Clinical trial NCT02158520
Conditions: Metastatic Melanoma Mucosal Melanoma Stage IV Cutaneous Melanoma AJCC v6 and v7 Stage IV Uveal Melanoma AJCC v7 Unresectable Melanoma
Sponsor: Academic and Community Cancer Research United
Start date: 2013-10-18; Completion date: 2019-10-30
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This randomized phase II trial studies how well nab-paclitaxel and bevacizumab or ipilimumab works as first-line therapy in treating patients with stage IV melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as nab-paclitaxel, 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. Bevacizumab may stop the growth of tumor cells by binding to a protein called vascular endothelial growth factor (VEGF) and by preventing the growth of new blood vessels that tumors need to grow. Ipilimumab blocks a substance called cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) on the surface of T cells and may help the immune system kill cancer cells. It is not yet known whether nab-paclitaxel and bevacizumab is more effective than ipilimumab in treating melanoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess whether the combination nab-paclitaxel and bevacizumab (AB) prolongs progression-free status relative to ipilimumab as a treatment in patients with unresectable stage IV melanoma.

SECONDARY OBJECTIVES:

I. To estimate the hazard of death among those randomized to AB then ipilimumab relative to those randomized to ipilimumab then AB as treatment in patients with unresectable stage IV melanoma.

II. To assess whether tumor response rate (as determined by Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria 1.1) differs with respect to first (1st) treatment course.

III. To estimate whether the tumor response rate differs with respect to second (2nd) treatment course for those who progressed during their first treatment course.

IV. To further examine the safety profile of each of these regimens.

CORRELATIVE OBJECTIVES:

I. To examine the pharmacokinetics of nab-paclitaxel when combined with bevacizumab therapy.

II. To examine pharmacodynamic changes of blood-derived parameters (biomarkers) of angiogenesis and immunity as a function of therapy.

III. To examine whether changes in serum biomarkers are also seen in the tumor.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.

ARM B: Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.

After completion of study treatment, patients are followed up for up to 5 years.

Arms: arm 1: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks. arm 2: Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.
Interventions: intervention 1: Bevacizumab intervention 2: Ipilimumab intervention 3: Laboratory Biomarker Analysis intervention 4: Nab-paclitaxel intervention 5: Pharmacological Study
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
Addendum 5 
 
ACCRU RU261206I 
 
 Academic and Community Cancer Research United (ACCRU) 
 
Randomized Phase II Study of AB (nab-paclitaxel [Abraxane™], Bevacizumab) versus Ipilimumab 
for Therapy of Unresectable Stage IV Metastatic Malignant Melanoma 
 
For any communications regarding this protocol, 
please contact the person listed on the Protocol Resource page. This is a stand alone document found on 
the ACCRU website (www/ACCRU.org). 
 
Study Chair:  
  Svetomir N. Markovic MD, PhD  
 Mayo Clinic 
 200 First Street, SW 
 Rochester, MN 55905 
 507/266-0800 (QCS) 
 507/538-0906 (FAX) 
markovic.svetomir@mayo.edu 
 
     FDA IND Sponsor/Investigator: 
 
 
                                Study Co-Chairs:  
 
 
 
 
 
 
 
 
 
 
  Statistician:        
 
 
Drug Availability 
Commercial Agents:  Ipilimumab 
Drug Company Supplied:  nab-paclitaxel (Abraxane™); bevacizumab (Avastin®)  
IND#: 118184 
 
√ Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-538-0906 
Document History 
Effective Date 
Pre-activation and Pre-activation Amendment 
July 5, 2013 
Activation ACCRU 
October 18, 2013 
Amendment 1 
November 7, 2014 
Amendment 2 
April 24, 2015 
Amendment 3 
May 15, 2015 
Amendment 4 
Amendment 5 
April 28, 2017 
October 26, 2018 
 
 


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Index 
 
Schema 
 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors 
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Criteria 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for 
follow-up information 
Footnotes follow on next page 
Arm B: 
Ipilimumab day 1 of a 21 day cycle2 
for a maximum of 4 cycles 
 
Discontinue 
treatment for 
reasons other than 
PD 
Completes 4 cycles 
without PD 
Discontinue treatment 
for PD 
Event monitoring4 
 
Observation until 
PD 
Does patient meet eligibility 
requirements to cross over at 
time of PD and patient is 
willing to begin 
bevacizumab/nab-paclitaxel? 
no 
yes 
Event 
Monitoring4 
bevacizumab 
days 1,15 
nab-paclitaxel 
days 1, 8, 15 
of a 28 day 
cycle1 
until PD 
Event 
Monitoring4 
Discontinue 
Observation for 
reasons other than 
PD 
Event Monitoring4 
Registration and Randomization 
 
