Clinical trial NCT00254410
Conditions: Chronic Lymphocytic Leukemia
Keywords: Chronic Lymphocytic Leukemia Untreated Fludarabine Fludara Cyclophosphamide Cytoxan Mitoxantrone Novantrone Rituximab Rituxan Pegylated Filgrastim Neupogen
Sponsor: M.D. Anderson Cancer Center
Start date: 2005-03-14; Completion date: 2017-09-14
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if using a combination of fludarabine, cyclophosphamide, and mitoxantrone plus rituximab, with the growth factor pegylated filgrastim, will improve the response to treatment, and increase the time this response lasts, for patients with previously untreated CLL. The safety of this combination will also be studied.

Detailed description:
Fludarabine, cyclophosphamide, and mitoxantrone are chemotherapy drugs that are used in the treatment of CLL. Rituximab is a monoclonal antibody that binds to CLL cells and causes cell death. Pegfilgrastim (Neulasta) is a growth factor that helps the bone marrow to produce white cells (neutrophils) and is an approved drug to treat the suppression of marrow function caused by chemotherapy.

If you are eligible to take part in the study, you will begin treatment. Rituximab will be given through a needle in your vein (IV) on Day 1 of Courses 1-6. The first infusion may take up to 8 hours. For every dose of rituximab after that, the infusion may take 2-4 hours. The length of the infusion time depends on whether you have any reactions to the infusion. The dose level of rituximab may be increased for Cycles 2-6 as well. The drugs acetaminophen (Tylenol) and diphenhydramine hydrochloride (Benadryl) will be given before each dose of rituximab. This will be done to decrease the risk of side effects. If side effects do occur during rituximab treatment, the drug may have to be stopped until the side effects go away and then restarted, so your time in the outpatient area may be longer if that occurs.

One day after the first dose of rituximab (Day 2), fludarabine and cyclophosphamide will be given by IV every day for 3 days (Days 2, 3, and 4), and mitoxantrone will be given by IV on Day 2. Fludarabine and cyclophosphamide will be given as 30-minute infusions, while the infusion of mitoxantrone will take 30-60 minutes. After the first treatment cycle, all the drugs will be given on Days 1, 2, and 3 for every cycle after that. Pegfilgrastim will be given as a subcutaneous injection (an injection under the skin) once per treatment cycle, right after you receive the last chemotherapy drug (in other words, on Day 4 during the first cycle, and on Day 3 for every cycle after that). Other IV fluids, such as saline, will be given on all of the treatment days to keep you hydrated, which means that each clinic visit will take about 6 hours. The combination will be repeated once every 4 to 6 weeks for a total of 6 courses.

The first treatment will be given at the University of Texas MD Anderson Cancer Center (UTMDACC) outpatient clinic. The other 5 courses can be performed either at UTMDACC or at home with your regular physician.

During each treatment cycle, you will have blood samples (about 1 teaspoon each) drawn once every 1-2 weeks. Bone marrow biopsies will be performed at the end of Cycles 3 and 6 of chemotherapy.

With the exception of rituximab, the same doses of all other drugs will be used throughout the study unless side effects become severe. In that case, the dose may be lowered or the treatment may be stopped. You will be taken off study if the disease gets worse.

After Course 6 of chemotherapy is finished, you will have blood tests (about 2 teaspoons each) performed every 6-12 months.

This is an investigational study. The FDA has approved all of the drugs used in this study, and they are commercially available. However, their use in this study and in this combination is considered investigational. Up to 30 patients will take part in the study. All will be enrolled at MD Anderson.

Arms: arm 1: Fludarabine 25 mg/m2 on Days 2,3,4 i.v. 5-30 mins for course 1, and on Days 1 - 3 for courses 2 - 6. Cyclophosphamide 250 mg/m2 on Day 2,3,4 i.v. 5-30 mins for course 1, and on Days1 - 3 for courses 2 - 6. Mitoxantrone 6 mg/m2 on Day 2 i.v. 30-60 mins for course 1, and on Day 1 for courses 2 - 6. Rituximab 375 mg/m2 on Day 1 i.v. 2-6 hours for course 1 and 500 mg/m2 on Day 1 for courses 2 - 6. Pegylated Filgrastim - 6 mg on Day 4,s.c. for course 1 and on Day 3 for courses 2 - 6.
Interventions: intervention 1: Fludarabine intervention 2: Cyclophosphamide intervention 3: Mitoxantrone intervention 4: Rituximab intervention 5: Filgrastim
Intervention descriptions: intervention 1: Fludarabine 25 mg/m2 on Days 2,3,4 i.v. 5-30 mins for course 1, and on Days 1 - 3 for courses 2 - 6 intervention 2: Cyclophosphamide 250 mg/m2 on Day 2,3,4 i.v. 5-30 mins for course 1, and on Days1 - 3 for courses 2 - 6. intervention 3: Mitoxantrone 6 mg/m2 on Day 2 i.v. 30-60 mins for course 1, and on Day 1 for courses 2 - 6. intervention 4: Rituximab 375 mg/m2 on Day 1 i.v. 2-6 hours for course 1 and 500 mg/m2 on Day 1 for courses 2 - 6. intervention 5: Pegylated Filgrastim - 6 mg on Day 4,s.c. for course 1 and on Day 3 for courses 2 - 6.

Protocol documents:
Prot_SAP_000.pdf: 
2005-0106
January 9, 2014
Page 1
Protocol Page
Phase 2 Study of the Activity and Safety of Fludarabine, Cyclophosphamide, and 
Mitoxantrone plus Rituximab (FCM-R) with Pegfilgrastim (Neulasta) as Frontline 
Therapy for Patients < 70 Years with Chronic Lymphocytic Leukemia
2005-0106
Core Protocol Information
Short Title 
Phase 2 Study of FCM-R (Fludarabine, Cyclophosphamide, Mitoxantrone, Rituximab) in 
Previously Untreated Patients with CLL < 70 Years
Study Chair: 
William G. Wierda
Additional Contact:
Ana B. Ayala
Jeannice Y. Theriot
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-745-0428
Unit:
428
Full Title: 
Phase 2 Study of the Activity  and Safety of Fludarabine, Cyclophosphamide, and Mitoxantrone 
plus Rituximab (FCM-R) with Pegfilgrastim (Neulasta) as Frontline Therapy for Patients < 70 
Years with Chronic Lymphocytic Leukemia
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 09/15/2017
Version:
07
Submitted by:
Jeannice Y. Theriot--1/9/2014 10:05:16 AM
OPR Action:
Accepted by:  Margaret Okoloise -- 1/27/2014 6:01:22 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2005-0106
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Protocol Body
1.0 Objectives
1.1
Primary
To determine the clinical response rate (combined morphological [NCI WG criteria] and flow 

cytometry criteria) following treatment with FCM-R in patients with previously untreated CLL.
1.2
Secondary
To determine the molecular response rate (PCR for IgH rearrangements) following treatment with 

FCM-R in patients with previously untreated CLL.
To determine the time to treatment failure.

To determine the toxicity profile of FCM-R.

