agreement within ninety 
(90) days, (or such additional period as Collaborator and Institution may agree) on the terms for an 
exclusive license for a particular Section A Invention, then for a period of three (3) months thereafter 
Institution agrees  not to offer to license the Section A Invention to any third party on materially better 
terms than those last offered to Collaborator without first offering such terms to Collaborator, in which 
case Collaborator  will have a period of thirty (30) days in which to accept or reject the offer.   If 
Collaborator elects to negotiate an exclusive commercial license to a Section A Invention, then 
Institution agrees to file and prosecute patent application(s) diligently and in a timely manner and to 


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give Collaborator an opportunity to comment on the preparation and filing of any such patent 
application(s).  Notwithstanding the above, Institution is under no obligation to file or maintain patent 
prosecution for any Section A Invention. 
     For all Section A Inventions, regardless of Collaborator’s decision to seek a commercial license, 
Institution agrees to grant Collaborator a paid-up, nonexclusive, royalty-free, world-wide license for 
research purposes only.  Institution retains the right to make and use any Section A Invention for all 
non-profit research, including for educational purposes and to permit other educational and non-profit 
institutions to do so.    
B.  The IP Option described in this Section B would apply to inventions not covered by Section 
A, but are nevertheless conceived or first actually reduced to practice pursuant to clinical or 
non-clinical studies utilizing the CTEP-provided Agent(s).  It  also applies to inventions that  are 
conceived or first actually reduced to practice pursuant to NCI CTEP-approved studies that use 
non-publicly available clinical data or specimens from patients treated with the CTEP-provided 
Agent (including specimens obtained from NCI CTEP-funded tissue banks) (“Section B 
Inventions”): 
     Institution agrees to grant to Collaborator(s): (i) a paid-up nonexclusive, nontransferable, royalty-
free, world-wide license to all Section B Inventions for research purposes only; and (ii) a 
nonexclusive, royalty-free, world-wide license  to  (a.) disclose Section B Inventions to a regulatory 
authority when seeking marketing authorization of the Agent, and  (b.) disclose Section B Inventions  
on a product insert or other promotional material regarding the Agent after having obtained marketing 
authorization from a regulatory authority.  Notwithstanding the above, Institution is under no 
obligation to file or maintain patent prosecution for any Section B Invention. 
C.   The IP Option described in this Section C would apply to inventions made by Institution’s 
investigator(s) or any other employees or agents of Institution, which are or may be patentable 
or otherwise protectable, as a result of research utilizing the CTEP-provided Agent(s), 
unreleased or non-publicly available clinical data or Agent treated specimens outside the scope 
of approval granted by the NCI CTEP (Unauthorized Inventions):    
     Institution agrees, at Collaborator's request and expense, to grant to Collaborator a royalty-free 
exclusive or co-exclusive license to Unauthorized Inventions.  Institution will retain a non-exclusive, 
non-sub-licensable royalty free license to practice the invention for research use purposes.  
D.  Institution Notification   


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     Institution agrees to promptly and confidentially notify NCI CTEP (NCICTEPpubs@mail.nih.gov) 
and Collaborator(s) in writing of any Section A Inventions, Section B Inventions, and Unauthorized 
Inventions upon the earlier of: (i) any submission of any invention disclosure to Institution of a 
Section A, Section B, or Unauthorized Invention, or (ii) the filing of any patent applications of a 
Section A, Section B, or Unauthorized Invention.  Institution agrees to provide a copy of either the 
invention disclosure or the patent application to the Collaborator and to NCI CTEP which will treat it 
in accordance with 37 CFR Part 401.   These requirements do not replace any applicable reporting 
requirements under the Bayh-Dole Act, 35 USC 200-212, and implementing regulations at 37 CFR 
Part 401.   
 
 
 
 


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APPENDIX XII – PATHOLOGY VERIFICATION FORM (04/06/2018) (04/05/2019) 
 
A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the 
NRG BB-Columbus. 
 
If a pathology report is not available for frozen tissue biospecimens (i.e., snap frozen, 
cryopreserved, and/or OCT frozen), a copy of the radiology report or operative report from the 
tissue collection procedure must be sent to the NRG BB-Columbus. A completed copy of this 
appendix (i.e., Pathology Verification Form) must also be submitted to the NRG BB-Columbus. 
 
Note: If this information is not provided with a frozen tissue biospecimen, it will not be accepted 
by the NRG BB-Columbus. 
 
 
Please have the Pathologist responsible for signing out this patient’s case complete the following: 
 
Bank ID: __ __ __ __ - __ __ - G __ __ __ 
 
Study ID: __ __ __ __ __ - G Y 0 0 7  - __ __ __ __ __ 
 
Date of Procedure (mm/dd/yyyy): _________________________________________ 
 
Tissue Type (circle one): 
Primary  
Metastatic 
 
 
 
 
Interval Primary 
Interval Metastatic 
 
 
 
 
 
 
 
Adjacent Normal 
 
Site Tissue Taken From: ________________________________________________ 
 
Diagnosis: ___________________________________________________________ 
 
Recurrent disease documented by: ________________________________________ 
 
I agree that this tissue may be released for research purposes only and that the release of this tissue 
will not have any impact on the patient’s care. 
 
 
___________________________________  
 
_____________________ 
Pathologist’s Signature 
 
 
 
 
Date 
 
 
___________________________________ 
Pathologist’s Printed Name 
 
 


NRG-GY007 
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APPENDIX XIII – PARTICIPATING INSTITUTIONS FOR PHASE I SAFETY LEAD-IN 
(04/06/2018)   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Institutions for Phase I Safety Lead-In 
PA075 
Abramson Cancer Center at the University of Pennsylvania 
AZ151 
Arizona Cancer Center 
OH027 
Cleveland Clinic Foundation 
PA086 
Fox Chase Cancer Center 
MD017 
Johns Hopkins University/Sidney Kimmel Cancer Center 
GA020 
Georgia Regents University 
CT009 
Hartford Hospital 
TX035 
M.D. Anderson Cancer Center 
NY016 
Memorial Sloan-Kettering 
WI013 
Froedtert and the Medical College of Wisconsin 
OH007 
Ohio State University 
OK003 
Oklahoma University 
NY158 
Roswell Park Cancer Institute 
PA121 
Thomas Jefferson University 
CA189 
UC Davis Medical Center 
CA088 
University of California Medical Center at Irvine-Orange Campus 
OH274 
UHHS – Chagrin Highlands Medical Center 
IL057 
University of Chicago 
CO070 
University of Colorado Cancer Center 
OH029 
Case Western Reserve University 
IA018 
University of Iowa Hospitals and Clinics 
PA015 
University of Pittsburgh Cancer Center 
VA009 
University of Virginia Health Systems 
VA010 
Virginia Commonwealth University 
MO011 
Washington University School of Medicine 
RI012 
Women’s and Infants Hospital