Arm A: 
Bevacizumab days 1, 15 
nab-paclitaxel days 1, 8, 15 of a 28 day cycle1 
Discontinue 
treatment for 
reasons other          
than PD 
 
Discontinue 
treatment for PD 
Event 
monitoring4 
Does patient meet eligibility 
requirements to cross over at 
time of PD and patient is 
willing to begin ipilimumab? 
Event 
Monitoring4 
Ipilimumab day 1 
of a 21 day cycle2 
for a maximum of 4 cycles 
Discontinue 
treatment for any 
reason 
Observation until 
PD or discontinue 
observation 
Completes 4 
cycles 
without PD 
no 
yes 


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1 Cycle (bevacizumab/nab-paclitaxel) = 28 days 
2  Cycle (ipilimumab) = 21 days 
3  Observation Phase:  Part of the Active Monitoring Phase of a study.  The time period following the 
active treatment phase when the participant continues to undergo evaluations and complete specimen 
submission in compliance with the Test Schedule.  (see Sections 4.2 and 4.3)  
4 Event Monitoring:  Not part of the Active Monitoring phase of a study.  During the Event Monitoring 
Phase of the study, consenting ACCRU institution are being asked to provide notification as to whether 
the participant  has  progressed, developed a new primary, and/or died.  Participants are not be required to 
return to their registering site to undergo any study related medical examinations or specimen collections. 
All treatment decisions are in the hands of the participant and their medical team. (see Section 13.0) 
 
 
 
Generic name:    Ipilimumab             
Brand name(s):   Yervoy™                 
ACCRU Abbreviation:   
IPILIMUMAB    
Availability:   Commercial 
Generic name:     Bevacizumab 
Brand name(s):   Avastin® 
ACCRU Abbreviation:    AVASTN 
Availability:  ACCRU Research 
Coordinating Pharmacy    
Generic name: nab-paclitaxel 
Brand name(s):   Abraxane™                 
ACCRU Abbreviation:   ABI007 
Availability:   ACCRU Research 
Coordinating Pharmacy   
 
 
 


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1.0 
Background 
 
Metastatic malignant melanoma remains an incurable condition with median OS of 6-10 months 
and a median progression free survival (PFS) of 40-60 days[1].  Effective systemic therapy capable 
of meaningful prolongation of OS in this patient population has remained elusive.  However, a 
phase III clinical trial of patients with previously treated unresectable metastatic melanoma found 
that ipilimumab (IPI, anti-CTLA-4 blocking antibody) significantly improved OS (OS = 10 
months) over a gp100 peptide vaccine (OS = 6.4 months).  Progression-free survival (PFS) was 
similar between the two treatment arms with median PFS of 2.86 months for IPIand 2.76 months 
for the peptide vaccine[2].   The most common of adverse events with IPI involved auto-immune 
reactions involving the colon, liver, skin, endocrine system and nervous systems. Management of 
immune-mediated adverse events included discontinuation of  and initiation of high dose 
corticosteroids.  In March 2011, based on these findings, the Food and Drug Administration (FDA) 
approved IPI (Yervoy®) for the treatment of unresectable or metastatic melanoma at a dose of 
3mg/kg administered every 3 weeks for a total of 4 doses (any “line” therapy).  Higher doses of IPI 
or maintenance therapy were not approved for use by the FDA.  Thus, IPI is now considered the 
standard of care, any “line” therapy for patients with metastatic melanoma.  Similarly, in August of 
2011, the FDA approved the use of vemurafenib (PLX-4302) for use in the therapy of patients with 
metastatic malignant melanoma exhibiting a specific mutation in the BRAF gene (V600E).  The 
drug was approved on the strength of a prematurely terminated phase 3 clinical trial (BRIM-3) 
comparing the efficacy of vemurafenib (VEM) vs dacarbazine (DTIC) in this patient population[3].  
Due to significant improvement of PFS in the VEM arm (5.3 months vs 1.6 months), the study 
was closed and VEM was approved for this indication (Zelboraf®).  Thus, in 2012 we now have two 
new approved agents for the treatment of advanced melanoma, in addition to DTIC and interleukin-
2.  However, despite these advances, nearly all patients with metastatic melanoma still progress on 
therapy and ultimately succumb to their disease.  The need for effective therapy remains acute. 
 