2.0 Background
2.1
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States and 
Western Hemisphere. Nearly two-thirds of patients with CLL are over 60 years of age, and the 
prevalence of this disease should parallel the steady increase in the population over 50 years of 
age. Interest in newer therapeutic agents has been poor until recently due partly to the usual 
advanced age of patients and often indolent course of disease. However, the natural history is 
diverse. Patients with lymphocytosis only (Rai stage 0) have a median survival in excess of 10 
years; those with evidence of marrow failure manifested by anemia (Rai stage III) or 
thrombocytopenia (Rai stage IV) have a median survival in excess of only 2 years. The National 
Cancer Institute Working Group on CLL has described clinical features of “active disease” which 
should be helpful in the decision to treat: 1) weight loss of > 10% body weight over the past 6 
months; 2) fever or night sweats in the absence of infection; 3) extreme fatigue; 4) worsening 
anemia or thrombocytopenia; 5) massive (> 6cm below the left costal margin) or progressive 
splenomegaly; 6) massive (> 10cm in the longest diameter) or progressive lymphadenopathy; 7) 
progressive lymphocytosis with rapid lymphocyte doubling time; 8) marked 
hypogammaglobulinemia or paraproteinemia [1].
The mainstay of therapy has been systemic chemotherapy consisting usually of an alkylator and 
a corticosteroid. Chlorambucil plus prednisone has been the standard initial therapy with 
response rates from 40-77%. Fewer than 15% of these responses have been complete [2-6]. 
Therapy in patients who are refractory to alkylating agents is unsatisfactory. The response rates 
are substantially lower (approximately 30%) with rare complete responses [3, 7-9].
Fludarabine has shown marked activity in several indolent lymphoproliferative disorders, 
including CLL, low-grade lymphoma, macroglobulinemia, and prolymphocytic leukemia [10-14]. 
Fludarabine administration in previously treated CLL patients has resulted in a 13% complete 
response rate and 44% partial response rate [10]. Fludarabine has also been given to patients 
with previously untreated CLL, resulting in even higher response rates with 33% complete 
response and 50% partial response [11].
Despite attainment of clinical complete response, most patients experience a recurrence at a 
median of approximately 2 years [15]. This is likely related to the fact that most patients in 
complete remission have residual disease that can be assessed by several parameters. In 
previously untreated patients, 55% of CR patients have residual nodules on bone marrow biopsy 
(nPR). At 2 years, 87% of CR patients are progresson-free, versus 55% of nCR patients [15].
Cyclophosphamide has been combined with vincristine (VCR) and prednisone (COP) to treat 


2005-0106
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lymphoproliferative disorders. Liepman and Votaw first reported on this combination to treat CLL 
in 1978. Thirty-six patients received this regimen, 23 were previously untreated. The response 
rate was 72%; 18 of 23 (78%) previously untreated patients responded; 8 of 13 (62%) patients 
previously receiving chlorambucil responded to COP [16]. Oken and Kaplan treated 18 patients 
with CLL with CVP (cyclophosphamide 800mg/m2 i.v. on day 1 or 400mg/m2 orally for 5 days, 
VCR 2mg i.v. on day 1 and prednisone 60-100mg/m2 on days 1-5). All patients were previously 
treated and 17 of 18 were refractory to chlorambucil. The response rate was 44% [17].
Two randomized trials have been performed. The French Cooperative Group on CLL randomized 
291 patients to daily chlorambucil (0.1 mg/kg) or COP, where the cyclophosphamide dose is 
300mg/m2 orally on days 1-5. The response rate with chlorambucil was 59%, and with COP was 
61% [18]. ECOG randomized the same COP regimen versus chlorambucil (30mg/m2 orally day 
1) and prednisone (80mg orally days 1-5). The response rate for COP was 82% and 72% for 
chlorambucil and prednisone. Median duration of response and survival were also similar [19]. In 
all these studies, toxicity was minimal and generally related to myelosuppression in a significantly 
immunocompromised group. However, VCR in CLL is questionable with two single agent trials 
reporting no activity in a small number of patients [20].
Fludarabine and cyclophosphamide (FC) has now been used in 128 patients with CLL at MDACC 
[21]. Thirty-four of these patients received FC as initial therapy. FC produced  80% overall 
response rate in all patients not refractory to fludarabine at the start of therapy as well as a 38% 
response rate in patients who were refractory to fludarabine. The CR rate was 35% in previously 
untreated patients, which was not significantly different from the CR rate in historical control 
patients treated with single-agent fludarabine. However, residual disease assessed by flow 
cytometry occurred in only 8% of previously untreated patients achieving CR, and median time to 
progression has not been reached after a meaidan follow up of 41 months. The FC combination 
thus seems to have a significant advantage over single-agent fludarabine in the salvage setting. 
Although the CR rate was not increased in previously untreated patients, residual disease 
detected by flow cytometry was rare and remission durations seemed to be prolonged in this 
subset.
2.2
Monoclonal Antibodies in CLL
Monoclonal antibodies have expanded the therapeutic possibilities for patients with 
lymphoproliferative disorders. Rituximab has been studied extensively in low-grade lymphomas. 
One hundred sixty-six patients with advanced stage low-grade or follicular lymphoma were 
enrolled in the pivotal phase II portion of the study [22]. Rituximab was administered at a dose 
level of 375mg/m2 once weekly for four weeks. There were 105 males and 61 females with a 
median age of 58 years (range, 22-79) and 40% of patients were over 60 years of age. All 
patients had relapsed with a median of 3 (range, 1-7) prior chemotherapy regimens. Of the 166 
patients, 161 completed all four infusions. Side effects (chills, fever, nausea, vomiting, 
headaches) were usually mild to moderate and associated with the first Rituximab infusion. The 
mean half-life of free (serum) antibody was 1.8 days following the first dose and 6.2 days 
following the fourth infusion. Quantifiable immunoreactivity (HAMA or HACA) was not observed. 
There were 80 responders (10 CRs and 70 PRs); a response rate of 48% (95% CI: 41-56%). The 
median time to onset of response was 50 days (range, 21-288 days). The median duration of 
response has not been reached after 9.2 months (range, 1.9 to 18.8+ months). The response 
rate in 23 patients previously treated with ABMT was 78% compared with a 43% response rate in 
patients who had not undergone ABMT. The response rate in patients with SLL (WDLL), the 
tissue counterpart of CLL, was only 12%.
Whereas Rituximab has been studied extensively in low grade lymphoma, fewer studies have 
been undertaken in CLL, and with less success at standard dose and schedule. To improve 
response rates, we have undertaken a dose escalation study with all patients receiving rituximab 
375mg/m2 on the first course of therapy and each week thereafter receiving doses ranging from 
500mg/m2 up to 2250 mg/m2 per day [23]. No unusual toxicity occurred after the first infusion. 


