Randomized Pilot Trial of Oral Cyclophosphamide Versus Oral Cyclophosphamide With Celecoxib for Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Phase: PHASE2
Conditions: Fallopian Tube Cancer, Peritoneal Cavity Cancer, Recurrent Ovarian Epithelial Cancer
Sponsor: City of Hope Medical Center

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CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
 
 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:  Randomized Pilot Trial of Oral Cyclophosphamide versus Oral Cyclophosphamide with Celecoxib 
for Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 03092   
VERSION: 
08  
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Submission (protocol version dated 11/07/03) 
00 
COH Amendment (protocol version dated 12/08/03) 
01 
COH Amendment (protocol version dated 12/22/04) 
02 
COH Amendment (Title page change only) 
03 
COH Amendment (protocol version dated 11/02/05) 
04 
 
COH Amendment (Protocol Version 07/01/08 
 
 
 
 
 
 
 
05 
COH Amendment (Personnel Change) 09/04/13  
 
 
 
 
 
 
06 
COH Amendment at Continuation (Personnel Change) 06/29/18  
 
 
 
 
07 
COH Amendment at Continuation (Personnel Change) 06/10/19  
 
 
 
 
08 
 
SITE:  
 
 
 
Ovary, Fallopian Tube, Peritoneum 
 
HISTOLOGY: 
 
 
Adenocarcinoma 
 
STAGE (If applicable): 
 
Recurrent 
 
 
MODALITY:  
 
 
Chemotherapy/Anti-angiogenesis 
 
TYPE:  
 
 
 
Phase II 
 
PRINCIPAL INVESTIGATOR: 
Vincent Chung, M.D. 
 
COLLABORATING INVESTIGATORS: Medical Oncology:  Robert Morgan, M.D. 
 
 
 
 
 
 
 
           
 
PARTICIPATING CLINICIANS: 
Medical Oncology:  Warren Chow, M.D., Mihaela Cristea, M.D., 
Marianna Koczywas, M.D., Steve Koehler, M.D., Dean Lim, M.D., 
Jana Portnow, M.D.,   
PARTICIPATING BIOSTATISTICIAN: Paul Frankel, Ph.D.  
PARTICIPATING INSTITUTIONS:  
City of Hope National Medical Center 
 
City of Hope Medical Group, Pasadena, California 
 
 
 

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TABLE OF CONTENTS 
SCHEMA 
Page No. 
1.0  OBJECTIVES......................................................................................................................3 
2.0  BACKGROUND AND HYPOTHESIS ..............................................................................3 
3.0  DRUG INFORMATION .....................................................................................................6 
4.0  STAGING CRITERIA.........................................................................................................9 
5.0  ELIGIBILITY CRITERIA.................................................................................................10 
6.0  TREATMENT PLAN........................................................................................................11 
7.0  TOXICITIES MONITORED AND DOSAGE MODIFICATIONS.................................13 
8.0  DATA SAFETY AND MONITORING............................................................................14 
9.0 
STUDY PARAMETERS AND CALENDAR ..................................................................16 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS.............................16 
11.0 
STATISTICAL CONSIDERATIONS...............................................................................19 
12.0 
REGISTRATION GUIDELINES......................................................................................19 
13.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE.............................20 
14.0 
MINORITIES AND WOMEN STATEMENT .................................................................20 
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................21 
16.0 
PATHOLOGY REVIEW...................................................................................................21 
17. 
REFERENCES ..................................................................................................................21 
 
APPENDICES (Appendices must be ordered as they appear in the document) 
 
Appendix A: NCI Common Toxicity 
 
Appendix B:    Gender and Ethnicity Tables 
 
 
 
