Clinical trial NCT01505868
Conditions: Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Lymphadenopathy Metastatic Prostate Carcinoma Prostate Adenocarcinoma Prostate Carcinoma Metastatic in the Bone Prostate Small Cell Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2012-07-11; Completion date: 2019-12-09
Enrollment: 170 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase I/II trial studies cabazitaxel with or without carboplatin in treating patients with previously treated prostate cancer that has spread to other areas of the body and does not respond to treatment with hormones. Drugs used in chemotherapy, such as cabazitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving cabazitaxel alone or with carboplatin is more effective in treating prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dosage (MTD) of cabazitaxel-carboplatin in the phase I portion of the study.

II. To evaluate progression free survival achieved with cabazitaxel-carboplatin versus cabazitaxel alone in men with metastatic castration resistant prostate cancer (mCRPC) in the phase II portion of the study.

SECONDARY OBJECTIVES:

I. To assess prostate-specific antigen (PSA) response rate (percentage of patients with \> 50 % decline).

II. To correlate changes in bone specific alkaline phosphatase and urine n-telopeptides with response.

III. To evaluate overall survival. IV. To evaluate safety and toxicity. V. To evaluate influence of the anaplastic phenotype on response to therapy. VI. To collect and archive serum, plasma, and urine samples in study patients for later hypothesis generating associations.

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

PHASE I: Patients receive cabazitaxel intravenously (IV) over 60-90 minutes and carboplatin IV over 60-90 minutes on day 1. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

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

ARM I: Patients receive cabazitaxel IV over 60-90 minutes on day 1. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cabazitaxel IV over 60-90 minutes and carboplatin IV over 60-90 minutes on day 1. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

Arms: arm 1: Patients receive cabazitaxel IV over 60-90 minutes on day 1. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive cabazitaxel IV over 60-90 minutes and carboplatin IV over 60-90 minutes on day 1. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cabazitaxel intervention 2: Carboplatin intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
2011-0727 
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Page 1 
 
 
 
 
 
THE UNIVERSITY OF TEXAS MD 
ANDERSON CANCER CENTER 
 
DIVISION OF CANCER MEDICINE 
 
An Open Label Phase I/II Study of Cabazitaxel with or without Carboplatin in 
Patients with Metastatic Castration-Resistant Prostate Cancer. 
Lead Institution: 
The University of Texas MD Anderson Cancer Center 
Supporter: 
Sanofi-aventis, U.S. 
55 Corporate Drive 
Bridgewater, NJ 08807 
 
Principal Investigator:   Paul Corn, M.D., Ph. D. 
1155 Pressler Street, Unit 1374 
Houston, TX 77030 
Telephone: (713) 792-2830 
Fax: (713) 745-1625 
E-mail: pcorn@mdanderson.org 
 
UTMDACC Coordinating Center: The University of Texas MD Anderson Cancer 
Center 
 
Participating Institutions:  
 
Barbara Ann Karmanos Cancer Institute/  
Wayne State University  
Elisabeth I. Heath, M.D.  
4100 John R  
4HWCRC  
Detroit, MI 48201  
Telephone: (313) 576-8715  
Fax: (313) 576-8767  
Email: heathe@karmanos.org


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List of abbreviations 
 
AE 
Adverse event 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
CAT ( or CT scan) 
Computed Axial Tomography 
CBC 
Complete Blood Count 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EKG 
Electrocardiogram 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigators’ Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IST 
Investigator-Sponsored Trial 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSAE 
Non-Serious Adverse Event 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
QOL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
ULN 
Upper Limit of Normal 
WBC 
White Blood Count 


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1.0 INTRODUCTION AND RATIONALE 
 
1.1 Disease Background and Trial Rationale 
 
Docetaxel-based chemotherapy remains first-line therapy for patients with 
metastatic castration-resistant prostate cancer (mCRPC). This practice was 
established in 2004, when data from two randomized phase III trials showed a 
median improvement in survival of approximately two months when 
docetaxel-based regimens were compared to mitoxantrone (1,2).  While the 
prolongation in survival in both studies was statistically significant, the 
relatively short duration of benefit underscored the need for novel agents. 
Although there has not been a standard second-line therapy after progression 
on docetaxel, mitoxantrone with corticosteroids has commonly been used 
based on its ability to provide symptom palliation (3). Other non-taxane 
microtubule targeting agents such as ixabepilone have produced only modest 
objective responses (in both PSA and measurable disease) in phase II trials 
(4). Thus, there is continued interest in identifying chemotherapy agents that 
are active following progression on docetaxel. 
 
The concept that patients can respond to another taxane after progressing on 
docetaxel is important. The recent approval of cabazitaxel by the FDA, based 
upon the results of the phase III TROPIC study demonstrating a survival 
benefit for cabazitaxel over mitoxantrone, provides further validation of this 
concept (5). Cabazitaxel is a novel semi-synthetic taxane developed 
specifically to overcome docetaxel-resistance. In this study, mCRPC patients 
that had progressed during and after treatment with docetaxel were 
randomized to cabazitaxel (25mg/m2 q 3wk) or mitoxantrone (12mg/m2 q 
3wk).  Both arms also received daily prednisone. The median overall survival 
for patients treated with cabazitaxel versus mitoxantrone was 15.1 versus 12.7 
months, respectively. Although not all patients in the TROPIC trial were 
“docetaxel-refractory” (defined by evidence of disease progression during 
therapy or within 30 days of the last taxane dose) it is clear that patients 
derived clinical benefit from cabazitaxel (6). Based on the TROPIC results, it 
is anticipated that cabazitaxel will become the new standard second-line 
therapy for patients with mCRPC who were previously treated with docetaxel. 
This promising advance suggests that further study of cabazitaxel is warranted 
to explore its potential to overcome taxane resistance. 
 
Early studies demonstrated that platinum analogues have demonstrated modest single 
agent activity in patients with mCRPC. Canobbio et al. administered weekly 
carboplatin and reported a pooled response rate of 17%, including reductions in 
prostate-specific antigen (PSA) levels (7). Using a similar weekly regimen, Miglietta 
et al. reported that 28% of patients experienced ≥ 50% decrease in PSA levels and a 
mean duration of response > 6 months (8).  Jungi et al. administered carboplatin on an 


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every-28-day schedule and reported a clinical benefit in 48% of patients, which 
included decreased pain, improved performance status, and stabilization of metastases 
(9). In all three studies, toxicities were rare. 
 
More recent studies have demonstrated clinical responses to platinum- based 
therapy in combination with other agents. The addition of a platinum 
compound to a taxane was first proposed as a rational therapy strategy based 
on preclinical models of ovarian cancer demonstrating synergy between the 
two classes of agents (10). In patients with mCRPC, multiple phase II studies 
have demonstrated significant activity of regimens combining carboplatin 
with a taxane and estramustine in the front-line setting (11-13). Several 
studies, however, have cast doubt on the contribution of estramustine to 
taxane/carboplatin regimens, particularly since estramustine is associated with 
higher toxicity (14,15). Ross et al., tested the activity of docetaxel/carboplatin 
in 34 patients that had progressed during or within 45 days after the 
completion of docetaxel (16). PSA declines of >50% were noted in 18 % of 
patients and measurable responses in 14% of patients. The median duration of 
PSA response was 5.7 months and the therapy was well tolerated. As patients 
in this study would not be anticipated to respond to “re-challenge” with 
docetaxel alone, these results support the hypothesis that carboplatin has the 
potential to overcome docetaxel resistance mechanisms. It has also been 
proposed that the activity of platinum agents in mCRPC is linked to a subset 
of advanced cancers with heterogeneous morphology that display a clinical 
course reminiscent of small-cell prostate carcinomas (SCPCs). We have 
named these variants “anaplastic” based on shared clinical features with 
SCPC, including their responsiveness to platinum-based chemotherapy 
(17,18). 
 
As predicted from their non-overlapping toxicity profiles, the addition of 
carboplatin to a taxane appears to be safe and well-tolerated. In a recent study 
of paclitaxel/carboplatin therapy in 25 patients with mCRPC previously 
treated with docetaxel, Grade 3 or 4 adverse hematologic events occurred in 
11/25 (44%) patients but without neutropenic fever or grade 3-4 non- 
hematological toxicity (19). In a small series of patients with mCRPC who 
received docetaxel/carboplatin after prior taxane-based therapy, mild to 
moderate fatigue was the main adverse event reported (20). There were no 
episodes of febrile neutropenia or peripheral neuropathy reported. In a third 
study of docetaxel/carboplatin in 34 patients with mCRPC who were 
refractory to docetaxel, Grade 3 or 4 adverse events occurred in 56% of 
patients but with only one episode of febrile neutropenia (16). The use of 
growth-factor support was not described in these three reports. 
 
With this background, there is a compelling biologic and clinical rationale to 
combine cabazitaxel with carboplatin. The purpose of the present study is to 
test the hypothesis that the addition of carboplatin to cabazitaxel will be 


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superior to cabazitaxel alone in the patients with mCRPC.  Using a 
randomized, open-label phase II study design, we hypothesize that 
progression-free survival will be longer in patients treated with 
cabazitaxel/carboplatin vs cabazitaxel alone. 
 
