Clinical trial NCT00936936
Conditions: Testicular Cancer
Keywords: Testis Relapsed Testicular Cancer Bevacizumab Avastin Anti-VEGF monoclonal antibody rhuMAb-VEGF Carboplatin Paraplatin Docetaxel Taxotere Etoposide VePesid Gemcitabine Gemcitabine Hydrochloride Gemzar Ifosfamide Ifex Melphalan Alkeran
Sponsor: M.D. Anderson Cancer Center
Start date: 2009-06-02; Completion date: 2024-01-11
Enrollment: 64 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if 2 cycles of high-dose chemotherapy can help to control germ-cell tumors. The first cycle of chemotherapy will include the drugs gemcitabine, docetaxel, melphalan, and carboplatin. The second cycle of chemotherapy will include the drugs ifosfamide, carboplatin, and etoposide. The safety of these drug combinations will also be studied.

This is an investigational study. Gemcitabine, docetaxel, melphalan, ifosfamide, carboplatin, and etoposide are all FDA-approved and commercially available for the treatment of germ-cell tumors.

Up to 67 patients will be enrolled in this study.

Detailed description:
The Study Drugs:

Carboplatin, melphalan, and ifosfamide are designed to damage the DNA (the genetic material) of cancer cells, which may cause the cancer cells to die.

Docetaxel and etoposide are designed to stop the growth of cancer cells, which may cause the cancer cells to die.

Gemcitabine is designed to disrupt the growth of cancer cells, which may cause cancer cells to die. It may also help docetaxel, carboplatin, and melphalan to be more effective by stopping tumor cells from repairing damage caused by these drugs.

Study Drug Administration:

You will receive 2 cycles of high-dose chemotherapy with stem-cell support, 1-2 months apart.

You will receive 1 dose of Outpatient IV at Bevacizumab 7.5mg/kg.

Starting on the first day of your hospital stay, you will begin gargling and swishing Caphosol and Glutamine in your mouth 4 times a day. This is done to help prevent mouth and throat sores.

On Day 2 of your stay in the hospital, through the CVC, you will receive gemcitabine over 4 hours and docetaxel over 2 hours.

On Days 3-5, through the CVC, you will receive gemcitabine over 4 hours, melphalan over 15 minutes, and carboplatin over 2 hours.

On Day 6, you will not receive any study drugs.

On Day 7, you will receive the stem cells through the CVC over about 30-60 minutes.

As part of standard care, you will receive G-CSF (filgrastim) as an injection under your skin daily, starting 5 days after the transplant, until your blood cell levels return to normal.

As part of standard mouth care you will be asked to do mouthwashes 4 times a day with caphosol (artificial saliva) and glutamine.

Two (2) to 4 weeks after you leave the hospital after Cycle 1, you will receive your second cycle of high-dose chemotherapy.

On Days 2-4 of your stay in the hospital, through the CVC, you will receive ifosfamide over 6 hours, etoposide over 2 hours, and carboplatin over 2 hours.

On Days 5-6, you will not receive any study drugs.

On Day 7, you will receive the stem cells through the CVC over about 30-60 minutes.

Study Visits:

About 1 month, 100 days, 6 months and 1 year after your second stem cell transplant, the following tests and procedures will be performed:

* To check the status of the disease, you will have CT scans of your chest, abdomen, and pelvis.
* Blood (about 3 tablespoons) will be drawn for routine tests.

Length of Study:

You will be off study after about 1 year from your second transplant. You will be taken off study early if the disease gets worse or if you experience any intolerable side effects.

Long-Term Follow-up:

If your doctor thinks it is needed, you may have follow-up visits.

Arms: arm 1: First Cycle High-dose (HD) chemotherapy followed by stem-cell infusion (PBPC)

HD Cycle #1: Gemcitabine/Docetaxel/Melphalan/Carboplatin + PBPC arm 2: Second Cycle High-dose (HD) chemotherapy followed by stem-cell infusion (PBPC)

HD Cycle #2: Ifosfamide/Carboplatin/Etoposide + PBPC
Interventions: intervention 1: Gemcitabine intervention 2: Docetaxel intervention 3: Melphalan intervention 4: Carboplatin intervention 5: Mesna intervention 6: Ifosfamide intervention 7: Etoposide intervention 8: Stem Cell Transplant
Intervention descriptions: intervention 1: 1800 mg/m\^2 IV over 3 hours on Days -5 to Day -2. intervention 2: Docetaxel 300 mg/m\^2 IV over 2 hours on Day -5. intervention 3: 50 mg/m\^2 IV over 15 minutes on Days -4 to Day -2. intervention 4: Cycle 1: 333 mg/m\^2 IV over 2 hours on Days -4 to -2.

Cycle #2: 300 mg/m\^2 IV over 2 hours on Days -6 to -3. intervention 5: 3,000 mg/m\^2 per day in 96-hour continuous infusion, starting 30 minutes prior to the first dose of ifosfamide, on Days -6 to -4. intervention 6: 3,000 mg/m\^2 IV over 6 hours on Days -6 to -3 intervention 7: 200 mg/m\^2 IV over 3 hours, every 12 hours on Days -6 to -4. intervention 8: Stem cell infusion on Day 0.

Protocol documents:
Prot_SAP_000.pdf: 
2008-0378
February 26, 2015
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Protocol Page
High-dose chemotherapy for poor-prognosis relapsed germ-cell tumors
2008-0378
Core Protocol Information
Short Title 
HIGH-DOSE CHEMOTHERAPY FOR POOR-PROGNOSIS RELAPSED GERM-CELL 
TUMORS
Study Chair: 
Yago Nieto
Additional Contact:
Celina Ledesma
Peggy S. LeCompte
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
713-792-8750
Unit:
423
Full Title: 
High-dose chemotherapy for poor-prognosis relapsed germ-cell tumors
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 10/15/2018
Version:
42
Submitted by:
Peggy S. LeCompte--9/6/2017 2:08:22 PM
OPR Action:
Accepted by:  Inar Y. Graur -- 9/13/2017 11:47:39 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


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Protocol Body
1.0 Objectives
Primary Endpoint
To derive estimates of the event-free survival (EFS) in the bevacizumab and 
non-bevacizumab cohorts 
Secondary Endpoints:
1.   To estimate the response rate (RR) and complete response (CR) rate among patients with 
measurable disease in both cohorts
2.   To describe the side effect profiles of 
Bevacizumab/Gemcitabine/Docetaxel/Melphalan/Carboplatin; 
Bevacizumab/Ifosfamide/Cartoplatin/Etoposide; and, 
Gemcitabine/Docetaxel/Melphalan/Carboplatin and Ifosfamide/Cartoplatin/Etoposide:
- Extramedullary side effects
-  Engraftment rate.
3. To estimate the overall survival (OS) in both cohorts.
4. To compare the EFS in both cohorts.
2.0 Background 
2.1.  Current Status of High-Dose Chemotherapy (HDC) for Germ-Cell Tumors 
(GCT)
First-line cisplatin-based standard-dose chemotherapy (SDC) combinations yield 
long-term EFS rates around 90% and 50% in patients with good-risk and poor-risk 
advanced disease, respectively. Salvage SDC regimens cure about 25% of patients in first 
relapse. Patients in second relapse or beyond or those with cisplatin-refractory tumors are 
considered largely incurable with SDC.
The use of HDC with autologous hematopoietic progenitor-cell support (AHPCS) for 
GCT has been studied in two different settings: as part of first-line therapy for metastatic 
disease, and in relapsed or refractory tumors. 
First-Line HDC for Metastatic NSGCT
Motzer and colleagues developed an elegant strategy of switching to HDC those patients 
with a reduced clearance of serum tumor markers during SDC [1, 2]. This approach 
yielded long-term 50% EFS, which seemed superior to their own historical controls. 
Schmoll et al. reported 69% long-term EFS rate in 221 patients with poor-prognosis 
advanced disease who received one cycle of SDC followed by three cycles of high-dose 
etoposide/ifosfamide/cisplatin.[3] Matched-pair comparisons with prior SDC trials 
suggested the superiority of HDC.[4] 


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A European randomized trial conducted in the 1980s that enrolled 115 untreated 
poor-risk patients failed to show differences between a control arm and an arm receiving 
a cisplatin-containing regimen at higher than standard doses with AHPCS.[5] The total 
platinum dose in this study was lower in the transplant than in the control arm. In an US 
Intergroup trial Bajorin et al. randomized 219 patients with newly diagnosed disease with 
intermediate or poor risk features to receive 4 cycles of SDC or 2 cycles of SDC followed 
by 2 cycles of HDC with cyclophosphamide/etoposide/carboplatin.[6] The complete 
remission rates did not differ significantly between the transplant and control arms (52% 
vs. 48%, p=0.5). There were no significant differences in EFS (p=0.4) or OS (p=0.9). A 
planned subset analysis according to early tumor marker clearance suggested a 
significant benefit of HDC among those patients experiencing a slow marker decline 
(p=0.03), in contrast with similar outcomes in both arms in the group of patients with a 
satisfactory marker drop (p=0.5). 
HDC for Refractory/Relapsed GCT
The use of tandem cycles of high-dose carboplatin/etoposide in patients with relapsed 
tumors was pioneered by Einhorn and collaborators at Indiana University. In the latest 
update of their results at a median follow-up of 4 years (range, 1 to 10 years), they have 
reported 63% EFS in 184 consecutive patients, with 1.6% treatment-related mortality 
(TRM).[7] The EFS rates in patients transplanted in first or in second or later relapse 
were 70% and 45%, respectively. The outcome was similar in patients with seminoma 
and non-seminoma histologies (74% v 60%). Of note, none of their patients had primary 
mediastinal tumors. 
Several groups have explored the addition of a third drug, such as ifosfamide or 
cyclophosphamide to the carboplatin/etoposide backbone. Margolin et al. treated 20 
patients with tandem cycles of ifosfamide/carboplatin/etoposide (ICE) with a 40% 
long-term EFS rate.[8] Subsequently, these authors treated 31 patients with high-dose 
paclitaxel/carboplatin/etoposide followed by paclitaxel/carboplatin/ifosfamide, with 36% 
EFS rate at 5 years.[9] Overall, high-dose triplets achieve 40-50% EFS rate in patients 
with cisplatin-sensitive tumors, and 4-20% in those with refractory disease.[10, 11] 
Beyer et al. conducted a multicenter multivariate analysis of 310 relapsed/refractory 
patients treated with high/dose carboplatin/etoposide.[12] These authors identified the 
following independent adverse predictors: refractoriness to cisplatin (progression within 
4 weeks after treatment with cisplatin), absolute refractoriness to cisplatin (no response to 
initial platinum chemotherapy), primary mediastinal tumor, and high tumor markers 
(HCG >1,000 U/L) at the time of HDC. A prognostic score based on these variables was 
developed (Table 1). The resulting good, intermediate, and poor risk groups presented 
2-year EFS of 51%, 27% and 5% (Table 2).
Table 1. Beyer’s Prognostic Scoring 
Factor
Score
Progressive disease before HDC
1
Mediastinal primary tumor
1


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Refractory disease before HDC 
(prior relapse within 4 weeks of completion of 1st line chemotherapy)
1
Absolute refractory disease before HDC 
(PD as best response to prior therapy)
2
HCG > 1,000 U/L before HDC
2
Table 2. Beyer’s Prognostic Model
Risk category
EFS
1 year
2 years
Good (score 0)
56%
51%
Intermediate (score 1 or 2)
28%
27%
Poor (score >2)
5%
5%
This prognostic score has been externally validated in an independent group of 45 
patients with cisplatin-refractory relapsed disease, treated with HDC using ICE x 2.[13] 
At median FU of 32 months, the EFS and OS rates were both 23.5%, with EFS curves 
plateauing after 17 months. The groups with good, intermediate and poor risk according 
to the prognostic score had 62%, 13% and 0% EFS rates, respectively.
Randomized Trials of HDC for Relapsed GCT
Pico and colleagues randomized 280 relapsed patients to receive three cycles of SDC 
followed by a single course of high-dose carboplatin/etoposide/cyclophosphamide or one 
more cycle of SDC.[14] At median follow-up of 45 months, the differences in EFS (42% 
vs. 35%, P=0.1) or OS (53% in both arms) were not statistically significant.  
Lorch et al. randomized 216 patients with relapsed or refractory disease to receive one 
cycle of very high-dose carboplatin/etoposide or two sequential cycles of those drugs at 
slightly lower doses, requiring in both arms AHPCS.[15] Accrual to this study stopped 
after an excessive 14% TRM was detected in the single cycle arm. At median FU of 3 
years, the differences in favor of the sequential HDC arm in EFS (40% v 37%) and OS 
rates (80% v 61%) did not reach statistical significance. 
 