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1.0 
OBJECTIVES 
The objectives of the study are: 
1.1. 
To assess the response rates in patients with recurrent or persistent epithelial 
ovarian, fallopian tube or primary peritoneal cancer who are treated with oral 
cyclophosphamide alone or oral cyclophosphamide with celecoxib. 
1.2. 
To assess the time to disease progression in this group of patients. 
1.3. 
To further describe the toxicities of oral cyclophosphamide with or without 
celecoxib in the above patient population. 
2.0 
BACKGROUND AND HYPOTHESIS 
2.1. 
Epidemiology 
Ovarian cancer is the fifth most common cancer in women in the United States.  
Among women who develop gynecologic malignancies, ovarian cancer is the 
most common cause of death.  An estimated 25,400 women in the U.S. will be 
diagnosed in 2003 and 14,300 will die (1). 
2.2. 
Cancer and Angiogenesis 
The standard initial therapeutic approach to advanced ovarian cancer includes 
debulking surgery followed by chemotherapy (2).   Combination chemotherapy 
has been shown to result in higher remission rates, larger numbers of complete 
responses, and a longer duration of survival compared to single agent 
chemotherapy (3). Through the late 1980’s and early 1990’s the standard 
combination chemotherapy was cisplatin and cyclophophamide. The optimal 
treatment for patients having residual disease or who relapse after initial therapy 
remains unclear and many chemotherapeutic approaches have been tried with 
variable results.  As of yet, there is no second-line chemotherapeutic regimen that 
is considered standard for these patients (4).  
Traditional therapeutic strategies for neoplastic diseases have focused on 
cytotoxic activity directed at the cancer cell.  These approaches have achieved 
relatively limited success despite aggressive treatment with highly toxic regimens 
(5). Because tumor growth and metastases are dependent upon the development of 
vascular supply (angiogenesis) (6-8), therapeutic strategies that target the 
microvasculature are being evaluated clinically (9).  Tumor angiogenesis results 
from a cascade of molecular and cellular events (7) initiated by the release of 
angiogenic growth factors (10-11).  Tumor cells express a variety of 
proangiogenic growth factors that diffuse in the direction of pre-existing blood 
vessels (6; 12).  These growth factors activate the normally quiescent vascular 
cells inducing: (i) proteolytic degradation of the basement membrane (13-14); (ii) 
migration of endothelial cells towards the angiogenic stimulus (15-16); (iii) 
endothelial cell proliferation (15; 17; 18); (iv) lumen formation (13; 15; 16; 19);  
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(v) pericyte capping (15; 20-22); and (vi) production of a new basement 
membrane.  Tumors can also acquire vasculature through vasculogenesis, the 
formation of blood vessels from progenitor endothelial cells, or angioblasts (23-
25).  Vasculogenesis was previously thought to be restricted to the embryo (26-
27), however, circulating stem cells in peripheral blood have been detected that 
can differentiate into endothelial cells and contribute to angiogenesis in the adult 
(28-31). 
Pharmacological targeting of the microvasculature in patients with neoplasms 
represents an attractive therapeutic approach because the inhibition of 
angiogenesis has been shown to prevent growth (32), and can induce regression of 
experimental solid tumors (33). Recent data suggests that selective inhibitors of 
cyclooxygenase-2 (COX-2) are potent inhibitors of angiogenesis (34-35) 
suggesting the potential utility of these agents in oncology. 
2.3. 
COX-2 and Apoptosis 
The increased tumorigenic potential of COX-2 overexpressing cells are also 
thought to be mediated in part by resistance to apoptosis (36).  Treatment with 
selective COX-2 inhibitors has been shown to induce apoptosis in a variety of 
cancer cells including colon (37-38), stomach (39), and prostate (40).  One 
mechanism for the pro-apoptotic activity of COX-2 inhibitors has been the down-
regulation of Bcl-2 (38). The subcellular localization of COX-2 is perinuclear (41-
44) providing a possible link between prostaglandins produced by COX-2 and 
Bcl-2 transcription (45).  Although the precise link between prostaglandin 
production and Bcl-2 synthesis has not been elucidated, it is interesting to 
speculate on the potential role of COX-2 in the increased expression of Bcl-2 that 
results in vascular endothelial cell survival.  Human microvascular endothelial 
cells that overexpress Bcl-2 are refractory to the apoptotic and angiosuppressive 
properties of thrombospondin-1, and appear to participate in a more vigorous and 
sustained angiogenic response (46).  More recently celecoxib, a potent and 
selective COX-2 inhibitor was shown to induce apoptosis in human prostate 
cancer cells by blocking Akt activation, independent of Bcl-2 (47).  The role of 
COX-2 in the potential activation of the survival serine threonine kinase, Akt, is 
unknown but such an interaction would have important implications for 
angiogenesis as the Akt system is a critical signaling pathway for vascular 
endothelial cell survival (48-51). 
Selective pharmacologic inhibition of COX-2 represents a viable therapeutic 
option for the treatment of malignancies.  These agents appear to be safe, and well 
tolerated suggesting that chronic treatment for angiogenesis inhibition is feasible 
(52-57).  Because these agents inhibit angiogenesis they should have at least 
additive benefit in combination with standard chemotherapy (57). Metronomic 
dosing regimens of standard chemotherapeutic agents without extended rest 
periods was shown to target the microvasculature in experimental animal models, 
and result in significant anti-tumor activity.  This antiangiogenic chemotherapy 
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regimen could be enhanced by the concurrent administration of an angiogenesis 
inhibitor (58-59).  Given the safety and tolerability of the selective COX-2 
inhibitors, and the potent antiangiogenic properties of these agents, the 
combination of antiangiogenic chemotherapy with a COX-2 inhibitor warrants 
clinical evaluation. 
2.4. 
Chemotherapy, Chemotherapy Scheduling and Antiangiogenesis 
Prior to 1996, cyclophosphamide plus cisplatin was the standard therapy with 
response rates ranging from 60-80%.  Complete responses were achieved in 
women optimally debulked: however, incompletely resected stage III disease only 
achieved less than 10% long term disease free control (60).  Cyclophosphamide 
alone has been shown to produce response rates of 33% (61). Previous clinical 
trials have used doses of IV cyclophosphamide ranging from 500 mg to 1000 mg 
every 3 to 4 weeks (62).  
Preclinical studies have demonstrated consistently that combinations of 
antiangiogenic and chemotherapeutic compounds have synergistic anti-tumor 
activity (63-64). It has also been reported that chemotherapeutic agents given at 
certain doses and schedules may themselves exhibit antiangiogenic effects.  
Cyclophosphamide is a cell-cycle-nonspecific alkylating agent with activity 
against many solid tumors including breast, lung, head and neck, prostate cancer 
and sarcoma (67). In murine models it has been found to reduce angiogenesis by 
inhibition of endothelial cell proliferation (64). In several recent reports 
continuous low-dose chemotherapy regimens in combination with angiogenesis 
inhibitors induced sustained tumor regression in animal tumor models (65-66).  In 
a study involving cyclophosphamide, mice were implanted with Lewis lung 
carcinoma or EMT-6 breast cancer.  Cyclophosphamide treatment with a 
conventional maximum tolerated dose (MTD) regimen only modestly delayed 
growth of both tumors in mice.  In contrast, when cyclophosphamide was 
administered at lower doses at more frequent intervals (metronomic doses) tumor 
growth was significantly impaired, although the tumors eventually progressed 
(65).  The relapse though could be prevented by combination therapy involving 
similar metronomic dosing of cyclophosphamide with the experimental 
angiogenesis inhibitor TNP-470.  In combination, cyclophosphamide and TNP-
470 eradicated aggressive, drug-resistant tumors in 32 out of 38 tumor-bearing 
mice (65). 
Previous clinical trials investigating second-line therapy for patients with 
recurrent ovarian cancer with oral cyclophosphamide have reported activity.    
Lokich et al have treated 21 patients with oral cyclophosphamide 150 mg/m2 for 5 
days with infusional cisplatin and reported a response rate of 74%.  Toxiciity 
included nephrotoxicity (38%) and neurotoxicity (24%).(68)  Continuous oral 
cyclophosphamide has been used for the treatment of advanced ovarian  
cystadenocarcinoma with partial and complete remission rate of 76%.(69) 
A City of Hope Phase I Trial of oral cyclophosphamide in combination with 
celecoxib in patients with advanced malignancies has currently completed 
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accrual.  The recommended phase II doses are: cyclophosphamide 50 mg po daily 
and celecoxib 400 mg po bid.  MTD has not been achieved and this dosing is well 
tolerated with 1 grade 3 hematologic toxicity.  One of two patients with ovarian 
cancer responded with resolution of pleural nodules and improvement of CA-125.  
At dose level 4 one patient with malignant mesothelioma and another with 
chondrosarcoma both have stable disease.   
Single agent cyclophosphamide has known activity against ovarian cancer with 
response rates of approximately 33%(61).  The combination of celecoxib (an 
antiangiogenic compound) with daily oral cyclophosphamide (chemotherapeutic 
compound with activity in variety of solid tumors and possible antiangiogenic 
activity) will exploit the possibility of synergistic antiangiogenic and anti-tumor 
activity of these compounds without apparent overlapping toxicities. Low doses 
of daily oral cyclophosphamide at 1 mg/kg/day are used in the treatment of 
rheumatologic disorders with favorable safety profile (70). Based upon the above 
data this phase II trial has been designed to evaluate oral cyclophosphamide alone 
or in combination with celecoxib for patients with recurrent or persistent 
epithelial ovarian, fallopian tube or primary peritoneal cancer. 
3.0 
DRUG INFORMATION 
3.1. 
Celecoxib 
3.1.1. Celecoxib (Celebrex) is a selective COX-2 inhibitor approved for use in 
the treatment of osteoarthritis and rheumatoid arthritis. 
3.1.2. Dosing information: An oral dose of 100 or 200 milligrams (mg) twice 
daily is effective in rheumatoid arthritis and osteoarthritis. 
3.1.3. Pharmacokinetics: Peak plasma levels occur within 2 hours of an oral 
dose, and bioavailability is enhanced with a high fat meal. The elimination 
half-life of celecoxib is approximately 10 hours. 
3.1.4. Caution: Headache, dizziness, and minor gastrointestinal disturbances 
have been reported.  Gastrointestinal ulceration or inhibition of platelet 
aggregation, were not observed with celecoxib in short-term studies. 
3.1.5. Clinical applications: celecoxib has demonstrated short-term efficacy in 
rheumatoid arthritis and osteoarthritis of the knee; the cyclooxygenase-2 
selectivity of this agent may reduce the risk of gastrointestinal ulceration 
and platelet and renal dysfunction compared to traditional nonsteroidal 
anti-inflammatory agents although this requires confirmation in long-term 
studies. 
3.1.6. Precautions 
− Conditions predisposing to gastrointestinal events (history of peptic 
ulcer, upper gastrointestinal disease, ulcerative colitis, smoking, 
advancing age, concurrent corticosteroids, alcohol abuse, stress) 
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− Patients with bleeding disorders (potential exacerbation) 
− Patients with hypertension or other cardiovascular disease (potential 
for fluid retention) 
− Liver disease (pharmacokinetic data lacking) 
− Renal impairment (pharmacokinetic data lacking; potential adverse 
renal effects, particularly in the elderly) 
− History of allergic phenomena related to ingestion of other 
nonsteroidal anti-inflammatory drugs 
3.1.7. Adverse Reactions 
3.1.7.1 Hematologic Effects 
Results of effects on platelets and bleeding time in larger clinical 
trials have not been published.  No significant effect on platelet 
function, bleeding time or thromboxane B2 levels was observed 
with doses up to 1200 mg daily in short term (7- to 10-day) studies 
involving healthy subjects 
3.1.7.2 Central Nervous System effects 
Headache and dizziness have been reported in short-term studies. 
Gastrointestinal Effects 
Abdominal discomfort and changes in bowel habits (unspecified) 
have been reported in short-term studies.  In limited endoscopic 
studies (one week), celecoxib 100 or 200 mg twice daily was not 
associated 
with 
peptic 
ulceration. 
 
