Clinical trial NCT01958580
Conditions: Stage IA Uterine Sarcoma Stage IB Uterine Sarcoma Stage IC Uterine Sarcoma Stage IIA Uterine Sarcoma Stage IIB Uterine Sarcoma Stage IIIA Uterine Sarcoma Stage IIIB Uterine Sarcoma Stage IIIC Uterine Sarcoma Stage IVA Uterine Sarcoma Stage IVB Uterine Sarcoma Uterine Corpus Leiomyosarcoma
Sponsor: Albert Einstein College of Medicine
Start date: 2013-09-17; Completion date: 2017-02-24
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies gemcitabine hydrochloride, docetaxel, and radiation therapy in treating patients with uterine sarcoma that has been removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and docetaxel, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill tumor cells. Giving combination chemotherapy with radiation therapy may kill any tumor cells that remain after surgery.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the toxicity and tolerability of adjuvant pelvic radiation in combination with gemcitabine (gemcitabine hydrochloride)/docetaxel chemotherapy in patients with stage 1 and 2 surgically-resected uterine leiomyosarcoma.

SECONDARY OBJECTIVES:

I. To assess the two year recurrence-free survival in patients with uterine leiomyosarcoma treated with chemotherapy and radiation therapy including defining the patterns of recurrence in patients with uterine leiomyosarcoma who were treated with this regimen.

OUTLINE:

CHEMOTHERAPY: Patients receive gemcitabine hydrochloride intravenously (IV) over 90 minutes on days 1 and 8 and docetaxel IV over 1 hour on day 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

RADIATION THERAPY: Beginning week 10, patients undergo 3 fractions of brachytherapy or intensity modulated radiation therapy (IMRT) over 3 weeks. Patients then undergo external beam radiation therapy (EBRT) once daily (QD) 5 days a week for 5 weeks.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Arms: arm 1: CHEMOTHERAPY: Patients receive gemcitabine hydrochloride IV over 90 minutes on days 1 and 8 and docetaxel IV over 1 hour on day 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

RADIATION THERAPY: Beginning week 10, patients undergo 3 fractions of brachytherapy or IMRT over 3 weeks. Patients then undergo EBRT QD 5 days a week for 5 weeks.
Interventions: intervention 1: Gemcitabine Hydrochloride intervention 2: Docetaxel intervention 3: Internal Radiation Therapy intervention 4: Intensity-Modulated Radiation Therapy intervention 5: External Beam Radiation Therapy intervention 6: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo brachytherapy intervention 4: Undergo IMRT intervention 5: Undergo EBRT intervention 6: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
A  Pilot  Safety  and  Toxicity  Trial  of  Adjuvant  Chemotherapy  with  Gemcitabine  and 
Docetaxel and Radiation Therapy for completely resected Uterine Leiomyosarcoma 
 
 
 
Principal Investigator: Akiva 
Novetsky, M.D. 
Division of Gynecologic Oncology 
Department of Obstetrics & Gynecology and Women’s Health 
1695 Eastchester Rd., Suite 601 
Bronx, NY 10461 
Phone: 718-405-8082 
Fax: 718-405-8087 
Email:   ANOVETSK@montefiore.org 
 
Co-Investigators: 
Gary L. Goldberg, M.D. 
Harriet Smith, M.D. 
Dennis Yi-Shin Kuo, M.D. 
Gloria S. Huang, M.D. 
David Smotkin, M.D. 
Nicole Nevadunsky, M.D.  
 
Radiation Oncology 
Keyur Mehta, M.D. 
 
Statistics 
Xiaonan (Nan) Xue, PhD 
 
Chemotherapy Nurses 
Lois Taylor-Pinnock, RN 
Eileen Burke, RN 
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INDEX 
 
SCHEMA 
 
1.0 
BACKGROUND 
2.0 
OBJECTIVES 
3.0 
PATIENT SELECTION 
4.0 
REGISTRATION  PROCEDURES 
5.0 
TREATMENT PLAN 
6.0 
TOXICITY 
7.0 
MEASUREMENT OF EFFECT 
8.0 
STUDY PARAMETERS 
9.0 
DRUG FORMULATION AND PROCUREMENT 
10.0 
STATISTICAL  CONSIDERATIONS 
11.0 
COLLECTION  PROCEDURES 
12.0 
RECORDS TO BE KEPT 
13.0 
PATIENT CONSENT AND PEER JUDGEMENT 
14.0 
MINORITIES AND WOMEN STATEMENT 
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
16.0 
DATA SAFETY MONITORING PLAN 
17.0 
ELIGIBILITY CHECKLIST 
18.1 
REFERENCES 
APPENDIX 
1. Study Schedule 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
Weeks 1-12 
Gemcitabine 900mg/m2/90 min days 1, 8 & Docetaxel 75mg/m2/1 hour day 8 
Repeat q 21 days x 4 cycles 
 
 
 
 
 
 
 
 
Weeks 10-12 
High Dose Rate (HDR) Brachytherapy x 3, or IMRT where appropriate 
Nucletron Microselectron Afterloading Technique 
5 Gy to 0.5cm Depth from the Vaginal Cylinder Surface 
Total Dose 15 Gy 
 
 
 
 
 
 
 
 
 
Weeks 13-17 
Pelvic +/- Para-aortic External Beam Radiation Therapy 
1.8 Gy Dose/Fx 
Total Dose 45Gy 
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1.0 
BACKGROUND 
Leiomyosarcoma is the most common form of sarcoma of the uterus, but accounts for 
only 2-3% of all cancers of the uterine corpus [1].  Leiomyosarcomas are  
characterized by early hematogenous spread.  Even those patients who present with 
early stage disease have recurrence rates of 53 to 71% [1].  Five-year survival rates   
for Stage I (confined to the uterus) is 50%, quickly dropping off to 25% for those with 
Stage II (pelvic spread), and essentially 0% for those with Stage III/IV [2] . 
 