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The response rate is 41% in 23 of 30 CLL patients evaluated and 50% in all patients treated. 
Higher doses have a higher response rate. In a similar dose escalation study, rituximab was 
given at 375mg/m2 i.v. three times weekly for 4 weeks [24]. Although dose increases were 
observed compared to the standard dose of rituximab, dose escalation trials have also 
highlighted the limitations of that approach: 1) financial considerations; 2) limited increase in 
response rates with moderately elevated doses; 3) dependence of response on antigen density 
and anatomic disease site; and 4) no improvement of responses in fludarabine-refractory 
patients.
Preclinical studies suggested synergistic activity of rituximab with chemotherapy agents including 
fludarabine and cyclophosphamide. We have conducted a phase II study of rituximab combined 
with fludarabine and cyclosphosphamide (FCR) for advanced or progressive CLL as well as initial 
therapy [25, 26]. One hundred and thirty-five previously untreated patients were treated. Using 
NCI WG criteria, 67% obtained a CR, 14% of the patients achieved a nodular partial remission 
(nPR), and 14% a partial response (PR). Eight-five (63%) of patients evaluated were able to 
obtain a flow cytometry remission with < 1% CD5/CD19 co-expressing cells and 41 (55%) of 74 
patients tested were able to become PCR negative for immunoglobulin heavy chain 
rearrangement in their bone marrow. Marrow PCR negativity was more common in those with CR 
(59%) compared with nPR (44%) and PR (50%) patients. The FCR regimen was well tolerated 
with grade 3-4 neutropenia being the most common toxicity being present in 56% of courses. The 
same combination has been used in previously treated patients with CLL. In a preliminary 
analysis, of 102 patients 23% achieved CR, 14% nPR, and 36% for an overall response rate of 
72%. Five of 13 patients (38%) in CR had undetectable IgH rearrangements by PCR. These 
results and others confirm that chemo-immunotherapy combinations are very active and appear 
to achieve far superior results compared to chemotherapy or monoclonal antibody therapy alone.
 
2.3
Mitoxantrone in the treatment of CLL
Mitoxantrone has been used frequently in patients with lymphoproliferative disorders including 
CLL. We have previoulsly conducted a phase II study of fludarabine plus mitoxantrone in 88 
patients with CLL [27]. Fludarabine was administered at 30mg/m2 i.v. daily for 3 days and 
mitoxantrone at 10mg/m2 on day 1. The OR was 66%. The response was 83% in previously 
untreated patients, 87% in patients previously treated with alkylating agents, 50% in patients 
whose disease was not refractory to fludarabine at the start of therapy, and 25% in patients with 
fludarabine-refractory CLL. The median progression-free survival was 24 months for all patients 
and 34 months for previously untreated patients. Experience with FC and mitoxantrone has been 
published in relapsed and refractory CLL [28]. Of 60 patients, 37 received fludarabine at 
25mg/m2 i.v. day 1-3, cyclophosphamide at 200mg/m2 i.v. day 1-3, and mitoxantrone 6mg/m2 
i.v. on day 1, at 4-week intervals for up to six courses. Twenty-three patients received FCM with 
cyclophosphamide at 600mg/m2 i.v. and mitoxantrone 8mg/m2 i.v. Overall, 50% of the patients 
achieved CR including 10 cases with molecular responses as assessed by PCR testing. 
Twenty-eight percent achieved PR for an overall response of 78%. FCM thus induced a high CR 
rate, including a significant number of patients with molecular responses in patients with 
previously treated CLL.
Given the positive experience with rituximab chemotherapy combinations, we propose to 
combine FCM with rituximab in patients with previously untreated CLL. There is extensive 
experience with these drugs in CLL although not with this particular combination. The FCM-R 
regimen is being explored in other low-grade lymphoproliferative disorders and mantle cell 
lymphoma. We do not expect any unusual toxicities. We propose this protocol for younger 
patients with good prognosis markers (beta-2-microglobulin </= 4 mg/dL) for the following 
reasons: i) chemoimmunotherapy results are more favorable in this age group than in patients 
over age 70 for whom alternative programs are being developed; ii) beta-2-microglobulin has 
emerged as an important prognostic marker in our FCR experience; iii) the addition of 
mitoxantrone to FCR is not a radical change in the overall rationale of FCR and good prognosis 
patients may benefit more from it than poor prognosis patients who again demonstrate an inferior 


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response and survival to the FCR; and iv) alternative programs are being developed for poor 
prognosis patients (based on beta-2-microglobulin levels). 
2.4
Pegfilgrastim
Pegfilgrastim (Neulasta™) is a covalent conjugate of recombinant methionyl human 
G-CSF(Filgrastim) and monomethoxypolyethylene glycol.  Filgrastim is a lineage-specific 
hematopoietic growth factor that preferentially stimulates the growth and differentiation of 
neutrophil precursors and the function of mature neutrophils.   
Pegfilgrastim is indicated to decrease the incidence of infection, as manifested by febrile 
neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer 
drugs associated with a clinically significant incidence of febrile neutropenia.  
For information on preclinical and toxicology studies, please refer to the Investigator’s Brochure.
Pegfilgrastim was evaluated in two randomized, double-blind, active-control studies, using 
doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles of 
the treatment of high risk and metastatic breast cancer.  Study 1 investigated the utility of a fixed 
dose of pegfilgrastim. Study 2 used a weight-adjusted dose.  In the absence of growth factor 
support, similar chemotherapy regimens have been reported to result in a 100% incidence of 
severe neutropenia (ANC < 0.5 x 109/L) with a mean duration of 5 to 7 days, and a 30 to 40% 
incidence of febrile neutropenia.
In study 1, 157 subjects were randomized to receive a single SC dose of 6 mg of pegfilgrastim on 
day 2 of each chemotherapy cycle or filgrastim 5 mg/kg/day SC beginning on day 2 of each cycle.  
In study 2, 310 subjects were randomized to receive a single SC injection of pegfilgrastim at 100 
m/kg on day 2 or filgrastim 5 mg/kg/day SC beginning on day 2 of each cycle of chemotherapy.  
Both studies met the primary objective of demonstrating that the mean days of severe 
neutropenia (ANC < 0.5 x 109/L) of pegfilgrastim-treated patients did not exceed that of 
filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy.  The rates of febrile 
neutropenia in the 2 studies were comparable for pegfilgrastim and filgrastim (in the range of 
10% to 20%).  Other secondary endpoints included days of severe neutropenia in cycles 2 to 4, 
the depth of ANC nadir in 
cycles 1 to 4, and the time to ANC recovery after nadir.  In both 
studies, the results for the secondary endpoints were similar between the two treatment groups.
Pegfilgrastim 6 mg will be administered subcutaneously as a single injection once per cycle 
following the end of chemotherapy.
3.0 Background Drug Information
3.1
Fludarabine
3.1.1
Supply: Sterile, 50 mg prepared as a white lyophilized powder with sodium hydroxide to adjust 
pH.
3.1.2 
Solution Preparation: Fludarabine for injection should be prepared for parenteral use by 
aseptically adding Sterile Water for Injection USP. When reconstituted with 2mL of Sterile Water 
for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the 
resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium 
hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 – 8.2. In clinical 
studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection USP or 0.9% 
Sodium Chloride USP.
Reconstituted Fludara for Injection contains no antimicrobial preservative and thus should be 
used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared 
solutions.  Parenteral drug products should be inspected visually for particulate matter and 