Significant 
adverse 
gastrointestinal events were not observed in short-term phase II 
studies. 
Data regarding gastrointestinal toxicity (including endoscopic 
evaluations) from large trials of longer duration are unavailable.  
Another selective cyclooxygenase-2 inhibitor, melxicam, has been 
associated with gastrointestinal perforation, ulcer, or bleeding in 
some patients.  It is unclear if the lower cyclooxygenase-2: 
cyclooxygenase-1 ratio of celecoxib will confer greater safety. 
Cardiovascular Effects 
FDA Alert 12/17/04:  Based on emerging information, 
including preliminary reports from one of several long term 
National Institutes of Health (NIH) prevention studies, the risk 
of cardiovascular events (composite endpoint including MI, 
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CVA and death) may be increased in patients receiving 
Celebrex.  FDA will be analyzing all available information 
from these studies to determine whether additional regulatory 
action is needed. 
3.2. 
Cyclophosphamide (Cytoxan®) 
3.2.1. Cyclophosphamide is an alkylating chemotherapeutic agent used in the 
treatment of variety of solid and hematologic malignancies and 
autoimmune disorders. 
3.2.2. Clinical pharmacology: 
Cyclophosphamide is biotransformed principally in the liver to active 
alkylating metabolites by a mixed function microsomal oxidase system.  
These metabolites interfere with the growth of susceptible proliferating 
malignant cells.  The mechanism of action is thought to involve cross-
linking of tumor cell DNA.  Cytoxan is well absorbed after oral 
administration with a bioavailability greater than 75%.  The unchanged 
drug has an elimination half-life of 3 to 12 hours. 
It is eliminated primarily in the form of metabolites, but from 5 to 25% of 
the dose is excreted in urine as unchanged drug. Several cytotoxic and 
noncytotoxic metabolites have been identified in urine and plasma.  
Concentrations of metabolites reach a maximum in plasma 2 to 3 hours 
after an intravenous dose.  Plasma protein binding of unchanged drug is 
low but some metabolites are bound to an extent greater than 60%.  It has 
not been demonstrated that any single metabolite is responsible for either 
the therapeutic or toxic effects of cyclophosphamide.  Although elevated 
levels of metabolites of cyclophosphamide have been observed in patients 
with renal failure, increased clinical toxicity in such patients has not been 
demonstrated. 
3.2.3. Indications and Usage: 
Malignant diseases - The following malignancies are often susceptible to 
cyclophosphamide treatment: malignant lymphomas, multiple myeloma, 
leukemias, mycosis fungoides, neuroblastoma, carcinoma of the ovary, 
head, and lung, retinoblastoma, and sarcomas. 
3.2.4. Toxicities: Alopecia, nausea, vomiting, stomatitis, diarrhea, skin rash, 
pancytopenia, sterility, decreased gonadal function, hemorrhagic cystitis, 
syndrome of inappropriate antidiuretic hormone secretion, immune 
suppression, interstitial pulmonary fibrosis, leukemogenic potential, and at 
extremely high doses, myocardial necrosis. 
3.2.5. Pharmaceutical Data:  Cyclophosphamide is available in 100 mg, 200 mg, 
and 500 mg ampules containing white powder.  The drug can be 
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reconstituted in normal saline or 5% dextrose and water.  The drug should 
be dissolved and given in approximately 250 cc of diluent as rapid iv 
infusion over 1 hour.  It is also available in 25 and 50 mg tablets. 
3.2.6. Stability: Store at room temperature.  Do not store at temperatures above 
90 degrees F. 
4.0 
STAGING CRITERIA 
4.1. 
Staging will be according to accepted criteria developed by the American Joint 
Committee on Cancer as specified below and will be used to determine initial 
stage for descriptive purposes:  
 