In 2011, we completed a multicenter randomized Phase 2 clinical trial in the North Central Cancer 
Treatment Group (NCCTG, protocol N0775) in which chemotherapy naïve patients with metastatic 
melanoma were treated with either a combination of nab-paclitaxel (Abraxane™, ABX, ABI007), 
bevacizumab and carboplatin (ABC regimen) or temozolomide and bevacizumab (TB regimen).   
The study was not designed to compare the clinical efficacy of the two treatments; each arm was 
compared to historic control rates with the intent of gaining insight into a potential superior 
chemotherapy back-bone for bevacizumab therapy combinations in metastatic melanoma[4].  The 
study accrued 51 patients to the ABC regimen and 41 patients to the TB regimen.  The regimens 
yielded median PFS/OS of 6.7/13.9 months for ABC and 3.8/12.3 for TB.  These results compare 
favorably to two other of our multicenter Phase 2 NCCTG trials in the same patient population 
(N047A and N057E).  For patients with stage IV melanoma treated with a 28 day cycle of 
paclitaxel (Taxol®, 80mg/m2 days 1, 8 and 15), bevacizumab (10mg/kg days 1 and 15) and 
carboplatin (AUC 6 on day 1) until tumor progression on N047A, the median PFS was 6 months 
and the median OS was 12 months[5].  In protocol N057E, two phase 2 clinical trials were 
conducted concurrently examining the antitumor activity of a 28 day cycle of nab-paclitaxel 
(100mg/m2 days 1, 8 and 15) and carboplatin (AUC 2 on days 1, 8 and 15) administered until 
progression in chemotherapy naïve and previously chemotherapy treated patients respectively[6]. 
Both patient cohorts were similar in terms of median PFS survival (approximately 4 months) and 
median OS (approximately 11 months).   Thus, in the phase 2 clinical trial setting, the combination 
of a taxane and carboplatin was found to provide clinical benefit in patients with malignant 
melanoma, and the addition of bevacizumab seemed to add further improvements in both PFS and 
OS.  Our best result was achieved with nab-paclitaxel as the “taxane” element of the three drug 
combination.   


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Recently presented results by Spitler et al, (ASCO 2011) testing the utility of the combination of 
nab-paclitaxel and bevacizumab (without carboplatin, AB regimen) at doses of 150mg/m2 days 1, 8 
and 15, and 10mg/kg on days 1 and 15 respectively, in chemotherapy naïve patients with metastatic 
melanoma (50 patients) revealed a median PFS of 7.6 months and OS of 16.8 months.  Main 
severe toxicities (grade 3 only, no grade 4) were: neutropenia (10 of 26), 
neuropathy (7 of 26) mucositis (4 of 26), fatigue (3 of 26), and proteinuria 
and hand/foot syndrome in 1 of 26 patients respectively.   The similarity 
(and small advantage) in the PFS/OS of this combination relative to our 
ABC regimen (above), as well as its superiority to the 
paclitaxel/carboplatin/bevacizumab regimen of N047A (PFS = 6 months, OS 
= 12 months), suggested a potential synergy/interaction between nab-
paclitaxel and bevacizumab.  As the only difference between the paclitaxel preparations was the 
vehicle (albumin nanoparticle 
versus Cremophor EL), we 
postulated that there could exist a 
here-to-for unrealized 
pharmacokinetic interaction 
between the albumin nanoparticle 
of nab-paclitaxel and the 
monoclonal antibody of 
bevacizumab.  With that in mind 
we conducted a series of 
experiments attempting to assess 
whether or not nab-paclitaxel 
could interact with bevacizumab in 
vitro.  
To our 
surprise 
(Fig. 1, 
nab-paclitaxel /bevacizumab column) in vitro mixing of nab-paclitaxel and 
bevacizumab resulted in the creation of macromolecular complexes.  In these 
experiments clinical grade nab-paclitaxel was fluorescently labeled and mixed in vitro (room 
temperature) with clinical grade (fluorescently labeled) bevacizumab (bevacizumab), trastuzumab 
(TRS) or rituximab (RTX).  These mixtures resulted in micro-complexes (approximately 1-2 
microns) that were analyzed via 
flow-cytometry and demonstrate that 
all nano-particles (nab-paclitaxel, 
single fluorescence) indeed bind the 
fluorescent antibodies (dual 
fluorescence of 
the mixture). 
This nab-
paclitaxel 
interaction with 
bevacizumab 
was not only a feature of 
bevacizumab, but, also could be 
identified in combinations of 
trastuzumab (Herceptin®) and  
rituximab (Rituxan®).  Microscopic examination of these particles (nab-paclitaxel + bevacizumab 
ABX* (FITC) + BEV
ABX + BEV* (ACP)
ABX* (FITC) + BEV* (ACP)