Like with most sarcomas, optimal surgical resection provides the most benefit to 
patients in terms of disease control and overall survival [3].  However, adjuvant 
therapy is clearly needed given the high recurrence rates and poor prognoses.  No 
specific adjuvant treatment has emerged as the standard of care.  Given the fact that 
40% of first recurrences are diagnosed in the lungs, chemotherapy would seem to be a 
rational choice for adjuvant therapy as it offers systemic delivery [1].  Currently, no 
standard chemotherapy regimens exist either in the adjuvant or advanced/recurrent 
settings.  Also, there are limitations in the existing literature.  Few randomized, 
controlled trials exist because of the low incidence of uterine leiomyosarcoma.  Many 
trials have pooled together all uterine sarcomas, including carcinosarcomas which are 
now classified as epithelial tumors, and those who have been able to do a subset 
analysis have demonstrated that there are differences in the behaviors and responses  
of leiomyosarcomas from other forms of sarcoma.  Other trials have extrapolated  
from all leiomyosarcomas, not just those originating in the uterus. 
 
CHEMOTHERAPY 
While many agents have been tested, few have been found to have efficacy against 
uterine leiomyosarcoma [4].  Currently, the most commonly used regimen for 
treatment of recurrent or advanced/unresectable uterine leiomyosarcoma had been the 
combination of doxorubicin with ifosfamide.  In a phase III trial for uterine sarcomas, 
the subset of subjects with advanced leiomyosarcoma demonstrated a 25% response 
rate to a doxorubicin 60mg/m2 dose [5].  The addition of ifosfamide 1g/m2 to 
doxorubicin 50mg/m2 was evaluated in a phase II trial of advanced uterine 
leiomyosarcoma and demonstrated a 30% response rate, albeit at the expense of  
nearly half of the patients getting a grade 3 and 4 neutropenia [6].  While not 
compared against single-agent doxorubicin in a trial, the combination became the 
most commonly used regimen based on this data.  Recently, single-agent liposomal 
doxorubicin was assessed in a phase II trial and showed only a 16% response rate, 
seemingly inferior to doxorubicin although not compared in a head-to-head fashion 
[7]. 
 
More recently, treatment studies have shown the combination of gemcitabine and 
docetaxel to be promising.  A phase II trial for patients with unresectable 
leiomyosarcoma was conducted using the combination of gemcitabine 900mg/m2 on 
day 1 and 8 and docetaxel 100mg/m2 for up to 8 cycles with a 25% dose-reduction for 
patients with prior pelvic radiation [8].  The trial included all leiomyosarcomas, 
although 85% were of uterine origin.  Furthermore, patients were eligible for up to   
two prior chemotherapies, and almost half had been pre-treated with a doxorubicin- 
based treatment. Prophylactic granulocyte-colony stimulating factors were given with 
each cycle.  The overall response rate was 53%.  Patients who had received prior 
doxorubicin-based therapy did not show any significant difference in response than 
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those who had not.  While single-agent docetaxel and gemcitabine had shown 
responses inferior to doxorubicin, the combination of the two agents results in a 
synergy that makes it as one of the most active drug combinations studied to date [8]. 
 
This study of patients with advanced stage unresectable disease led to the evaluation  
of gemcitabine/docetaxel in the adjuvant setting following surgical resection to 
decrease the high rate of recurrence.  A single-institution trial of gemcitabine 
900mg/m2 on day 1 and 8 and docetaxel 75mg/m2 with GCSF support for 4 cycles 
found a 45% 2-year progression-free survival [9].  The subset analysis of the 15 
patients with Stage 1 disease and 3 with Stage 2 disease demonstrated a 59% 2-year 
progression-free survival.  The overall survival at 5 years was around 60%, compared 
to the historical 50% overall survival for Stage 1 disease found in the large Norwegian 
study [2].  Furthermore, the regimen was associated with very acceptable toxicity that 
was found to be lower than the prior trial for those with unresectable leiomyosarcoma. 
 
RADIATION THERAPY 
There were several retrospective studies of uterine sarcomas that suggested prevention 
of local recurrence after adjuvant radiation therapy (RT), with no additional survival 
benefit.  In those studies, benefit was usually limited to carcinosarcoma or   
endometrial stromal sarcoma.  These early studies led to a prospective, randomized- 
controlled trial that was performed to assess the benefit of adjuvant RT in 
leiomyosarcoma [10].  After surgery, stage I/II patients were randomized to receive   
50 Gray of external beam in 28 fractions over 5 to 6 weeks or not to receive any 
radiation therapy.  While there was a decrease in the rate of recurrence in the 
carcinosarcoma patients who received RT, there was no difference in the recurrence 
rates in the leiomyosarcoma patients when compared to no RT.  This study also 
revealed that the rate of distant recurrence for leiomyosarcoma was 25%, more than 
twice that for carcinosarcoma.  While there was a trend towards decreased local 
recurrence, this study discredited the idea that achieving local control would reduce  
the rate of distant metastases and did not impact overall survival. 
 
In order to try to prevent both distant and local recurrence, the concept of using both 
chemotherapy and RT following surgical resection was evaluated in a small 
prospective trial with 13 stage I/II optimally cytoreduced leiomyosarcoma patients 
who received adriamycin, cisplatin, and ifosfamide every 3 weeks for 3 cycles 
followed by external beam pelvic radiation and, for some, brachytherapy [11].  Of the 
5 patients that recurred, none had pelvic recurrences, and the overall 2-year survival 
was 78%. 
 
A larger study using a multimodal approach is necessary to assess the efficacy and 
toxicity associated with chemotherapy and radiation therapy.  Furthermore, given the 
recent data suggesting the gemcitabine and docetaxel combination as having superior 
activity than some of the older doxorubicin-based treatments, a regimen containing 
these two drugs would be ideal to use in the adjuvant setting with radiation therapy. 
 