 
Primary Tumor (T)  
 
 
 
TX      Primary tumor cannot be assessed  
 
 
T0      No evidence of primary tumor  
 
 
 
T1      Tumor limited to the ovaries  
 
 
T1a   Tumor limited to one ovary; capsule intact, no tumor on ovarian surface 
 
 
T1b 
Tumor limited to both ovaries; capsules intact, no tumor on ovarian 
 
 
 
surface 
 
 
T1c 
Tumor limited to one or both ovaries with any of the following: capsule 
 
 
 
ruptured, tumor on ovarian surface, malignant cells in ascites, or 
 
 
 
peritoneal washing 
 
 
 
T2 
Tumor involves one or both ovaries with pelvic extension 
 
 
T2a 
Extension and/or implants on uterus and/or tube(s) 
 
 
T2b 
Extension to other pelvic tissues  
 
 
T2c 
Pelvic extension (2a or 2b) with malignant cells in ascites or  
 
 
 
peritoneal washing 
 
 
 
T3 
Tumor involves one or both ovaries with microscopically confirmed 
 
 
 
peritoneal metastasis outside the pelvis and/or regional lymph node 
 
 
 
metastasis 
 
 
T3a 
Microscopic peritoneal metastasis beyond pelvis  
 
 
T3b 
Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest 
 
 
 
dimension  
 
 
T3c 
Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension 
 
 
 
and/or regional lymph node metastasis 
 
 
 
Regional Lymph Nodes (N): 
  
Regional lymph nodes include hypogastric, (obturator), common iliac, external 
iliac, internal iliac, lateral sacral, para-aortic, and inguinal. 
  
 
 
NX 
Regional lymph nodes cannot be assessed 
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N0 
No regional lymph node metastasis 
 
 
N1 
Regional lymph node metastasis 
 
 
 
Distant Metastasis (M)  
 
 
MX 
Presence of distant metastasis cannot be assessed  
 
 
M0 
No distant metastasis  
 
M1 
Distant metastasis (excludes peritoneal metastasis)   
 
 
 
 
Stage Grouping  
 T  
 
 N  
 
 M  
  
 
 
Stage  IA 
T1a 
 
N0 
 
M0  
 
 
  
IB 
T1b 
 
N0 
 
M0  
 
 
IC 
T1c 
 
N0 
 
M0  
 
 
 
Stage  IIA 
T2a 
 
N0 
 
M0  
 
           IIB 
T2b 
 
N0 
 
M0  
 
 
           IIC 
T2c 
 
N0 
 
M0      
 
 
 