The primary endpoint of this study is to demonstrate a 50% improvement in 
median progression free survival (from 2.8 to 4.2 months) when carboplatin is 
added to cabazitaxel versus cabazitaxel alone in patients with mCRPC. 
 
Progression Free Survival (PFS) is the primary endpoint. PFS will be a 
composite endpoint defined as the time from study entry to first occurrence of 
any of the following: 
• Progression of measurable disease by RECIST criteria. To be considered 
measurable, baseline lymph nodes, visceral metastases, and soft tissue 
metastases must be > 1.5 cm in longest dimension. Equivocal RECIST 
progression must be confirmed by a follow up scan > 6 weeks later. 
• Two or more new areas by bone scan attributable to prostate cancer (rather 
than flare) OR new/increasing size of lytic lesions by CT scan or MRI. 
Equivocal progression on bone scan must be confirmed by other imaging 
modalities (eg, CT or MRI) and/or performing a confirmatory bone scan > 
6 weeks later. 
• Need for palliative radiation involving more than one site 
• Surgery or kyphoplasty to any neoplastic bone lesion 
• Cancer-associated clinical deterioration as determined by the treating 
physician. 
 Receipt of any additional prostate cancer specific therapy as prescribed by 
the treating physician. 
 
 
PSA progression alone will not be used to define progression. 
 
With regard to secondary endpoints, we will explore the potential for 
biochemical markers of bone turnover to predict response to therapy. Skeletal 
complications are a major cause of morbidity and mortality in men with 
CRPC. Previous studies have demonstrated that bone specific alkaline 
phosphatase (BAP) and urine N-telopeptides (uNtx) correlate with the 
presence and extent of bone metastases, prognosis, and response to treatment 
(21-23). In this study, we will further explore the potential for BAP and uNtx 
as predictive and prognostic biomarkers in patients with mCRPC receiving 
cabazitaxel-based therapy. 
 
1.2 Drugs 
 
Cabazitaxel (also known as XRP6258 and RPR116258A) is a new taxoid, 
which promotes tubulin assembly in vitro and stabilizes microtubules against 
cold-induced depolymerization as efficiently as docetaxel. Cabazitaxel was 
selected for development based on its pharmacological profile, including a 


2011-0727 
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reduced recognition by the P-glycoprotein (coded by mdr-1 gene), efficacy in 
a broad spectrum of tumor models sensitive as well as resistant or refractory 
to docetaxel and activity against intra-cranial tumors. 
 
Three single-agent dose and schedule finding studies in solid tumors (V101- 
103) to determine the Maximum Tolerated Dose (MTD) and dose-limiting 
toxicities (DLT) of cabazitaxel in patients with advanced solid tumors have 
been completed (24-26). These studies have demonstrated a promising safety 
profile and early clinical activity especially in patients with breast cancer, 
sarcoma, and prostate cancer. A total of 77 patients were treated with 
approximately 241 cycles of the treatment. Doses of 10-30 mg/m2 were 
administered as a one-hour infusion every three weeks in studies V-101 and 
103. The MTD in study V-101 was 30 mg/m2, while it was 25 mg/m2 in study 
V-103. The DLTs were grade 4 neutropenia >5 days and febrile neutropenia 
in V-101 while grade 3 diarrhea at 15 mg/m2 and febrile neutropenia and 
grade 4 neutropenia > 5 days at 25 mg/m2 were DLTs in study V-103. 1.5-12 
mg/m2 doses were administered as a one-hour infusion weekly for 4 weeks 
followed by one-week rest in study V-102. The MTD in study 102 was 12 
mg/m2 while the DLT was grade 3 diarrhea. Major treatment emergent 
adverse events reported regardless of relationship in these phase 1 studies 
were: Fatigue (62-88%), Diarrhea (52-76%), Pain Due to Tumor (43-77%), 
Nausea (32-72%), Sensory Neuropathy (24-60%), Vomiting (24-44%) 
Infection/Febrile Neutropenia (19-39%), Fever (19-33%), Cough (13-29%), 
Dyspnea (13-36%), and Bone Pain (7-28%). 
 
Serious adverse events (SAEs) occurred with similar frequency in study V- 
101 and V-102 (42.9 and 45.2%, respectively), while they occurred in 24% of 
patients in study V-103. The most common SAE was febrile neutropenia and 
most of the SAEs occurred in 1or 2 patients. In study V-101, two patients 
withdrew from the study due to neutropenic infection and peripheral ischemia, 
and 17 deaths were reported, all due to disease progression. In study V-102, 
eight patients withdrew due to adverse events (2 asthenia, 1 sensory 
neuropathy, 1 diarrhea, 1 peripheral edema, 1 dysuria/hematuria, 1 bile duct 
obstruction, and 1 elevated transaminases), and 15 deaths were reported, all 
due to disease progression, except one death due to pneumonia. In study V- 
103, no patient withdrew from the study due to adverse events, and 22 deaths 
were reported, all due to disease progression. 
 
Because of differing MTD reached in studies, the dose of 20 mg/m² 
administered every 3 weeks as a one-hour intravenous (IV) infusion was 
initially selected for further development. A Phase II study (Study 
ARD6191/2001) was performed in metastatic breast cancer (MBC) patients 
who were resistant to prior taxane therapy given either as adjuvant therapy 
(Stratum 1) or as first-line or second-line therapy (Stratum 2) (27). Safety and 
anti-tumoral activity were assessed at the dose of 20 mg/m² every 3 weeks at 


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the first cycle, with possible intra-patient escalation to 25 mg/m2 at Cycle 2 
was allowed in the absence of any toxicity grade >2 at Cycle 1. A total of 71 
patients were treated with a total of 345 cycles of treatment in Arm A. Two 
(2) CR and 8 PR were observed in as treated patients with an overall response 
rate (ORR) of14.1%. The response rates were 14.6% and 9.5% in stratum 1 
and stratum 2, respectively. The median progression free survival time (PFS) 
was 2.7 months and the median overall survival (OS) was 12.3 months. Grade 
3 or 4 neutropenia was reported in 73% in the overall population. Major 
treatment emergent adverse events reported regardless of relationship in this 
phase II study were Fatigue (51%),  Nausea (44%),  Diarrhea (40%),  Myalgia 
(25%), Anorexia (25%),  Weight loss (25%),  Vomiting (24%) 
Infection/Febrile Neutropenia (18%), Headache (18%), Sensory Neuropathy 
(17%), Constipation (16%), and Bone Pain (16%). 
 
In this study, 29.6% of patients reported serious adverse events; most common 
SAEs were hypersensitivity reaction (4.2%), and infection without 
neutropenia (4.2%). Four patients withdrew from the study due to non-fatal 
adverse events (2 elevated transaminases, 1 hepatitis, 1 hypersensitivity 
reaction), while 52 deaths were reported during the study, 50 of them were 
due to disease progression, 1 patient died due to unknown cause, while the 
other died due to shock with respiratory failure. One phase I/II study 
combining Cabazitaxel with capecitabine in Metastatic Breast Cancer patients 
whose disease progressed after anthracycline and taxane is ongoing. The 
MTD in this study was reached with Cabazitaxel at 20mg/m2 on Day 1 and 
capecitabine at 1,000 mg/m2 bid day1 –14, Q3W. Patients in the part 2 
component of the study are being treated with this dose. Cabazitaxel at 25 
mg/m2 in combination with Prednisone every 3 weeks was recently 
investigated in a phase III randomized study in hormone refractory metastatic 
prostate cancer previously treated with a docetaxel-containing regimen. 
Preliminary safety data from both the above studies have shown an acceptable 
safety profile of cabazitaxel either in combination with capecitabine or with 
prednisone. 
 
In the recently completed TROPIC trial, the most common toxic effects of 
cabazitaxel were hematological (5). The most frequent hematological grade 3 
or higher adverse events were neutropenia (82%), leukopenia (68%), and 
anemia (11%). The incidence of febrile neutropenia was 8% but these events 
occurred prior to the routine incorporation of growth factor support. The most 
common nonhematological grade 3 or higher adverse event was diarrhea, 
which was managed expectantly. Grade 3 peripheral neuropathy was 
uncommon (reported in three [1%] patients). Overall, peripheral neuropathy 
(all grades) was reported during the study in 52 (14%) patients in the 
cabazitaxel group. Peripheral edema (all grades) occurred in 34 (9%) patients. 


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Taxanes (paclitaxel or docetaxel) are now commonly used in combination with 
platinum agents (Cisplatin or Carboplatin). The duplets have become the 
mainstay of treatment for NSCLC, ovarian cancer, and several other common 
tumor types (28-31) . A phase I study of weekly Docetaxel and Carboplatin 
(continuous weekly therapy for up to 12 weeks) showed DLT (grade 3/4 
myelotoxicity) at doses of Docetaxel 35 mg/m2 and Carboplatin AUC: 2.5. The 
MTD on this continuous weekly regimen was Docetaxel: 35 mg/m2 and 
Carboplatin AUC: 2 weekly (32). A phase II study of docetaxel (75 mg/m2) 
and carboplatin (AUC=6) as second-line treatment in NSCLC showed the 
median survival was 31 weeks and 1-year survival was 32% (33).  For a full 
list of adverse events related to treatment with carboplatin, please reference the 
prescribing information at the following link: 
 
http://www.health.gov.il/units/pharmacy/trufot/alonim/242.pdf 
 
 
 
2.0 OBJECTIVES 
 
2.1 Primary Objectives 
 
 
• To determine the maximum tolerated dosage (MTD) of cabazitaxel- 
carboplatin in the phase I portion of the study. 
 