In summary, there is no consensus yet as to whether HDC should be administered to all 
relapsed patients. Because of the excellent results of tandem cycles of HDC as salvage 
treatment many experts consider HDC a valuable salvage option.[16] The National 
Comprehensive Cancer Network (NCCN) guidelines contemplate HDC as the preferred 
option for patients with an incomplete response or relapse after salvage SDC, for those 
with unfavorable prognostic features for conventional salvage therapy, such as an 
incomplete response to 1st line treatment, or for patients requiring 3rd line therapy.[17] 
It seems likely that more than one cycle of HDC is necessary, particularly in refractory 
patients, as it appears that a single cycle may either not be sufficient, or too toxic if 
administered at ultra-high doses.  


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2.2. 
High-Dose Gemcitabine/Docetaxel/Melphalan/Carboplatin (Gem-DMC).
The HDC regimen we will first use in our tandem cycle strategy, Gem/DMC, was 
developed by adding gemcitabine to a prior combination of 
docetaxel/melphalan/carboplatin (DMC). In the phase I trial of DMC, which enrolled 59 
patients with advanced refractory tumors, the maximally tolerated dose (MTD) of 
docetaxel was established at 400 mg/m2, in combination with melphalan (150 mg/m2) 
and carboplatin (1,000 mg/m2).[18] Docetaxel presented linear pharmacokinetics (PK) 
over the range of doses tested. This regimen showed high activity with 97% response rate 
(RR), 47% CR rate, and 3-year EFS and OS rates of 26% and 36%, respectively. 
In a subsequent phase I study that enrolled 52 patients, gemcitabine was administered at 
fixed dose rate of 10 mg/m2/min prior to DMC in each treatment day.[19] The MTD of 
gemcitabine was defined at 5 hours/day x 4 (total 20 hours, total dose 12,000 mg/m2). 
This dose level was tolerable, with a reversible profile of stomatitis (28% grade 3), 
enteritis (12% G3), diarrhea (8% G3), constipation (8% G3), and skin rash (8% G3), and 
no G4-5 toxicities. A high level of activity was again seen, with 97% RR, 50% CR rate, 
and encouraging 2-year EFS and OS rates of 56% and 78%, respectively. The PK 
exposure to gemcitabine across the dose range was linear, with no changes in clearance.
A total of 10 patients with refractory GCT were treated in these two trials: 6 with DMC 
and 4 with Gem-DMC. Eight patients had tumors in refractory relapse and 2 had relapsed 
primary mediastinal tumors. The median number of prior chemotherapy lines was 3 (1-5). 
Only 2 patients were in partial remission at the time of HDC, and the other 8 patients had 
progressive disease. All 10 patients responded to HDC, with 9 CRs and 1 PR. Six 
patients went on to receive a second cycle of HDC off study, with either 
carboplatin/etoposide or ICE. Six of the ten patients are alive in complete remission, 3 to 
6 years after HDC. 
2.3.
Vascular Endothelial Growth Factor (VEGF) in Germ Cell Tumors
The VEGF family of ligands consistes of five glycoproteins referred to as VEGF-A (or 
VEGF),  VEGF-B, C, D, and E. VEGF binds to two receptor tyrosine kinases: VEGFR-1 
(Flt-1) and VEGFR-2 (Flk-1/KDR), which are present on the surface of endothelial cells 
(ECs), and bind with high affinity to VEGF. Activation of VEGFR-2 leads to 
autophosphorylation and signal activation. VEGFR-1 is thought to act as a decoy 
receptor on ECs, although it may play a role in hematopoiesis. There is a third receptor, 
VEGFR-3 (Flt-4), involved in the regulation of the lymphatic system, which 
preferentially binds VEGF-C and VEGF-D. 
VEGF is one of the most potent inducers of tumors angiogenesis. The expression of 
VEGF depends on the oxygenation status and the VHL gene. Under normoxia and normal 
VHL function, oxygen promotes hydroxylation of the hypoxia inducible factor 
(HIF)-1alpha at a proline residue. VHL protein then binds to this hydroxylated residue, 
leading to ubiquitin attachment and proteasomal degradation of HIF-1alpha. Under 


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hypoxia, low pH or abnormal VHL function, HIF-1alpha dimerizes with HIF-1alpha, 
leading to transcription of hypoxia-inducible genes, such as VEGF. VEGF expression can 
also be triggered during early stages of neoplastic transformation by genetic mutations, 
e.g., K-ras, p53 or HER2. Antineoplastic treatment itself may increase VEGF production.
VEGF is overexpressed in most human tumors, with a direct correlation with tumor 
progression or risk of recurrence. Because of the relatively low expression levels in adult 
healthy tissues, VEGF constitutes an attractive therapeutic target. In the case of GCT, 
metastatic tumors express higher levels of VEGF than nonmetastatic tumors.[20] A direct 
correlation between tumor microvessel counts and VEGF levels in metastatic GCt has 
been reported, as well as an independent adverse prognostic effect of VEGF 
overexpression.[21] 
2.4.
Bevacizumab (Avastin ®)
Bevacizumab is a chimeric monoclonal antibody (mAb) that targets VEGF. Bevacizumab 
has a reduced immunogenicity and longer half-life than its murine counterpart. Phase I 
studies demonstrated linear pharmacokinetics and no interactions with chemotherapy.[22, 
23] 
A direct and rapid antivascular effect of bevacizumab has been shown on human tumors 
by Jain and coworkers.[24] Twelve days after a single dose of bevacizumab to patients 
with rectal carcinoma, bevacizumab decreased tumor perfusion, vascular volume, 
microvascular density, tumor interstitial fluid pressure (IFP), and circulating ECs and 
endothelial progenitor cells. Elevated IFP, a hallmark of solid tumors, is a result of 
abnormalities in tumor vessels, and constitutes a major impediment for drug access to the 
inner layers of the tumor lesion. These authors also observed an increase in vessel 
pericyte coverage after a single dose of bevacizumab, with no changes in tumor uptake in 
PET despite a 40-50% reduction in its microvessel density, suggesting that the residual 
normalized vasculature was more efficient. 
Additionally, bevacizumab appears to have direct cytotoxic antitumor effects, through 
blockade of VEGF binding to the neuropilin-1 receptor, which can result in apoptosis. A 
single dose of bevacizumab has been shown to cause a 67% decrease in expression of 
phosphorylated VEGR-2 and a 130% increase in tumor apoptosis in breast cancer 
patients.[25]  
In consequence, bevacizumab is synergistic with chemotherapy. VEGF inhibition 
transiently ‘normalizes’ the disorganized and dysfunctional tumor vasculature, improving 
the delivery of oxygen and cytotoxic drugs to tumor cells.[26] The bevacizumab-induced 
drop in IFP leads to a hydrostatic pressure gradient across the tumor vasculature, which 
enhances penetration of large molecules in tumors.[27] Additionally, increased 
oxygenation sensitizes cancer cells to cytotoxics. Finally, bevacizumab counteracts the 
chemotherapy-induced VEGF upregulation and increased tumor resistance.[28] 
Phase III studies of bevacizumab combined with chemotherapy have shown efficacy in 


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multiple metastatic settings, such as colorectal cancer,[29, 30] breast cancer,[31] or 
non-small cell lung cancer.[32] 
2.5. 
Toxicity Profile of Bevacizumab 
1.  
Hypertension is its most common side effect, with a 10-15% incidence of grade 3 
events, and rare grade 4 cases. Its mechanism may be the decrease of nitric oxide 
production. It responds well to treatment with angiotensin converting enzyme 
inhibitors or calcium channel blockers. It usually resolves once bevacizumab is 
discontinued.
2.  
Proteinuria is seen in 23% of patients, and is largely asymptomatic.
3. 
Minor bleeding complications, particularly epistaxis, occur in 20-40% of patients, 
without changes in biochemical, coagulation or hematologic parameters. 
Life-threatening intratumor hemorrhages have been reported in patients with 
centrally located, cavitated squamous cell lung cancer, or in parenchymal brain 
metastases.
4. 
While there appears to be no increase in the risk of venous thromboembolism, 
there is a small increase in the risk of arterial thrombosis (<4%). 
5. 
Wound healing complications can occur in up to 10% of pts undergoing surgery 
during bevacizumab treatment, but there appears to be no increased risk in 
patients who had surgery more than 30 days prior to bevacizumab.
6.
Bowel perforation. This complication has been observed in up to 11% of patients 
with heavily pretreated epithelial ovarian cancers. It has been reported in 1% of 
the patients with colorectal cancer treated with bevacizumab, and has not been 
seen in any other tumor type treated with bevacizumab.    
2.6.
Clinical Experience with Bevacizumab in Pediatric Patients
Bevacizumab is well tolerated in children at the same doses used in adults.[33, 34] The 
side effects in the pediatric population are mild and similar to that previously observed in 
adults: proteinuria, epistaxis, and neutropenia. 
2.7.
Rationale for Combining Bevacizumab with High-Dose Chemotherapy
The combination of bevacizumab and Gem/DMC and ICE may result in major synergy. 
In murine models, the combination of bevacizumab and paclitaxel significantly reduced 
tumor growth compared to paclitaxel alone.[35] In vitro and in vivo preclinical studies 
show that VEGF protects endothelial cells against the antiangiogenic effects of docetaxel 
and that this action is inhibited by bevacizumab.[36] Encouraging activity has been 
observed using bevacizumab and docetaxel in patients with metastatic breast cancer.[37] 
Synergy between platinum compounds and bevacizumab has also been shown in murine 


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models.[38] There is also good evidence of synergy between gemcitabine and 
bevacizumab [39,40]. 
The synergy between bevacizumab and chemotherapy seem to be due, at least in part, to 
bevacizumab-induced drop in intratumor IFP, which results in an improved 
chemotherapy delivery to the tumor cells. Thus, this augmentation effect likely depends 
on the peak concentration of the cytotoxic agent and a more rapid diffusion down a 
concentration gradient into the permeabilized tumor. This may explain why bevacizumab 
seems to add more efficacy to chemotherapy when this is administered intravenously 
than when given in prolonged oral treatments, such as capecitabine.[41]  
Additionally, the IFP changes induced by bevacizumab are transient by nature,[42] which 
suggests that this benefit is likely to disappear through long-term chronic treatments, as 
seen in all randomized trials comparing chemotherapy with or without bevacizumab 
where the tails of the EFS curves merge. This should not apply to the limited use of 
bevacizumab prior to each of the two HDC cycles as proposed in this study.
We are currently testing the combination of bevacizumab with Gem/DMC in a separate 
phase II trial for patients with relapsed ovarian cancer (#2007-0368).
3.0 Patient Eligibility
3.1.  Inclusion: 
3.1.1.   Male or female patients, age 12 to 65 years.  
3.1.2. Patients with seminomatous or nonseminomatous GCT in one of the following 
groups:
3.1.2.1. 
First relapse/progression or second response, with an 
intermediate or high risk according to the Beyer model.
3.1.2.2.  
Second relapse or beyond. 
3.1.3.  Adequate renal glomerular and tubular function, as defined by estimated serum 
creatinine clearance >/=50 ml/min and/or serum creatinine </= 1.8 mg/dL, and 
urinary protein excretion </=500 mg/day. 
3.1.4. Adequate hepatic function, as defined by ALT and AST</=3 x upper limit of 
normal (ULN); serum bilirubin and alkaline phosphatase </=2 x ULN or 
considered not clinically significant.
3.1.5. Adequate pulmonary function with FEV1, FVC and DLCO >/=50% of predicted, 
corrected for volume and/or hemoglobin.  
3.1.6. Adequate cardiac function with left ventricular ejection fraction >/= 40%. No 
uncontrolled arrhythmias or symptomatic cardiac disease. 
3.1.7.   Zubrod performance status 0-2.  
3.1.8.   A minimum apheresis collection of 5 million
 CD34+ cells/kg of autologous 
hematopoietic progenitor cells (AHPC).
3.1.9. Written informed consent by patients and/ or their parents or legal guardians. 
Assent for those patients inclusive of ages 12 to 17.
3.2.  
Exclusion:


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3.2.1. Growing teratoma syndrome, defined as enlarging tumor masses with normal 
serum markers during chemotherapy for nonseminomatous GCT.
3.2.2. Major surgery within 30 days before the initiation of study treatment.
3.2.3.   Radiotherapy within 21 days prior to initiation of study treatment.
3.2.4. Prior whole brain irradiation.
3.2.5.   Patients with active CNS disease, defined as brain or meningeal metastases that 
are not in complete remission.
3.2.6. Patients with active hepatitis B, either active carrier (HBsAg +) or viremic (HBV 
DNA >/=10,000 copies/mL, or >/= 2,000 IU/mL).
3.2.7. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients who either show 
chronic hepatitis C or positive hepatitis C serology.
3.2.8. Active infection requiring parenteral antibiotics.
3.2.9. HIV infection, unless the patient is receiving effective antiretroviral therapy with 
undetectable viral load and normal CD4 counts.
3.2.10. Patients who have had a previous autologous or allogeneic stem cell transplant in 
the previous 12 months.
3.2.11. Positive pregnancy test in a female patient of childbearing potential defined as not 
post menopausal for twelve months or no previous surgical sterilization.
4.0 Pretreatment evaluation
The following tests are performed to determine eligibility within 30 days before treatement, and 
do not need to be repeated prior to start treatment unless the treatment is delayed for more than 
30 days.
      For autologous stem cell transplantation:
a) History and physical examination.
b) CBC, differential and platelet count, coagulation profile (PT and PTT)
c) Chemistry panel including creatinine, albumin, electrolytes, glucose,albumin, total 
protein, alkaline phosphatase, ALT, AST, bilirubin, LDH.
d) Infection disease panel 
e) β-HCG in women of child-bearing potential
g) Left ventricular ejection fraction by MUGA or echocardiogram, EKG
h) Spirometry with DLCO
i)
Chest x-ray
j)
Urine dipstick. If proteinuria >/= 2+, a 24-hour urine collection for total protein will 
be performed.
Disease specific:
k) CT scans of chest, abdomen, and pelvis.
l)
Tumor markers (AFP and B-HCG)
m) MRI of the brain