Stage  IIIA 
T3a 
 
N0 
 
M0  
 
 
           IIIB 
T3b 
 
N0 
 
M0  
 
 
           IIIC 
T3c 
 
N0 
 
M0 
 
 
  
Any T  
N1 
 
M0  
 
 
 
Stage  IV        
Any T  
any N  
M1  
 
 
 
*T = Tumor description, N = Node status; M = Metastases 
 
5.0 
ELIGIBILITY CRITERIA 
5.1. 
Inclusion Criteria 
5.1.1. Patients with recurrent or residual epithelial ovarian, Fallopian tube, or 
primary papillary peritoneal cancer, which has been histologically 
confirmed regardless of prior treatment. 
5.1.2. Patients with measurable disease or rising CA-125 to levels at least twice 
normal.  The CA-125 increase must be documented by two independent 
measurements at least 4 weeks apart. 
5.1.3. Patient must have adequate renal function documented by a creatinine      
< 1.5 
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5.1.4. Patients must have adequate bone marrow function as evidenced by an 
absolute neutrophil count of >1.5 x109 /L and a platelet count>100 x 109 
/L. 
5.1.5. Patients must have a Karnofsky performance status of 60-100%. 
5.1.6. Patients must be at least 18 years of age. 
5.1.7. Patient must be capable of understanding the nature of the trial and must 
give written informed consent. 
5.1.8. Patients must have life expectancy of at least three months. 
5.1.9. Patients with brain metastases which at the time of study enrollment are 
controlled and do not require treatment with corticosteroids are eligible. 
5.2. 
Exclusion Criteria 
5.2.1. Patients who have had radiotherapy or chemotherapy within three weeks 
prior to anticipated first day of dosing.  Patients must be fully recovered 
from the acute effects of any prior chemotherapy or radiotherapy. 
5.2.2. Patients with unstable or severe intercurrent medical conditions or active, 
uncontrolled infection. 
5.2.3. Patients with a history of allergic reactions to non-steroidal anti-
inflammatory drugs. 
5.2.4. Patients with history of bleeding peptic ulcer within last 3 months. 
5.2.5. Patients undergoing therapy with other investigational agents.  Patients 
must have recovered from all acute effects of previously administered 
investigational agents and sufficient time must have elapsed since last 
administration to ensure the drug interactions not occur during this study. 
5.2.6. Patients who are allergic to sulfa drugs. 
5.2.7. Pregnant women will be excluded from this study due to the potential of 
harm to the fetus. 
5.2.8. Patients 
with 
clinically 
significant 
cardiovascular 
disease 
(e.g. 
uncontrolled hypertension, myocardial infarction unstable angina), New 
York heart association grade II or greater congestive heart failure, serious 
cardiac arrhythmia requiring medication, or grade II or greater peripheral 
vascular disease. within 1 year prior to study entry. Subjects with 
hypertension are eligible if their blood pressure h as been normal while on 
a stable dose of medication for at least one year. 
6.0 
TREATMENT PLAN 
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6.1. 
Patients will be randomized to one of two treatment arms.  Arm A consists of oral 
cyclophosphamide 50 mg daily (each cycle will be 4 weeks) and Arm B consists 
of oral cyclophosphamide 50 mg daily and celecoxib 400 mg twice daily.  
 Treatment Schedule:  
ARM A 
 
Cyclophosphamide 50 mg po daily 
ARM B 
 
Cyclophosphamide 50 mg po daily 
 
Celecoxib 400 mg po twice daily 
 
Cyclophosphamide --------------------------------------------------------------------- 
 
Celecoxib               --------------------------------------------------------------------- 
                                           Week 1    Week 2     Week 3    Week 4    Week 1 ……  
                                          CYCLE 1                                                     CYCLE 2  
 
6.2. 
Duration of Therapy 
The treatments will continue for all patients having adequate renal and bone 
marrow as defined for patient eligibility (Sections 5.1.3, 5.1.4).  Those patients 
requiring temporary discontinuation of protocol therapy due to toxicity may have 
treatment resumed upon resolution of toxicities to ≤ grade 2 using CTCv2.0. A 
treatment may be stopped for up to 21 days to allow for recovery from toxicities. 
Patients unable to safely resume treatment at that point will be taken off study.  
Criteria for Removal From Treatment 
6.2.1. Disease progression. 
6.2.2. Treatment delay > 3 weeks. 
6.2.3. Unacceptable toxicity. 
6.2.4. The patient may withdraw from the study at any time for any reason. 
6.3. 
Patients may not receive concurrent therapy with any other investigational drug, 
or any other antineoplastic therapy. Standard medical care for the health and 
comfort of the patient is appropriate. 
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6.4. 
After discontinuation of treatment patients will be followed per good medical 
practice and follow-up information including potential long-term side effects will 
be obtained until patients’ death.  
7.0 
TOXICITIES MONITORED AND DOSAGE MODIFICATIONS 
7.1. 
Patients will be examined and graded at least once every 4 weeks for 
subjective/objective evidence of toxicities according to NCI CTC v2.0 which can 
be found at the CTEP website: http://ctep.info.nih.gov. (see Appendix A). 
7.2. 
Management of Anticipated Toxicities 
No hematologic toxicities and neuropathy are expected with celecoxib.  Diarrhea, 
gastritis and gastrointestinal bleeding may occur at higher doses of celecoxib. 
Toxicities of daily oral cyclophosphamide may include neutropenia, cystitis and 
alopecia. 
7.2.1. Management of celecoxib toxicities 
7.2.1.1 
Celecoxib has not been reported to cause significant 
hematologic toxicity.  Therefore, no dose modifications in 
the study drug are required for hematologic toxicity which 
should be attributed to cyclophosphamide.   
7.2.1.1 
Non-hematologic toxicity 
Grade 1-2 diarrhea will be treated with antidiarrheal agent 
per investigator’s choice, grade 1-2 gastritis will be treated 
with antacid, H2 blocker or proton inhibitor per 
investigator’s choice. 
7.2.1.1 
Other Toxicities 
The investigator must use the available data and clinical 
judgement in deciding whether an adverse event is 
attributable to celecoxib. The following modifications 
should be followed in the event of celecoxib-related 
toxicity: 
Grade 
Percent of full dose of celecoxib 
0-2 
100% 
3 
Hold 
4 
Hold 
 