• To evaluate progression free survival achieved with cabazitaxel- 
carboplatin versus cabazitaxel alone in men with metastatic castration 
resistant prostate cancer (mCRPC) in the phase II portion of the study. 
 
The objective of this study is to demonstrate a 50% improvement in 
median progression free survival (from 2.8 to 4.2 months) when 
carboplatin is added to cabazitaxel versus cabazitaxel alone in patients 
with mCRPC. 
 
Progression Free Survival (PFS) is the primary endpoint. PFS will be a 
composite endpoint defined as the time from study entry to first occurrence of 
any of the following: 
• Progression of measurable disease by RECIST criteria. To be considered 
measurable, baseline lymph nodes, visceral metastases, and soft tissue 
metastases must be ≥1.5 cm in longest dimension. Equivocal RECIST 
progression must be confirmed by a follow up scan > 6 weeks later. 
• Two or more new areas by bone scan attributable to prostate cancer (rather 
than flare) OR new/increasing size of lytic lesions by CT scan or MRI. 
Equivocal progression on bone scan must be confirmed by other imaging 
modalities (eg, CT or MRI) and/or performing a confirmatory bone scan >6 
weeks later. 
• Need for palliative radiation involving more than one site 
• Surgery or kyphoplasty to any neoplastic bone lesion 
• Cancer-associated clinical deterioration as determined by the treating 
physician. 


2011-0727 
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• Receipt of any additional prostate cancer specific therapy as prescribed by 
the treating physician. 
 
                  PSA progression alone will not be used to define progression. 
 
2.2 Secondary Objectives 
• To assess PSA response rate (percentage of patients with >50 % decline) 
• To correlate changes in bone specific alkaline phosphatase and urine n- 
telopeptides with response 
• To evaluate overall survival. Overall survival is defined as the time 
interval between the time of study entry and date of death. 
• To evaluate safety and toxicity 
• To evaluate influence of the anaplastic phenotype on response to therapy 
• To collect and archive serum, plasma, and urine samples in study patients 
for later hypothesis generating associations. 
 
 
3.0 STUDY PLAN 
 
3.1 Description of the Protocol 
 
This is a multi-center, open label, randomized phase I/II study. Prior to 
initiating randomization, a dose-escalation phase I study will be conducted (at 
MDACC only) to identify the starting doses of cabazitaxel and carboplatin to 
be used in combination for cycle #1 in arm B (see section 5.0). Once those 
doses are established, eligible patients will subsequently be randomized 1:1 
during the phase II portion of the trial to treatment with either: 
 
(A) Cabazitaxel alone 25 mg/m2, plus prednisone 
or 
(B) Cabazitaxel (25 mg/m2) + carboplatin (AUC 4), plus prednisone 
 
All patients receiving treatment in both arms will receive primary prophylaxis 
with colony stimulating factor, either filgrastim or pegfilgrastim. 
 
Randomization between the two treatment arms will occur during the phase II 
portion of the trial. Randomization will be stratified based on: 
• ECOG PS 0 versus ECOG 1/2 
• Chemotherapy naïve vs received prior docetaxel-based chemotherapy 
(responder) vs. received prior docetaxel-based chemotherapy (non- 
responder) vs. received prior chemotherapy other than docetaxel 


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• Anaplastic phenotype (as defined in Inclusion criteria #2) vs 
adenocarcinoma 
 
3.2 Duration of Study Participation 
 
Each patient will be treated until disease progression, death, unacceptable 
toxicity, patient withdrawal, or for a maximum of ten cycles. 
 
 
 
4.0 SELECTION OF PATIENTS 
 
This study will enroll castrate-resistant prostate cancer patients with metastatic 
disease. 
 
4.1 Inclusion Criteria 
 
Inclusion Criteria for All Patients 
 
1.   Histologic evidence of prostate adenocarcinoma. 
 
2.   In addition to patients with adenocarcinoma, patients with “anaplastic” 
features are also eligible as defined by at least one of the following: 
a) Histologic evidence of small cell prostate cancer (patients with small cell 
carcinoma on histology are not required to demonstrate castration-
resistant progression) 
 
b ) Any of the following metastatic presentations:  
(i)  exclusive visceral metastases  
(ii)  radiographically predominant lytic bone metastases identified by 
plain X-ray or CT scan  
(iii)  bulky (>5 cm in longest dimension) lymphadenopathy 
(iv)  Bulky (≥5cm)  tumor mass in the prostate/pelvis 
( v )  Low PSA (≤ 10 ng/ml) at initial presentation (prior to androgen 
ablation or at symptomatic progression in the castrate-setting) 
plus high volume (≥20) bone metastases 
(vi)  Elevated serum LDH (≥ 2 x ULN) or elevated serum CEA (≥ 2 x 
ULN) in the absence of other etiologies 
(vii) Short interval (≤ 180 days) to castrate-resistant progression 
following initiation of hormonal therapy 
 
3.   Castration-resistant prostate cancer. Patients must have surgical or 
ongoing chemical castration (with LHRH agonists or LHRH antagonists), 
with a baseline testosterone level < 50ng/dL. 
 
4.   Metastatic disease. Patients must have evidence for metastatic prostate 
cancer by bone scan and/or CT/MRI (i.e., soft tissue, visceral, lymph 
node). If lymph node, visceral and/or soft-tissue metastases are the only 
evidence of metastasis, at least one lesion must be ≥1.5 cm in diameter. 


2011-0727 
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5.   Patients may have received prior treatment with androgen ablative 
therapies (such as bicalutamide, ketoconazole, DES, abiraterone, Xtandi, 
ARN-509) and/or “targeted” therapies (such as tyrosine kinase inhibitors).   
Androgen ablative therapies must be discontinued >3 days prior to 
initiation of study treatment with the exception of abiraterone and/or 
enzalutamide, which may be continued during study treatment per the 
practice preference of the treating physician. Patients who are predicted to 
benefit from an antiandrogen withdrawal response should be tested for this 
possibility before being considered for eligibility to this study. Targeted 
therapies must be discontinued > 2 weeks before initiation of study 
treatment.  
 
6.   Both chemotherapy-naïve and patients previously treated with 
chemotherapy are eligible. Chemotherapy pretreated patients  may have 
received a maximum of two prior systemic cytotoxic chemotherapies 
completed at least 3 weeks prior to initiation of study treatment. 
 
7.   Patients must have documented evidence of progressive disease as 
defined by any of the following: 
a)  PSA progression: minimum of 2 rising values (3 measurements) 
obtained a minimum of 7 days apart with the last result being at least > 
2.0 ng/mL 
b)  New or increasing non-bone disease (RECIST) 
c)  Positive bone scan with 2 or more new lesions (PCWG2). 
 
8.   For purposes of stratification, patients will be categorized as “responders” 
or “non-responders” based on their response to prior docetaxel-based 
therapy. 
• Responders will have demonstrated objective responses to first- 
line docetaxel as determined by any of the following: 
1.   Decrease in PSA level >50% from baseline, maintained for 
>6 weeks 
2.   Partial or complete response in lymph nodes and soft tissue 
metastases by RECIST 
 
Responders must have received ≥ 225mg/m2 (~ 3 cycles) of 
docetaxel. 
 
• Patients not meeting response criteria above will be considered as 
non-responders. We anticipate 2 general categories of non- 
responders based on the following disease phenotypes: 
1.   Progressive disease on therapy without any objective 
evidence of response (“primary-resistant disease”) 
2.   Progressive disease on therapy with prior objective 
evidence of response, but response duration is < 6 weeks 
(“docetaxel refractory disease”). 
 
Non-responders are eligible even if they have received 
<225mg/m2 of docetaxel 


2011-0727 
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Page 12 
 
 
9.   If present, peripheral neuropathy must be < grade 2 
 
10. The following pretreatment laboratory data within 14 days before 
registration: 
a)  Absolute neutrophil count (ANC) ≥ 1,500/ml(unless due to bone 
marrow infiltration by tumor in which case ANC >500/ml are allowed) 
b)  Platelets ≥ 100,000/ml (unless due to bone marrow infiltration by tumor 
in which case >50,000/ml are allowed) 
c)  Total bilirubin ≤ Upper Limit of Normal with the exception of isolated 
hyperbilirubinemia due to Gilbert’s syndrome or if the patient has liver 
metastases and/or acute tumor-associated illness < 4x ULN.  
d)  SGPT, (ALT) AND/OR SGOT (AST) ≤ 1.5 × the ULN or if patient has 
liver metastases and/or acute tumor-associated illness, ≤  4x ULN.  
e)  Patient has creatinine clearance >30 ml/min. using the Cockroft-Gault 
equation. 
 
 
11.Men whose partner is a woman of childbearing potential must be willing 
to consent to using effective contraception while on treatment and for at 
least 3 months thereafter. 
 
12. Patient or his legally authorized representative must provide written 
informed consent. 
 
13. Age ≥ 18 
 
14. ECOG performance status < 2 
 
4.2 Exclusion Criteria 
 
1.   Radiation therapy (including palliative radiotherapy to a metastatic lesion) 
within 14 days or major surgery (e.g., open abdominal, pelvic, thoracic, 
orthopedic or neurosurgery) within 28 days of the date of the first dose. 
 