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5.0 Autologous HPCs Collection
A bilateral bone marrow aspiration and biopsy is recommended before mobilization 
of AHPCs. The collection of autologous hematopoietic progenitor cells will be 
performed following standard practice and is not part of this study. Either G-CSF 
alone or G-CSF plus chemotherapy can be use as a mobilization regimens as per the 
discretion of the treating physician. The target collection will be 10 million CD34+ 
cells/kg to support both high-dose cycles. A minimum of 5 million CD34+ cells/kg 
will be required. As an alternative, pelvic bone marrow may be used if it is not 
possible to collect sufficient AHPCs. 
6.0 Treatment Plan
At least twenty-one days from patient's last radiation administration and or 
thirty days from major surgery must have elapsed prior to initiating study 
treatment.
6.1.
High-dose course #1: 
Gemcitabine/Docetaxel/Melphalan/Carboplatin
D-6
Admission and start hydration
D-5
Gemcitabine 1,800 mg/m2 IV over 3 hours / Docetaxel 300 mg/m2 IV 
over 2 hours
D-4 
Gemcitabine 1,800 mg/m2 IV over 3 hours / Melphalan 50 mg/m2 IV over 
15 minutes / carboplatin 333 mg/m2 IV over 2 hours
D-3 
Gemcitabine 1,800 mg/m2 IV over 3 hours / Melphalan 50 mg/m2 IV over 
15 minutes / Carboplatin 333 mg/m2 IV over 2 hours
D-2 
Gemcitabine 1,800 mg/m2 IV over 3 hours / Melphalan 50 mg/m2 IV over 
15 minutes / Carboplatin 333 mg/m2 IV over 2 hours
D-1 
Rest
D0
Hematopoietic progenitor-cell infusion 
Every effort will be made to admit the patient for prehydration on any day but Sunday or 
Monday, so that the AHPC infusion can proceed during a week day.
Gemcitabine will be administered on days -5 to -2, at 1,800 mg/m2 IV over 3 
hours. Docetaxel will be administered at 300 mg/m2 IV over 2 hours on day 
-5, starting immediately after completion of the gemcitabine infusion. 
Dexamethasone premedication for docetaxel will be at 8 mg IV bid, from day 
-6 (PM dose) to day -2 (AM dose). Melphalan will be administered at 50 
mg/m2, over 15 minutes, on days -4 to -2, starting immediately after 
completion of the gemcitabine infusion. Patients will keep ice chips or 
popsicles in their mouths during the infusion and for 15 minutes afterwards. 
Carboplatin will be administered at 333 mg/m2 over 2 hours, on days -4 to -2, 
starting immediately after completion of the gemcitabine infusion and at the 
same time as the melphalan infusion.


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Patients with creatinine >1.2 mg/dL or performance status of 2 will receive a 
reduced version of this regimen:
D-6            Admission and start hydration
D-5            Gemcitabine 1,500 mg/m2 IV over 3 hours / Docetaxel 275 mg/m2 IV over 2 
hours
D-4            Gemcitabine 1,500 mg/m2 IV over 3 hours / Melphalan 35 mg/m2 IV over 15 
minutes / Carboplatin 275 mg/m2 IV over 2 hours
D-3            Gemcitabine 1,500 mg/m2 IV over 3 hours / Melphalan 35 mg/m2 IV over 15 
minutes / Carboplatin 275 mg/m2 IV over 2 hours
D-2            Gemcitabine 1,500 mg/m2 IV over 3 hours / Melphalan 35 mg/m2 IV over 15 
minutes / Carboplatin 275 mg/m2 IV over 2 hours
D-1            Rest                 
D0             Hematopoietic progenitor-cell infusion 
Specific supportive care for HDC course #1: 
-
Caphosol mouthwashes (2-minute swishing and then spitting) will start on 
day -5 at 30 mL TID. 
-
Glutamine mouthwashes (2-minute swishing and then swallowing) will 
start on day -5,at 10 g TID, to be done 15 minutes following the caphosol 
rinse. 
-
From day +1 to day +10, 6-methylprednisolone will be administered at 40 
mg IV bid. 
-
Piridoxine will be started at 100 mg IV/PO on day -1.
After the patient is released from the hospital, they will be seen in the Outpatient Clinic 
until reversal of the acute  toxicities. Patients with increasing serum tumor markers or 
other clinical or radiographic evidence of tumor progression before HDC cycle #2 will be 
taken off protocol. Otherwise, all patients who have recovered from the acute toxicities 
associated with cycle 1 will start cycle 2 at 30-60 days from day 0 of HDC #1. 
6.2.
High-dose course #2: Ifosfamide/Carboplatin/Etoposide
D-7
Admission and start hydration
D-6 to -4 
Mesna 3,000 mg/m2/day in 24-hour continuous infusion, starting 30 minutes 
prior to the first dose of ifosfamide
Ifosfamide 3,000 mg/m2 IV over 6 hours
Etoposide 200 mg/m2
 IV over 3 hours Q12h  
Carboplatin 300 mg/m2 over 2 hours
D-3
Mesna 3,000 mg/m2/day in 24-hour continuous infusion, starting 30 minutes 
prior to the first dose of ifosfamide
Ifosfamide 3,000 mg/m2 IV over 6 hours 
Carboplatin 300 mg/m2 over 2 hours
D-2 
Rest 
D-1 
Rest 


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D0 
Hematopoietic progenitor-cell infusion
Every effort will be made to admit the patient for prehydration on any day but Saturday 
or Sunday, so that the stem-cell infusion can proceed during a week day. 
The order of chemotherapy on days -6 to -3 will be as follows: The 96-hour infusion of 
Mesna will be started on day -6 thirty minutes prior to the first dose of Ifosfamide.The 
first of the two daily doses of Etoposide will be given after the Ifosfamide infusion is 
complete. The daily dose of Carboplatin will be given after the first daily dose of 
Etoposide. 
Patients with creatinine >1.2 mg/dL or performance status of 2 will receive a reduced 
version of this regimen:
D-7
Admission and start hydration
D-6 to -4 
Mesna 2,500 mg/m2/day in 24-hour continuous infusion, starting 30 minutes 
prior to the first dose of ifosfamide
Ifosfamide 2,500 mg/m2 IV over 6 hours
Etoposide 200 mg/m2
 IV over 3 hours Q12h  
Carboplatin 250 mg/m2 over 2 hours
D-3
Mesna 2,500 mg/m2/day in 24-hour continuous infusion, starting 30 minutes 
prior to the first dose of ifosfamide
Ifosfamide 2,500 mg/m2 IV over 6 hours 
Carboplatin 250 mg/m2 over 2 hours
D-2 
Rest 
D-1 
Rest 
D0 
Hematopoietic progenitor-cell infusion
Patients with prior allergic reactions to etoposide will receive, instead, the etoposide 
phosphate formulation at 200 mg/m2 IV over 3 hours Q12 hours on days -6 to -4 (same 
dose and schedule as regular etoposide for those patients without an allergy to this drug). 
6.3.
Concomitant medications for each course
G-CSF is administered at a dose of approximately 5 mcg/kg (given as the closest highest 
dose resulting in administration of a complete vial) daily from day +5 until granulocytes 
>1.0 x 10e9/l or longer per the discretion of the treating physician.
Administration of antiemetics during chemotherapy is recommended, following the 
departmental standards. The use of concomitant medications should be avoided whenever 
possible to minimize potentially harmful interactions. Medically necessary medications 
or procedures shall ultimately be at the discretion of the treating physician. 
Acetaminophen (Tylenol) shall not be administered for 72 hr before and on the day of 
administration of carboplatin or melphalan. 
Prophylactic antimicrobials are not to be administered during the chemotherapy 


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treatments, and should start on day-1, following departmental standards.
6.4.
Determination of Dosing Body Surface Area (BSA)
For patients whose actual body weight (BW) is </= 20% above the ideal BW, the actual 
BW is used to calculate the BSA. For patients whose actual BW is >20% above ideal 
BW, an “adjusted BW”, defined as the midpoint between the actual and ideal BW, will be 
used to calculate an “adjusted BSA” for chemotherapy dosing calculation purposes.
7.0 Post Treatment Evaluation
During each course
Adverse events (toxicity) assessment while admitted in hospital, patients will be 
monitored on a daily basis by the in-patient team. Once discharged, once a week until 
admission for course 2.
Between course 1 and 2:
a) CBC, differential and platelet count, coagulation profile (PT and PTT)
b) Chemistry panel including creatinine, albumin, electrolytes, glucose,albumin, total 
protein, alkaline phosphatase, ALT, AST, bilirubin, LDH.
c) Chest x-ray
d) Urine dipstick. If proteinuria >/= 2+, a 24-hour urine collection for total protein will 
be performed.
e) Tumor markers (AFP and/or B-HCG)
On Approximately D+30, D+100, 6 month, and 1 year  of treatment completion (course 
2):
Once discharged, from course 2, the patient will come once a week or as determined by 
primary physician until day +30. From that time on, patients will be evaluated every 1-2 
months until day +100, at which time treatment safety completion assessment will be 
performed with:  
1- Adverse events (toxicity) assessment (standard for autologous stem cell 
transplantation):
a)
History and physical examination.
b)
CBC, differential and platelet count, coagulation profile (PT and PTT).
c)
Chemistry panel including creatinine, albumin, electrolytes, glucose,albumin, 
total 
protein, alkaline phosphatase, ALT, AST, bilirubin, LDH.
2- Disease specific:
d)
CT scans of chest, abdomen, and pelvis and/or PET/CT.
e)
Tumor markers (AFP and/or B-HCG)-HCG).
 f)
MRI of the brain (if clinically indicated).
Six-month disease status evaluation: The disease status of each patient 
(progression/relapse vs. remission/no progression) will be assessed for purpose of the 


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early trial stopping rule for futility described in section 11.
Tumor response evaluation: will be assessed using response criteria appendix E. 
Return visits: weekly while between courses, at approximately D+30, D+100, 6-month 
and 1-year of treatment completion (Course 2). 
Off-Study Criteria:   
Evidence of tumor progression.
Unexpected pattern of toxicity.
Patient request.
At 1 year of treatment completion (course 2).
8.0 Evaluation Criteria
8.1.1
Neutrophil recovery: is defined as the first day of a sustained absolute 
neutrophil count (ANC) > 0.5 x 10
9/L for 3 consecutive days by day 28. 
Graft Failure is defined as failure to achieve an ANC > 0.5 x 10
9/L for 3 
consecutive days by day 28, with <10% cellularity on bone marrow biopsy.
Secondary graft failure is defined as a sustained decline of ANC <0.5 x 10
9/L for 3 
consecutive days after initial documented engraftment. 
8.1.2
Response definitions: See Appendix E.
            
8.1.3 
Overall survival will be estimated from HDC #1 start (day -6) until last clinic visit 
if the patient is alive, or death from any cause
8.1.4
Event-free survival will be estimated from the first day of HDC #1 (day-6) until 
tumor progression, relapse, or death from any cause. 
9.0 Adverse Events and Reporting Requirements
The intensity of adverse events (AE) will be assessed according to the Common 
Terminology Criteria v3.0 (CTCAE).  Collection of adverse events will reflect the 
onset and resolution date and maximum grade.  Intermittent events should be 
labeled as such and followed until resolution. If a patient is taken off study while 
an event is still ongoing, this will be followed until resolution unless another 
therapy is initiated.  Pre-existing medical conditions will be recorded only if an 
exacerbation occurs during the active treatment period. Co-morbid events will not 
be scored separately.
Adverse events (toxicities) known to be produced by the chemotherapy regimen:
1- Mucositis: It starts early after transplant, peaks in severity around day +2.
2- Diarrhea: It presents in the first hospital week after transplant.
3- Constipation/Ileus: It can occur in the first week after transplant.