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discoloration prior to administration.
3.1.3 
Handling and Disposal: Procedures for proper handling and disposal should be considered.  
Consideration should be given to handling and disposal according to guidelines issued for 
cytotoxic drugs. Several guidelines on this subject have been published. There is no general 
agreement that all of the procedures recommended in the guidelines are necessary or 
appropriate.  
Caution should be exercised in the handling and preparation of Fludara for Injection solution. The 
use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of 
the vial or other accidental spillage. If the solution contacts the skin or mucous membrane, wash 
thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by 
inhalation or by direct contact of the skin or mucous membranes.  
3.1.4 
Stability: Fludarabine phosphate is relatively stable in aqueous solution. Over a pH range of 
approximately 4.5 to 8 in aqueous buffer solutions stored at 65C, approximately 11% 
decomposition occurred in one day. From this pH profile, the optimum pH was determined to be 
approximately 7.7. At concentration of 25 mg/ml in distilled water stored at room temperature in 
normal laboratory light, fludarabine phosphate exhibited less than 20% decomposition in 16 days.
Diluted to concentration of 1 mg/ml in 5% dextrose injection, USP, or in 0.9 sodium chloride 
injection, USP, less than 3% decomposition occurred in 16 days at room temperature under 
normal laboratory light.
CAUTION: The single-use lyophilized dosage form contains no antibacterial preservatives.  
Therefore, it is advised that the reconstituted product be discarded eight hours after 
reconstitution.
3.1.4 
Route of Administration: Intravenous.
3.2
Cyclophosphamide:
3.2.1
Formulation: Cyclophosphamide is available as powder for injection in vials of 100 mg, 200 mg, 
and 500 mg. Add 5 mL of sterile H2O for injection or normal saline for injection to a 100 mg vial, 
10 mL to a 200 mg vial, and 25 mL to a 500 mg vial. The resulting concentrations will be 20 
mg/mL. For infusion, cyclophosphamide is diluted further with 100 to 250 mL of D5W or NS and 
infused as directed.
3.2.2.
Storage: Vials containing undiluted cyclophosphamide for injection should be stored at room 
temperature. After mixing, the solution is stable for 24 hours at room temperature and 6 days if 
refrigerated.
3.3
Mitoxantrone:
3.3.1
Dosage Forms: Injection: 2 mg/mL (10 mL, 12.5 mL, 15 mL)
3.3.2
Administration: Maximum concentration: 2 mg/mL. Standard IVPB fluid: 100 mL. Maximum IVPB 
rate: 15 minutes; can be administered as IV push (2-5 minute infusion) if ordered by physician. 
Room temperature stability: 14 days. Refrigeration stability: 14 days. Special precautions: 
vascular irritant.
3.3.3
Route of administration: intravenous.
3.4
Pegfilgrastim (Neulasta)
3.4.1 
Packaging and Formulation: Pegfilgrastim 6 mg fixed dose (0.6 mL of a 10 mg/mL solution) will 


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be presented as a clear, colorless, sterile liquid in a pre-filled staked needle syringe with 
UltraSafe® Needle Guards.  The formulation is 10.0 mg PEGr-metHuG-CSF per mL of 10 mM 
Sodium Acetate, 5% Sorbitol, 0.004% Polysorbate 20, pH 4.0. Each subject box will contain 1 
pre-filled syringe. 
3.4.2 
Storage: Pegfilgrastim must be stored at 5 +/- 3C. Exposure of the material to excessive 
temperature above or below this range should be avoided.  Do not allow pegfilgrastim to freeze 
and do not use if contents freeze in transit or in storage. As the product contains no 
preservatives, pre-filled syringes are designed for single use only.  
3.4.3 
Preparation: No preparation is required for administration of pegfilgrastim.  Each subject will 
receive the 6 mg fixed dose pegfilgrastim.  The entire contents of the 0.6 mL pre-filled syringe 
should be administered irrespective of the subject’s actual weight.
3.5
Rituximab
Rituximab is a highly purified, 1328-amino acid antibody with an approximate molecular mass of 
145 kD.  The chimeric mouse/human anti-CD20 antibody is a glycosylated IgG1  immunoglobulin 
containing murine light and heavy chain variable regions and human 1 heavy chain and  light 
chain constant regions.
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) 
administration. Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 
500 mg (50 mL) single-use vials. The product is formulated for intravenous administration in 9.0 
mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and 
Sterile Water for Injection. The pH is adjusted to 6.5.
4.0 Patient Eligibility
Inclusion:
4.1
Untreated CLL, CLL/PLL, or SLL (small lymphocytic lymphoma) with indication for therapy 
(Indications for therapy include at least one of the following): i) one or more disease-related 
symptoms [fever, night sweats, weight loss, pronounced fatigue]; ii) advanced stage disease (Rai 
stage >/= 3 or Binet stage C); iii) autoimmune anemia and/or thrombocytopenia that is 
unresponsive to other therapies; iv) massive or progressive hepatomegaly and/or splenomegaly 
and/or lymphadenopathy; iv) recurrent infections; v) rapid lymphocyte doubling time of < 6 
months). 
4.2
Age < 70 years.
4.3
Adequate liver function (total bilirubin </= 2.5 mg/dL, SGPT </=4 x ULN) and renal function 
(serum creatinine </= 2.0 mg/dL). Patients with renal or liver dysfunction due to suspected organ 
infiltration by lymphocytes may be eligible after discussion with the Principal Investigator, but 
upper limits for creatinine even under these circumstances must be creatinine < 3mg/dL and 
bilirubin < 6 mg/dL. Patients with Gilbert's syndrome may be entered on study with bilirubin levels 
</= 4 mg/dL.
4.4
Beta-2-microglobulin </= 4 mg/dL.
4.5
ECOG performance status </= 2.
4.6
Signed informed consent in keeping with the policies of the hospital.


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4.7
Male and female patients who are fertile agree to use an effective barrier method of birth control 
(ie, latex condom, diaphragm, cervical cap, etc.) to avoid pregnancy. Female patients of 
childbearing potential (non-childbearing is defined as >/= 1 year postmenopausal or surgically 
sterilized) need a negative serum or urine pregnancy test within 14 days of study enrollment.
Exclusion:
4.8
Active hepatitis B (at least one of the following markers positive: HBsAg, HBeAg, IgM anti-HBc, 
HBV DNA).
4.9
Concurrent chemotherapy or immunotherapy.
4.10
Pregnant patients.
4.11
History of HIV
4.12
Symptomatic CNS disease
4.13
Symptomatic heart disease (NYHA class >/= 3) or LV ejection fraction < 40% (by MUGA or 
echocardiogram)
5.0 Treatment Plan
5.1
General
This is a non-randomized, open-label phase 2 study of FCM-R for patients with previously 
untreated CLL. The doses of FCM and R have been established in earlier and published trials. All 
drugs are commercially available.
5.2
Treatment Plan
Up to 6 courses can be administered.
Course 1:
Agent
Dose
Day(s)
Route
Time
Fludarabine
25mg/m
2/day
2,3,4
i.v.
5-30 mins.
Cyclophosphamide
250mg/m
2/day
2,3,4
i.v.
5-30 mins.
  Mitoxantrone
6mg/m
2/day
2
i.v.
30-60 mins.
  Rituximab
375mg/m
2/day
1
i.v. 
2-6 hours
Pegylated Filgrastim
6mg
4
s.c.
NA
Courses 2 - 6:
Agent
Dose
Day(s)
Route
Time
Fludarabine
25mg/m
2/day
1-3
i.v.
5-30 mins.
Cyclophosphamide
250mg/m
2/day
1-3
i.v.
5-30 mins.
  Mitoxantrone
6mg/m
2/day
1
i.v.
30-60 mins.
  Rituximab
500mg/m
2/day
1
i.v. 
2-6 hours
Pegylated Filgrastim
6mg
3
s.c.
NA
Cyclophosphamide will be given after the dose of fludarabine, and mitoxantrone after completion 
of the cyclophosphamide infusion. Rituximab will start before fludarabine. Pegylated filgrastim is 
given after chemotherapy.