2.   Samarium-153 within 28 days of registration, or Strontium-89 within 12 
weeks (84 days) of registration.  Patients who have received 2 or more 
doses of bone-seeking radioisotopes are not eligible. 
 
3.   Current treatment on another therapeutic clinical trial. 
 
4.   Prior treatment with cabazitaxel and/or carboplatin 
 
5.   Impending complication from bone metastases (fracture and/or cord 
compression). Properly treated or stabilized fractures and/or cord 
compression is allowed. 


2011-0727 
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Page 13 
 
 
6.   Presence of ongoing urinary obstruction (e.g., urinary retention, 
hydronephrosis) requiring medical intervention. Properly treated urinary 
obstruction is allowed. 
 
7.   Patient has an uncontrolled intercurrent illness (e.g., uncontrolled diabetes, 
uncontrolled hypertension). 
 
8.   Patient has another serious medical or psychiatric illness that could, in the 
investigator’s opinion, potentially interfere with the patient’s ability to 
provide informed consent or with the completion of treatment according to 
this protocol. 
 
9.   Patients with a history of severe hypersensitivity reaction to JEVTANA® 
(cabazitaxel) or other drugs formulated with polysorbate 80. 
 
10. Patients with an active second malignancy that could, in the investigator’s 
opinion, potentially interfere with the patient’s ability to participate and/or 
complete this trial. 
 
 
 
5.0 STUDY DRUG ADMINISTRATION 
 
5.1 Dosing Regimens for phase I 
 
Prior to initiating the randomized phase II portion of the study, a dose 
escalation phase  I schema will be utilized  to acquire safety data and select the 
optimal starting doses of cabazitaxel and carboplatin for cycle # 1 for 
subsequent patients enrolled on Arm B. 
 
As shown below, cohorts of 3 to 6 patients will be treated with cabazitaxel and 
carboplatin every 3 weeks. The starting dose for cabazitaxel will be 20 mg/m2 
and the starting dose for carboplatin will be an AUC of 3 (dose level 0). 
 
 
 
Table 1. Dose Escalation Schedule 
 
Dose Levels 
Cabazitaxel 
Carboplatin 
0 
20 
AUC 3 
 
1 
20 
 
2 
25 
AUC 4 
 
AUC 4 


2011-0727 
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Page 14 
 
 
The dose escalation criteria as described in Table 1 must be met at each dose 
level during cycle 1 in order to enroll and treat patients at the next dose level. 
 
Applying the 3+3 design, the first cohort of 3 patients will be treated at dose level 
0. The algorithm is as follows: (1) If 0 out of 3 patients experiences DLT, the next 
cohort of 3 patients will be treated at the next higher dose level.  (2) If 1 out of 3 
patients develop a DLT, additional 3 patients will be treated at the same dose level.  
If no more DLT develops at the dose, i.e. 1 out of a total of 6 patients develops 
DLT, the dose escalation continues for the next cohort of 3 patients. 
(3) At any given dose, if greater than 1 out 3 patients or 1 out of 6 patients 
experience DLT, the dose level exceeds the MTD and 3 more patients will be 
treated at the next lower dose if there are less than 6 patients already treated at that 
dose.  The MTD is the highest dose studied in which one or fewer of 6 patients 
have a DLT. 
 
Dose-Limiting Toxicities (DLT) and Maximum Tolerated Dose 
(MTD): 
To qualify for DLT, the clinical adverse event (AE) or laboratory 
abnormality should be drug related as assessed by the treating physician, principal 
investigator, or sponsor. The DLTs will be defined (according to NCI-CTCAE v 4 
grading scale) during the first treatment cycle as follows: 
 
Non-hematological toxicity (grade 3 or 4 only) except: 
• Grade 3 fever without documented infection 
• Grade 3 nausea, vomiting, or diarrhea in the absence of effective maximal 
therapy 
• Grade 3 mucositis/stomatitis in the absence of effective 
symptomatic treatment 
• Grade 3 fatigue 
• Grade 3 anorexia 
• Grade 3 Liver function test abnormalities elevation that returns to baseline 
prior to next treatment cycle 
• Peripheral neuropathy grade 3 that returns to grade 1 or less at the initiation of 
next treatment cycle 
 
Hematological toxicity: 
• Febrile neutropenia: fever with  clinically or microbiologically 
documented infection ≥ 38.5°C with neutropenia grade 3 or 4 
• Neutropenia grade 4 lasting >7 days 


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• Thrombocytopenia grade 4 >7 days 
 
In case of the occurrence of one DLT at the first cycle, 3 additional patients will be 
included at the same dose level in order to reach the total number of 6 evaluable 
patients. A patient will be considered to be evaluable for the toxicity if s/he has 
received at least one administration of Cabazitaxel and has adequate follow-up in 
the 1st cycle. Patients who are not treated or are withdrawn during the first 3 weeks 
of treatment for reasons other than DLT and before the MTD is determined will be 
replaced. 
 
Analysis of safety data from these patients will be utilized by the Principal 
Investigator and Supporter to select the optimal starting doses of cabazitaxel to 
be used in combination with carboplatin for subsequent patients enrolled on the 
Randomized Phase II portion of the study. Although we do not expect severe 
toxicity with the proposed combinations, we will assure patient safety through 
clinical vigilance during the combination phase. The assigned research nurse 
and the Principal Investigator will review all study patients at weekly intervals 
during the combination treatment portion of the trial. Any unusual clinical 
observations will be discussed immediately with the Principal Investigator or a 
sub-investigator if the PI is absent or not available.  
 
Results from these analyses will be reported to an independent Data Monitoring 
Committee (DMC) convened at MDACC. The DMC will assess results along with 
supportive data including other efficacy outcomes and safety data. It will use this 
data to possibly recommend early stopping or other study modifications. 
 
5.2 Dosing Regimens for phase II 
 
Arm A: Cabazitaxel 25 mg/m² intravenously on Day 1 of each 3 week cycle, 
plus prednisone 5 mg PO BID. 
 
Arm B: Cabazitaxel 25 mg/m² + carboplatin AUC 4 intravenously on 
Day 1 of each 3 weeks cycle, plus prednisone 5 mg PO BID 
 
All patients in Arms A and B will receive primary prophylaxis with colony 
stimulating factor, either filgrastim or pegfilgrastim. 
 
Cabazitaxel and carboplatin each will be administered intravenously over 60 
minutes. 
 
5.3 Pre-medications: 
Cabazitaxel will be given before carboplatin to limit myelosuppression. 
Required IV premedications will include an antihistamine (diphenhydramine 
25 mg, or other antihistamine), steroid (dexamethasone 20 mg or equivalent 
steroid), and H2 antagonist (Ranitidine or other H2 antagonist with the 
exception of cimetidine). These premedications will be administered by IV 
infusion, at least 30 minutes prior to each dose of cabazitaxel.  Antiemetic 


2011-0727 
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prophylaxis with ondansetron, granisetron, or dolasetron can be administered 
whenever it is necessary. 
 
All patients will receive primary prophylaxis with growth factor support per 
standard practice. 
 
5.4 Description of Cycles/Treatment Delay 
Each cycle will be 3 weeks in duration. For cycles 2 through 10, new cycles of 
therapy may not begin until ANC ≥ 1,500/mm3, platelet count ≥ 75,000/mm3, 
and non-hematological toxicities (except alopecia) have recovered to grade ≤ 
1. Patients will be monitored closely for toxicity. In addition to optimizing 
supportive care, chemotherapy doses may be adjusted after the first cycle of 
therapy and/or recovery to grade ≤ 1. Each patient will be treated until disease 
progression, death, unacceptable toxicity or for a maximum of up to ten 
cycles. At completion of study treatment, prednisone may be discontinued per 
the practice preference of the treating physician. 
 
5.5 Cabazitaxel is a substrate of the cytochrome P450 (CYP) 3A4 isoenzyme and 
P-glycoprotein (Pgp).  Concomitant use of cabazitaxel with strong CYP3A4 
inhibitors is expected to increase cabazitaxel concentrations, and should be 
avoided if possible.  Concomitant use with strong CYP3A4 inducers is 
expected to reduce cabazitaxel concentrations, and should be avoided if 
possible.  Consider alternative therapies that do not inhibit or induce the 
CYP3A4 isoenzyme. 
 
 
 
6.0 PATIENT EVALUATION 
6.1 Pretreatment Evaluation: 
 
6.1.1 History and physical examination within 28 days of trial registration, 
to include: prior local therapies, prior and/or current hormonal 
treatment, prior systemic therapies (chemotherapy, strontium-89, etc), 
current symptoms and performance status, current medications and 
cardiovascular assessment, residual toxicities from prior therapies 
should be recorded using CTCAE v.4.0, vital signs, height and weight. 
 
6.1.2 Laboratory studies to be obtained within 28 days of trial registration: 
serum chemistries (sodium, potassium, chloride, carbon dioxide, 
magnesium, glucose, calcium, phosphorus, BUN, albumin, total 
protein, bone specific and total alkaline phosphatase, total bilirubin, 
LDH), testosterone, PSA, CEA, PAP, chromogranin A, calcitonin, 
somatostatin, Circulating Tumor Cells (CTCs) and urine for N-
telopeptides. 
 