7.2.2. Management of Toxicities of Cyclophosphamide 
Interruption or delays in the administration of cyclophosphamide will be 
allowed for up to 3 weeks. In the event of toxicities attributable to 
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celecoxib, no dose modification of cyclophosphamide will be required, 
however, cyclophosphamide will be held until resolution of toxicities 
(grade ≤2) allows restarting of treatment with cyclophosphamide. 
7.2.3. Hematologic Toxicity 
The following modifications should be followed for cyclophosphamide-
related hematologic toxicity: 
Absolute neutrophil count (x106/L)
Platelets (x106/L) 
Cyclophosphamide dose 
≥ 1500 
≥ 100,000 
 100% dose 
< 1500 
<100,000 
*Hold 
* Delay treatment for up to 3 weeks.  If toxicities have not resolved in 3 weeks then the 
patient is removed from the protocol.  Once toxicities resolve, if the nadir ANC < 300 
or platelet count < 30,000 then cyclophosphamide 50 mg will be given every other day.  
If the hematologic toxicities recur then the patient will be removed from the protocol. 
7.2.4. Non-Hematologic Toxicities 
Non-hematologic toxicities of cyclophosphamide include fatigue, nausea, 
vomiting, alopecia, cystitis.  The following modifications should be 
followed in the event of cyclophosphamide-related non-hematologic 
toxicity (excluding alopecia): 
Grade 
Cyclophosphamide dose 
0-2 
100 % dose  
3 
*Hold 
4 
*Hold 
* If toxicities have not resolved in 3 weeks then the patient is 
removed from the protocol. 
8.0 
DATA SAFETY AND MONITORING 
8.1. 
Definition of Risk Level 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures 
for Data and Safety Monitoring for In-House Trials at City of Hope”, 
http://www.infosci.coh.org/gcrc/doc/dsmp.doc because it is a pilot Phase II clinical trial 
where the risks are balanced by the potential benefit to subjects and the 
importance of the knowledge that may result. 
 
8.2 
Monitoring and Personnel Responsible for Monitoring 
 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA, protocol nurse, and statistician is responsible for monitoring 
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the data and safety of this study, including implementation of any stopping rules 
for safety and efficacy.  
 
Data and safety will be reported to the COH DSMB. Protocol specific data 
collection will be analyzed at the interim accrual goal for each arm (13 patients).  
In addition, reporting of data and safety to the DSMB will occur annually using 
the PMT report. 
 
 
8.3 
Adverse Events 
 
Reporting: Adverse events must be reported to the COH DSMB, IRB and GCRC 
according to definitions and guidelines at 2http://www.infosci.coh.org/gcrc/doc/dsmp.doc 
and 3Hhttp://resadmin.coh.org/doc/irb3810.doc, which are defined below.  AEs will be 
monitored by the PMT. Less than serious adverse events will be reported only at 
the time of protocol continuation reports. This study will use the Common 
Toxicity Criteria version 2 (4Hhttp://ctep.cancer.gov/reporting/CTC-3test.html) to 
evaluate and grade adverse events 
 
Adverse Event - An adverse event (AE) is any untoward medical experience or 
change of an existing condition that occurs during or after treatment, whether or 
not it is considered to be related to the protocol intervention. All AEs occurring 
during this study, whether observed by the physician, nurse, or reported by the 
patient, will be recorded on the City of Hope National Medical Center Adverse 
Events (COH AER) form (5Hhttp://resadmin.coh.org/doc/irb3820.doc).    
 
Serious Adverse Event- A serious adverse event (SAE) is defined as any expected 
or unexpected adverse event (AE, generally equivalent to CTCAE grades 3, 4 or 
5) that is related or unrelated to the intervention that results in any of the 
following outcomes: 
• Death 
• A life-threatening event 
• In-patient hospitalization (not required as part of the treatment) or   
             prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Causes cancer 
• Is an overdose 
 
Certain medical events that may not result in death, be life-threatening, or require 
hospitalization, may also be considered a serious adverse event when appropriate 
medical or surgical intervention is necessary to prevent one of the outcomes listed 
above. 
 
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Unexpected Adverse Event – Any event in which the severity or specificity is not 
consistent with the risk information described in the protocol, and the event is not 
anticipated from the subject's disease history or status. 
 
Expected Adverse Event - Any event in which the severity or specificity is 
consistent with the risk information described in the protocol or is anticipated 
based on the subject's medical history. 
 