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only) confirms this impression (Fig. 2).  The size of the nab-paclitaxel/bevacizumab complexes can 
be varied dependent on the relative concentrations of each component (Fig. 3).  Additional in vitro 
data demonstrate that the binding of nab-paclitaxel and bevacizumab can be inhibited by normal 
plasma as well as soluble albumin, the complexes appear to be stable at room temperature for at 
least 4 hours, and that upon 
incubation in fresh human plasma at 
37oC/5% CO2, their half-life is on 
the order of 30 seconds (data not 
shown).   All of these preliminary 
data suggest that one potential 
explanation for the therapeutic 
advantage of the replacement of 
nab-paclitaxel for paclitaxel in 
combination with bevacizumab 
could be there result of a 
pharmacokinetic interaction taking 
place during the infusion of nab-
paclitaxel that immediately follows 
the infusion of bevacizumab in the 
two cited trial regimens of ABC and 
AB (
.  Due to the rapid saturation of the bevacizumab (antibody) binding 
sites on nab-paclitaxel by normal plasma, the efficiency of this complex formation during 
sequential infusions of the agents into patients is likely very small.  However, it is conceivable that 
the higher concentration of nab-paclitaxel used in Dr. Spitler’s study (150mg/m2) vs ours (100 or 
80mg/m2) could have created the complexing advantage postulated by these laboratory studies.   
 
Based on these data, it appears that both the ABC regimen (nab-
paclitaxel/bevacizumab/carboplatin) and nab-paclitaxel/bevacizumab (AB) offer therapeutic results 
in chemotherapy naïve patients with metastatic melanoma that are superior to those of ipilimumab 
therapy, the currently FDA approved agent for the treatment of patients with metastatic melanoma, 
with heavy clinical use in patients who do not harbor the BRAF V600E mutation.  The small 
PFS/OS advantage of the AB over the ABC regimen may be the result of this unexpected 
pharmacokinetic interaction of bevacizumab and the higher dose of nab-paclitaxel (150mg/m2 vs 
100mg/m2).  Additionally, the AB regimen appears significantly less toxic.  Therefore, in the 
current study, we propose to compare the clinical efficacy of the AB regimen (nab-paclitaxel 
150mg/m2 days 1, 8 and 15; bevacizumab = 10mg/kg, days 1 and 15) in patients undergoing 
therapy for metastatic melanoma and compare to the current standard, ipilimumab.  The AB 
regimen will be uniformly administered with bevacizumab infusion preceding the infusion of nab-
paclitaxel in all study patients.  Study participants will be stratified based on M sub-stage (M1c vs 
other), BRAF 600 mutation present (yes vs. not or metastatic melanoma is of uveal origin), and 
prior treatment in the metastatic setting (yes vs. no).   
 
The primary end aim of this study is to assess whether there is a 33% increase in PFS with AB 
relative to IPI. At the time of first disease progression, patients will cross over to the other treatment 
regimen, Correlative pharmacokinetic (testing the possibility of creation of the nab-
paclitaxel/bevacizumab complexes, and persistence of paclitaxel in circulation), and 
pharmacodynamic (effects of therapy on parameters of immunity and angiogenesis), will also be 
performed.  The former, in combination with ongoing pre-clinical studies, will provide the 
foundation for a future study of pre-infusion mixing of nab-paclitaxel and bevacizumab, creating 
nab-paclitaxel/bevacizumab complexes prior to infusion into patients and an introduction of a novel 
therapeutic platform in which the albumin nanoparticle of nab-paclitaxel may serve as the 


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chemotherapeutic carrier delivering concentrated chemotherapeutics to the sites of cancer directed 
by complexed monoclonal therapeutic antibodies (at least bevacizumab and potentially 
trastuzumab, and rituximab).  Analysis of the immunological and anti-angiogenic outcomes of AB 
and IPI therapy will yield critical insights into potential mechanisms of action and lay the 
foundation for future combinatorial strategies us AB as the chemotherapy “back-bone” of non-
BRAF mutated metastatic melanoma (concurrent or sequential therapy concepts). 
 
 
2.0 
Goals 
 
2.1 
Primary Goal 
 
2.11 
To assess whether the combination nab-paclitaxel and bevacizumab (AB) prolongs 
progression-free status relative to ipilimumab as a treatment in patients with 
unresectable stage IV melanoma  
 
2.2 
Secondary Goals 
 
2.21 
To estimate the hazard of death among those randomized to AB then ipilimumab 
relative to those randomized to ipilimumab then AB as treatment in patients with 
unresectable stage IV melanoma. 
 
2.22 
To assess whether tumor response rate (as determined by RECIST criteria 1.1) 
differs with respect to 1st treatment course. 
  
2.23 
To estimate whether the tumor response rate differs with respect to 2nd treatment 
course for those who progressed during their first treatment course. 
 
2.24 
To further examine the safety profile of each of these regimens. 
 
2.3 
Correlative Goals  
 
2.31 
For patients accrued at Mayo Clinic in Rochester, MN ONLY (mandatory):  
To examine the pharmacokinetics of nab-paclitaxel when combined with 
bevacizumab therapy 
 
2.32 
For patients accrued at Mayo Clinic in Rochester, MN ONLY (mandatory):  
To examine pharmacodynamic changes of blood-derived parameters (biomarkers) 
of angiogenesis and immunity as a function of therapy. 
 