2005-0106
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Page 9
CAUTION: DO NOT ADMINISTER RITUXIMAB AS AN INTRAVENOUS PUSH OR BOLUS !
Rituximab will be given on days 1 at a dose of 375mg/m
2 during course 1 and on day 1 at a dose 
of 500mg/m
2 during courses 2-6.   
Recommended premedication: 500 to 1000 mg of acetaminophen orally and 12.5 to 25 mg of 
diphenhydramine hydrochloride orally or intravenously to be administered 30 to 60 minutes prior 
to starting each infusion of Rituximab.
Rituximab may be administered via a peripheral or central intravenous line.
During the Rituximab infusion, the patient’s vital signs (blood pressure and pulse) should be 
monitored every 30 minutes times one hour or until stable and then hourly until the infusion is 
discontinued. Assessment of temperature and respiration as clinically mandated. Available at the 
bedside prior to Rituximab administration will be epinephrine for subcutaneous or i.v. injection, 
diphenhydramine hydrochloride for intravenous injection, and resuscitation equipment for 
emergency management of anaphylactoid reactions.
The initial dose rate at the time of the first Rituximab infusion should be 50 mg/hr for the first 
hour. If no toxicity is seen, the dose rate may be escalated gradually to a maximum of 400 
mg/hour. If the first dose of Rituximab is well tolerated, the starting flow rate for the administration 
of the subsequent doses may be 100 mg/hour and then increased gradually not to exceed 400 
mg/hour.
Rituximab is associated with hypersensitivity reactions (hypotension, bronchospasm, or 
angioedema), which may respond to adjustments in the infusion rate. Transient fever and rigors 
may occur. Rituximab should be interrupted for severe reactions and resumed at a lower rate 
until symptoms have completely resolved. Supportive care such as IV saline, diphenhydramine, 
and acetaminophen should be available and instituted as clinically mandated.  Upon resolution of 
all side effects and in the judgment of the investigator, the patient’s dose may be gradually 
escalated to a maximum rate of 400 mg/hour.  
Infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias. 
Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during 
and after subsequent infusions of Rituximab. Patients with pre-existing cardiac conditions 
including arrhythmias and angina have had recurrences of these events during Rituximab therapy 
and should be monitored closely. Consideration should be given to withholding anti-hypertensive 
medications the day of the first infusion, since transient hypotension may occur.
Rate reductions of up to 50% should occur for: (1) fever > 38.5
oC, (2) mild to moderate rigors, (3) 
mild to moderate mucosal congestion/edema, (4) > 30 mm Hg decrease over baseline in systolic 
blood pressure, or (5) other reaction according to the judgment of the investigator. 
Courses will be repeated every 28 to 42 days (+/- 7 days) depending on recovery of peripheral 
blood counts and toxicities for a maximum of 6 courses. Patients will be evaluated for response 
after 3 and 6 courses. Patients will be taken off study after 3 courses for progressive disease, but 
are otherwise allowed to complete 6 courses. 
5.3
Dose adjustments
All previously experienced treatment-related toxicities should have recovered to at least grade 1 
(exception: alopecia, lymphopenia, fatigue, weakness, nausea/vomiting that can be controlled 
with supportive care measures) by the time the next course is started. Dose adjustments (one 
level reduction, see table below) will be made for any  grade 3 treatment-related toxicities during 
the preceding course (exception: alopecia, lymphopenia, fatigue, weakness, nausea/vomiting that 
can be controlled with supportive care measures or infusion-related toxicities that may occur with 


2005-0106
January 9, 2014
Page 10
rituximab).
For patients who started therapy with platelets >/= 100 x 10
9/L and an ANC >/= 1 x 10
9/L, the 
platelet count should be >/= 60 x 10
9/L and/or the ANC >/= 1 x 10
9/L prior to continuation. For 
patients whose platelets are < 100 x 10
9/L or ANC < 1 x 10
9/L at the start of therapy, blood counts 
should at least have recovered to within 20% of pretreatment baseline levels prior to starting the 
next course. If recovery of the platelet count or ANC either to the level of prior to therapy or the 
parameters above exceeds 42 days, the dose will be decreased by 1 level.
Dose Levels (for courses 2 to 6):
0
-1
-2
Fludarabine
25 mg/m
2 daily 
x 3d
20 mg/m
2 daily 
x 3d
20 mg/m
2 daily 
x 3d
Cyclophosphamide
250 mg/m
2 
daily x 3d
200 mg/m
2 
daily x 3d
200 mg/m
2 
daily x 3d
Mitoxantrone
6 mg/m
2 daily 
x 1d
6 mg/m
2 daily x 
1d
4.5 mg/m
2 daily 
x 1d
Rituximab
500 mg/m
2 
daily x 1d
500 mg/m
2 
daily x 1d
500 mg/m
2 
daily x 1d
No dose escalations are allowed.
Recommended dose reductions of fludarabine in patients with impaired renal function (applies to 
all courses):
Cl Cr 30 to 70 mL/min: reduce dose by 25%
Cl Cr < 30 mL/min: administration of fludarabine not recommended.
 
If subsequent courses cannot be administered within 3 weeks following day 42 of therapy 
because of treatment-related toxicities, doses should be reduced by at least one level regardless 
of recovery of these toxicities to  grade 1.
Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV 
infection and for signs of hepatitis throughout their study participation.
5.4
Concomitant Medications/Therapy
Necessary supportive measures for optimal medical care will be given throughout the study as 
determined by the treating physician and the patient’s medical need. No concomitant 
chemotherapy, immunotherapy, or therapy with other monoclonal antibodies except for rituximab 
will be allowed during the study. Investigational agents that are not used for the treatment of the 
leukemia per se (e.g. anti-infective prophylaxis or therapy) will be allowed.
Use of erythropoietin is at the discretion of the treating physician and is permitted if judged in the 
patient’s best medical interest. Use of G-CSF of GM-CSF should be discussed with the principal 
investigator.
Prophylactic antibiotics and antiviral agents are recommended (e.g. trimethoprim 
sulfamethoxazole, valacyclovir); however, the use of these or other drugs will be left to the 
treating physician’s discretion.
5.5
Expected adverse events from study drugs
All drugs individually and possibly more so in combination may cause myelosuppression which 
may be associated with bleeding, bruising, fatigue, or shortness of breath. Transfusion of blood 