Attribution - For reporting purposes, attribution is the assessment of the likelihood 
that an AE is caused by the research agent or protocol intervention.  The 
attribution is assigned by the Principal Investigator after considering the clinical 
information, the medical history of the subject, and past experience with the 
research agent/intervention.  This is recorded using the Adverse Event Report 
(COH AER) form (6Hhttp://resadmin.coh.org/doc/irb3820.doc) in one of 5 categories 
scored as the following: 5=related, 4=probably related, 3=possibly related, 
2=unlikely related and 1=unrelated.  The attribution is subject to change as 
follow-up information becomes available, and it can be changed by the DSMB or 
by the IRB in the process of review. 
 
9.0 
STUDY PARAMETERS AND CALENDAR 
Assessment 
Prior to 
Therapy 
Approx 
 Day 15 
 
Each 
cycle 
(every 4 
weeks) 
Every 2 
cycles (every 
8 weeks) 
History and Physical Exam 
X 
X 1 
 
X 
 
Weight and KPS 
 
X 
X 1 
 
X 
 
Toxicity using CTC v2.0 
 
X 1 
 
X 
 
CBC, Diff, Plts,  
 
 
Na, K, Cl, CO2, Creatinine, BUN, 
glucose, Calcium, phosphorus, 
albumin, LDH, 
SGPT(ALT),SGOT (AST), 
Alkaline Phos, Total Bilirubin  
X 
 
 
 
X 
 
 
 
X 1 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Urine Pregnancy Test (if 
applicable) 
X 
 
 
 
EKG 
X 
 
 
 
Chest X-Ray,  
X 
 
 
 
Tumor markers (if applicable) 
X 
 
X 
 
Tumor Measurements (if 
applicable) 
X 
 
 
X 
Formatted Table
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1During cycle #1 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
10.1. Disease Status 
10.1.1. Measurable disease: Lesions that can be accurately measured in at least 
one dimension by 1) plain x-ray, CT, MRI or other imaging technique 
with longest diameter greater than 2 cm or 2) spiral CT with longest 
diameter 1 cm or greater. 
10.1.2. Non-measurable disease: All other lesions including lesion too small to be 
considered measurable (longest diameter < 2 cm with conventional 
techniques or < 1 cm with spiral CT), pleural or pericardial effusions, 
ascites, bone disease, leptomeningeal disease, lymphangitis, pulmonitis, 
abdominal masses not confirmed or followed by imaging techniques and 
cystic lesions. (CA-125, a marker, which has been shown to be highly 
correlated, with extent of disease is also considered to be evaluable.) 
10.2. Objective Status at each evaluation: All measurable lesions up to a maximum of 
ten lesions representative of all involved organs should be identified as target 
lesions at baseline.  If there are more than ten measurable lesions, the remaining 
are identified as non-target lesions and are included as non-measurable disease.  
Measurements must be provided for target measurable lesions while presence or 
absence must be noted for non-target measurable and non-measurable disease 
10.2.1. Complete response (CR):  Complete disappearance of all measurable and 
non-measurable disease.  No new lesions.  No disease-related symptoms.  
Normalization of CA-125 and other abnormal lab values.  All measurable 
and non-measurable lesions must be assessed using the same technique as 
baseline. 
10.2.2. Partial response (PR):  Defined by either of two sets of criteria outlined 
below: 
1) Greater than or equal to 30% decrease under baseline of the sum of the 
longest diameters of all target measurable lesions with no new lesions.  
No progression of non-measurable disease. All measurable and non-
measurable lesions must be assessed using the same technique as 
baseline. 
2) A decline in CA-125 by at least 50% confirmed by a second CA-125 
four or more weeks later.  The reference CA-125 should be measured 
within 3 weeks prior to starting therapy. No progression of measurable 
or non-measurable disease during this time period. 
10.2.3 Stable:  Does not qualify for CR, PR, or progression.  All measurable and 
evaluable sites must be assessed using the same techniques as baseline. 
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10.2.4 Progression:  One or more of the following must occur: 20% increase in 
the sum of the longest diameters of target measurable lesions over smallest 
sum observed (over baseline if no decrease during therapy) using same 
techniques as baseline. Increase in CA-125 by at least 25% on two 
sequential measurements 4 weeks apart. Increasing CA-125 alone in 
patients with coexisting measurable disease shall not define progression 
when accompanied by responding or stable measurable disease. 
Unequivocal progression of non-measurable disease in the opinion of the 
treating physician (an explanation must be provided). Appearance of any 
new lesion/site. Death due to disease without prior documentation of 
progression and without symptomatic deterioration. 
10.2.5 Symptomatic deterioration: Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  
Efforts should be made to obtain objective evidence of progression after 
discontinuation. 
10.2.6 Assessment inadequate, objective status unknown: Progression or 
symptomatic deterioration has not been documented, and one or more 
target measurable lesions have not been assessed or inconsistent 
assessment methods were used. 
10.3 Best Response: Calculated from the sequence of objective statuses 
a) CR: Two or more objective statuses of CR a minimum of 4 weeks apart 
documented before progression or symptomatic deterioration. 
b) PR: Two or more objective statuses or PR or better a minimum of 4 weeks 
apart documented before progression or symptomatic deterioration but not 
qualifying as CR. 
c) Unconfirmed CR: One objective status of CR documented before progression 
or symptomatic deterioration but not qualifying as CR or PR. 
d) Unconfirmed PR: One objective status of PR documented before progression 
or symptomatic deterioration but not qualifying as CR, PR. Or unconfirmed 
CR. 
e) Stable: At least one objective status of stable / no response documented at 
least 6 weeks after registration and before progression or symptomatic 
deterioration, but not qualifying as anything else above. 
f) Increasing disease: Objective status of progression or symptomatic 
deterioration within 12 weeks of registration, not qualifying as anything else 
above. 
g) Inadequate assessment, response unknown: Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
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10.4 Time-Related Endpoint Definitions  
10.4.1 Survival: Defined as the time from registration to time of death due to any 
cause.  If a patient is not known to have died, survival time is censored at 
the time of last follow-up. 
10.4.2 Progression-free survival: Defined as the time from registration to the first 
observation of disease progression or death due to any cause.  If a patient 
has not progressed or died, progression-free survival is censored at the 
time of last follow-up. 
10.4.3 Time to treatment failure: Defined as the time from registration to the first 
observation of disease progression, death due to any cause, or early 
discontinuation of treatment.  If failure has not occurred, failure time is 
censored at the time of last follow-up. 
11.0 
STATISTICAL CONSIDERATIONS 
Once all pretreatment evaluations have been completed and informed consent obtained, 
the patient will be registered in the study. The Department of Biostatistics will randomly 
assign each patient to one of two arms as described above. 
 