2.33 
All sites (optional):  To examine whether changes in serum biomarkers are also 
seen in the tumor. 
 
 
 
 


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3.0 
Patient Eligibility  
 
3.1 
Inclusion criteria 
 
3.11 
Histologic or cytologic  proof of surgically unresectable stage IV malignant 
melanoma - including that of uveal and mucosal origin  
 
Note: Biopsy can be of locoregional disease in setting of clinically evident stage IV 
disease. A biopsy of the primary tumor alone does not fulfill this requirement. 
 
3.12 
No more than 2 prior courses of systemic therapy for metastatic melanoma. 
 
3.13   For patients with metastatic melanoma not of uveal origin, BRAF V600 mutation 
determination using a CLIA-approved testing method on metastatic tumor tissue.  
 
 
NOTE: Patients with metastatic melanoma of uveal origin do not need to have 
formal BRAF testing due to low probability of a BRAF V600 mutation in their 
metastatic tumor. 
 
3.14 
Measurable disease defined in Section 11.2.   
 
Note:  Disease that is measurable by physical examination only is not eligible.  
 
3.15 
Life expectancy of ≥ 4 months. 
 
3.16 
Age ≥18 years.  
 
3.17 
ECOG performance status (PS) 0 or 1.   
 
3.18 
The following laboratory values obtained ≤14 days prior to 
registration/randomization: 
 
• 
Absolute neutrophil count  ≥1500/mL 
• 
Platelet count  ≥100,000 x 109/L 
• 
Hemoglobin  ≥9 g/dL (patients may be transfused to meet this requirement) 
• 
Creatinine ≤1.5 x ULN.  Institutional norms are acceptable. 
• 
Total bilirubin ≤ 1.5 mg/dL (exception: patients with documented Gilbert’s 
syndrome are allowed to participate despite elevated bilirubin) 
• 
SGOT (AST) ≤2.5 x ULN and SGPT (ALT) ≤2.5 x ULN 
• 
Alkaline phosphatase ≤2.5 x ULN.  If  bone metastasis is present in the absence 
of liver metastasis then ≤5 x ULN 
• 
Urine dipstick for proteinuria <2+ (patients discovered to have ≥2+ proteinuria 
on dipstick urinalysis at baseline should undergo a 24 hour urine collection and 
must demonstrate ≤1g of protein in 24 hours to be eligible). 
 
3.19a 
Negative serum pregnancy test done ≤7 days prior to registration/randomization, 
for women of childbearing potential only. 
 
 
 


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Note: 
Females: Adequate contraception must be used by both patient and partner while 
receiving study drug  and for 12 weeks after the last dose of study drug.   
 
Males: Adequate contraception must be used by both patient and partner while 
receiving study drug.  Men who have a partner of childbearing age should also 
avoid fathering a child for 6 months after the last dose of study drug.   
 
3.19b Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.19c 
Mayo Rochester patients only: Willingness to provide mandatory blood samples 
for research purposes (see Section 14.0). 
 
3.2 
Exclusion Criteria 
 
3.21 
Brain metastases per MRI or CT.   
 
Note: Patients who have had therapy for brain metastasis (i.e., surgical resection, 
whole brain radiation, or SRS even if stable) are not eligible. 
 
3.22 
Other investigational agents ≤ 4 weeks prior to registration/ randomization. 
 
3.23 
Anti-cancer therapy (including immunotherapy) ≤ 4 weeks prior to 
registration/randomization. Exception:  adjuvant Leukine® ≤  14 days  prior to 
registration/randomization.  
 
3.24 
Prior treatment in the adjuvant or metastatic setting with any of the following: 
• 
agents disrupting VEGF activity or targeting VEGFR;  
• 
ipilimumab;  
• 
or taxane based chemotherapy regimens (including paclitaxel, docetaxel, 
cabizataxel or nab-paclitaxel). 
 
3.25 
Major surgical procedure, open biopsy, or significant traumatic injury ≤4 weeks 
prior to registration/randomization. (Port-a-cath placement does not count as a 
major surgical procedure and patients can be enrolled at any time after placement). 
 
3.26 
Fine needle aspirations or core biopsies ≤7 days prior to registration/ 
randomization. 
 
3.27 
Planned/or anticipated major surgical procedure during the course of the study. 
 
3.28 
Other medical conditions including but not limited to: 
• 
History of liver disease such as cirrhosis, chronic active hepatitis, chronic 
persistent hepatitis or hepatitis B or C 
• 
Active infection requiring parenteral antibiotics 
• 
Poorly controlled high blood pressure (≥150 mm Hg systolic and/or 100 mmHg 
diastolic) despite treatment. 