At Montefiore, we have performed a number of sequential chemotherapy and RT 
trials in high risk uterine cancers using various doublets with full EBRT and 
brachytherapy [12-14].  Given the limitations of either chemotherapy alone or RT 
alone, we think the combination of both for early stage leiomyomsarcoma in an 
adjuvant setting might hold promise.  Our experience in patients with other high risk 
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uterine cancers with larger doses and more cycles of chemotherapy and RT has 
confirmed predictable toxicities that are manageable.  This trial is designed to assess 
the safety and tolerability of sequential gemcitabine and docetaxel, the current optimal 
regimen for leiomyosarcoma, followed by RT to limit pelvic recurrences. 
 
 
 
2.1 
OBJECTIVES 
 
2.2 
Primary Objective: To evaluate the toxicity and tolerability of adjuvant pelvic 
radiation in combination with gemcitabine/docetaxel chemotherapy in patients 
with stage 1 and 2 surgically-resected uterine leiomyosarcoma. 
 
2.3 
Exploratory Objective: To assess the two year recurrence-free survival in 
patients with uterine leiomyosarcoma treated with chemotherapy and radiation 
therapy including defining the patterns of recurrence in patients with uterine 
leiomyosarcoma who were treated with this regimen. 
 
 
 
3.1 
PATIENT SELECTION 
 
3.2 Inclusion Criteria 
 
Patients may be included in the study if all of the following criteria are met: 
 
a. Histologically  documented  uterine  leiomyosarcoma  with  no  visible 
residual disease. 
 
b. Surgical staging to include total hysterectomy, +/- removal of ovaries 
and fallopian tubes, +/-  lymph node sampling. 
 
c. Patients must be entered no more than 12 weeks post operatively 
 
d. Age > 18 years. 
 
e. ECOG performance status of < 2. 
 
f. Written voluntary informed consent. 
 
3.3 Exclusion Criteria 
 
Exclusion from the study will be required if: 
 
1. 
Patient has impairment of hepatic, renal or hematologic function as defined by 
the following baseline laboratory values: 
 
a. Serum SGOT and /or SGPT > 2.5 times the institutional upper limit of 
normal 
b. Total serum bilirubin > 1.5 mg/dl 
c. History of chronic or active hepatitis 
d. Serum creatinine > 2.0 mg/dl 
e. Platelets < 100,000/mm3 
f. Absolute neutrophil count (ANC) < 1500/mm3 
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g. Hemoglobin < 8.0 g/dl (the patient may be transfused prior to study 
entry) 
 
2. Patients with severe or  uncontrolled  concurrent  medical  disease  (eg. 
uncontrolled diabetes, unstable angina, myocardial infarction within 6 months, 
congestive heart failure, etc.) 
3. Patients with any prior chemotherapy or radiotherapy for pelvic malignancy. 
4. Patients who have had prior therapy with gemcitabine or docetaxel. 
5. Patients with known hypersensitivity to gemcitabine or docetaxel. 
6. Patients with known hypersensitivity to Pefilgrastim and Filgrastim. 
7. Patients with any history of cancer with the exception of non-melanoma skin 
cancer are excluded if there is any evidence of other malignancy being present 
within the past five years. 
8. Patients with dementia or altered mental status that would prohibit the giving 
and understanding of informed consent at the time of study entry. 
 
4.0 
REGISTRATION  PROCEDURES 
 
All patients must be registered by calling Loraine Centrilla RN at (718) 405-8082 and 
faxing registration forms to (718) 829-2408. Any questions regarding eligibility may 
be addressed with the P.I. or research coordinator. 
 
 
5.1 
TREATMENT PLAN 
 
5.2 Chemotherapy 
5.2.1 Gemcitabine, Gemzar® is commercially available. Gemcitabine 900 mg/m2 
on days 1 and 8 will be given intravenously over 90 minutes. 
 
 
5.2.2 Docetaxel, Taxotere® is commercially available. Docetaxel 75 mg/m2 will be 
given intravenously on day 8 over one hour following gemcitabine. Premedication 
for Docetaxel for the prevention of severe fluid retention and hypersensitivity reaction 
is as follows: Dexamethasone 8 mg orally x 2 doses the day prior to chemotherapy 
(day 7), and 8mg orally twice daily for the next 2 days (days 8-9). The 
dexamethasone dosing schedule may be adjusted per the discretion of the physician. 
Patients who develop peripheral edema as a side effect of docetaxel may be treated 
with diuretics at the discretion of the treating physician. Recommended treatment for 
edema includes starting with Dyazide (25/37.5) or (25/50) up to three times per day. 
Furosemide may be used if Dyazide does not adequately control the edema. 
 
 
5.2.3 Pegfilgrastim, Neulasta® is commercially available. Pefilgrastim, granulocyte-
colony stimulating factor, will be given as a subcutaneous injection of 6 mg on day 
9. 
 
 
Chemotherapy will be administered every 21 days for 4 cycles. This will be followed 
by radiotherapy. 
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5.3 Radiotherapy 
 
HDR vaginal cuff brachytherapy or Intensity Modulated Radiation Therapy (IMRT) 
vaginal cuff boost when brachytherapy is not feasible will begin with the 4th cycle of 
chemotherapy (week 10). HDR brachytherapy, or Intensity Modulated Radiation 
Therapy (IMRT) where appropriate, involves a proximal 1/2 - 2/3 vaginal boost using 
the Nucletron microSelectron remote afterloading technique.  The vaginal boost may 
be extended to include the distal vagina when gross vaginal involvement is present. 
Three fractions of 5 Gy each will be prescribed to 0.5cm depth from the vaginal 
cylinder surface. Three doses of HDR will be completed prior to beginning external 
beam irradiation. 
 