6.1.3 Laboratory studies within 14 days of trial registration: CBC with 
differential and platelets, creatinine, ALT and/or AST, total 
bilirubin 


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Page 17 
 
6.1.4  Between 42 days prior and 28 days after  trial registration,  patients 
with small cell  cancer must  have an MRI scan of the brain or CT 
scan of the brain with IV contrast. Patients with anaplastic cancer 
(i.e. those meeting by criteria OTHER than small cell) should be 
strongly considered for brain imaging according to the same 
guidelines at the final discretion of the treating physician. 
 
6.1.5 Within 28 days prior to trial registration, ECG, bone scan, chest x-ray, 
and CT or MRI scan of the abdomen /pelvis.  Patients with abnormal 
findings on chest x-ray should have chest CT scan per the judgment of 
the treating physician. 
 
6.1.6 MDACC Only: 
With consent of the patient, blood, bone marrow biopsy and aspirate 
will be collected within 28 days of treatment start for all patients 
enrolled on the phase II portion of the study (see Appendix D). 
Previously collected specimens (if obtained and available within 12 
weeks of protocol entry) may be requested to substitute for the pre-
treatment procedure (to obviate the need for a second biopsy prior to 
initiating therapy on study). For patients enrolled on the phase I 
portion of the study, this procedure is optional. Patients on the phase 
II portion of the study will also be asked for optional collections at 
time of best response and/or progressive disease. 
 
6.2 On-study Evaluation: 
 
6.2.1 Before every cycle of chemotherapy (+2 days), disease specific 
physical examination (by physician and/or advanced practice nurse), 
interim history pertaining to any change from baseline, current 
medications, assessment of ECOG performance status, and 
treatment-related toxicities will be taken. Laboratory studies should 
include CBC with differential and platelets and serum chemistries 
(sodium, potassium, chloride, carbon dioxide, glucose, magnesium, 
calcium, phosphorus, albumin, total protein, BUN, creatinine, LDH, 
AST and/or ALT, total alkaline phosphatase, total  bilirubin), bone 
specific alkaline phosphatase, PSA and urine for N-telopeptides. Lab 
studies should be performed within 7 days prior to each cycle of 
chemotherapy. 
 
At each visit and when reported by the patient, concomitant treatments 
and medications must be recorded. 
 
6.2.2 After each cycle of chemotherapy: Laboratory studies including CBC 
with differential and platelets, electrolytes (sodium, potassium, 
chloride, carbon dioxide), BUN, creatinine, magnesium, total bilirubin 
and ALT and/or AST  are to checked 7-10 days after the administration 
of cycle #1 of chemotherapy. For subsequent cycles, these labs are 
strongly recommended but not mandated. 
 
 


2011-0727 
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Page 18 
 
6.2.3    After every 2 cycles of chemotherapy, tumor response will be 
assessed. This should include bone scan and CT or MRI scan of 
abdomen/pelvis. Patients with abnormal findings on baseline 
CT scan of the chest should have repeat chest CT scan per the 
judgment of the treating physician. 
Tumor response will be assessed after every 2 cycles of therapy. In 
practice, this will correspond to evaluations performed prior to 
initiating cycles 3, 5, 7, 9 and 10 of therapy.  Two cycles will typically 
take 6 weeks. However, since up to a 2 week delay in treatment for any 
reason is permitted, 2 cycles may last up to (and including) 8 weeks. 
Restaging studies should be performed within 7 days of initiating the 
next cycle of chemotherapy. 
 
Testosterone will be repeated at restaging timepoints. CEA, PAP 
and CTCs will be repeated at restaging timepoints IF elevated at 
baseline. 
 
6.2.4 Optional blood/tissue collection at maximal response and at disease 
progression (MDACC only).  At the time of maximal response and/or 
at End of Treatment, blood, bone marrow biopsy and aspirate will be 
collected as described in Appendix D. Maximal response will be 
determined by the treating physician when PSA levels have reached a 
nadir and/or radiographic studies demonstrate best overall response. 
 
6.2.5 End of Treatment evaluation. +/-14 days of the time when the 
patient is taken off treatment, the following will be obtained: 
 
• Physical examination, interim history pertaining to any change 
from baseline, current medications and treatment-related toxicities 
will be taken and recorded. 
• CBC with differential and platelets and serum chemistries (sodium, 
potassium, chloride, carbon dioxide, glucose, magnesium, calcium, 
phosphorus, albumin, total protein, BUN, creatinine, LDH, AST 
and/or ALT, total alkaline phosphatase, total  bilirubin), bone 
specific alkaline phosphatase, PSA, testosterone and urine for N-
telopeptides.  CEA, PAP and CTCs will only be performed IF 
elevated at baseline. 
• Imaging studies used for the assessment of response (bone scan, 
CT or MRI of abdomen and pelvis will be obtained if not done 
within 28 days of the off-treatment date.  Patients with abnormal 
findings on baseline CT scan of the chest should have repeat 
chest CT scan per the judgment of the treating physician. 
 
6.2.6 Survival update: Survival updates will take place at 6 month intervals 
from the off treatment date. This will consist of a phone call or 
medical record review 


2011-0727 
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Page 19 
 
6.3 Study Calendar 
 
 
Screening 
Cycle 
 
Day 7 -10 
(cycle 1 only) 
After 
Every 2 
cycles 
End of  
i 
Treatment 
Follow- 
Upf 
Chemotherapy 
 
x 
 
 
 
 
Medical History 
xa 
x 
 
 
x 
 
Physical examination 
xa 
x 
 
 
x 
 
Height and Weight 
xa 
 
 
 
 
 
ECOG performance status 
xa 
x 
 
 
x 
x 
Adverse Event Monitoring 
 
x 
 
 
 
 
CBC, differential, platelet 
count 
x
c
 
x 
xe 
 
 
x 
 
Serum Chemistryd 
xa,c 
x 
xe 
 
x 
 
Testosterone  
x 
 
 
x 
 
 
PSA, Bone Specific Alkaline 
Phosphatase, uNTX, 
xa 
 
x 
 
 
 
x 
 
CEA, PAP, Circulating Tumor 
Cells (CTCs) 
xa 
 
 
xg 
xg 
 
chromogranin A, calcitonin, 
somatostatin 
xa 
 
 
 
 
 
 CT/MRI  Abd and Pelvis 
xa 
 
 
 
x 
 
x 
 
Chest X-ray 
xa 
 
 
 
 
 
CT/MRI of the chest  
xj 
 
 
xj 
xj
 
 
Bone scan 
xa 
 
 
x 
x 
 
Brain CT or MRI scan 
xb 
 
 
 
 
 
ECG 
xa 
 
 
 
 
 
Survival Follow-up 
 
 
 
 
 
x 
Blood for Correlative Studies 
xh 
xh 
 
 
xh 
 
BMA/BX for Correlative 
Studies 
h 
x 
 
 
 
xh 
 
a Within 28 days of registration 
b Between 42 days prior and 28 days after  trial registration,  patients with small cell  cancer must  have 
an MRI scan of the brain or CT scan of the brain with IV contrast. Patients with anaplastic cancer (i.e. 
those meeting by criteria OTHER than small cell) should be strongly considered for brain imaging 
according to the same guidelines at the final discretion of the treating physician. 
c Within 14 days of registration 
d Serum chemistries consist of sodium, potassium, chloride, carbon dioxide, glucose, magnesium, calcium, 
phosphorus, albumin, total protein, BUN, creatinine, LDH, AST and/or ALT, total alkaline phosphatase, 
total  bilirubin,. At screening, creatinine, ALT and/or AST, and total bilirubin must be done within 14 
days of registration. The remaining chemistry tests must be done within 28 days of 
registration. 
e Laboratory studies to be done Day 7 to 10 of Cycle 1 include CBC with differential and platelets, 
electrolytes (sodium, potassium, chloride, carbon dioxide), BUN, creatinine, magnesium, total 
bilirubin and ALT and/or AST are to be checked 7-10 days after the administration of Cycle 1 of 
chemotherapy. For subsequent cycles, these labs are strongly recommended but not mandated. 
f  Every 6 months from off treatment date. 
g Only repeat IF elevated at baseline. 
h Fo r p atie nts o n p ha s e II: blood, bone marrow biopsy and aspirate will be collected for 
correlative studies at screening (mandatory) and again at the time of maximal response and/or at disease 
progression (optional). Blood will also be collected after every 3 weeks before each cycle. 


2011-0727 
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Page 20 
 
 
i Within 14 days of stopping treatment on the study. Imaging scans will only be repeated at this visit 
if not done within the past 28 days. 
j At the judgment of the treating physician 
 
 
 
7.0 CORRELATIVE STUDIES (MD ANDERSON ONLY) 
 
In an attempt to develop biomarkers that predict response to taxane-based 
therapy, blood, bone marrow aspirate, and tissue will be collected, analyzed 
and archived to serve as a resource for future IRB approved studies.  Refer to 
Appendix D for collection and storage procedures.  Refer to Appendix H for 
description of biomarker analysis. 
 