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• 
New York Heart Association class II-IV congestive heart failure (available on 
ACCRU web site at 
https://ACCRU.mayo.edu/ACCRU/forms/NonProtocolSpecificForms). 
• 
Serious cardiac arrhythmia requiring medication. 
• 
Myocardial infarction or unstable angina ≤6 months prior to 
registration/randomization. 
• 
Clinically significant peripheral vascular disease. 
• 
Deep venous thrombosis or pulmonary embolus ≤1 year of 
registration/randomization 
• 
Ongoing need for full-dose oral or parenteral anticoagulation. 
• 
Ongoing anti-platelet treatment other than low-dose aspirin (i.e., aspirin 81 mg 
by mouth daily). 
• 
Active bleeding or pathological conditions that carry high risk of bleeding 
(e.g., known esophageal varices, etc.). 
• 
Serious, non-healing wound (including wounds healing by secondary 
intention), ulcer or bone fracture. 
• 
History of abdominal fistula, gastrointestinal perforation or intra-abdominal 
abscess ≤6 months prior to registration/randomization. 
• 
History of CNS disease (e.g.,  vascular abnormalities, etc.), clinically 
significant stroke or TIA ≤6 months prior to registration/randomization, 
seizures not controlled with standard medical therapy. 
• 
Radiographically documented tumor invading major blood vessels. 
• 
History of hypertensive crisis or hypertensive encephalopathy. 
 
3.29a 
Any of the following as this regimen may be harmful to a developing fetus or 
nursing child: 
• 
Pregnant women. 
• 
Nursing women. 
• 
Men and women of reproductive potential who are not using effective birth 
control methods.   
 
Note: Women of childbearing potential must have a negative serum pregnancy 
test ≤7 days prior to registration/randomization.  Adequate contraception must 
be used while receiving study drug  and for 12 weeks after the last dose of 
study drug, by both women and men and by both patient and partner.   
 
Men who have a partner of childbearing potential should also avoid fathering a 
child for 6 months after the last dose of study drug.   
 
3.29b Existence of peripheral sensory neuropathy ≥grade 2 (from any cause). 
 
3.29c 
History of other malignancy ≤5 years with the exception of basal cell or squamous 
cell carcinoma of the skin, treated with local resection only, or carcinoma in situ 
(e.g. of the cervix, breast, prostate, etc.). 
 
3.29d Radiation therapy  (other than palliative) ≤ 2 weeks prior to randomization. Note: 
Patients who have had >25% of their functional bone marrow irradiated are not 
eligible for this trial. 
3.29e 
Active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood   per 
episode) ≤30 days prior to registration/randomization. 


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3.29f 
Known hypersensitivity to any of the components of ipilimumab, bevacizumab, or 
nab-paclitaxel. 
 
3.29g History of inflammatory bowel disease (e.g., Crohn’s, ulcerative colitis) - Note 
patients with irritable bowel syndrome are eligible.  
 
3.29h Diagnosis of autoimmune disease (i.e., rheumatoid arthritis, scleroderma, SLE, 
autoimmune vasculitis, Guillain-Barre Syndrome, etc.), regardless if patient is 
currently receiving treatment at time of registration/randomization. 
 
3.29i 
Systemic corticosteroids use ≤2 weeks, regardless of indication.  
 
Note: Patients who are on inhaled corticosteroids are eligible. 
 
4.0 
Test Schedule  
 
4.1  
Tests and procedure prior to registration/randomization Arm A & B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
For women of childbearing potential only (must be done ≤7 days prior to registration). 
2. 
All patients must have a urinalysis ≤48 hour prior to Day 1 of the cycle. For treatment 
modifications for bevacizumab based on proteinuria, see Section 8.4. 
3.  
 ≤28 days prior to registration/randomization. 
4. 
See Appendices II and III for imaging guidelines and image submission instructions.  
Excluding brain MRI and/or CT scan of the head with contrast, images should represent the 
entire radiologic assessment for the tumor.   
5.   
BRAF V600 metastatic tumor tissue typing may be done at any time prior to study 
registration but must be done on a site of metastasis, not the primary lesion (patients with 
uveal melanoma are not required to undergo formal testing). 
6.  
≤ 30 days prior to registration/randomization- see Section 17.0 for additional details 
R.   
Research funded. 
Tests and Procedures 
≤ 14 days prior to 
registration/randomization 
History, exam, wt., ECOG Performance Status (PS) 
X 
Serum Pregnancy Test 
X1 
Height 
X 
ANC, WBC, PLT, Hgb, Absolute monocyte count (AMC), 
absolute lymphocyte count (ALC), eosinophils 
X 
Chemistry group SGOT (AST), ALT, total bilirubin, Alk 
Phos, Creatinine, potassium, sodium, LDH 
X 
TSH 
X 
Blood Pressure  
X 
Urinalysis for proteinuria 
X2 
Brain MRI (or CT with contrast of the head  if MRI cannot 
be performed) 
X3 
AE assessment  
X 
Tumor Measurement/evaluation 
X3,4 
BRAF V600 analysis of metastatic melanoma 
X5 
Optional research tissue sample6,R 
X 