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4- Enterocolitis (abdominal pain with/without bleeding, diarrhea or constipation): It can 
occur in the second week, and lasts for around one week. 
5- Hepatic: early and transient elevations of liver function enzymes, typically 
starting around day -3 and resolving within 1 week.
6- Pulmonary: manifested as progressive or acute dyspnea, tachypnea, 
hypoxemia and pulmonary infiltrates on chest radiograph that are sometimes 
accompanied by fever and cough, due to pulmonary edema, egnraftment 
syndrome or, more rarely, toxic interstitial pneumonitis.
7- Skin: mild to moderate in severity, appearing in the first week after transplant 
as a macular or finely granular maculopapular pruritic eruption on the trunk and 
extremities usually responds to moisturizing petrolatum ("Aquaphore") or topical 
corticosteroids
8- Nails: Asymptomatic partial or complete nail loss can occur weeks after 
transplant. Nails grow back within 2 to 3 months.
9- Hand-foot syndrome: it appears in the first week after transplant and can be 
treated successfully with piridoxine.
10- Myoarthralgia: It appears early, typically around day -3, and lasts for around 2-3 more 
days.
11- Asthenia (fatigue): it is the most prominent symptom after hospital discharge. Most 
cases respond rapidly to mehtylphenidate ("Ritalin").
12- Neurologic: peripheral neuropathy that starts around 1-2 weeks after 
transplant and improves within a few weeks. A few patients can experience 
neuropathic pain. 
13- Neutropenic fever of unknow origin with negative cultures during the 
second week. It is thought to be largely related to cytokine release. It can be 
prevented in many patients using steroids, a strategy that has been shown to be 
safe.
Adverse events (toxicities) known to be produced by other components of the 
treatment:
The following events are not considered to be significant in relationship with the 
study treatment, would not be considered adverse events, and would not be 
collected in the study database.
Nausea and vomiting, anorexia.
Events related to Myelosuppression: thrombocytopenia, bleeding, platelets and 
RBCs transfusions.
Flu-like symptoms: fever of any grade frecuently associated with headache, chills, 
cough, rhinitis, sweating and insomnia.
Mood alteration: depression, anxiety, and agitation
Readmissions (lasting <10 days)
Low blood pressure due to dehydration requiring fluid replacement
Fluid overload due to fluid replacement rarely leading to cardiac dysfunction
Laboratory serum metabolic values not reflecting end-organ (hepatic, renal) 
function and or those considered associated to the original disease 
Events that are identified to be related to the supportive treatment (concomitant 


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medications) including steroid- related side effects.
Adverse Events Considered Serious (SAEs):
a) Prolonged hospitalization due to infections and/or organ failure requiring 
extensive supportive care (i.e. dialysis, mechanical ventilation)
b) Readmissions from any cause resulting in a prolonged hospitalization (>10 
days).
c) Any expected or unexpected event resulting in an irreversible condition and/ or 
leading to death.
Reporting Requirements:
Drug toxicities will be evaluated according to CTC version 3 (Appendix A). Serious and 
unexpected adverse events occurring during the patient participation on this study will be 
reported to the PI or his designate, who in turn will notify the IRB and Clinical Research 
Compliance (CRC) office. 
In order to assure appropriate monitoring for toxicities, each patient will be followed for 
30 days after transplant or until documentation of reversal of all toxicities is obtained. 
Additionally, the patient will be seen approximately 3 months (range 2-4 months) after 
transplant for follow-up of therapeutic and toxic effects.
All other life-threatening (grade 4) or fatal (grade 5) events with possible, probable or 
definite attribution to the study drug must have a written report transmitted within 24 
hours (next working day) of knowledge of the event to the CRC office and the original 
submitted to the IRB
This study will be conducted as described in this protocol, except for an emergency 
situation in which the protection, safety and well-being of the patient requires immediate 
intervention, based on the judgment of the investigator or his/her designee. In the event 
of a significant deviation from the protocol, the investigator will notify the IRB.
All laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using 
anonymous identifiers. Linkage to patient identity is only possible after accessing 
a password-protected database. Access to the database is only available to 
individuals directly involved in the study.
Information gathered for this study will not be reused or disclosed to any other 
person or entity, or for other research. Once the research has been completed, 
identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point will be destroyed.
10.0 Statistical Design
10.1.
Objectives


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The original primary objective of this phase II trial was to evaluate the efficacy of treating testicular 
cancer patients with the proposed treatment of tandem high-dose cycles of 
bevacizumab/gemcitabine/docetaxel/melphalan/carboplatin and 
bevacizumab/ifosfamide/carboplatin/etoposide.  The primary endpoint is 2-year event-free survival 
(EFS).  The currently used HDC regimens in patients with relapsed disease are associated with a 2-year 
EFS rate of 15% in the population targeted in this trial, and it is expected that the proposed treatment may 
increase 2-year EFS to 50%.  In December 2014, because of data available from patients with the same 
indication treated without bevacizumab, the study will be modified to treat a new cohort of patients with a 
similar treatment regimen, which will no longer include bevacizumab.  The modified primary objective is 
to evaluate EFS separately in the two patient cohorts.  A secondary objective to compare outcomes 
between the two cohorts has been added.  A total of 40 patients were treated as part of the original cohort, 
and we will treat a total of 40 patients in this new cohort.
10.2.  Efficacy Monitoring
The efficacy of the original cohort of patients was monitored using a Bayesian one-arm 
time-to-progression (TTP) design.  Details are provided in Appendix K.  A total of 40 patients was treated 
in this cohort, and the trial did not stop early for lack of efficacy.
In February 2015 the trial is modified to add a second cohort of patients.  This cohort will be treated with 
the same regimen as the original cohort, except that patients will not receive bevacizumab.  We will use a 
similar monitoring rule to monitor patient data in the second cohort of patients treated without 
bevacizumab.  We assume in this cohort that event-free survival (EFS) follows an exponential distribution 
and first note that, under this assumption, an EFS rate of 15% at 24 months corresponds to a median EFS 
of 8.77 months.  Patients who are lost to follow-up before disease progression will be censored at the time 
of last follow-up in the calculation of EFS.  We note that a 50% EFS rate at 24 months corresponds to a 
median EFS of 24 months.  We assume that the median EFS for the standard of care (historical controls) 
has an inverse gamma (IG) distribution with parameters (21.23, 177.40), which has a mean of 8.77 
months and a variance of 4.0 months.  These prior parameters can be interpreted as providing information 
based on about 21 events observed over 177 months of trial time. The prior distribution for the median 
EFS for the experimental group in this trial is set to be IG(3, 17.54), which has the same mean, 8.77 
months, but a greater variance of 77 months. This wider variance reflects our uncertainty regarding the 
EFS rate in the experimental group.  
A maximum of 40 patients will be enrolled in this cohort. We will continuously monitor EFS in the 
cohort based on the following futility monitoring rule: 
Stop accrual if Pr(Te2 > Ts+15 | data from the trial) < 0.01
where Te2 and Ts are the median EFS of the experimental arm (without bevacizumab) and historical 
controls, respectively.  Ts is distributed as IG(21.23, 177.40) as specified previously. In other words, if at 
any time during the course of the trial, the probability that the median EFS is at least 15 months longer 
than the median EFS for historical controls is less than 1%, we will stop the trial.  The stopping 
boundaries for this trial will be incorporated into the Clinical Trial Conduct Monitoring website for this 
study found at https://biostatistics.mdanderson.org/ClinicalTrialConduct.  
Assuming an accrual rate of 1 patient/2 months and following the monitoring boundaries according to the 
above rule, we summarize operating characteristics based upon 2000 simulations of the trial under two 
scenarios: 1) a true EFS rate of 15% at 2 years, and 2) a true EFS rate of 50% at 2 years.  Under the first 
scenario, we will have a 98.2% chance of stopping the trial early and declaring that the treatment does not 
work (and thus a 1.2% chance of falsely concluding that the treatment dose work).  An average of 14.3 


2008-0378
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patients will be treated in this scenario.
Under the second scenario, we will have a 4.0% chance of stopping the trial early and falsely concluding 
that the trial does not work. In this scenario, an average of 38.7 patients will be treated.
10.3. Safety Monitoring
In the original study design, in addition to monitoring EFS, we also used a monitoring rule to ensure that 
the rate of treatment-related mortality (TRM) at 3 months is low.  Patients were monitored separately by 
risk (standard-risk and high-risk), and details are provided in Appendix K.  Safety in the new cohort of 
patients treated without bevacizumab will be monitored using a similar rule, using the method of Thall, 
Simon, and Estey (1995) to monitor TRM, starting with the 5th patient in the trial.  Separate monitoring 
rules are provided for standard-risk patients in the trial and high-risk patients, defined as those patients 
with a creatinine > 1.2 mg/dL or performance status of 2.  We expect two-thirds of the new cohort (27 
patients) to be standard-risk and the rest (13 patients) to be high-risk.
We will monitor the safety of the standard-risk patients by using the following Bayesian decision 
monitoring rule: stop accrual of standard-risk patients if at any time during the course of the trial
Pr{TRM > 5% | data from the trial} > 0.95
In other words, we will stop if the probability is > 95% at any time that the rate of 3-month TRM in the 
standard-risk patients is > 5%.  We will assume a Beta(0.1,1.9) prior distribution for the TRM rate in 
these patients.  A Beta(0.1, 1.9) prior distribution has a mean of 5%, the targeted maximum TRM rate, but 
carries little information.  This decision rule leads to the following stopping rule: stop the trial if 
[# of standard-risk patients with TRM at 3 months / # of standard-risk
patients evaluated at 3 months]:  >/=  2/2, 3/8, or 4/18
The operating characteristics of this rule based upon 10000 simulations of the trial are shown in the Table 
4.  The table provides the proportion of the time that the standard-risk group in the second cohort in the 
trial will stop early for different assumptions about the true 3-month TRM rate as well as the median and 
quartiles for the sample size.  For example, if the true TRM rate in the standard-risk patients in this cohort 
is 5%, the cohort will stop early 8.5% of the time.  If the true rate of TRM is 20%, the cohort will 
terminate early more than 80% of the time.
Table 4. Operating Characteristics for the TRM Monitoring Rule in Standard-Risk Patients
True TRM 
True TRM Rate
Probability of 
Stopping Early
P25
Median
P75
2%
1.1%
27
27
27
5%
8.5%
27
27
27
10%
34.6%
16
27
27
20%
84.0%
5
12
21
30%
98.2%
4
6
11
We provide a separate monitoring rule for the high-risk patients in the second cohort.  We expect to enroll 
13 such patients.  We will stop entry into this group if at any time during the course of the trial
Pr{TRM > 10% | data from the trial} > 0.95


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In other words, we will stop entry in high-risk patients if the probability is > 95% at any time that the rate 
of 3-month TRM in the high-risk patients is > 10%.  We will assume a Beta(0.2, 1.8) prior distribution for 
the TRM rate.  This prior distribution has a mean of 10%, the targeted maximum TRM rate, but carries 
little information.  This decision rule leads to the following stopping rule: stop the trial if 
[# of high-risk patients with TRM at 3 months / # of high-risk
patients evaluated at 3 months]: >/=  2/2, 3/4, or 4/9
The operating characteristics of this rule based upon 10000 simulations of the trial are shown in the Table 
4.  The table provides the proportion of the time that the high-risk group in the second cohort will stop 
early for different assumptions about the true 3-month TRM rate as well as the median and quartiles for 
the sample size.
Table 5. Operating Characteristics for the TRM Monitoring Rule in High-Risk Patients
True TRM Rate
Probability of 
Stopping Early
P25
Median
P75
2%
0.1%
13
13
13
5%
1.3%
13
13
13
10%
6.2%
13
13
13
20%
28.2%
11
13
13
30%
58.9%
5
11
13
10.4 Analysis Plan
The response rate (RR) and complete response (CR) rate will be estimated and reported along with 95% 
confidence intervals separately for each cohort and by risk subgroups.
Because the two cohorts of patients are not randomized, propensity score analysis will be used to compare 
EFS and OS between the two patient cohorts.  We will explore both propensity score matching and 
inverse probability weighting techniques.  The response rates RR and CR will also be compared between 
the two patient cohorts by using propensity score analysis methods.
Safety data will be summarized, including the extramedullary side effect profile and the engraftment rate 
for Bev/Gem/DMC and Bev/ICE.  Overall survival (OS) and event-free survival (EFS) will be estimated 
using the method of Kaplan and Meier.
Categorical variables will be summarized using frequency tables.  The Cox proportional hazards 
regression model will be used to assess the association between covariates of interest on EFS and OS.  
Logistic regression will be used to assess the effects of covariates of interest upon RR and CR.
11.0 Background Drug Information
11.1.  
Melphalan (Alkeran®)
Melphalan is an alkylating agent of the bischloroethylamine type.  As a result, its 
cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, 