All samples will be encoded with a unique identifier at the time of collection.  
This unique identification number will be cross-referenced to the GU Research 
Laboratory database that stores the medical records of the patients who have 
consented to this protocol.  Access to the database is limited to the research 
personnel of the GU Medical Oncology research office.  All requests for use of 
this material must be in the context of IRB approved protocols. 
 
 
 
8.0 DOSE MODIFICATIONS/TOXICITY MANAGEMENT FOR CYCLES 2 
THROUGH 10 
 
Criteria for Toxicity and Treatment Modification: All toxicities encountered 
during the study will be evaluated according to the grading system in NCI 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0).  
Every effort will be made to administer the full dose regimen to maximize 
dose-intensity. If possible, toxicities will be managed symptomatically. If 
toxicity occurs, the appropriate treatment will be used to ameliorate signs and 
symptoms including antiemetics for nausea and vomiting, and antidiarrheals 
for diarrhea.  
 
If cabazitaxel and carboplatin treatment must be delayed due to toxicity, a 
maximum of 2 weeks delay is allowed. If treatment has to be delayed for 
more than 2 weeks for toxicity, the patient should come off treatment. 
 
 
8.1 Dose reductions 
 
The cabazitaxel dose can be reduced one time from 25 to 20 mg/m2 when 
necessary as described below. The carboplatin dose can be reduced two 
times from AUC 4 to AUC 3, and from AUC 3 to AUC 2 when 
necessary as described below. Once reduced, doses cannot be re-
escalated. 
 
 
 


2011-0727 
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Page 21 
 
Table 3. Permissible Dose Reductions 
Initial 
dose 
First Dose 
Reduction 
Second Dose 
Reduction 
Third Dose 
Reduction 
cabazitaxel 
25 mg/m2 
20mg/m2 
None, must come 
off treatment 
Not applicable 
carboplatin 
AUC 4 
AUC 3 
AUC 2 
None, must 
come off 
treatment 
 
 
8.2 Dose modifications for hematologic toxicity 
 
No dose reductions or interruptions are required for anemia as it can be 
managed by RBC transfusion. According to the value observed at the 
date of the planned retreatment, new cycles of therapy may not begin 
until ANC ≥ 
1,500/mm3, platelet count ≥ 75,000 /mm3. 
 
If cabazitaxel and carboplatin treatment must be delayed due to 
hematologic toxicity, a maximum of 2 weeks delay is allowed. If 
treatment has to be delayed for more than 2 weeks for toxicity, the 
patient should come off treatment.  
 
Table 4: Dose modifications for hematologic toxicity, worst grade 
during previous cycle1. 
Arm A 
Arm B 
Toxicity 
Cabazitaxel2 
Cabazitaxel2 
Carboplatin3 
Grade 3-4 neutropenia 
for < 7days 
None 
None 
None 
Grade 4 neutropenia for 
>7 days 
Dose Reduce 
Dose Reduce 
None 
Grade 3-4 febrile 
neutropenia 
Dose Reduce 
Dose Reduce 
Dose Reduce 
Grade 4 
Thrombocytopenia 
Dose Reduce 
None 
Dose Reduce 
 
1All toxicities encountered during the study will be evaluated 
according to the grading system in NCI Common Terminology 
Criteria for Adverse Events v4.0 (CTCAE v4.0). 
2May reduce cabazitaxel to a minimum dose of 20 mg/m2. If 
further toxicity, the patient must come off treatment. 
3May reduce carboplatin to a minimum dose of AUC 2. If further 
toxicity, the patient must come off treatment. 
 
8.3 Dose modifications for hepatic toxicity 
In case of increase of ALT and/or AST to > 1.5 x ULN or bilirubin to > 
ULN, delay study drug treatment for up to 2 weeks until ALT and/or AST 
returned to ≤ 1.5 x ULN and bilirubin to ≤ ULN. In patients with liver 
metastases who had elevated values at baseline up to < 4x ULN, delay 
study treatment for up to 2 weeks until ALT and/or AST and/or bilirubin 


2011-0727 
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Page 22 
 
have returned to <baseline values. Then retreat patient at reduced dose of 
cabazitaxel for the next cycle. The cabazitaxel dose may be reduced to a 
minimum of 20 mg/m2. 
8.4 Dose modifications for renal insufficiency 
Carboplatin dose should be held if creatinine clearance drops to ≤ 15 ml/min. 
The cause of renal insufficiency will be investigated and corrected if possible. 
If creatinine clearance returns to ≥ 16 ml/min based on the Cockroft-Gault 
formula within 2 weeks of treatment interruption, treatment can be resumed at 
the prior carboplatin dose. 
 
8.5 Nausea and vomiting 
A prophylactic anti-emetic treatment should be given to the patients in all 
cycles. The use of a 5HT3 antagonist is recommended, for example 
ondansetron 8-16 mg IV or equivalent.More aggressive anti-emetic 
prophylaxis (i.e., ondansetron, etc.) should be given to the patient who has 
experienced grade ≥ 3 nausea/vomiting in a preceding cycle. If despite the 
appropriate medication, grade ≥ 3 nausea/vomiting still occur, reduce the 
cabazitaxel dose. If further toxicity, the patient must come off treatment. 
If despite dose reduction, nausea/vomiting still occur at grade ≥ 3, the patient 
will go off treatment. 
 
8.6 Diarrhea 
No prophylactic treatment for diarrhea is recommended in Cycle 1. However, 
following the first episode of diarrhea, the patient should receive symptomatic 
treatment with loperamide 4 mg orally and then 2 mg orally following each 
new episode until recovery of diarrhea (no more than 16 mg daily). If despite 
the use of loperamide, grade ≥3 diarrhea still occurs, reduce the cabazitaxel 
dose.  If despite dose reduction, diarrhea still occurs at grade ≥3, the patient 
will go off study. 
 
8.7 Hypersensitivity Reactions 
Hypersensitivity reactions that occur despite premedication are very likely to 
occur within a few minutes of start of the first or of the second infusion of 
cabazitaxel. Therefore, during the 1st and the 2nd infusions, careful evaluation 
of general sense of wellbeing and of blood pressure and heart rate will be 
performed for at least the first 15 minutes, so that immediate intervention 
would occur in response to symptoms of an untoward reaction. Facilities and 
equipment for resuscitation along with the medications (i.e., antihistamine, 
corticosteroids, and epinephrine) must be immediately available. If a reaction 
occurs, the specific treatment that can be medically indicated for a given 
symptom (e.g., epinephrine in case of anaphylactic shock, etc.) will be 
instituted as per Institutional Guidelines and/or physician preference. For 
management suggestions of acute hypersensitivity, please see Appendix E. 


2011-0727 
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Page 23 
 
8.8 Stomatitis 
If grade 3 or worse stomatitis occurs, study drug(s) should be withheld until 
resolution to grade ≤ 1. Treatment may then be resumed, but the dose of study 
drug(s) should be reduced as permissible for all subsequent doses. In case of 
grade 4 stomatitis, the patient will go off treatment. 
 
 
8.9 Peripheral neuropathy 
In case of symptoms or signs experienced by the patient, dose modification 
should be performed 
Grade ≤1: No change 
Grade 2: Re-treat with reduced dose of cabazitaxel 
Grade 3: Patient will go off protocol therapy 
 
8.10  Other Toxicities 
Alopecia and nail changes will not require dose modification. 
 
In case of DVT/PE, treatment (all chemotherapy drugs) will be held at least 
for 1 week and restarted after initial treatment of the thromboembolic event, if 
the attending physician and the PI concur that this is to the benefit of the 
patient. 
 
For other Grade 2 non-hematological toxicity that is troublesome and 
intolerable, treatment should be held and patient re-evaluated.  If toxicity 
resolves to Grade 1 or less, therapy can be resumed at the same dose if 
deemed safe by the treating physician. . 
 
For Grade 3 or 4 non-hematological toxicity, treatment must be held and 
patient re-evaluated.  If toxicity resolves to Grade 1 or less, therapy may be 
resumed at the same dose if deemed safe by the treating physician. In cases of 
Grade 3-4 non-hematological toxicity that resolves to Grade 2 or less, therapy 
will be resumed with a reduced dose of cabazitaxel. 
 
Recurrent Grade 3 or 4 non-hematological toxicities not resolved with 
permissible dose reductions or any delay in scheduled therapy for more than 2 
weeks secondary to any form of toxicity must result in study withdrawal. 
 
 
 
9.0 ASSESSMENT OF RESPONSE 
 
Anti-tumor activity will be assessed using computerized tomography (CT) or 
magnetic resonance imaging (MRI) and bone scan. Complete imaging of the chest, 
abdomen, pelvis (by CT or MRI) and skeleton (by bone scan).  After treatment 
initiation, these assessments will be repeated after every 2 cycles of therapy, 


2011-0727 
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Page 24 
 
 
whenever disease progression is suspected, and at the end of treatment/withdrawal 
visit. 
 