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4.2 
Arm A:  Bevacizumab in combination with nab-paclitaxel (AB) followed by ipilimumab after progression 
 
 
 
Bevacizumab and nab-paclitaxel Treatment phase 
Ipilimumab Treatment and Observation phase 
Tests and Procedures* 
Prior to 
first dose 
of nab-
Pac/BEV 
Mayo 
Clinic-R 
patients 
only 
Prior to 
each cycle 
of 
treatment1 
 
Day 8 & 15 
of each cycle 
of treatment 
At time of 
progression 
 
Prior to first 
dose of 
Ipilimumab 
Mayo Clinic-
R patients 
only 
 
 
Prior to each 
dose of 
Ipilimumab2 
 
Observation 
until PD 
(every 8 weeks 
after 
completion of 4 
cycles of 
ipilimumab) 
 
 
At time of 
Progression 
Physical exam, wt., ECOG PS 
 
X 
 
X 
 
X 
X 
X 
ANC, AMC, ALC, WBC, PLT, 
Hgb 
 
X 
 
X3 
X 
 
X 
X 
X 
Chemistry group ( AST, ALT, 
total bili, Alk Phos, 
Creatinine, potassium, 
sodium, LDH) 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Blood Pressure 
 
X4 
X4 
X 
 
 
 
 
TSH 
 
 
 
 
 
X 
X 
X 
Urinalysis for proteinuria 
 
X5 
 
X 
 
 
 
 
Mandatory research blood 
samples,R 
X6 
 
 
 
X6 
 
 
 
AE assessment 
 
X 
 
X 
 
X 
X 
X 
Tumor 
Measurement/evaluation7 
 
X8 
 
X7 
 
X9, 10,11 
X 
X7 


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1. 
If tests have been done ≤21 days prior to registration/randomization, they need not be 
repeated for the first cycle. 
2. 
If tests have been done ≤ 21days prior to cycle 1 day 1 of  ipilimumab treatment they 
need not be repeated for the first cycle of ipilimumab treatment. 
3. 
May be done up to 48 hours prior to days 1, 8, 15 of each cycle of treatment. 
 
4. 
Blood pressure must be measured weekly for cycle 1 and then before each bevacizumab 
infusion (i.e., on days 1 and 15). Though the primary oncologist is expected to see the 
patient only on day 1 of every cycle, if blood pressure is found to be elevated (i.e., systolic 
blood pressure ≥150 mmHg and/or diastolic blood pressure ≥ 100 mmHg) on day 15 
during the first cycle or on day 15 during subsequent cycles, the treating physician  should 
be notified. 
5. 
All patients must have urinalysis ≤48 hours prior to day 1 of the cycle. For treatment 
modifications for bevacizumab based on proteinuria, see Section 8.6. 
6. 
For patients accrued at Mayo Clinic in Rochester, Minn. ONLY:  See Section 14.0 for 
collection, preparation, and delivery instructions. 
7. 
See Appendix II for imaging guidelines and Appendix III for image submission process.  
Images should be submitted on CD: (1) following progression on AB; (2) following 
progression on IpI, and (3) at the end of protocol treatment for reasons other than 
progression. Excluding brain MRI and/or CT scan of the head with contrast, images 
should represent the entire radiologic assessment for the tumor.   
8. 
Tumor measurements during bevacizumab and nab-paclitaxel treatment phase are to be 
taken: prior to cycle 4 (i.e., approximately week 12) and then prior to every other cycle 
(i.e., prior to cycles 6, 8, etc.) until progression (PD).  EXCEPTION:  If a patient is 
experiencing a complete tumor response at the year 3 post-randomization time point, 
tumor measurement schedule can be modified so that tumor measurements are taken every 
6 months until disease progression. 
9. 
Tumor measurements must be repeated prior to the start of ipilimumab treatment phase if 
more than 28 days have elapsed since last tumor measurements were taken. 
10. 
Patients who progress on Bevacizumab and nab-paclitaxel and who wish to crossover to 
Ipilimumab therapy must undergo an assessment for brain metastases with an MRI (if 
MRI not possible due to contraindications, contrast CT will be acceptable) 
11. 
Tumor measurements during ipilimumab treatment phase: The first scan after patients 
have initiated therapy with ipilimumab should be taken approximately 3 weeks after the 
fourth dose of ipilimumab (i.e., approximately week 12 after start of ipilimumab) and then 
every 8 weeks until disease progression. EXCEPTION:  If a patient is experiencing a 
complete tumor response at the year 3 post-crossover time point, tumor measurement 
schedule can be modified so that tumor measurements are taken every 6 months until 
disease progression. 
R. 
Research funded. 
 