For HDR and IMRT, a report on the dose to bladder and rectum is mandatory. A 3- 
dimensional CT scan will be obtained with the applicator in place for brachytherapy 
planning. The brachytherapy plan will be made on the Nucletron Oncentra software 
using the planning CT, and dose-volume histograms will report the bladder and rectal 
dose levels. The vaginal surface dose may be calculated at the vaginal surface lateral 
to the midpoint of the surface of the cylinder. 
 
The patient will commence external beam radiation therapy (EBRT) after completion 
of brachytherapy (week 13). The total dose of EBRT is 45 Gy over 5 weeks. Patients 
will be treated once a day, 5 days a week, with a daily fraction size of 1.8 Gy. Four- 
field 3-dimensional conformal technique (AP-PA opposed and lateral opposed fields) 
or an IMRT technique will be used with a megavoltage beam of ≥ 6MV. The fields 
may be extended to include the para-aortic lymph nodes in the case of ≥ 2 positive 
pelvic nodes or documented para-aortic lymph node disease. 
 
Pretreatment CT scan of the abdomen and pelvis will be used for planning. Full and 
empty bladder scans will be performed in preparation for creation of an ITV  for 
planning purposes. Oral contrast will be given prior to the CT, and vaginal contrast 
placed at the time of simulation to help identify internal anatomy. All fields treated 
require portal verification on the treatment unit. Sites of known positive nodes should 
be marked at the time of surgery with identifiable hemoclips. 
 
Fields should be calculated by optimizing the dose distribution by obtaining isodose 
curves of the pelvis. All fields should be treated  daily  throughout  the  treatment 
course. The specification of target dose is in terms of a dose to a point at or near the 
center of the target volume. For the following portal arrangements, the target dose 
will be specified. For a 4-field arrangement of beams: at the isocenter of the beams, 
the maximum dose in the target volume should not exceed the central dose by more 
than 10%.  Doses to critical structures must be recorded. 
 
Pelvic Portal (AP-PA fields): Includes a superior border between L4 and L5; a lateral 
border 1.5-2.0 cm lateral to the widest true pelvic diameter; and an inferior border at 
the bottom of the obturator foramen and at least 4 cm beyond the vaginal cuff. A 
radio-opaque marker  in the vagina to  mark the vaginal cuff will help to facilitate 
proper placement of the lower border. 
 
Pelvic Portal (lateral fields): Includes superior and inferior borders identical to the 
AP-PA  fields;  an  anterior  border  through  the  symphysis  pubis  and  at  least  1  cm 
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anterior to common iliac nodes at L5-S1; a posterior border to include at least S1-S2. 
 
Para-aortic Portal: Includes a superior border of T11-T12 or 3 cm superior to the 
positive node site; an anterior border 2-3 cm anterior to the vertebral body; lateral 
borders 2-3 cm lateral to the vertebral body; and a posterior border that will exclude 
the spinal canal. 
 
 
 
5.4 Prevention of Anticipated Toxicity 
 
The major toxicities to be expected from the combined modalities of treatment are 
hematologic and gastrointestinal. Complete blood counts will be monitored for 
evidence of toxicity. Antiemetics and hydration will be  administered  to  prevent 
nausea and vomiting. 
 
Toxicities particular to Docetaxel include hypersensitivity  reactions  and  fluid 
retention. Premedication for the prevention of severe fluid retention and 
hypersensitivity reaction is as follows: Dexamethasone 8 mg orally x 2 doses the day 
prior to chemotherapy (day 7), and 8mg orally twice daily for the next 2 days (days 8- 
9). The dexamethasone dosing schedule may be adjusted per the discretion of the 
physician. Patients who develop peripheral edema as a side effect of Docetaxel may 
be treated with diuretics at the discretion of the treating physician. Recommended 
treatment for edema includes starting with Dyazide (25/37.5) or (25/50) up to three 
times per day. Furosemide may be used if Dyazide does not adequately control the 
edema. Premedications with diphenhydramine and H2 blockers  will  be  added  to 
reduce the incidence and severity of hypersensitivity  reactions, but do not provide 
complete protection. Emergency agents (diphenhydramine, steroids and epinephrine) 
will be available. IV sites should be evaluated regularly for signs of infiltration as 
infusion site reactions can occur. 
 
Toxicities particular to Gemcitabine include hematologic (anemia, thrombocytopenia, 
neutropenia), and gastrointestinal (nausea and vomiting). Premedication with anti- 
emetics on day 1 and day 8 will be given to reduce the incidence and severity of 
nausea and vomiting. The administration of Pefilgrastim on day 9 appears to reduce 
the incidence and severity of neutropenia. Complete blood counts will be monitored 
for evidence of toxicity. 
 
Toxicities particular to Pefilgrastim include transient bone pain that can be controlled 
with non-narcotic analgesics and transient increases in alkaline phosphatase, lactate 
dehydrogenase and uric acid that will be monitored with each cycle. 
 
Expected radiation toxicities are fatigue, diarrhea, nausea, vomiting, rectal irritation, 
urinary frequency and dysuria, loss of pubic hair, reddening and irritation of skin in 
the irradiated field, and depression of blood counts. Long-term  side  effects  may 
include chronic malabsorption, rectal ulcer, bleeding or stricture, dysuria, hematuria, 
bowel obstruction, dryness and shortening of the vagina, dyspareunia, vaginal vault 
necrosis and fistula formation between pelvic tissues. While unlikely, in order to 
minimize the potential for radiation recall effects, external beam radiation will begin 
three weeks after the last cycle of chemotherapy (two weeks after the last dose of 
gemcitabine) [15]. 
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5.5 Treatment Modifications 
 
Dose reductions of one dose level equate to 25% reduction of prior dose: 
 
Drug 
100% Dose 
25% Dose Reduction 
Gemcitabine 
900mg/m2 
675mg/m2 
Docetaxel 
75mg/m2 
56mg/m2 
 
 
 
 
5.5.1 Hematologic Toxicity: 
5.4.11 Initial treatment modifications will consist of cycle delay and/or dose 
reduction as indicated below. 
Patients will NOT receive prophylactic thrombopoietic agents unless 
they experience recurrent grade 4 thrombocytopenia after treatment 
modifications as specified below. 
 