2008-0378
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probably by binding at the N
7 position of guanine.  Like other bifunctional alkylating 
agents, it is active against both resting and rapidly dividing tumor cells.
Formulation:  Melphalan for injection is supplied as a sterile, nonpyrogenic, freeze-dried 
powder.  Each single-use vial contains melphalan hydrochloride equivalent to 50 mg 
melphalan and 20 mg povidone.
Preparation:  Melphalan for injection must be reconstituted by rapidly injecting 10 mL of 
the supplied diluent directly into the vial of lyophilized powder using a sterile needle and 
syringe.  This provides a 5 mg/mL solution of melphalan.  Immediately dilute the dose to 
be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater 
than 0.45 mg/mL.  Administer the diluted product over a minimum of 15 minutes.  
Complete the administration within 60 minutes of reconstitution.
Storage and stability:  Melphalan for injection vials should be stored at controlled room 
temperature 15
o to 30
o C (59
o to 86
o F) and protected from light.  The time between 
reconstitution/dilution and administration of melphalan should be kept to a minimum 
because reconstituted and diluted solutions of melphalan are unstable.  Over as short a 
time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted 
material from the reaction of melphalan with the diluent.  Upon further dilution with 
saline, nearly 1% label strength of melphalan hydrolizes every 10 minutes.  A precipitate 
forms if the reconstituted solution is stored at 5
o C.  Do not refrigerate the reconstituted 
product. 
Adverse events associated with melphalan:  The following information on adverse 
reactions is based on data from both oral and IV administration of melphalan as a single 
agent, using several different dose schedules for treatment of a wide variety of 
malignancies.  Please refer to the Adverse Reactions and Warnings sections of the 
product package insert.
Hematologic:  The most common side effect is bone marrow suppression.  White blood 
cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with 
recovery in 4 to 5 weeks after treatment.  Irreversible bone marrow failure has been 
reported.
Gastrointestinal:  Gastrointestinal disturbances such as nausea and vomiting, diarrhea, 
and oral ulceration occur infrequently.  Hepatic toxicity, including veno-occlusive 
disease, has been reported.
Hypersensitivity:  Acute hypersensitivity reactions including anaphylaxis were reported 
in 2.4% of 425 patients receiving melphalan for myeloma.  These reactions were 
characterized by urticaria, pruritus, edema, and in some patients, tachycardia, 
hypotension and bronchospasm.  These patients appeared to respond to antihistamine and 
corticosteroid therapy.  If a hypersensitivity reaction occurs, IV or oral melphalan should 
not be readministered since hypersensitivity reactions have also been reported with oral 
melphalan.
Carcinogenesis:  Secondary malignancies, including acute nonlymphocytic leukemia, 


2008-0378
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myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer 
treated with alkylating agents (including melphalan).
Other:  Other reported adverse reactions include skin hypersensitivity, skin ulceration at 
injection site, skin necrosis rarely requiring skin grafting, vasculitis, alopecia, hemolytic 
anemia, pulmonary fibrosis and interstitial pneumonitis. 
11.2. 
Gemcitabine
SYNONYM(S):Gemcitabine hydrochloride, 
difluorodeoxycytidine,2',2'-difluorodeoxycytidine, dFdC, LY 188011
COMMON TRADE NAME(S): Gemzar® (notice of compliance,1 December 1996; 
patent expires2 March 2004)
CLASSIFICATION: Antimetabolite, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions 
apply.
MECHANISM OF ACTION: 
Gemcitabine, a pyrimidine analog, is structurally similar to cytarabine, but has a wider 
spectrum of antitumour activity due to its different cellular pharmacology and mechanism 
of action.3 Gemcitabine is metabolized intracellularly to two active metabolites, 
gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). The 
cytotoxic effects of gemcitabine are exerted through incorporation of dFdCTP into DNA 
with the assistance of dFdCDP, resulting in inhibition of DNA synthesis and induction of 
apoptosis. emcitabine is a radiation-sensitizing agent.5 It is cell-cycle phase specific (S 
and G1/S-phases).
PHARMACOKINETICS: 
Interpatient variability: 3- to 4-fold interpatient and intrapatient variability
Distribution: widely distributed into tissues; also present in ascitic fluid 
Volume of distribution: IV infusion < 70 min: 50 L/m2;IV infusion 70-285 min: 370 
L/m2
Plasma protein binding: < 10%
Metabolism: Metabolized intracellularly by nucleoside kinases to active metabolites 
dFdCDP and dFdCTP; also metabolized intracellularly and extracellularly by cytidine 
deaminase to inactive metabolite difluorodeoxyuridine (dFdU)
Excretion: Urine 92-98% over one week (89% as dFdU, < 10% as gemcitabine) after a 
single dose of 1000 mg/m2 given over 30 minutes
Half life: Terminal half life IV infusion < 70 min: 0.7-1.6 h. IV infusion 70-285 min: 


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4.1-10.6 h
Clearance:  ClearanceIV infusion < 70 min: 41-92 L/h/m2 (male), 31-69 L/h/m2 (female) 
Gender: decreased volume of distribution and clearance in women
Elderly: decreased clearance and increased half-life with increasing age
SPECIAL PRECAUTIONS: 
Carcinogenicity: No information found.
Mutagenicity: Not mutagenic in Ames test but mutagenic in mammalian in vitro 
mutation test. Gemcitabine is clastogenic in mammalian in vitro and in vivo chromosome 
tests. 
Fertility: Decreased spermatogenesis and fertility in male mice.5 
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, 
but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the 
drug is needed in a life-threatening situation or for a serious disease for which safer drugs 
cannot be used or are ineffective).
Breastfeeding is not recommended due to the potential secretion into breast milk 
SIDE EFFECTS: 
ORGAN SITE
SIDE EFFECT
Dose-limiting side effects are in bold, italics
I = immediate (onset in hours to days); 
E = early (days to weeks);
D = delayed (weeks to months); L = late (months to 
years)
ONSET
Allergy/immunology
allergic reaction (4%, severe 0.2%)30
I
anemia (68%, severe 8%)
E
leukopenia (62%, severe 9%)
E
neutropenia (63%, severe 25%) 
nadir 7-10 days, recovery within 7 days31
E
Blood/bone marrow
thrombocytopenia (24%, severe 5%) 
E


2008-0378
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nadir 7-10 days, recovery within 7 days31
Cardiovascular 
(arrhythmia)
cardiac arrhythmia (2%, severe 0.2%)30
E
Cardiovascular (general) edema/peripheral edema (28%, severe 3%)32
ED
Coagulation
hemolytic uremic syndrome (0.3%)
D
asthenia (42%, severe 2%)30
E
Constitutional symptoms
fever (37%, severe < 1%)
IE
extravasation hazard: none4,30
alopecia (14%)
D
Dermatology/skin 
skin rash (25%, severe < 1%)
IE
emetogenic potential: low moderate33
constipation (8%, severe < 1%)
E
diarrhea (12%, severe < 1%)
E
nausea and vomiting (64%, severe 18%)
I
Gastrointestinal
stomatitis (8%, severe < 1%)
E
Hemorrhage
hematuria (31%, severe < 1%)
E
elevated alkaline phosphatase (55%, severe 
9%)
E
elevated AST (67%, severe 9%)
E
elevated ALT (68%, severe 10%)
E
Hepatic
elevated bilirubin (13%, severe 2%)
E
Infection
infection (9%, severe 1%)
E
decreased level of consciousness (9%, severe < 
1%)
E
Neurology
peripheral neuropathy (3%)17
ED
Pain
pain (16%, severe 1%)
ED
Pulmonary
dyspnea (8%, severe 1%)
IE
elevated BUN (16%, severe 0%)
E
elevated creatinine (7%, severe < 1%)
E
Renal/Genitourinary
proteinuria (36%, severe < 1%)
E
Syndromes
flu-like symptoms (19%, severe 1%)30
E
Hemolytic uremic syndrome has been infrequently reported and is characterized by 
microangiopathic hemolytic anemia, thrombocytopenia and renal failure. The syndrome 
can present either acutely with severe hemolysis, thrombocytopenia and rapidly 
progressive renal failure, or more insidiously with mild or no thrombocytopenia and 
slowly progressive renal failure. The etiology of hemolytic uremic syndrome is 
unknown.The onset of the syndrome has been reported to occur during and shortly after 
gemcitabine therapy. If not treated promptly, the syndrome may result in irreversible 


2008-0378
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renal failure requiring dialysis. Therefore, patients with impaired renal function should be 
monitored closely while being treated with gemcitabine.
Elevated liver enzymes: Gemcitabine causes transient and reversible elevations of liver 
function enzymes in about two-thirds of patients. However, these increases are rarely of 
clinical significance and there is no evidence of increasing hepatic toxicity with either 
longer duration of gemcitabine treatment or cumulative dose.
 Fever/Flu-like symptoms: Fever of any severity was reported in 37% of patients. It is 
frequently associated with other flu-like symptoms such as headache, chills, cough, 
rhinitis, myalgia, fatigue, sweating and insomnia. These symptoms are usually mild and 
transient, and rarely dose-limiting. The use of acetaminophen may provide symptomatic 
relief. 
Severe pulmonary toxicity: Acute dyspnea may sometimes occur with gemcitabine 
therapy, but is usually self-limiting. However, severe pulmonary toxicities such as 
pulmonary edema, interstitial pneumonitis and adult respiratory distress syndrome have 
rarely been reported. The symptoms are manifested as progressive dyspnea, tachypnea, 
hypoxemia and pulmonary infiltrates on chest radiograph that are sometimes 
accompanied by fever and cough. Pulmonary toxicities usually occur after several cycles 
of gemcitabine, but have also been seen as early as the first cycle. Risk factors for 
pulmonary toxicities include prior radiation to the mediastinum. Because of its structural 
similarities to cytarabine, gemcitabine is thought to cause lung injury by the same 
mechanism by inducing pulmonary capillary leakage. Management of pulmonary 
toxicities consists of discontinuation of gemcitabine and early supportive care with 
bronchodilators, corticosteroids, diuretics, and/or oxygen. Although pulmonary toxicities 
may be reversible with treatment, fatal recurrence of severe pulmonary symptoms was 
reported in one patient upon rechallenge with gemcitabine.
Skin rash: Typically mild to moderate in severity, with macular or finely granular 
maculopapular pruritic eruption on the trunk and extremities. It is not dose-limiting and 
usually responds to topical corticosteroidsIf needed, antihistamines such as 
diphenhydramine can be used.
INTERACTIONS:
AGENT
EFFECT
MECHANISM
MANAGEMENT
Warfarin
increased 
anticoagulant effect 
of warfarin
possibly decreased 
metabolism of warfarin 
and decreased hepatic 
synthesis of clotting 
factors
monitor INR carefully 
during and for 1-2 
months after 
gemcitabine therapy; 
adjust warfarin dose as 
needed


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SOLUTION PREPARATION AND COMPATIBILITY: 
Injection: 200 mg and 1000 mg vials (as the hydrochloride salt). Store at room 
temperature. 
Reconstitute 200 mg vial with 5 mL of NS without preservative and 1000 mg vial with 
25 mL of NS without preservative to yield a gemcitabine concentration of 38 mg/mL. 
Reconstitution of concentrations greater than 40 mg/mL may result in incomplete 
dissolution and should be avoided. Reconstituted solution is stable for 24 hours at room 
temperature and should not be days at room temperature and under refrigeration. 
However, the manufacturer recommends that the admixture be used within 24 hours since 
the solution does not contain preservatives.
Bacterial challenge: Gemcitabine 2.4 mg/mL diluted in NS did not exhibit a substantial 
antimicrobial effect on the growth of four organisms inoculated into the solution. Diluted 
solutions should be stored under refrigeration whenever possible and that the potential for 
microbiological growth should be considered when assigning expiration periods.
Compatibility: The following are compatible via Y-site injection: amifostine, bleomycin, 
carboplatin, carmustine, cisplatin, cyclophosphamide, cytarabine, dactinomycin, 
daunorubicin, dexamethasone, dexrazoxane, diphenhydramine, docetaxel, dopamine, 
doxorubicin, etoposide, fludarabine, fluorouracil, granisetron, heparin, hydrocortisone, 
hydromorphone, idarubicin, ifosfamide, leucovorin, lorazepam, mannitol, meperidine, 
mesna, metoclopramide, mitoxantrone, morphine, ondansetron, paclitaxel, plicamycin, 
potassium chloride, ranitidine, sodium bicarbonate, streptozocin, teniposide, thiotepa, 
topotecan, vinblastine, vincristine, vinorelbine.
Incompatibility: The following are incompatible via Y-site injection: furosemide, 
irinotecan, methotrexate, methylprednisolone, mitomycin, prochlorperazine.
11.3. 
Carboplatin
Carboplatin injection
WARNING
Carboplatin for injection should be administered under the supervision of a qualified 
physician experienced in the use of cancer chemotherapeutic agents. Appropriate 
management of therapy and complications is possible only when adequate treatment 
facilities are readily available.
Bone marrow suppression is dose related and may be severe, resulting in infection and/or 
bleeding. Anemia may be cumulative and may require transfusion support. Vomiting is 
another frequent drug-related side effect.
Anaphylactic-like reactions to carboplatin have been reported and may occur within 
minutes of carboplatin administration. Epinephrine, corticosteroids, and antihistamines 
have been employed to alleviate symptoms.