2005-0106
January 9, 2014
Page 11
products may become necessary. 
5.5.1 Rituximab:
No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse events 
including fever, chills, headache, nausea, vomiting, rhinitis, and mild hypotension, occurred 
primarily during rituximab infusions and typically responded to an interruption of the infusion and 
resumption at a slower rate.  Other adverse events included neutropenia, thrombocytopenia, 
asthenia, other hematologic events, cardiac and cardiopulmonary events, and tumor lysis 
syndrome. 
Hematologic Events:  In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of 
patients treated with rituximab; these include: lymphopenia (40%), neutropenia (6%), leukopenia 
(4%), anemia (3%), and thrombocytopenia (2%).  The median duration of lymphopenia was 14 
days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 to 116 days).  A single 
occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic 
anemia following Rituximab therapy were reported. 
In addition, there have been a limited number of postmarketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia (defined as occurring 40 days after 
the last dose of rituximab) in patients with hematologic malignancies.  In reported cases of late 
onset neutropenia (NCI-CTC Grade 3 and 4), the median duration of neutropenia was 10 days 
(range 3 to 148 days).  Documented resolution of the neutropenia was described in 
approximately one-half of the reported cases; of those with documented recovery, approximately 
half received growth factor support.  In the remaining cases, information on resolution was not 
provided.  More than half of the reported cases of delayed onset neutropenia occurred in patients 
who had undergone a prior autologous bone marrow transplantation.  In an adequately designed, 
controlled, clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 neutropenia was higher 
in patients receiving rituximab in combination with fludarabine as compared to those receiving 
fludarabine alone (76% [39/51] vs. 39% [21/53]).
Cardiac Events:  Patients with preexisting cardiac conditions, including arrhythmia and angina, 
have had recurrences of these cardiac events during rituximab infusions.
Cardiopulmonary Events:  In rare cases, severe and fatal cardiopulmonary events, including 
hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, and 
cardiogenic shock, have occurred (4-7/10,000 patients or 0.04-0.07%.)  Nearly all fatal 
infusion-related events occurred in association with the first infusion.
Tumor Lysis Syndrome:   Although rare, tumor lysis syndrome has been reported in 
postmarketing studies and is characterized in patients with a high number of circulating malignant 
cells (>25,000 ul) by rapid reduction in tumor volume, renal insufficiency, hyperkalemia, 
hypocalcemia, hyperuricemia, and hyperphosphatemia.
Hepatitis B Reactivation:  Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic 
failure, and death has been reported in some patients with hematologic malignancies treated with 
rituximab.  The majority of patients received rituximab in combination with chemotherapy.  The 
median time to the diagnosis of hepatitis was approximately four months after the initiation of 
rituximab and approximately one month after the last dose.
Renal Events:  Rituximab has been associated with severe renal toxicity including acute renal 
failure requiring dialysis, and in some cases has lead to death.  Renal toxicity has occurred in 
patients with high numbers of circulating malignant cells (>25,000/mm2 ) or high tumor burden 
who experience tumor lysis syndrome.  
Mucocutaneous Reactions:  Severe bullous skin reactions, including fatal cases of toxic 


2005-0106
January 9, 2014
Page 12
epidermal necrolysis, have been reported rarely in patients treated with rituximab.  
Paraneoplastic pemphigus has been reported very rarely in NHL and CLL patients undergoing 
chemotherapy plus rituximab treatment.  The onset of reaction has varied from 1 to 13 weeks 
following rituximab exposure.
 
Additional Safety Signals:  The following immune serious adverse events have been reported 
to occur rarely (<0.1%) in patients following completion of rituximab infusions: arthritis, disorders 
of blood vessels (vasculitis, serum sickness and lupus-like syndrome), lung disorders including 
pleuritis and scarring of the lung (bronchiolitis obliterans), eye disorders (uveitis and optic 
neuritis), and severe bullous skin reactions (including toxic epidermal necrolysis and pemphgus) 
that may result in fatal outcomes.  Patients may have these symptoms alone or in combination 
with rash and polyarthritis
See the rituximab Investigator Brochure for additional details regarding safety experience with 
rituximab.
5.5.2 Cyclophosphamide:
Diarrhea, nausea, vomiting, and/or loss of appetite. Electrolyte abnormalities. Cystitis. 
Cyclophosphamide may cause a metallic taste immediately after it is given. Mucositis, gastritis, 
and/or temporary alopecia. It may cause headache, dizziness, stuffy nose, and/or testicular 
shrinkage. It may also cause loss of menstrual periods and/or allergic reaction.
5.5.3 Fludarabine:
Loss of appetite, fatigue, confusion, numbness, nausea, vomiting, and/or diarrhea. Fatigue and 
weakness. Vision and/or hearing problems. Neurotoxicity (inlcuding seizures and coma). Skin 
rash, mucositis/stomatitis and/or alopecia. Congestive heart failure, pulmonary fibrosis, 
hematuria. Hepatotoxicity. Nephrotoxicity. Sterility (may be permanent).
5.5.4 Mitoxantrone:
Loss of appetite, fatigue, weakness, nausea, vomiting, and/or diarrhea. Mucositis/stomatitis. 
Alopecia. Hepatotoxicity. Nephrotoxicity. Sterility (may be permanent).
5.5.5 Pegfigrastim:
Pain, burning, swelling, bleeding/bruising, or infection at the injection site. It may generate bone 
pain for which pain medications are sometimes required.
6.0 Pretreatment evaluation
Procedure
Comments
Schedule
Informed consent
Obtain standard informed consent 
approved by IRB
Within 14 days of study 
start
Medical History
Includes history of present illness, 
prior cancer history as far as 
traceable and relevant, and past 
medical/surgical history as far as 
relevant
Within 14 days of study 
start
Physical examination
Includes vital signs (temperature, 
heart rate, respiratory rate, blood 
pressure) and performance status
Within 14 days of study 
start


2005-0106
January 9, 2014
Page 13
Concomitant medications
Document concomitant 
medications
Within 14 days of study 
start
Hematology
CBC with differential and platelet 
count
Within 14 days of study 
start
Biochemistry
Creatinine, uric acid, LDH, total 
bilirubin, SGPT or SGOT) 
Within 14 days of study 
start
Beta-2-microglobulin
Within 14 days of study 
start
Pregnancy test
Serum or urine
Within 14 day of study start
HBV screening
Unless a negative test can be 
documented within the preceding 
6 months
Within 6 months of study 
start
Bone marrow
Aspirate/biopsy including flow 
cytometry and PCR testing for 
IgH gene rearrangements
Within 6 months prior to 
study start
MUGA or echocardiogram Assessment of LV ejection fraction
Within 3 months prior to 
study start
7.0 Evaluation During Study
Procedure
Comments
Schedule
Physical examination
Includes vital signs (temperature, 
heart rate, respiratory rate, blood 
pressure) and performance status
Prior to each cycle within 
3-5 days. Following 3rd and 
6th course, and every 6 
months (+/- 2 months) as 
long as on study thereafter.
Hematology
CBC with differential and platelet 
count
Every 1 to 2 weeks as long 
as on therapy, and during 6 
monthly follow up visits as 
long as on study
Biochemistry
At least creatinine, total bilirubin, 
SGPT or SGOT 
Every 2 to 4 weeks as long 
as on therapy, and during 6 
monthly follow up visits as 
long as on study
Beta-2-microglobulin
Following the 3rd and 6th 
course
Bone marrow
Aspirate/biopsy including flow 
cytometry and PCR testing for 
IgH gene rearrangements
After 3rd and 6th course. 
No marrow is necessary at 
the end of therapy if 
non-response or 
pro-gressive disease can 
be diagnosed from 
peripheral blood tests.
Upon completion of therapy (maximum of 6 courses), patients will return to MDACC every 6 to 12 
(+/- 3) months thereafter for as long as on study. Each visit will include a CBC with differential 
and platelet count, and at least the parts of the SMA-12 as specified in Table 7.0. Bone marrow 
aspirate/biopsy will be performed as judged indicated by the treating physician or Principal 
Investigator.