Patients may receive erythropoietin for management of anemia after 
documentation of hemoglobin less than 10 g/dL (CTC grade 2). 
 
5.4.12 For patients who experience  febrile  neutropenia,  a  platelet  count  of 
<10,000/microliter or CTC grade 3 associated with bleeding or platelet 
transfusion, and/or documented grade 4 neutropenia persisting ≥ 7 days, the 
doses of both gemcitabine and docetaxel will be reduced by 25% of the prior 
dose for all subsequent cycles for that patient. 
 
5.4.13 All Day 1 chemotherapy will be held pending hematologic recovery to 
ANC ≥ 1000/microliter and platelet count greater than or equal to 
100,000/microliter. Due to patients receiving G-CSF, day 1 of cycle may be 
given with ANC ≥ 1000 cells/uL, to allow for transient reductions in ANC 
after discontinuation of G-CSF.  Patients in whom counts have not recovered 
after a 2 week delay will be removed from the study. 
 
5.4.14 Day 8 dose adjustments should be made according to the table below 
 
Drug 
ANC≥1000 
and 
Plt ≥100,000 
ANC  500-999  or 
Plt 50-99,000 
ANC <500 or 
Plt <50,000 
Gemcitabine 
900mg/m2 
675mg/m2 
Omit 
Docetaxel 
75mg/m2 
56mg/m2 
Omit 
 
 
5.5.2 Hepatotoxicity: If bilirubin is greater than institutional upper limits of normal 
on day  1, repeat level on day 8 prior to giving Docetaxel. If bilirubin has 
returned to normal, then proceed with administration of Docetaxel on day 8. 
If bilirubin remains greater than institutional upper limits of normal on day 8, 
then give only gemcitabine.  If bilirubin does not recover by day 8 of the next 
cycle, the patient will be removed  from study due to hepatic dysfunction. Grade 
3 (or greater) elevations in SGOT  (AST),  SGPT  (ALT),  or  alkaline 
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phosphatase requires dose reduction of 25% and delay in subsequent therapy 
for a maximum of 14 days until recovered to grade 1. 
 
5.5.3 Neurotoxicity:   For grade 3 or 4 neurotoxicity, treatment will be delayed 1 
week.   At the time of re-evaluation, if neurotoxicity is ≤ grade 2, then the 
patient may  continue on study with subsequent docetaxel dose reduction of 
25%. If the grade 3 or 4 neurotoxicity has not resolved to ≤ grade 2 after one 
week  delay,  the  patient  will be  removed  from  study.  Grade  2  or  greater 
peripheral  neuropathy  requires   dose  reduction  of  25%  and  a   delay   of 
subsequent cycles for a maximum 14 days until recovered to grade 1. 
 
5.5.4 Nephrotoxicity:   Grade 2 or greater renal toxicity requires dose reduction of 
25%  and a delay of subsequent cycles for  a  maximum  of  14  days  until 
recovered to grade 1. 
 
5.5.5 Patients who develop grade 4 edema will be removed from study. 
 
5.5.6 Other non-hematologic toxicities that are grade 2 or greater, with an impact in 
organ function will require dose reduction of 25% and a delay of subsequent 
cycles for a maximum of 14 days until recovered to grade 1 or to pre-therapy 
baseline. 
 
5.5.7 Radiation Recall: In the event of signs or symptoms of radiation recall effect, 
Topical  or systemic corticosteroids or nonsteroidal anti-inflammatory agents 
can   be   used   to   decrease   signs   or   symptoms   of   inflammation   
[16]. Antihistamines   may   be used for symptomatic relief. These supportive 
measures can be used at the discretion of the provider. Re-challenge can be 
performed with premedication with corticosteroids and a 25% dose reduction 
of the offending chemotherapeutic agent or the dose per fraction of radiation. 
 
Grade 2 or greater radiation recall will require a delay in chemotherapy and/or 
radiation therapy for one week. Then the patient will be re-evaluated. If the 
effects are persistent, the patient will undergo another week of delay for a 
maximum of 14 days. If the effects continue, the patient will be withdrawn 
from study and undergo exit visit procedures. 
 
5.6 Adverse Event Reporting 
 
An adverse event refers to any adverse medical change from the patient’s baseline (or 
pretreatment) condition which occurs during the course of a clinical study,  after 
starting treatment, whether considered treatment related or not. 
 
Adverse events may be volunteered spontaneously by the patient, or be discovered as 
a result of general questioning by the investigator or by physical examination. Also to 
be reported is any patient requiring hospitalization while on protocol or any grade 4 
hematologic or grade 3 or 4 non-hematologic toxicity. 
 
All adverse events occurring during this clinical study must be reported to the 
principal investigator and accurately recorded in the adverse events form within 10 
days of the toxic event. 
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Both chemotherapy and radiation treatment breaks should be noted and the reasons 
should be documented. 
 
6.0 
TOXICITY 
 
Toxicities will be graded according to the NCI Common Toxicity Criteria (version 4). 
Myelosuppressive toxicity shall be reported as the lowest observed white blood and 
platelet counts.  Anemia and red blood cell transfusions will be noted. 
 
Gastrointestinal toxicities shall be reported and hospitalizations for nausea, vomiting 
and diarrhea will be documented. 
 
Patients will be followed for potential long-term toxicities with complete histories and 
physical examinations. 
 