Progression Free Survival (PFS) is the primary endpoint. PFS will be a composite 
endpoint defined as the time from study entry to first occurrence of any of the 
following: 
• Progression of measurable disease by RECIST criteria. To be considered 
measurable, baseline lymph nodes, visceral metastases, and soft tissue 
metastases must be ≥1.5 cm in longest dimension. Equivocal RECIST 
progression must be confirmed by a follow up scan > 6 weeks later. 
• Two or more new areas by bone scan attributable to prostate cancer (rather than 
flare) OR new/increasing size of lytic lesions by CT scan or MRI. Equivocal 
progression on bone scan must be confirmed by other imaging modalities (eg, 
CT or MRI) and/or performing a confirmatory bone scan > 6 weeks later. 
• Need for palliative radiation involving more than one site 
• Surgery or kyphoplasty to any neoplastic bone lesion 
• Cancer-associated clinical deterioration as determined by the treating 
physician. 
• Receipt of any additional prostate cancer specific therapy as prescribed by the 
treating physician. 
 
PSA progression alone will not be used to define progression. 
 
 
 
10.0  CRITERIA FOR RESPONSE AND PROGRESSION 
 
10.1  Measurable Disease Evaluation 
Evaluation of measurable disease response will follow the Response 
Evaluation Criteria in Solid Tumors (RECIST) Guidelines. All tumor 
measurements must be recorded in centimeters. 
 
10.1.1  RECIST CRITERIA 
Target Lesions: All measurable lesions up to a maximum of five lesions per 
organ and 10 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. Target 
lesions should be > 1.5 cm in longest dimension and have suitability for 
accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest dimension for all target lesions will be 
calculated and reported as the baseline sum of longest diameter. The 
baseline sum of longest dimensions will be used as the reference by which 
the objective tumor response is characterized. For equivocal RECIST 
progression, assessment must be confirmed by a second scan 6 or more 
weeks later at the discretion of the treating physician. 


2011-0727 
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Non-target Lesions: All other lesions (or sites of disease) should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up. 
 
10.2  Criteria for Response 
 
10.2.1  Evaluation of Target Lesions: 
 
Complete Response: The disappearance of all target lesions. 
 
Partial Response: At least a 30% decrease in the sum of the longest 
diameter of target lesions, taking as reference the baseline sum longest 
diameter. 
 
Progressive Disease: At least a 20% increase in the sum of the longest 
diameter of target lesions, taking as reference the smallest sum longest 
diameter recorded since the treatment started or the appearance of one 
or more new lesions. 
 
Stable Disease: Insufficient shrinkage to qualify for partial response, or 
insufficient increase to qualify for progressive disease, taking as 
reference the smallest sum longest diameter since the treatment started. 
 
10.2.2  Non-Measurable Disease Evaluation 
 
Criteria for Evaluation of Bone Disease 
 
Progression of Bone disease is defined as two or more new areas by 
bone scan attributable to prostate cancer (rather than flare) OR 
new/increasing size of lytic lesions by CT scan or MRI. Equivocal 
progression   on bone scan must be confirmed by other imaging 
modalities (e.g., CT or MRI) and/or performing a confirmatory bone 
scan > 6 weeks later. 
 
 
 
11.0  CRITERIA FOR REMOVAL OF PATIENTS FROM STUDY 
 
Patients will be removed from study if they meet any of the following criteria: 
• Receipt of 10 cycles of therapy 
• Disease progression 
• Unacceptable toxicity 


2011-0727 
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Page 26 
 
 
• Patient decision to withdraw 
• Palliative radiation involving more than one site if in the judgment of the 
investigator, further treatment would not be in the best interest of the patient. 
 
 
12.0  PHARMACY 
 
12.1  Drug Formulations 
 
JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL (NDC 0024-5824-11) is 
supplied as a kit consisting of the following: 
• JEVTANA Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 
mL polysorbate 80, 
• Diluent for JEVTANA Injection 60 mg/1.5 mL: contains approximately 
5.7 mL of 13% (w/w) ethanol in water for injection 
 
Please refer to the Package Insert (Appendix G) for preparation instructions 
and other additional information about the study drug. 
 
 
Commercially available carboplatin will be used for this study and will be 
billed to the patient’s medical insurance. Carboplatin is a crystalline powder 
with the molecular formula of C6H12N204Pt 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 5-7. Carboplatin Injection is supplied as a sterile, pyrogen- 
free solution available in 10 mg/mL multiple-dose vials containing 50 mg, 150 
mg, or 450 mg of carboplatin for administration by intravenous infusion. Each 
mL contains: carboplatin 10 mg and water for injection to volume. 
 
Commercially available prednisone will be used for this study. As a standard 
treatment, it should be billed to the patient’s medical insurance. 
 
12.2  Packaging and labeling 
 
This is an open-label study. The investigational product (cabazitaxel) will be 
packaged in sealed, sterile, single-use vials. The vials containing the 
investigational product and the kits they are packaged in will be labeled as 
follows: 
a.   Supporter’s name and address 
b.   Study number 
c.   Dosage form 


2011-0727 
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d.   Storage conditions 
e.   Packaging reference number 
 
Batch number and number of vials dispensed to each subject must be recorded 
in the eCRF/drug accountability form. Each clinical site will be responsible 
for obtaining commercially available carboplatin. 
 
 
12.3  Storage Conditions 
 
The investigator or pharmacist will inventory and acknowledge receipt of all 
shipments of the investigational product. The investigational product must be 
kept in a locked area with restricted access. The investigational product must 
be stored and handled in accordance with local regulations, labeling 
specifications, policies, and procedure. 
 
The investigator or pharmacist will also keep accurate records of the 
quantities of the investigational products dispensed and used for each subject. 
The study monitor will periodically check the supplies of investigational 
product held by the investigator or pharmacist to verify accountability of all 
investigational product used. 
 
12.4  Concomitant Medications and Therapy 
 
Concomitant therapy with other investigational drugs or immunotherapy is not 
permitted. 
 
Concomitant radiotherapy is not permitted, except when radiotherapy is used 
to palliate bone lesions involving ≤ 25% of the bone marrow. 
 
Supportive care, including but not limited to antiemetic medications, may be 
administered at the discretion of the Investigator. Concurrent treatment with 
bisphosphonates or RANK Ligand inhibitors is allowed for those patients who 
received stable doses prior to study entry. However, patients are not allowed 
to initiate these agents during the study. 
 
 
13.0  STATISTICAL CONSIDERATIONS 
 
This is a randomized, phase II trial to compare cabazitaxel alone (control) versus 
cabazitaxel/carboplatin (experimental). The primary endpoint is progression free 
survival. We hypothesize that progression-free survival will be longer in patients 
treated with cabazitaxel/carboplatin vs cabazitaxel alone. Recent phase III data 
comparing cabazitaxel to mitoxantrone monotherapy showed that cabazitaxel 


2011-0727 
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improved overall survival (from 12.7 to 15.1 months) and progression-free survival 
(from 1.4 to 2.8 months) over mitoxantrone. 
 
13.1  Group sequential design: 
 
The primary outcome for treatment evaluation will be progression free 
survival (PFS) time. The goal will be to test the hypothesis that 
cabazitaxel/carboplatin provides a 50% improvement in m = median PFS, 
from 2.8 to 4.2 months. An accrual rate of 3 patients per month will be 
assumed. A two-sided group sequential procedure will be used  with overall 
type I error 0.1 and power 0.80 to detect the alternative m = 4.2 months, with 
interim tests  including both outer bounds for superiority and inner bounds for 
futility (34).  The alpha-spending function corresponds to the O'Brien- 
Fleming boundaries.  The final data analysis will be performed after the last 
patient has been followed at least 6 months or at least 150 events are 
observed.  We will conclude the experimental arm is better than the control 
arm if the z-score in the final analysis is greater than 1.662. All tests will be 
based on a standardized log rank statistic, and will be performed using the 
following cut-offs (35).  The number of patients accrued (sample size) 
required to achieve the necessary numbers of events required by the group 
sequential tests will be 160 in total (80 per arm). 
 
Table 5: The outer bounds for superiority and inner bounds for futility in the interim 
analysis based on a group sequential design using statistical software East version 
5.2. 
 
No. Events 
Z-score cut-off to reject the null 
hypothesis (Superiority) 
Z-score cut-off to accept the null 
hypothesis (Futility) 
78 
+/- 2.538 
+/- 0.246 
 
13.2  Secondary outcomes: 
Additional outcomes that will be recorded and analyzed will include overall 
survival (OS) time, grade 3 or 4 toxicity. In each treatment arm, the 
probability of a life-threatening drug-related toxicity will be monitored based 
on a beta-binomial model, assuming a priori that p = Prob(toxicity) ~ beta(0.5, 
1.5). The trial will be terminated if 
Prob(p > 0.25 | data) > 0.85. 
 
 
This rule will stop a treatment arm if [# patients with toxicity]/[# patients 
evaluated]  >= 2/3, 3/6, 4/9, 5/12, 6/15, 7/18, 8/22, 9/25, 10/29, 11/32, 12/35, 
13/39, 14/42,15/46, 16/49, 17/53, 18/56, 19/60, 20/64, 21/67, 22/71, 23/74, 
24/78 or 25/80. The operating characteristics for toxicity are summarized in 
Table 6. 
 