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Carboplatin Description
Carboplatin for Injection USP is supplied as a sterile, lyophilized white powder available 
in single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin for 
administration by intravenous infusion. Each vial contains equal parts by weight 
carboplatin and mannitol.
Carboplatin is a platinum coordination compound that is used as a cancer 
chemotherapeutic agent. The chemical name for carboplatin is platinum, diammine 
[1,1-cyclobutane-dicarboxylato(2-)-0,0’]-, (SP-4-2).
Carboplatin is a crystalline powder with the molecular formula of C6H12N2O4Pt and a 
molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, 
and the pH of a 1% solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and 
dimethylacetamide.
Carboplatin - Clinical Pharmacology
Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather 
than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The 
aquation of carboplatin, which is thought to produce the active species, occurs at a slower 
rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin 
and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions 
and biological effects. The differences in potencies for carboplatin and cisplatin appear to 
be directly related to the difference in aquation rates.
In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of 
intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 
300 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 
to 2 hours (N=6), and the post-distribution plasma half-life (beta) was found to be 2.6 to 
5.9 hours (N=6). The total body clearance, apparent volume of distribution and mean 
residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax 
values and areas under the plasma concentration vs time curves from 0 to infinity (AUC 
inf) increase linearly with dose, although the increase was slightly more than dose 
proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing 
range studied (300 to 500 mg/m2 ).
Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, 
ultrafilterable platinum-containing species other than carboplatin are present in plasma. 
However, platinum from carboplatin becomes irreversibly bound to plasma proteins and 
is slowly eliminated with a minimum half-life of 5 days.
The major route of elimination of carboplatin is renal excretion. Patients with creatinine 
clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine 
within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour 
urine is present as carboplatin. Only 3 to 5% of the administered platinum is excreted in 
the urine between 24 and 96 hours. There are insufficient data to determine whether 
biliary excretion occurs.


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In patients with creatinine clearances below 60 mL/min the total body and renal 
clearances carboplatin decrease as the creatinine clearance decreases. Carboplatin 
dosages should therefore be reduced in these patients.
The primary determinant of carboplatin clearance is glomerular filtration rate (GFR) and 
this parameter of renal function is often decreased in elderly patients. Dosing formulas 
incorporating estimates of GFR to provide predictable carboplatin plasma AUCs should 
be used in elderly patients to minimize the risk of toxicity.
Contraindications
Carboplatin is contraindicated in patients with a history of severe allergic reactions to 
cisplatin or other platinum-containing compounds.
Carboplatin should not be employed in patients with severe bone marrow depression or 
significant bleeding.
Warnings
Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is 
dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be 
frequently monitored during carboplatin treatment and, when appropriate, until recovery 
is achieved. Median nadir occurs at day 21 in patients receiving single-agent carboplatin. 
In general, single intermittent courses of carboplatin should not be repeated until 
leukocyte, neutrophil, and platelet counts have recovered.
Since anemia is cumulative, transfusions may be needed during treatment with 
carboplatin, particularly in patients receiving prolonged therapy.
Bone marrow suppression is increased in patients who have received prior therapy, 
especially regimens including cisplatin. Marrow suppression is also increased in patients 
with impaired kidney function. Initial carboplatin dosages in these patients should be 
appropriately reduced and blood counts should be carefully monitored between courses. 
The use of carboplatin in combination with other bone marrow suppressing therapies 
must be carefully managed with respect to dosage and timing in order to minimize 
additive effects.
Carboplatin has limited nephrotoxic potential, but concomitant treatment with 
aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution 
must be exercised when a patient receives both drugs. Clinically significant hearing loss 
has been reported to occur in pediatric patients when carboplatin was administered at 
higher than recommended doses in combination with other ototoxic agents.
Carboplatin can induce emesis, which can be more severe in patients previously 
receiving emetogenic therapy. The incidence and intensity of emesis have been reduced 
by using premedication with antiemetics. Although no conclusive efficacy data exist with 
the following schedules of carboplatin, lengthening the duration of single intravenous 
administration to 24 hours or dividing the total dose over five consecutive daily pulse 
doses has resulted in reduced emesis.


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Although peripheral neurotoxicity is infrequent, its incidence is increased in patients 
older than 65 years and in patients previously treated with cisplatin. Pre-existing 
cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving 
carboplatin as secondary treatment.
Loss of vision, which can be complete for light and colors, has been reported after the use 
of carboplatin with doses higher than those recommended in the package insert. Vision 
appears to recover totally or to a significant extent within weeks of stopping these high 
doses.
As in the case of other platinum coordination compounds, allergic reactions to 
carboplatin have been reported. These may occur within minutes of administration and 
should be managed with appropriate supportive therapy. There is increased risk of 
allergic reactions including anaphylaxis in patients previously exposed to platinum 
therapy. 
High dosages of carboplatin (more than four times the recommended dose) have resulted 
in severe abnormalities of liver function tests.
Carboplatin may cause fetal harm when administered to a pregnant woman. Carboplatin 
has been shown to be embryotoxic and teratogenic in rats. There are no adequate and 
well-controlled studies in pregnant women. If this drug is used during pregnancy, or if 
the patient becomes pregnant while receiving this drug, the patient should be apprised of 
the potential hazard to the fetus. Women of childbearing potential should be advised to 
avoid becoming pregnant.
PRECAUTIONS 
General
Needles or intravenous administration sets containing aluminum parts that may come in 
contact with carboplatin should not be used for the preparation or administration of the 
drug. Aluminum can react with carboplatin causing precipitate formation and loss of 
potency.
Drug Interactions 
The renal effects of nephrotoxic compounds may be potentiated by carboplatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility 
The carcinogenic potential of carboplatin has not been studied, but compounds with 
similar mechanisms of action and mutagenicity profiles have been reported to be 
carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It 
has also been shown to be embryotoxic and teratogenic in rats receiving the drug during 
organogenesis. Secondary malignancies have been reported in association with 
multi-drug therapy.


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Pregnancy
Teratogenic Effects; Pregnancy Category D.
Nursing Mothers
It is not known whether carboplatin is excreted in human milk. Because there is a 
possibility of toxicity in nursing infants secondary to carboplatin treatment of the mother, 
it is recommended that breast feeding be discontinued if the mother is treated with 
carboplatin.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 
395 patients were treated with carboplatin in combination with cyclophosphamide. Of 
these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age 
was not a prognostic factor for survival. In terms of safety, elderly patients treated with 
carboplatin were more likely to develop severe thrombocytopenia than younger patients. 
In a combined database of 1942 patients (414 were ꞏ65 years of age) that received single 
agent carboplatin for different tumor types, a similar incidence of adverse events as seen 
in patients 65 years and older and in patients less than 65. Other reported clinical 
experience has not identified differences in responses between elderly and younger 
patients, but greater sensitivity of some older individuals cannot be ruled out. Because 
renal function is often decreased in the elderly, renal function should be considered in the 
selection of carboplatin dosage.
Adverse Reactions
Hematologic Toxicity
Bone marrow suppression is the dose-limiting toxicity of carboplatin. Thrombocytopenia 
with platelet counts below 50,000/mm3 occurs in 25% of the patients (35% of pretreated 
ovarian cancer patients); neutropenia with granulocyte counts below 1000/mm3 occurs in 
16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC 
counts below 2000/mm3 occurs in 15% of the patients (26% of pretreated ovarian cancer 
patients). The nadir usually occurs about day 21 in patients receiving single-agent 
therapy. By day 28, 90% of patients have platelet counts above 100,000/mm3; 74% have 
neutrophil counts above 2000/mm3; 67% have leukocyte counts above 4000/mm3.
Marrow suppression is usually more severe in patients with impaired kidney function. 
Patients with poor performance status have also experienced a higher incidence of severe 
leukopenia and thrombocytopenia.
The hematologic effects, although usually reversible, have resulted in infectious or 
hemorrhagic complications in 5% of the patients treated with carboplatin, with drug 
related death occurring in less than 1% of the patients. Fever has also been reported in 
patients with neutropenia.


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Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who 
started therapy with a baseline above that value. The incidence of anemia increases with 
increasing exposure to carboplatin. Transfusions have been administered to 26% of the 
patients treated with carboplatin (44% of previously treated ovarian cancer patients).
Bone marrow depression may be more severe when carboplatin is combined with other 
bone marrow suppressing drugs or with radiotherapy.
Gastrointestinal Toxicity
Vomiting occurs in 65% of the patients (81% of previously treated ovarian cancer 
patients) and in about one-third of these patients it is severe. Carboplatin, as a single 
agent or in combination, is significantly less emetogenic than cisplatin; however, patients 
previously treated with emetogenic agents, especially cisplatin, appear to be more prone 
to vomiting. Nausea alone occurs in an additional 10 to 15% of patients. 
Both nausea and vomiting usually cease within 24 hours of treatment and are often 
responsive to antiemetic measures. Although no conclusive efficacy data exist with the 
following schedules, prolonged administration of carboplatin, either by continuous 
24-hour infusion or by daily pulse doses given for five consecutive days, was associated 
with less severe vomiting than the single dose intermittent schedule. 
Emesis was increased when carboplatin was used in combination with other emetogenic 
compounds. Other gastrointestinal effects observed frequently were pain, in 17% of the 
patients; diarrhea, in 6%; and constipation, also in 6%.
Neurologic Toxicity
Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin 
(6% of pretreated ovarian cancer patients) with mild paresthesias occurring most 
frequently. Carboplatin therapy produces significantly fewer and less severe neurologic 
side effects than does therapy with cisplatin. However, patients older than 65 years 
and/or previously treated with cisplatin appear to have an increased risk (10%) for 
peripheral neuropathies. In 70% of the patients with pre-existing cisplatin-induced 
peripheral neurotoxicity, there was no worsening of symptoms during therapy with 
carboplatin. Clinical ototoxicity and other sensory abnormalities such as visual 
disturbances and change in taste have been reported in only 1% of the patients. Central 
nervous system symptoms have been reported in 5% of the patients and appear to be most 
often related to the use of antiemetics.
Although the overall incidence of peripheral neurologic side effects induced by 
carboplatin is low, prolonged treatment, particularly in cisplatin pretreated patients, may 
result in cumulative neurotoxicity.
Nephrotoxicity
Development of abnormal renal function test results is uncommon, despite the fact that 
carboplatin, unlike cisplatin, has usually been administered without high-volume fluid 


2008-0378
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hydration and/or forced diuresis. The incidences of abnormal renal function tests reported 
are 6% for serum creatinine and 14% for blood urea nitrogen (10% and 22%, 
respectively, in pretreated ovarian cancer patients). Most of these reported abnormalities 
have been mild and about one-half of them were reversible.
Creatinine clearance has proven to be the most sensitive measure of kidney function in 
patients receiving carboplatin, and it appears to be the most useful test for correlating 
drug clearance and bone marrow suppression. Twenty-seven percent of the patients who 
had a baseline value of 60 mL/min or more demonstrated a reduction below this value 
during carboplatin therapy.
Hepatic Toxicity
The incidences of abnormal liver function tests in patients with normal baseline values 
were reported as follows: total bilirubin, 5%; SGOT, 15%; and alkaline phosphatase, 
24%; (5%,19%, and 37%, respectively, in pretreated ovarian cancer patients). These 
abnormalities have generally been mild and reversible in about one-half of the cases, 
although the role of metastatic tumor in the liver may complicate the assessment in many 
patients. In a limited series of patients receiving very high dosages of carboplatin and 
autologous bone marrow transplantation, severe abnormalities of liver function tests were 
reported.
Electrolyte Changes
The incidences of abnormally decreased serum electrolyte values reported were as 
follows: sodium, 29%; potassium, 20%; calcium, 22%; and magnesium, 29%; (47%, 
28%, 31%, and 43%, respectively, in pretreated ovarian cancer patients). Electrolyte 
supplementation was not routinely administered concomitantly with carboplatin, and 
these electrolyte abnormalities were rarely associated with symptoms.
Allergic Reactions
Hypersensitivity to carboplatin has been reported in 2% of the patients. These allergic 
reactions have been similar in nature and severity to those reported with other 
platinum-containing compounds, i.e., rash, urticaria, erythema, pruritus, and rarely 
bronchospasm and hypotension. Anaphylactic reactions have been reported as part of 
postmarketing surveillance. These reactions have been successfully managed with 
standard epinephrine, corticosteroid, and antihistamine therapy.
Injection Site Reactions
Injection site reactions, including redness, swelling, and pain, have been reported during 
postmarketing surveillance. Necrosis associated with extravasation has also been 
reported. 
Other Events
Pain and asthenia were the most frequently reported miscellaneous adverse effects; their 
relationship to the tumor and to anemia waslikely. Alopecia was reported (3%). 
Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in 6% 
or less of the patients. Cardiovascular events (cardiac failure, embolism, cerebrovascular 


2008-0378
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accidents) were fatal in less than 1% of the patients and did not appear to be related to 
chemotherapy. Cancer-associated hemolytic uremic syndrome has been reported rarely.
Malaise, anorexia and hypertension have been reported as part of postmarketing 
surveillance.
Overdosage
There is no known antidote for carboplatin overdosage. The anticipated complications of 
overdosage would be secondary to bone marrow suppression and/or hepatic toxicity.
Formula Dosing
Another approach for determining the initial dose of carboplatin for injection is the use of 
mathematical formulae, which are based on a patient's pre-existing renal function or renal 
function and desired platelet nadir. Renal excretion is the major route of elimination for 
carboplatin for injection. The use of dosing formulae, as compared to empirical dose 
calculation based on body surface area, allows compensation for patient variations in 
pretreatment renal function that might otherwise result in either underdosing (in patients 
with above average renal function) or overdosing (in patients with impaired renal 
function).
A simple formula for calculating dosage, based upon a patients glomerular filtration rate 
(GFR in mL/min) and carboplatin for injection target area under the concentration versus 
time curve (AUC in mg/mL•min), has been proposed by Calvert. In these studies, GFR 
was measured by 51Cr-EDTA clearance.
  