Any patient who receives at least one course of therapy and has follow-up information 
will be included for observation of toxicity. 
 
 
 
7.0 
MEASUREMENT OF EFFECT 
 
Recurrence-Free Survival 
 
Recurrence-free survival is defined as date of entry to date of reappearance of disease. 
Site(s) and date of relapse will be recorded. Recurrent disease will be defined as 
pelvic or distant. Pelvic sites will be specified as vaginal or other, and distant sites 
will be specified as to their anatomic location. Relapse should be confirmed  by 
histologic or cytologic evaluation when possible. 
 
 
 
8.1 
STUDY PARAMETERS 
 
8.2 
Pre Study Evaluation 
 
This evaluation requires completion within 14 days of registration, unless otherwise 
described. Baseline requirements will consist of a thorough history and physical 
examination, including pelvic and rectovaginal exam. Tests include, CBC with 
differential, platelet count, serum chemistry, including electrolytes, creatinine, BUN, 
glucose, magnesium, calcium, albumin, phosphorous, liver function  tests,  and 
urinalysis. 
 
Histologic documentation of uterine leiomyosarcoma is required.  Prestudy CT scan 
of chest, abdomen and pelvis (within 28 days of therapy), and CXR (not required if 
CT of the chest) will be obtained. 
 
8.3 
Tests During Treatment 
 
Day 8: CBC with differential and platelet count, liver function tests if needed as 
described in section 5.4.2 
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Every 3 weeks (prior to each cycle of chemotherapy): CBC with differential and 
platelet count electrolytes, BUN, creatinine, glucose,  magnesium,  calcium, 
phosphorous, albumin, liver enzymes and liver function tests (AST, ALT, alkaline 
phosphatase, bilirubin). 
 
After each Cycle: Complete review of systems and complete physical examination, 
including pelvic examination.  Weight and performance status will be documented. 
 
8.4 
End of Study Evaluation 
 
This evaluation includes a complete history and physical examination and 
documentation of weight and performance status. Laboratory tests include a complete 
blood count with differential and platelet count, electrolytes, BUN, creatinine, 
glucose, magnesium, calcium, phosphorous, albumin, and urinalysis. 
 
CT scan of chest, abdomen and pelvis will be obtained at the completion of the entire 
protocol or earlier if indicated. 
 
8.5 
Follow-up 
 
Patients will be evaluated as per the current standard of care which is every 3 months 
for the first 2 years and every 6 months for the next 3 years.  Evaluation at each visit 
is as per the current standard of care which includes a complete history and physical 
examination and documentation of weight and performance status. Laboratory tests 
include a complete blood count with differential and platelet count, electrolytes, BUN, 
creatinine, glucose, magnesium, calcium, phosphorous, albumin, and urinalysis. CT 
scans will be performed annually or earlier if clinically indicated. After a total of 5 
years, patients will be seen annually. 
 
8.6 
Secondary Endpoints 
 
Staining of the pathologic specimens for ER/PR, will be performed by 
immunohistochemisty and will be correlated with progression-free survival and 
prognosis. 
 
8.7 
Discontinuation 
 
Criteria for stopping treatment include recurrence of disease; the development of 
unacceptable toxicity; and/or patient request. 
 
9.1 
DRUG FORMULATION AND PROCUREMENT 
 
9.2 
Drug Information: 
Docetaxel 
Other Names:  Taxotere, NSC 628503 
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Classification: Belongs to the class of plant alkaloids and other natural  products, 
taxanes. 
 
Mechanism of Action: It is an antimicrotubule agent. It promotes and stabilizes 
microtubule assembly, while preventing physiological microtubule disassembly thus 
preventing mitotic cell division and initiating apoptosis. 
 
Storage and Stability: 20 mg vials may be stored for 24 months below 25°C away 
from light and 80 mg vials for 26 months in the same conditions. Freezing does not 
adversely affect the product. Premixed Docetaxel solutions should be used within 4 
hours. 
 
Route of Administration:  Intravenous 
A single dose vial must be combined with the dilutent (13% ethanol in water for 
injection) to obtain a premixed solution of Docetaxel 10mg/mL. Then withdraw the 
desired amount of Docetaxel and dilute it in a 250 mL infusion bag containing normal 
saline or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL. 
In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl 
phthalate), which may be leached from PVC infusion bags or sets, the final Docetaxel 
dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags 
(polypropylene, 
polyolefin) 
and 
administered 
through 
polyethylene-lined 
administration sets. 
 
Dose Specifics: Docetaxel is given at a dose of 75-100 mg/m2 infused over one hour 
and repeated every 21 days. All patients should be premedicated with oral 
corticosteroids such as dexamethasone 16 mg per day (8 mg BID) for 3 days starting 
one day prior to Docetaxel administration in order to reduce the  incidence  and 
severity of fluid retention as well as the severity of hypersensitivity reactions. 
 
Drug Interactions: Cisplatin is known to interact with some CYPs and has in some 
cases been shown to reduce Docetaxel clearance by up to 25%, which may increase 
myelosuppression. Erythromycin, ketoconazole and cyclosporine  are  CYP3A4 
inhibitors and therefore inhibit the metabolic pathway of Docetaxel. Anticonvulsants 
induce some metabolic pathways relevant to Docetaxel. 
 
Adverse Effects Profile: Neutropenia, thrombocytopenia, anemia, alopecia, injection 
sites reactions, rash, nausea, vomiting, mucositis, typhlitis, increased liver enzymes, 
hepatic failure, sensory changes, peripheral neuropathy, arthralgia and myalgia, mood 
alterations, motor and autonomic neuropathy, hypersensitivity, fluid retention, cardiac 
dysrythmias, syncope, hypotension, myocardial infarction,  hypertension.  Other: 
fatigue, headaches, light-headedness, myopathy, elevated serum creatinine, elevated 
serum triglycerides, and visual abnormalities. 
 