2005-0106
January 9, 2014
Page 14
8.0 Criteria for Response
(as per NCI Working Group Criteria)
8.1
Complete Remission (CR):
Normal physical examination (including nodes, liver, spleen).

No constitutional symptoms (B-symptoms absent). 

Peripheral blood: Absolute lymphocyte count (ALC) </= 4 x 10
9/L with Hb > 11 g/dL, absolute 

neutrophil count (ANC) >/= 1.5 x 10
9/L, and platelet count > 100 x 10
9/L.
Bone marrow: < 30% lymphocytes on aspirate with no evidence of disease on biopsy. [CRu 

(CR/unconfirmed): increased number or size of lymphoid aggregates without cytologic or architectural 
atypia).
Other disease sites: Disappearance of all palpable lymph nodes, spleen and liver without the 

appearance of new lesions.
8.2
Partial Remission (PR):
Peripheral blood: ALC reduced by  50%, with either Hb > 11 g/dL or 50% improvement in 

deviation from normal, or ANC >/= 1.5 x 10
9/L or 50% improvement in deviation from normal, or 
platelet count > 100 x 10
9/L or 50% improvement in deviation from normal.
Other disease sites: Reduction in size of  50% of all palpable lymph nodes, spleen, and liver 

without appearance of new lesions. 
8.3
Nodular Partial Response (nPR):
Peripheral blood: ALC </= 4 x 10
9/L with Hb > 11 g/dL, ANC >/= 1.5 x 10
9/L and platelet count > 

100 x 10
9/L.
Bone marrow: < 30% lymphocytes on aspirate with lymphoid nodules seen on biopsy.

Tumor: Disappearance of all palpable lymph nodes, spleen, and liver without the appearance of 

new lesions.
8.4
Stable Disease (SD):
Failure to meet criteria for response and failure to meet criteria for disease progression.

8.5
Progressive Disease (PD):
Peripheral blood: 50% increase in ALC with a level > 10 x 10
9/L on at least 2 occasions 2 weeks 

apart.
Tumor: An increase of a lesion by 50% over the size present at entry on study or for patients who 

respond, the size at the time of maximum regression and/or the appearance of new areas of 
malignant disease. Reappearance of bone marrow disease. A deterioration in performance status 
or increasing symptoms do not constitute disease progression.
8.6
Molecular Response (MR):
Negative result by PCR testing for IgH gene rearrangements.

9.0 Criteria for Removal from the Study
9.1
Progressive disease.
9.2
Failure to achieve at least stable disease after 3 courses.
9.3
Grade 4 adverse events in the absence of therapeutic benefit.


2005-0106
January 9, 2014
Page 15
9.4
Investigator thinks that a change of therapy would be in the best interest for the patient.
9.5
If the patient has intercurrent, non-leukemia-related illness that would, in the judgment of the 
investigator, affect assessment of clinical status to a significant degree.
9.6
Active HBV infection or hepatitis.
9.7
Severe or life-threatening anaphylaxis or hypersensitivity reaction.
9.8
Patient request.
9.9
Patient is non-compliant with protocol requirements.
9.10
Subjects who are carriers of hepatitis B at the time of discontinuation from study treatment will 
continue to be followed for clinical and laboratory signs of active HBV infection and for signs of 
hepatitis.
9.11
The Principal Investigator has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to:
If the incidence or severity of adverse events indicates a potential health hazard to patients.

If the patient enrollment is unsatisfactory.

10.0 Evaluation of Toxicity
Toxicities will be reported according to NCI CTC Version 3 (NCI-CTCAE). See Appendix B for details.
11.0 Reporting Requirements
See Appendix A and F (Leukemia) for Reporting Requirements
In the event of an adverse event, the first concern will be for the safety of the subject.  Investigators are 
required to report to Genentech Drug Safety any serious adverse event, whether expected or 
unexpected, regardless of causality to either rituximab.  All events meeting these criteria will be reported 
for the time period beginning with any amount of exposure to rituximab through the protocol-defined 
follow-up period.  Serious criteria, definitions, and guidance for reporting follow.
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational trial or protocol regardless of causality assessment.  An adverse event can be an 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, syndrome or 
disease associated with or occurring during the use of an investigational product whether or not 
considered related to the investigational product.
Serious adverse events (SAE) are adverse events occurring at any dose which meet one or more of the 
following serious criteria:
· Results in death (i.e. the AE caused or lead to death)
· Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it does not apply to an AE 
which hypothetically might have caused the death if it were more severe)
· Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-hour inpatient 
hospitalization or prolonged a hospitalization beyond the expected length of stay; hospitalizations for 
elective medical/surgical procedures, scheduled treatments, or routine check-ups are not SAEs by this 
criterion)


2005-0106
January 9, 2014
Page 16
· Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability to carry out normal life 
functions)
· Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a subject exposed 
to the trial drug prior to conception or during pregnancy)
· It does not meet any of the above serious criteria but may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above
SAEs include any sign, symptom or medical condition that meets any of the above criteria and emerges 
during rituximab treatment or during a post-treatment follow-up period that (1) was not present at the start 
of treatment and is not a chronic condition that is part of the patient’s medical history, OR (2) was present 
at the start of treatment or as part of the patient’s medical history but worsened in severity and/or 
frequency during therapy.
Expected adverse events are those adverse events that are listed or characterized in the current 
Investigator Brochure. 
Unexpected adverse events are those not listed in the current Investigator Brochure or not identified.  
This includes adverse events for which the specificity or severity is not consistent with the description in 
the Investigator Brochure  For example, under this definition, hepatic necrosis would be unexpected if the 
Investigator Brochure only referred to elevated hepatic enzymes or hepatitis.
Reporting of Serious Adverse Events Associated with Rituximab
All serious adverse events (SAEs) regardless of causality to rituximab (this applies to both expected and 
unexpected events) should be recorded on a MedWatch 3500A Form (Appendix J) and faxed to:
Genentech Drug Safety 
Tel:
(888) 835-2555
Fax:
(650) 225-4682 or (650) 225-4683
AND:
The Principal Investigator of the Study and the IRB
MedWatch 3500A Reporting Guidelines:
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description (section 5) of the MedWatch 3500A 
form:
· Treatment regimen (dosing frequency, combination therapy)
· Protocol description (and number, if assigned)
· Description of event, severity, treatment, and outcome if known
· Supportive laboratory results and diagnostics
· Investigator’s assessment of the relationship of the adverse event to each investigational product and 
suspect medication
Follow-up information:  
Additional information may be added to a previously submitted report by any of the following methods:
· Adding to the original MedWatch 3500A report and submitting it as follow-up
· Adding supplemental summary information and submitting it as follow-up with the original MedWatch 