CALVERT FORMULA FOR CARBOPLATIN DOSING
Total Dose (mg) = (target AUC) x (GFR + 25) 
Note: With the Calvert formula, the total dose of carboplatin injection is calculated in 
mg, not mg/m2.
The target AUC of 4 to 6 mg/mL•min using single agent carboplatin for injection appears 
to provide the most appropriate dose range in previously treated patients. This study also 
showed a trend between the AUC of single agent carboplatin for injection administered 
to previously treated patients and the likelihood of developing toxicity. 
Geriatric Dosing
Because renal function is often decreased in elderly patients, formula dosing of 
carboplatin based on estimates of GFR should be used in elderly patients to provide 
predictable plasma carboplatin AUCs and thereby minimize the risk of toxicity. 
PREPARATION OF INTRAVENOUS SOLUTIONS
Immediately before use, the content of each vial must be reconstituted with either Sterile 
Water for Injection, 5% Dextrose in Water (D5W), or 0.9% Sodium Chloride Injection, 
to a carboplatin concentration of 10 mg/mL.
Carboplatin for injection can be further diluted to concentrations as low as 0.5 mg/mL 
with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection.
STABILITY


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Unopened vials of carboplatin for injection are stable for the life indicated on the package 
when stored at 20° to 25°C (68° to 77°F). See USP controlled room temperature and 
protect from light.
When prepared as directed, carboplatin solutions are stable for 8 hours at room 
temperature 25°C (77°F). Since no antibacterial preservative is contained in the 
formulation, it is recommended that carboplatin solutions be discarded 8 hours after 
dilution.
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit.
STORAGE
Store the unopened vials at 20° to 25°C (68° to 77°F). See USP controlled room 
temperature. Protect unopened vials from light. Solutions for infusion should be 
discarded 8 hours after preparation.
11.4. 
Docetaxel
WARNING
Docetaxel Injection Concentrate should be administered under the supervision of a 
qualified physician experienced in the use of antineoplastic agents. Appropriate 
management of complications is possible only when adequate diagnostic and treatment 
facilities are readily available.
The incidence of treatment-related mortality associated with Docetaxel therapy is 
increased in patients with abnormal liver function, in patients receiving higher doses, and 
in patients with non-small cell lung carcinoma and a history of prior treatment with 
platinum-based chemotherapy who receive Docetaxel as a single agent at a dose of 100 
mg/m2 .
Docetaxel should generally not be given to patients with bilirubin > upper limit of normal 
(ULN), or to patients with SGOT and/or SGPT >1.5 x ULN concomitant with alkaline 
phosphatase > 2.5 x ULN. Patients with elevations of bilirubin or abnormalities of 
transaminase concurrent with alkaline phosphatase are at increased risk for the 
development of grade 4 neutropenia, febrile neutropenia, infections, severe 
thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with 
isolated elevations of transaminase > 1.5 x ULN also had a higher rate of febrile 
neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, 
SGOT or SGPT, and alkaline phosphatase values should be obtained prior to each cycle 
of Docetaxel therapy and reviewed by the treating physician.
Docetaxel therapy should not be given to patients with neutrophil counts of < 1500 
cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and 
result in infection, frequent blood cell counts should be performed on all patients 
receiving Docetaxel .


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Severe hypersensitivity reactions characterized by generalized rash/erythema, 
hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in 
patients who received the recommended 3-day dexamethasone premedication. 
Hypersensitivity reactions require immediate discontinuation of the Docetaxel infusion 
and administration of appropriate therapy. Docetaxel must not be given to patients who 
have a history of severe hypersensitivity reactions to Docetaxel or to other drugs 
formulated with polysorbate 80. 
Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day 
dexamethasone premedication regimen. It was characterized by one or more of the 
following events: poorly tolerated peripheral edema, generalized edema, pleural effusion 
requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal 
distention (due to ascites).
DESCRIPTION
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of 
yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-
tert-butyl ester, 13-ester with 5ß-20-epoxy-1,2 ,4,7ß,10ß,13
-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel has the 
following structural formula: 
Docetaxel is a white to almost-white powder with an empirical formula of 
C43H53NO14• 3H2O, and a molecular weight of 861.9. It is highly lipophilic and 
practically insoluble in water. Docetaxel Injection Concentrate is a clear yellow to 
brownish-yellow viscous solution. Docetaxel is sterile, non-pyrogenic, and is available in 
single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) docetaxel (anhydrous). 
Each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80.
Docetaxel Injection Concentrate requires dilution prior to use. A sterile, non-pyrogenic, 
single-dose diluent is supplied for that purpose. The diluent for Docetaxel contains 13% 
ethanol in water for injection, and is supplied in vials.
CLINICAL PHARMACOLOGY
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in 
cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free 
tubulin and promotes the assembly of tubulin into stable microtubules while 
simultaneously inhibiting their disassembly. This leads to the production of microtubule 
bundles without normal function and to the stabilization of microtubules, which results in 
the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the 
number of protofilaments in the bound microtubules, a feature which differs from most 
spindle poisons currently in clinical use.


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HUMAN PHARMACOKINETICS
The pharmacokinetics of docetaxel have been evaluated in cancer patients after 
administration of 20-115 mg/m2 in phase I studies. The area under the curve (AUC) was 
dose proportional following doses of 70-115 mg/m2 with infusion times of 1 to 2 hours. 
Docetaxel's pharmacokinetic profile is consistent with a three-compartment 
pharmacokinetic model, with half-lives for the , ß, and phases of 4 min, 36 min, and 
11.1 hr, respectively. The initial rapid decline represents distribution to the peripheral 
compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of 
docetaxel from the peripheral compartment. Mean values for total body clearance and 
steady state volume of distribution were 21 L/h/m2 and 113 L, respectively. Mean total 
body clearance for Japanese patients dosed at the range of 10-90 mg/m2 was similar to 
that of European/American populations dosed at 100 mg/m2, suggesting no significant 
difference in the elimination of docetaxel in the two populations.
A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was 
eliminated in both the urine and feces following oxidative metabolism of the tert-butyl 
ester group, but fecal excretion was the main elimination route. Within 7 days, urinary 
and fecal excretion accounted for approximately 6% and 75% of the administered 
radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted 
during the first 48 hours as 1 major and 3 minor metabolites with very small amounts 
(less than 8%) of unchanged drug.
A population pharmacokinetic analysis was carried out after Docetaxel treatment of 535 
patients dosed at 100 mg/m2. Pharmacokinetic parameters estimated by this analysis 
were very close to those estimated from phase I studies. The pharmacokinetics of 
docetaxel were not influenced by age or gender and docetaxel total body clearance was 
not modified by pretreatment with dexamethasone. In patients with clinical chemistry 
data suggestive of mild to moderate liver function impairment (SGOT and/or SGPT >1.5 
times the upper limit of normal [ULN] concomitant with alkaline phosphatase >2.5 times 
ULN), total body clearance was lowered by an average of 27%, resulting in a 38% 
increase in systemic exposure (AUC). This average, however, includes a substantial 
range and there is, at present, no measurement that would allow recommendation for dose 
adjustment in such patients. Patients with combined abnormalities of transaminase and 
alkaline phosphatase should, in general, not be treated with Docetaxel .
Clearance of docetaxel in combination therapy with cisplatin was similar to that 
previously observed following monotherapy with docetaxel. The pharmacokinetic profile 
of cisplatin in combination therapy with docetaxel was similar to that observed with 
cisplatin alone.
The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with 
solid tumors had no influence on the pharmacokinetics of each individual drug.
A population pharmacokinetic analysis of plasma data from 40 patients with 


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hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance 
in combination with prednisone is similar to that observed following administration of 
docetaxel alone.
A study was conducted in 30 patients with advanced breast cancer to determine the 
potential for drug-drug-interactions between docetaxel (75 mg/m2), doxorubicin (50 
mg/m2), and cyclophosphamide (500 mg/m2) when administered in combination. The 
coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and 
cyclophosphamide when the three drugs were given in combination compared to 
coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin 
and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs 
were given in combination compared to historical data for docetaxel monotherapy. 
In vitro studies showed that docetaxel is about 94% protein bound, mainly to 1-acid 
glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to 
plasma proteins was found to be approximately 97%. Dexamethasone does not affect the 
protein binding of docetaxel.
In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 
isoenzyme, and its metabolism can be inhibited by CYP3A4 inhibitors, such as 
ketoconazole, erythromycin, troleandomycin, and nifedipine. Based on in vitro findings, 
it is likely that CYP3A4 inhibitors and/or substrates may lead to substantial increases in 
docetaxel blood concentrations. No clinical studies have been performed to evaluate this.
CONTRAINDICATIONS
Docetaxel is contraindicated in patients who have a history of severe hypersensitivity 
reactions to docetaxel or to other drugs formulated with polysorbate 80.
Docetaxel should not be used in patients with neutrophil counts of <1500 cells/mm3.
WARNINGS
Docetaxel should be administered under the supervision of a qualified physician 
experienced in the use of antineoplastic agents. Appropriate management of 
complications is possible only when adequate diagnostic and treatment facilities are 
readily available.
Premedication Regimen
All patients should be premedicated with oral corticosteroids (see below for prostate 
cancer) such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day 
prior to Docetaxel to reduce the severity of fluid retention and hypersensitivity reactions. 
This regimen was evaluated in 92 patients with metastatic breast cancer previously 
treated with chemotherapy given Docetaxel at a dose of 100 mg/m2 every 3 weeks.
The pretreatment regimen for hormone-refractory metastatic prostate cancer is oral 
dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Docetaxel infusion.


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Hypersensitivity Reactions
Patients should be observed closely for hypersensitivity reactions, especially during the 
first and second infusions. Severe hypersensitivity reactions characterized by generalized 
rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have 
been reported in patients premedicated with 3 days of corticosteroids. Hypersensitivity 
reactions require immediate discontinuation of the Docetaxel infusion. Patients with a 
history of severe hypersensitivity reactions should not be rechallenged with Docetaxel .
Hematologic Effects
Neutropenia (< 2000 neutrophils/mm3) occurs in virtually all patients given 60-100 
mg/m2 of Docetaxel and grade 4 neutropenia (< 500 cells/mm3) occurs in 85% of 
patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of 
blood counts is, therefore, essential so that dose can be adjusted. Docetaxel should not be 
administered to patients with neutrophils < 1500 cells/mm3.
Hepatic Impairment
Docetaxel should generally not be given to patients with bilirubin > upper limit of normal 
(ULN), or to patients with SGOT and/or SGPT >1.5 x ULN concomitant with alkaline 
phosphatase > 2.5 x ULN. Patients with elevations of bilirubin or abnormalities of 
transaminase concurrent with alkaline phosphatase are at increased risk for the 
development of grade 4 neutropenia, febrile neutropenia, infections, severe 
thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with 
isolated elevations of transaminase > 1.5 x ULN also had a higher rate of febrile 
neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, 
SGOT or SGPT, and alkaline phosphatase values should be obtained prior to each cycle 
of Docetaxel therapy and reviewed by the treating physician.
Fluid Retention
Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day 
dexamethasone premedication regimen. It was characterized by one or more of the 
following events: poorly tolerated peripheral edema, generalized edema, pleural effusion 
requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal 
distention (due to ascites).
Acute Myeloid Leukemia
Treatment-related acute myeloid leukemia (AML) has occurred in patients given 
anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast 
cancer. AML occurred in 3 of 744 patients who received Docetaxel , doxorubicin and 
cyclophosphamide and in 1 of 736 patients who received fluorouracil, doxorubicin and 
cyclophosphamide
Pregnancy
Docetaxel can cause fetal harm when administered to pregnant women. Studies in both 
rats and rabbits at doses > 0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the 
daily maximum recommended human dose on a mg/m2 basis), administered during the 
period of organogenesis, have shown that Docetaxel is embryotoxic and fetotoxic 