 
 
 
 
 


2011-0727 
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Table 6. Operating characteristics based on 1000 simulation study 
 
true Prob(tox) 
Pr(stop) 
Mean # Pts (25%, 75%) 
0.05 
0.01 
80 (80, 80) 
0.15 
0.11 
72 (80, 80) 
0.25 
0.47 
50 (9, 80) 
0.35 
0.93 
21 (2, 28) 
0.45 
0.99 
9 (2, 11) 
0.55 
1.00 
5 (2, 7) 
 
 
13.3  Data analyses: 
 
Descriptive statistical analysis will be calculated, including histograms or box- 
plots, proportions, range, means and standard deviations. All adverse events 
will be analyzed and described, cross-tabulated with treatment arm, and the 
rates compared using a Fisher exact test. Unadjusted PFS and OS times will 
be estimated using the Kaplan-Meier method (36).  Covariate adjusted 
comparisons will be done using a Cox model or other appropriate time-to- 
event regression model to be determined by preliminary goodness-of-fit 
analyses (37;38). 
 
 
 
14.0 LEAD SITE REPORTING OBLIGATION TO SUPPORTING AGENCY 
 
IND-exempt studies: All serious  adverse events (regardless of relationship or 
expectedness) will be reported and documented on MD Anderson SAE form and 
forwarded directly to Sanofi-aventis Pharmaceuticals US Pharmacovigilance 
within 24 hours of learning of the event using the Serious Adverse Event 
Reporting Fax Cover Page provided by Sanofi-aventis. 
 
These reports may be sent by FAX or E-MAIL to: 
 
Reports by FAX should be sent to Sanofi-aventis Pharmaceuticals US 
Pharmacovigilance (908-2037783), within 24 hours of receipt by investigator / 
sponsor. 
 
FAX transmission should include the following on the provided IST SAE 
REPORT, fax cover form (below): 
 
Investigator-Sponsored (IST #) study number:  
Study Title: 
Name of Principal Investigator: 
 
 
 


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Reports by E-MAIL should be sent to: USPVmailbox@sanofi-aventis.com, 
within 24 hours of receipt by investigator/sponsor.  E-Mail transmission should 
include the following: 
 
Investigator-Sponsored (IST #) study number:  
Study Title: 
Name of Principal Investigator: 
 
For Comparator Drugs / Secondary Suspects (Concomitant Medications), all 
serious adverse experiences will be forwarded to the product manufacturer. 
 
 
 
 
15.0   PATIENT REGISTRATION PROCEDURES  
 
         15.1  For registration procedures for this protocol, please refer to the Multicenter 
         Management Plan in Appendix F. 
 
 
 
16.0   DATA AND PROTOCOL MANAGEMENT 
 
Protocol Compliance: The attending physician or advanced practice nurse must see 
each patient at each treatment visit. All required interim and pretreatment data 
should be available, and the physician must assess tumor response and must provide 
a detailed description of toxicity, when appropriate.  If dose modifications or 
treatment interruptions are necessary, the details must be carefully documented. 
Performance status must be documented at each toxicity assessment. 
Data Capture: Data will be entered in the MD Anderson Genitourinary 
departmental oracle system.  Registration data entry and randomization will occur 
prior to initiation of therapy.  All eligibility criteria must be satisfied. 
 
Accuracy of Data Collection: The MD Anderson Principal Investigator will be the 
final arbiter of response and toxicity, should a difference of opinion exist. 
 
Results from these analyses will be reported to an independent Data Monitoring 
Committee (DMC) convened at MDACC. The DMC will assess results along with 
supportive data including other efficacy outcomes and safety data. It will use this 
data to possibly recommend early stopping or other study modifications. 
 
         16.1   Schedule of Data Submission 
 
       MD Anderson protocol specific Case Report Forms and/or electronic Case      
                  Report Forms will be used for collection of all study data. The schedule for    
                   submission of case report forms and pertinent source documents to MD 
                  Anderson is as follows: 
 
 


2011-0727 
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Case Report Forms/Source Documents 
Schedule for Submission 
Informed Consent/Patient Authorization for 
Prior to study registration 
the Release of Personal Health Information 
Eligibility Checklist 
Prior to study registration 
On-Study Form 
Supporting Source Documents (e.g. 
Pathology reports, Medical Administration 
Records, Radiology/Laboratory Reports, 
History and Physical, Progress Notes) 
14 days after treatment initiation 
Chemotherapy/Treatment by Cycle Form 
(Chemotherapy, Laboratory Results, 
Concomitant Medications) 
Supporting Source Documents 
14 days after cycle completion 
Adverse Event Form 
Supporting Source Documents 
14 days after cycle completion 
Response Assessment Forms (Disease 
Measurements) 
Supporting Source Documents 
14 days after protocol defined imaging 
assessment 
Off Treatment 
Supporting Source Documents 
14 days after last treatment date 
Survival Update Form 
Supporting Source Documents 
14 days after protocol defined survival 
review 
Off Study Form 
Supporting Source Documents 
14 days after patient removed from study 
 
 
 
 
17.0  MULTICENTER PROCEDURES 
 
Participating multicenter institutions will follow the guidelines as addressed   
below, in the MD Anderson Multicenter Management Plan (Appendix F), and 
throughout this protocol. 
 
 
 


2011-0727 
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            17.1     Principal Investigators 
 
The principal investigator(s) will be responsible for the conduct of the 
study and monitoring its progress.  The responsibility for all reports and 
data required by MD Anderson will be that of the principal investigator(s). 
 
 
             17.2 
Centralized Patient Registration and Randomization 
 
Patients who are candidates for the study will first be evaluated for 
eligibility by the local investigator. All patients will be registered by 
designated research staff in the GU department. 
 
All multicenter patients must be registered both locally and centrally with 
MD Anderson. 
 
At the time of registration, participating institutions will be required to 
submit a completed and signed eligibility checklist and informed consent 
document with supporting source documentation. 
 
17.2.1  Eligibility Exceptions 
 
All exceptions to eligibility must first be approved by the Protocol Chair 
with appropriate rationale following MD Anderson guidelines. If 
eligibility clarifications are required from participating institutions, all 
eligibility questions should be routed to the MD Anderson GU Department 
in order to document the question and Protocol Chair response. 
 
17.3 
Guidelines for Reporting Participating Site Serious Adverse Events to MD 
Anderson: 
 
Any Serious Adverse Event (SAE) will be reported to the MD Anderson 
GU Department within 24 hours of knowledge of the event.   The 
participating institution will submit the SAE to its own IRB according to 
institutional policy and must forward a copy of the report to MD Anderson 
within 5 calendar days. The MD Anderson GU Department will submit 
participating site SAE reports to the MDACC IRB and Sanofi-aventis. 
 
 
 
SAE notifications and reports will be submitted to: 
 
Fax or email a completed SAE Form to: 
 
MD Anderson GU Department (notifications and reports) 
Attn: 2011-0727 
Fax: 713-563-0857 
Email: GU2011-0727@mdanderson.org 


2011-0727 
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AND 
 
GU2011-0727@mdanderson.org (notifications only) 
 
MD Anderson will maintain documentation of all Serious Adverse Events 
from each institution. MD Anderson will notify all investigators of any 
serious and unexpected adverse experiences that are possibly related to the 
study therapy.  The investigators are to file a copy in the protocol file and 
send a copy to their IRB according to their local IRB’s policies and 
procedures. 
 
17.4 
Guidelines & Procedures for reporting Violations, Deviations and 
Unanticipated Problems. 
 
The Protocol Chair: is responsible for ensuring that clear documentation 
is available in the medical record to describe all protocol deviations, 
violations, and unanticipated problems. The Protocol Chair will also be 
responsible for ensuring that all protocol deviations, violations, and 
unanticipated problems are reported to the MD Anderson IRB per MD 
Anderson institutional guidelines. 
 
Participating Institutions: Protocol deviations, violations, and 
unanticipated problems occurring at a participating institution will be 
submitted to that institution’s own IRB. A copy of the participating 
institution’s IRB deviations, violations, and unanticipated problems report 
will be forwarded to MD Anderson by facsimile or via email within 7 
calendar days after the original submission. 
 
17.4.1  Definitions 
 
The definitions for protocol violation and deviation as described by the 
MD Anderson IRB will be applied for reporting purposes for all 
institutions participating in the trial. 
 
Protocol Deviation: Noncompliance with the protocol that does not have 
a significant effect on the subject’s rights, safety, welfare, and/or the 
integrity of the data. Deviations may be caused by the action of the 
subject, the investigator, the research staff, or natural events. 
 
Protocol Violation: Changes to protocol procedures without prior 
approval of the IRB/Sponsor. Violations may significantly alter the 
clinical effectiveness of the treatment or the evaluation of its toxicity and 
adversely affect patient's safety and rights. 


2011-0727 
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Page 34 
 
 
Unanticipated Problems: An incident, experience or outcome, that is 
unexpected, related or possibly related to participation in the research and 
suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) that 
was previously known or recognized. These incidents do not meet the 
definition of an adverse event. Unanticipated problems are not limited to 
study participants, and may also include others such as family members 
and research staff. 
 
MD Anderson GU Department:  Upon receipt of the 
violation/deviation/unanticipated problem report from the participating 
institution, the Protocol Chair will review and submit the report to the MD 
Anderson IRB for review. 
 
17.5 
Research Team Teleconferences 
 
The MD Anderson and participating institution’s PIs and study teams will 
participate in teleconferences as needed to discuss the following 
information: 
 
• Status of patients enrolled at sites including 
o Eligibility for trial 
o Status of treatment 
o Adverse Events 
o Response evaluation 
o Any questions or concerns 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2011-0727 
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