Supplier:  Commercially available. 
 
Gemcitabine 
 
Other Names:  Gemzar®,  NSC 613327 
Classification: Antimetabolites, pyrimidine analogs. 
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Mechanism of Action: Inhibition of DNA synthesis by inhibition of ribonucleotide 
reductase. 
 
 
Storage and Stability: Gemcitabine is supplied in 200 mg  (10mL)  and  1000  mg 
(50mL) sterile single use vials. Unopened vials of Gemcitabine are stable until the 
expiration date indicated on the package when stored at controlled room temperature 
20° to 25°C (68° to 77°F). 
 
 
Route of Administration:  Continuous infusion over 90 minutes. 
Gemcitabine is reconstituted by adding 5 or 25 mL of injectable normal saline to the 
200-mg or 1-gram vial, respectively, creating a concentration of 38mg/mL of 
Gemcitabine. The resultant solution is a clear, colorless to light straw-colored 
solution. Incomplete dissolution may occur if Gemcitabine is reconstituted to a 
concentration greater than 40 mg per mL. The resulting solution may  be  further 
diluted with injectable normal saline, if necessary, to a concentration as low as 0.1 mg 
per mL. Once the drug has been reconstituted, it should be stored at controlled room 
temperature and used within 24 hours. 
 
 
 
Dose Specifics:  600-1250 mg/m2 
 
Drug Interactions: Gemcitabine may alter the pharmacodynamic response to warfarin 
resulting in an increased INR and risk of bleeding. 
 
Adverse Effects Profile: Neutropenia, thrombocytopenia, anemia, rash, mild alopecia, 
nausea, vomiting, diarrhea, constipation, stomatitis, dyspnea, fever, irritation, pain or 
redness at the injection site increased liver enzymes, reversible proteinuria, elevation 
of 
BUN 
and 
creatinine, 
edema, 
bronchospasm, 
pareshesia, 
somnolence 
cerebrovascular accident, myocardial  infarction,  dysrythmia.  Other  (rare): 
hemorrhage, allergic reaction, pneumonitis, pulmonary edema, hemolytic uremic 
syndrome. 
 
Supplier:  Commercially available. 
 
Pegfilgrastim 
 
Other Names:  Neulasta®, NSC 725961 
Classification:  Granulocyte colony stimulating factor 
 
Mechanism of Action: Acts on hematopoietic cells by binding to specific cell surface 
receptors, thereby stimulating proliferation, differentiation, commitment, and end cell 
functional activation. 
 
Storage and Stability: Pegfilgrastim should be refrigerated between 2° to 8°C (36° to 
46°F) in the carton to protect from light.   Do not shake.   Discard syringes stored at 
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room temperature for more than 48 hours. Avoid freezing; if frozen, thaw in the 
refrigerator before administration.  Discard syringe if frozen more than once. 
 
 
Route of Administration:  Subcutaneous injection. 
Pegfilgrastim is supplied in 0.6 mL pre-filled single use syringes for subcutaneous 
injection. Each syringe contains 6 mg Pegfilgrastim (based on protein weight), in a 
sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 
mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in water for 
injection, USP. 
 
Dose Specifics:  6 mg 
 
Drug Interactions: No formal drug interactions studies have been done with 
Pegfilgrastim. 
 
Adverse Effects Profile: Bone pain, reversible elevations of alkaline phosphatase, 
lactate dehydrogenase and uric acid, allergic  reactions  including  anaphylaxis, 
urticaria, severe sickle cell crisis in sickle cell patients, ARDS. Other (rare): splenic 
rupture. 
 
Supplier:  Commercially available. 
10.0 
STATISTICAL  CONSIDERATIONS 
 
To assess the two year recurrence-free survival in patients with uterine 
leiomyosarcoma treated with a combination of chemotherapy and radiation therapy - 
including defining the patterns of recurrence in patients with uterine leiomyosarcoma 
who were treated with this regimen.  A total of 18 patients will be accrued to this 
study.  Two-year recurrence-free survival probability will be estimated, with 95% 
confidence limits based on exact methods for the binomial distribution.  In the event 
of censoring before two years, a Kaplan-Meier estimate of the survival probability 
will be used and a Kaplan-Meier survival curve will be estimated and presented as 
well.  Conservatively, the sample size indicated will provide a 95% confidence 
interval with width of +/- 0.23.  Frequencies will also be provided for side effects and 
adverse events. 
 
Based on past accrual rates in this patient population, it is expected that accrual will 
be at most 4-6 per year for a total accrual period of about 48 months. Follow up will 
be a minimum of one year after the last patient is accrued in order to assess response. 
Therefore, total study time is expected to be 3.4-4.0 years. 
 
 
 
11.0 
COLLECTION  PROCEDURES 
 
Paraffin embedded tissue from uterine leiomyosarcoma tumors will be stained for 
ER/PR, by immunohistochemistry. 
 
 
 
12.0 
RECORDS TO BE KEPT 
 
Forms                                                   To Be Submitted 
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Pathology Report 
Within one week of registration 
 
ECOG CTC Flow Sheet (#466R) 
Baseline within one week of registration. 
On Treatment:  Every month 
Off Treatment:  See Follow-up 
 
 
 
13.0 
PATIENT CONSENT AND PEER JUDGEMENT 
 
All institutional, state, and national guidelines concerning informed consent and peer 
review will be observed. 
 
 
 
14.0 
MINORITIES AND WOMEN STATEMENT 
 
This  study  will  be  initially  open  to  patients  undergoing  treatment  at  Montefiore 
Medical Center. 
Although distributions  may  vary  by  disease  type,  our  recruitment procedures  have 
been developed to enroll patients who are representative of the target population. 
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
All institutional, NCI and Federal regulations concerning the Informed Consent form 
will be fulfilled. 
 
Annual reports will be provided to the Montefiore IRB. 
 