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(characterized by intrauterine mortality, increased resorption, reduced fetal weight, and 
fetal ossification delay). The doses indicated above also caused maternal toxicity.
There are no adequate and well-controlled studies in pregnant women using Docetaxel . 
If Docetaxel is used during pregnancy, or if the patient becomes pregnant while receiving 
this drug, the patient should be apprised of the potential hazard to the fetus or potential 
risk for loss of the pregnancy. Women of childbearing potential should be advised to 
avoid becoming pregnant during therapy with Docetaxel .
PRECAUTIONS
General
Responding patients may not experience an improvement in performance status on 
therapy and may experience worsening. The relationship between changes in 
performance status, response to therapy, and treatment-related side effects has not been 
established. 
Hematologic Effects
In order to monitor the occurrence of myelotoxicity, it is recommended that frequent 
peripheral blood cell counts be performed on all patients receiving Docetaxel . Patients 
should not be retreated with subsequent cycles of Docetaxel until neutrophils recover to a 
level > 1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3.
A 25% reduction in the dose of Docetaxel is recommended during subsequent cycles 
following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile 
neutropenia, or a grade 4 infection in a Docetaxel cycle.
Hypersensitivity Reactions
Hypersensitivity reactions may occur within a few minutes following initiation of a 
Docetaxel infusion. If minor reactions such as flushing or localized skin reactions occur, 
interruption of therapy is not required. More severe reactions, however, require the 
immediate discontinuation of Docetaxel and aggressive therapy. All patients should be 
premedicated with an oral corticosteroid prior to the initiation of the infusion of 
Docetaxel .
Cutaneous
Localized erythema of the extremities with edema followed by desquamation has been 
observed. In case of severe skin toxicity, an adjustment in dosage is recommended. The 
discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer 
patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there 
were no cases of severe skin toxicity reported and no patient discontinued Docetaxel due 
to skin toxicity.
Fluid Retention
Severe fluid retention has been reported following Docetaxel therapy. Patients should be 
premedicated with oral corticosteroids prior to each TAXOTERE administration to 


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reduce the incidence and severity of fluid retention. Patients with pre-existing effusions 
should be closely monitored from the first dose for the possible exacerbation of the 
effusions.
When fluid retention occurs, peripheral edema usually starts in the lower extremities and 
may become generalized with a median weight gain of 2 kg.
Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid 
retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative 
dose to onset of moderate or severe fluid retention was 819 mg/m2. 9.8% (9/92) of 
patients discontinued treatment due to fluid retention: 4 patients discontinued with severe 
fluid retention; the remaining 5 had mild or moderate fluid retention. The median 
cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2. 
Fluid retention was completely, but sometimes slowly, reversible with a median of 16 
weeks from the last infusion of Docetaxel to resolution (range: 0 to 42+ weeks). Patients 
developing peripheral edema may be treated with standard measures, e.g., salt restriction, 
oral diuretic(s).
Neurologic
Severe neurosensory symptoms (paresthesia, dysesthesia, pain) were observed in 5.5% 
(53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 
6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, 
treatment should be discontinued Patients who experienced neurotoxicity in clinical trials 
and for whom follow-up information on the complete resolution of the event was 
available had spontaneous reversal of symptoms with a median of 9 weeks from onset 
(range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal 
extremity weakness occurred in 4.4% (42/965).
Asthenia
Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients 
but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness 
may last a few days up to several weeks and may be associated with deterioration of 
performance status in patients with progressive disease.
Drug Interactions
There have been no formal clinical studies to evaluate the drug interactions of Docetaxel 
with other medications. In vitro studies have shown that the metabolism of docetaxel may 
be modified by the concomitant administration of compounds that induce, inhibit, or are 
metabolized by cytochrome P450 3A4, such as cyclosporine, terfenadine, ketoconazole, 
erythromycin, and troleandomycin. Caution should be exercised with these drugs when 
treating patients receiving Docetaxel as there is a potential for a significant interaction.
Carcinogenicity, Mutagenicity, Impairment of Fertility
No studies have been conducted to assess the carcinogenic potential of Docetaxel . 
Docetaxel has been shown to be clastogenic in the in vitro chromosome aberration test in 
CHO-K1 cells and in the in vivo micronucleus test in the mouse, but it did not induce 
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assays. Docetaxel 


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produced no impairment of fertility in rats when administered in multiple IV doses of up 
to 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m2 basis), but decreased 
testicular weights were reported. This correlates with findings of a 10-cycle toxicity 
study (dosing once every 21 days for 6 months) in rats and dogs in which testicular 
atrophy or degeneration was observed at IV doses of 5 mg/kg in rats and 0.375 mg/kg in 
dogs (about 1/3 and 1/15 the recommended human dose on a mg/m2 basis, respectively). 
An increased frequency of dosing in rats produced similar effects at lower dose levels.
Pregnancy
Pregnancy Category D. 
Nursing Mothers
It is not known whether Docetaxel is excreted in human milk. Because many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in 
nursing infants from Docetaxel , mothers should discontinue nursing prior to taking the 
drug.
Pediatric Use
The safety and effectiveness of Docetaxel in pediatric patients have not been established.
Geriatric Use
In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 
patients (36%) in the Docetaxel +cisplatin group were 65 years of age or greater. There 
were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In 
the Docetaxel +cisplatin group, patients less than 65 years of age had a median survival 
of 10.3 months (95% CI : 9.1 months, 11.8 months) and patients 65 years or older had a 
median survival of 12.1 months (95% CI : 9.3 months, 14 months). In patients 65 years 
of age or greater treated with Docetaxel +cisplatin, diarrhea (55%), peripheral edema 
(39%) and stomatitis (28%) were observed more frequently than in the 
vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). 
Patients treated with Docetaxel +cisplatin who were 65 years of age or greater were more 
likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and 
stomatitis (28%) compared to patients less than the age of 65 administered the same 
treatment (43%, 31%, 31% and 21%, respectively).
When Docetaxel was combined with carboplatin for the treatment of 
chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or 
greater (28%) experienced higher frequency of infection compared to similar patients 
treated with Docetaxel +cisplatin, and a higher frequency of diarrhea, infection and 
peripheral edema than elderly patients treated with vinorelbine+cisplatin.
Of the 333 patients treated with Docetaxel every three weeks plus prednisone in the 
prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 
patients were older than 75 years. In patients treated with Docetaxel every three weeks, 
the following TEAEs occurred at rates > 10% higher in patients 65 years of age or greater 
compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail 
changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.


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In the adjuvant breast cancer trial (TAX316), Docetaxel in combination with doxorubicin 
and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years 
of age or greater. The number of elderly patients who received this regimen was not 
sufficient to determine whether there were differences in safety and efficacy between 
elderly and younger patients.
Among the 221 patients treated with Docetaxel in combination with cisplatin and 
fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients 
were older than 75 years. In this study, the number of patients who were 65 years of age 
or older was insufficient to determine whether they respond differently from younger 
patients. However, the incidence of serious adverse events was higher in the elderly 
patients compared to younger patients. The incidence of the following adverse events (all 
grades): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic 
infection occurred at rates > 10% higher in patients who were 65 years of age or older 
compared to younger patients. Elderly patients treated with TCF should be closely 
monitored.
Of the 174 patients who received the induction treatment with Docetaxel in combination 
with cisplatin and fluorouracil for SCCHN (TAX323), 18 (10%) patients were 65 years 
of age or older.
The clinical study of Docetaxel in combination with cisplatin and fluorouracil in patients 
with SCCHN (TAX323) did not include sufficient numbers of patients aged 65 and over 
to determine whether they respond differently from younger patients. Other reported 
clinical experience with this treatment regimen has in responses between elderly and 
younger patients.
11.5. 
ETOPOSIDE
DESCRIPTION: Etoposide (VP-16) is a semisynthetic podophyllotoxin derivative with 
antineoplastic activity.
PHARMACEUTICAL DATA: VP-16 is supplied as 100 mg/5cc ampules. 
SOLUTION PREPARATION: The contents of the ampule are diluted with 50 volumes 
of NaCl solution for injection, USP.
ROUTE OF ADMINISTRATION: Oral or slow IV infusion
KNOWN SIDE-EFFECTS: Myelosuppression, primarily granulocytopenia is the 
dose-limiting toxicity. Other side effects include gastrointestinal toxicity comprising of 
nausea, emesis and mucositis. At high doses reversible hepatotoxicity is seen. Acute side 
effects include occasional bronchospasm and hypotension. These can be avoided by slow 
intravenous administration.
PHARMACOKINETICS: The main site of metabolism is in the liver. Major metabolites 
of etoposide are hydroxy acids and cistactone which appear in the plasma and urine. The 


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half-life of the drug is 4 to 11 hours. 
MECHANISM OF ACTION: Two different dose dependent responses are seen. At high 
concentrations (10 ug/ml) lysis of cells entering mitosis is seen. At low concentrations 
(0.3 to 10 ug/ml) cells are inhibited from entering prophase. The predominant 
macromolecular affect of etoposide appears to be the induction of DNA strand breaks by 
an interaction with DNA topoisomerase II or by the formation of free radicals.
11.6.
IFOSFAMIDE
DESCRIPTION: Ifosfamide is a chemotherapeutic agent chemically related to nitrogen 
mustards and a synthetic analogue of cyclophosphamide.
PHARMACEUTICAL DATA: Ifosfamide is available in vials of 1g or 3g. 
SOLUTION PREPARATION: It is reconstituted with sterile water for an approximate 
concentration of 50 mg/ml. Intact vials should be stored at room temperature (22 to 25 
degrees Centigrade) or below. Ifosfamide will liquefy at temperatures above 35 degrees 
Centigrade. Intact vials have an expiration date of 5 years from the date of manufacture. 
Reconstitution as recommended results in a solution that is chemically stable for 7 days 
when stored at room temperature and for 6 weeks when refrigerated (2 to 8 degrees 
Centigrade). Further dilution of the reconstituted solution to concentrations of 16 mg/ml 
and 0.6 mg/ml in compatible infusion solutions results in a 1 to 5% degradation in 7 days 
at room temperature and no degradation in 6 weeks under refrigeration. In 6 weeks at 
room temperature, decomposition generally ranges from 12 to 18%.
ROUTE OF ADMINISTRATION: IV infusion
EXPECTED ADVERSE EVENTS: Myelosuppression
UNEXPECTED ADVERSE EVENTS: Nephrotoxicity and urotoxicity. The incidence of 
urotoxicity can be reduced significantly by the use of Mesna, hydration and fractionation 
of the dose. Central nervous system toxicity like somnolence, confusion, hallucinations 
and coma is also seen and may require cessation of therapy.
PHARMACOKINETICS: Pharmacokinetics of Ifosfamide are dose-dependent. Single 
doses of 3.8-5 g/m
2 exhibit a biphasic elimination with a half-life of 15 hours; doses of 
1.6 to 2.4 g/m2/day are eliminated monoexponentially with a terminal half-life of 
approximately 7 hours. Ifosfamide is extensively metabolized. The percent of metabolites 
and parent drug renally excreted is dose-dependent. 
11.7. 
MESNA
Mesna is used to reduce the incidence of ifosfamide-induced hemorrhagic cystitis. Mesna 
disulfide is reduced to the free thiol compound, mesna, which reacts chemically with the 
urotoxic ifosfamide metabolites, resulting in their detoxification.


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Pharmacokinetics
Absorption
Urinary bioavailability of oral mesna is 45% to 79%.
Distribution
Protein binding is 69% to 75%; Vd is 0.652 L/kg.
Metabolism
The major metabolite is dimesna.
Elimination
Approximately 32% is excreted in urine within 24 h. The t ½ is 1.2 to 8.3 h (after IV plus 
oral dose); the plasma Cl is 1.23 L/kg/h. The mesna disulfide is reduced to the free thiol 
compound that reacts chemically with the urotoxic ifosfamide metabolites, resulting in 
their detoxification. At doses of 2 to 4 g, the terminal elimination t ½ is approximately 4 to 
8 h. It is rapidly eliminated by the kidneys.
Indications and Usage
Prevention of ifosfamide-induced hemorrhagic cystitis.
Unlabeled Uses
Prevention of cyclophosphamide-induced hemorrhagic cystitis.
Contraindications
Standard considerations.
Dosage and Administration
Adults 
IV Mesna dose is given as bolus injections in a dosage equal to 20% of ifosfamide dose 
at time of administration, 4 h after, and 8 h after each ifosfamide dose (eg, for ifosfamide 
1,200 mg/m 
2 , give mesna 240 mg/m 
2 at 0, 4, and 8 h after each ifosfamide dose). The 
total daily dose of mesna is 60% of the ifosfamide dose. Repeat this dosing schedule on 
each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted, 
modify the dose of mesna accordingly.
Adults 
PO Following the initial IV mesna dose (20% of ifosfamide dose), the oral mesna dose is 
40% of ifosfamide dose 2 and 6 h after each ifosfamide dose.
General Advice
Repeat the oral dose or administer IV bolus dose if patient vomits within 2 h of 
administration. 
For IV bolus administration only. Not for intradermal, subcutaneous, IM, or intra-arterial 
administration. 


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Dilute IV concentrate to final concentration of 20 mg/mL with a compatible IV fluid 
following manufacturer's recommendations. 
Do not administer injection if cloudiness or particulate matter is noted. 
Storage/Stability
Store tablets at controlled room temperature (68° to 77°F). Store vials at controlled room 
temperature (68° to 77°F). Multidose vial can be used for up to 8 days following initial 
opening. Diluted solutions are stable for up to 24 h if stored at temperature less than 
77°F. Discard any unused solution after 24 h.
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