Each arm of this randomized pilot trial will be conducted independently.  Responders will 
include patients with best response as either PR, CR, PRNM, or Stable disease. Simon's 
Two-Stage minimax Phase II design will be used for each arm.  We will assume that a 
true response rate of 20% would warrant further study for an arm, while a true response 
rate of less than 5% would not warrant any further study of that arm. For each arm, the 
first stage of accrual will consist of 13 patients. If no responses are seen, that arm will 
stop accrual, with the conclusion that the regimen is not promising for further study. 
Provided that one or more responses are observed in the first 13 evaluable patients, 
continuation of that arm will continue, and an additional 14 evaluable patients will be 
accrued to that arm during the second stage of accrual. Four or more responses out of the 
27 patients will be considered evidence that the regimen warrants further study, provided 
that other factors such as toxicity and survival also appear to be favorable. Using this 
design, the probability of correctly declaring that an arm with a true response rate of 20% 
warrants further study is 0.80 (power), and the probability of falsely declaring that an arm 
with only a 5% true response rate warrants further study is 0.05 (alpha).   
 
At the conclusion of the conduct of this study, there are four distinct possibilities. Neither 
arm may prove promising, one arm may prove promising while the other does not, or 
both arms may prove promising.  In the last scenario, the decision on which arm to 
pursue will be made based on a simple play-the-winner rule, assuming all other factors 
appear equivalent. In that case, under the null hypothesis of equivalence, there is equal 
probability of choosing each arm. However, if one arm has a true response rate of 20%, 
and the other arm a true response rate of 34%, there is an 80% probability of choosing the 
correct arm. 
  
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Exact 95% confidence intervals will be calculated for response rates, and time to 
treatment failure, duration of response and survival will be estimated using the product-
limit method of Kaplan and Meier. Toxicity information recorded will include the type, 
severity, course at onset, and the probable association with the study regimen. Tables will 
be constructed to summarize the observed incidence by severity and type of toxicity. 
 
12.0 
REGISTRATION GUIDELINES 
Registration will be done at City of Hope.  
Note: Following registration, randomization will be carried out by Biostatistics at 
(626) 359-8111, ext. 62468 
12.1. Procedures for On-Study and Treatment Deviations 
The PI must approve all waivers (i.e.deviations in eligibility) prior to patient 
registration, and all treatment deviations prior to treatment.  The treating 
physician must contact the PI.  Upon approval, the PI must submit an amendment 
to the protocol to the IRB. 
13.0 
DATA COLLECTION FORMS AND SUBMISSION SCHEDULE 
All data will be collected using COH Biostatistics Information Tracking System (BITS) 
data collection forms.  The completed forms will be submitted to data entry and stored in 
a secure location. 
 
13.1. The Protocol Nurse will complete the Eligibility Checklist Worksheet at the time 
of registration. 
13.2. Patient Consent Form:  At the time of registration, three signed and dated copies 
of the patient Informed Consent form and the Experimental Subject’s Bill of 
Rights for Treatment Studies must be available for the patient, the patient's 
medical chart and the Biostatistics Office. 
13.3. Confidentiality of Records:  The forms will be kept in secure cabinets in the 
Department of Biostatistics. 
13.4. Within four weeks of completion of each course of treatment, the data manager 
must complete the following: 
13.4.1 Within two weeks of registration, the data manager will complete the On-
Study Form (Form OS). 
13.4.2 Treatment and Adverse Event Form 
13.4.3 Supplemental Data Form (if applicable) 
13.4.4 Flow Sheets (These are to be submitted along with each treatment form.) 
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13.4.5 Each time a patient is evaluated for response and/or new follow-up 
information is obtained the data manager will complete the Response/Off-
Study/Follow-Up Form. 
14.0 
MINORITIES AND WOMEN STATEMENT 
This is a Phase II trial in patients with recurrent ovarian, Fallopian tube, or primary 
peritoneal cancer.  As such, only women will be enrolled.  Patients of all racial/ethnic 
groups are eligible for this study if they meet the eligibility criteria outlined in Section 
5.0.  To date, there is no information that suggests that differences in drug metabolism or 
disease response would be expected in one group compared to another.  Efforts will be 
made to accrue a representative sample.  If differences in outcome appear to be 
associated with ethnic identity, then a follow-up study will be designed to investigate 
those differences more fully.  
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
All institutional, NCI, Federal, and State of California regulations concerning the 
Informed Consent form will be fulfilled. 
16.0 
PATHOLOGY REVIEW 
All patients will have advanced malignancy confirmed by review of their biopsy 
specimens by the Division of Pathology of the City of Hope National Medical Center. 
17.0 
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