2005-0106
January 9, 2014
Page 17
3500A form 
· Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. D.O.B. 
initial, subject number), protocol description and number, if assigned, suspect drug, brief adverse event 
description, and notation that additional or follow-up information is being submitted  (The patient 
identifiers are important so that the new information is added to the correct initial report)
Occasionally Genentech may contact the reporter for additional information, clarification, or current status 
of the subject for whom and adverse event was reported.  For questions regarding SAE reporting, you 
may contact the Genentech Drug Safety representative noted above.
Study Drug Relationship:
The investigator will determine which events are associated with the use of the study drugs.  For 
reporting purposes, an AE should be regarded as possibly related to the use of the investigational 
product if the investigator believes:
· There is a clinically plausible time sequence between onset of the AE and rituximab administration; 
and/or
· There is a biologically plausible mechanism for rituximab causing or contributing to the AE; and
· The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or procedures.
12.0 Statistical Considerations
This is a phase II study with an objective of determining the clinical response rate in CLL patients treated with 
fludarabine, cyclophosphamide, mitoxantrone, and rituximab (FCM-R).  Eligible patients will be previously 
untreated, < 70 years of age and have a favorable Beta-2-microglobulin level of ≤ 4mg/dL.  The addition of 
mitoxantrone to the regimen is expected to favorably affect patient response.  In addition to the FCM-R 
regimen, patients will receive Neulasta to shorten the duration of neutropenia and reduce the infection rate.  
Patients will receive a maximum of 6 courses of therapy, with courses repeated every 28 – 42 days (± 7 
days).  The maximum total sample size will be 30 patients, with accrual estimated to be 2-5 per month.
A previous phase II clinical trial of patients with fludarabine, cyclophosphamide, and rituximab (FCR) resulted 
in an overall response rate at 6 months of approximately 95%.  In addition to overall response, flow cytometry 
was measured at 3 months and at 6 months after the start of treatment.  The phase II FCR trial found that 
patients who maintain a flow cytometry <1% have better survival than those whose flow cytometry is ≥ 1%.  
Therefore, examining the flow cytometry at 3 months is a useful tool for early assessment of the later 
outcome of survival.
The method of Thall, Simon, and Estey (1996), will be employed to perform interim efficacy and safety 
monitoring.  The patient outcomes of interest are F = [patients who have a flow cytometry < 1% at 3 months] 
and N = [grade III-IV neutropenia during 3 months after start of treatment].  We will denote the probability of F 
for the patients treated with FCR by θS, F and for the experimental therapy, FCM-R patients by 
θE, F.  Similarly, we will denote the probability of N for the patients treated with FCR by θS, N and for 
experimental FCM-R therapy patients by θE, N.
Historical data is from a phase II trial of 189 previously untreated patients treated with FCR.  
(Beta-2-microglobulin levels were not considered in the inclusion/exclusion criteria.)  The FCR trial found that 
34.4% of the patients had a flow cytometry < 1% at 3 months and 74.6% of the patients had grade III-IV 
neutropenia.  Thus the historical data suggest the probability of a flow cytometry <1% at 3 months to be 
θS, F =65/189 (34.4%), and we assume that θS, F ~ beta(65, 124).  We assume θE, F ~ beta (1.37, 2.62).  This 
distribution has the same mean (0.344) but a larger variance than the standard therapy counterpart.  The 
data from the FCR trial also suggest an estimate of the probability of grade III-IV neutropenia within the first 3 


2005-0106
January 9, 2014
Page 18
months to be θS, N = 141/189 (74.6%) and we assume that θS, N ~ beta(141/48).  We assume θE, N ~ beta(2.98, 
1.02).  This distribution has the same mean (0.746) but a larger variance than the standard therapy 
counterpart.
The goal of the trial is to achieve an increase in patients with favorable flow cytometry to 50%, an increase of 
approximately 15%, while not allowing the neutropenia rate to increase.  At most 30 patients will be treated.  
We will begin monitoring after 10 patients have been enrolled and then monitor continuously.  However, we 
will not suspend accrual to wait for patients to be evaluated.
Our monitoring rules for these two endpoints are described below:
Flow Cytometry <1% at 3 months
Pr[ θS, F + 0.15 <  θE, F | data ] ≤ 0.01
That is, if at any time during the trial we determine that we have less than a 1% chance of showing that the 
average rate of patients with flow cytometry <1% at 3 months is at least 15% higher than would be expected 
on the standard of care (i.e. 35%) we will stop the study.  Stopping boundaries corresponding to this 
probability criterion are to terminate the trial if
(# of patients with Flow Cytometry <1% at 3 months) / (# patients evaluated)
 ≤ 1/11, 2/14, 3/17, 4/20, 5/23, 6/26, 7/29.
Grade III-IV Neutropenia
Pr[ θS, N <  θE, N | data ]  ≥ 0.99
That is, if at any time during the study we determine that there is more than a 99% chance that the average 
rate of grade III-IV neutropenia is more than would be expected on the standard of care (i.e. 75%) we will 
stop the study.  Stopping boundaries corresponding to this probability criterion are to terminate the trial if
(# patients with grade III-IV neutropenia) / (# patients evaluated)  
≥ 14/14, 15/15, 16/16, 17/17, 18/18, 19/19, 20/20, 21/22, 22/23, 23/24, 24/25, 25/26, 26/27, 27/29.
The operating characteristics of this study design are illustrated in Table 1.
Table 1.  Operating Characteristics for Monitoring Rules
Clinical Scenario
Early Stopping Probability Achieved Sample Size
25th
50th
75th
Percentiles
Rate of flow cytometry <1% at 3 months is 0.50
Rate of grade III-IV neutropenia is 0.75
0.06
30
30
30
Rate of flow cytometry <1% at 3 months is 0.50
Rate of grade III-IV neutropenia is 0.85
0.25
29
30
30
Rate of flow cytometry <1% at 3 months is 0.40
Rate of grade III-IV neutropenia is 0.75
0.22
30
30
30
Rate of flow cytometry <1% at 3 months is 0.35
Rate of grade III-IV neutropenia is 0.85
0.49
15
30
30


2005-0106
January 9, 2014
Page 19
Rate of flow cytometry <1% at 3 months is 0.25
Rate of grade III-IV neutropenia is 0.85
0.81
10
15
24
In addition to flow cytometry at 3 months we will also determine the flow cytometry at 6 months and present it 
along with its corresponding 95% credible interval.  The secondary objectives include determining the 
molecular response rate, time to treatment failure, and toxicity profile of FCM-R.  Molecular response rate will 
be defined as the percentage of patients who have a negative result by PCR testing for IgH gene 
rearrangements and will be presented along with its corresponding 95% credible interval.  Time to treatment 
failure will be estimated using the Kaplan-Meier estimator.  Patients who experience a relapse or die will be 
considered to be a treatment failure event.  Patients who are alive without relapse at their last follow-up will 
be considered as censored.  Finally, descriptive statistics such as frequencies and percentages will be used 
to summarize the occurrence of any toxicities.
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