 
 
16.0 
DATA SAFETY MONITORING PLAN 
 
This study will be added to the Montefiore Einstein Cancer Center Date Safety 
Monitoring Committee’s (DSMC) agenda for internal study review. As per the DSMC 
protocol, all adverse events will be forwarded to the DSMC, and monitored on a 
monthly basis. 
 
 
 
 
17.0 
ELIGIBILITY CHECKLIST 
 
 
 
Histologically documented uterine leiomyosarcoma 
with no visible residual disease 
 
Surgical staging to include total abdominal 
hysterectomy, +/- bilateral salpingo-oophorectomy, 
+/- lymph node sampling. 
Yes 
No 
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Age ≥ 18 years 
 
ECOG performance status of < 2 
Written voluntary informed consent. 
Patient has no impairment of renal, hepatic or 
hematologic function as defined in section 3.2 
 
Patient does not have severe or uncontrolled 
concurrent medical disease (eg. uncontrolled 
diabetes, unstable angina, myocardial infarction 
within 6 months, congestive heart failure, etc.) 
 
Patient has not had any prior chemotherapy 
or radiotherapy for pelvic malignancy. 
 
Patients has no dementia or altered mental 
status that would prohibit the giving and 
understanding of informed consent at the 
time of study entry. 
 
Patient Name  
 
 
Patient MR#  
 
 
Treating Physician  
 
 
Principal Investigator  
 
(Signature) 
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18.0  REFERENCES 
 
1. 
Major, F.J., et al., Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group 
study. Cancer, 1993. 71(4 Suppl): p. 1702-9. 
2. 
Abeler, V.M., et al., Uterine sarcomas in Norway. A histopathological and prognostic survey of a total 
population from 1970 to 2000 including 419 patients. Histopathology, 2009. 54(3): p. 355-64. 
3. 
Dinh, T.A., et al., The treatment of uterine leiomyosarcoma. Results from a 10-year experience (1990- 
1999) at the Massachusetts General Hospital. Gynecologic oncology, 2004. 92(2): p. 648-52. 
4. 
Hensley, M.L., Role of chemotherapy and biomolecular therapy in the treatment of uterine sarcomas. 
Best practice & research. Clinical obstetrics & gynaecology, 2011. 
5. 
Omura, G.A., et al., A randomized study of adriamycin with and without dimethyl triazenoimidazole 
carboxamide in advanced uterine sarcomas. Cancer, 1983. 52(4): p. 626-32. 
6. 
Sutton, G., J.A. Blessing, and J.H. Malfetano, Ifosfamide and doxorubicin in the treatment of advanced 
leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecologic oncology, 1996. 
62(2): p. 226-9. 
7. 
Sutton, G., et al., Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced 
leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecologic oncology, 2005. 
96(3): p. 749-52. 
8. 
Hensley, M.L., et al., Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: 
results of a phase II trial. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology, 2002. 20(12): p. 2824-31. 
9. 
Hensley, M.L., et al., Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high 
grade uterine leiomyosarcoma: Results of a prospective study. Gynecologic oncology, 2009. 112(3): p. 
563-7. 
10. 
Reed, N.S., et al., Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in 
the treatment of uterine sarcomas stages I and II: an European Organisation for Research and 
Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). European journal of 
cancer, 2008. 44(6): p. 808-18. 
11. 
Pautier, P., et al., Adjuvant chemotherapy with cisplatin, ifosfamide, and doxorubicin followed by 
radiotherapy in localized uterine sarcomas: results of a case-control study with radiotherapy alone. 
International journal of gynecological cancer : official journal of the International Gynecological 
Cancer Society, 2004. 14(6): p. 1112-7. 
12. 
Einstein, M.H., et al., Phase II trial of adjuvant pelvic radiation "sandwiched" between ifosfamide or 
ifosfamide plus cisplatin in women with uterine carcinosarcoma. Gynecologic oncology, 2012. 124(1): 
p. 26-30. 
13. 
Einstein, M.H., et al., Phase II trial of adjuvant pelvic radiation "sandwiched" between combination 
paclitaxel and carboplatin in women with uterine papillary serous carcinoma. Gynecologic oncology, 
2012. 124(1): p. 21-5. 
14. 
Fields, A.L., et al., Pilot phase II trial of radiation "sandwiched" between combination 
paclitaxel/platinum chemotherapy in patients with uterine papillary serous carcinoma (UPSC). 
Gynecologic oncology, 2008. 108(1): p. 201-6. 
15. 
Haffty, B.G., et al., Timing of Chemotherapy after MammoSite radiation therapy system breast 
brachytherapy: analysis of the American Society of Breast Surgeons MammoSite breast brachytherapy 
registry trial. International journal of radiation oncology, biology, physics, 2008. 72(5): p. 1441-8. 
16. 
Camidge, R. and A. Price, Characterizing the phenomenon of radiation recall dermatitis. Radiotherapy 
and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2001. 59(3): 
p. 237-45. 
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APPENDIX 1: STUDY SCHEDULE 
 
Parameter 
Pre- 
treatment 
Day 8 
(Cycles 1-4) 
Each 
Cycle 
Completion 
of  Study 
Follow-up 
Visit 
History & Physical 
Exam 
X 
X 
X 
X 
Pelvic Exam 
X 
X 
X 
X 
Weight, Performance, 
Status 
X 
X 
X 
X 
CBC with differential, 
platelets 
X 
X 
X 
X 
X 
Electrolytes, Mg, BUN, 
Cr 
X 
X 
X 
X 
SGOT, Bili 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
CXR 
X4 
X1 
CT chest/abd/pelvis 
X3 
X 
X2,1 
ER/PR 
X 
1. If clinically indicated. 
2. Annually 
3. Within 28 days of therapy 
4. CXR not needed if CT chest performed 
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