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4.3  
Arm B:    Ipilimumab followed by nab-paclitaxel and bevacizumab (AB) after progression
 
Ipilimumab Treatment and Observation Phase 
Bevacizumab and nab-paclitaxel Treatment phase 
Tests and 
Procedures 
Prior to 
first dose 
of 
Ipilimuma
b Mayo 
Clinic- R 
patients 
only 
Prior to 
each cycle 
of 
treatment1 
Observation 
until PD 
(every 8 weeks 
after 
completion of 
4 cycles of 
ipilimumab) 
At time of 
progression 
Prior to first 
dose of nab-
Pac/BEV 
Mayo 
Clinic-R 
patients only 
 
Prior to 
each 
subsequent 
cycle of AB 
Day 8 & 
15  
of each 
cycle of 
treatment 
 
At time of  
progression 
AE 
Monitoring 
(4 weeks after 
completion of 
nab-paclitaxel/ 
BEV) 
Physical exam, wt., 
ECOG PS 
 
X 
X 
X 
 
X 
 
X 
 
ANC, AMC,ALC, 
WBC, PLT, Hgb 
 
X 
X 
X 
 
X2 
X3 
X 
 
Chemistry group ( 
AST, ALT, total 
bili, Alk Phos, 
Creatinine, 
potassium, 
sodium, LDH 
 
X 
X 
X 
 
X 
 
X 
 
Blood Pressure 
 
 
 
 
 
X4 
X4 
 
 
TSH  
 
X 
X 
X 
 
 
 
 
 
Urinalysis for 
proteinuria  
 
 
 
 
 
X5 
 
 
 
Mandatory 
research blood 
samplesR 
X6 
 
 
 
X6 
 
 
 
 
 
 
AE assessment  
 
X 
X 
X 
 
X 
 
X 
X 
Tumor 
Measurement/ 
    Evaluation7 
 
X8 
X8 
X7 
 
X9, 10,11 
 
X7 
 


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1. 
If tests have been done ≤ 21days prior to  registration/randomization they need not be 
repeated for the first cycle. 
2. 
If tests have been done ≤ 21days prior to cycle 1 day 1 of  bevacizumab and nab-
paclitaxel treatment they need not be repeated for the first cycle of bevacizumab and 
nab-paclitaxel treatment. 
3. 
May be done up to 48 hours prior to treatment days 1, 8, 15. 
4. 
Blood pressure must be measured before each bevacizumab infusion (e.g. on days 1 
and 15). Though the primary oncologist is expected to see the patient only on day 1 of 
every cycle, if blood pressure is found to be elevated (i.e., systolic blood pressure ≥150 
mmHg and/or diastolic blood pressure ≥ 100 mmHg) on day 15 during the first cycle or 
on day 15 during subsequent cycles, the treating physician should be notified.  
5. 
All patients must have urinalysis ≤48 hours prior to day 1 of the cycle. For treatment 
modifications for bevacizumab based on proteinuria, see Section 8.4. 
6. 
For patients accrued at Mayo Clinic in Rochester, Minn. ONLY: See section 14.0 
for collection, preparation, and delivery instructions. 
7. 
See Appendix II for imaging guidelines and Appendix III for image submission 
process.  Images taken during the study should be submitted on CD: (1) following 
progression on AB; (2) following progression on IpI, and (3) at end of protocol 
treatment for reasons other than progression.  Excluding brain MRI and/or CT scan of 
the head with contrast, images should represent the entire radiologic assessment for the 
tumor.   
8. 
Tumor measurements during ipilimumab treatment phase:   The first scan after patients 
have initiated therapy with ipilimumab should be taken approximately 3 weeks after the 
fourth dose of ipilimumab (i.e., approximately week 12 after start of ipilimumab) and 
then every 8 weeks thereafter until progression.   
 
EXCEPTION:  If a patient is experiencing a complete tumor response at the year 3 
post randomization  time point, tumor measurement schedule can be modified so that 
tumor measurements are taken every 6 months until disease progression 
9. 
Tumor measurements must be repeated prior to the start of  bevacizumab and nab-
paclitaxel treatment phase if more than 28 days have elapsed since last  tumor 
measurements were taken. 
10. 
Patients who progress on  Ipilimunab and who wish to crossover to bevacizumab and 
nab-paclitaxel therapy must undergo an  assessement for brain metastases with an MRI 
((if MRI not possible due to contraindications, contrast CT will be acceptable) 
11. 
Tumor measurements after initiating bevacizumab and nab-paclitaxel treatment phase 
are to be taken prior to the fourth cycle of AB (i.e., approximately week 12 after start of 
AB) and then prior to every other cycle (i.e., prior to cycles 6, 8, etc.) until progression. 
 
EXCEPTION:  If a patient is experiencing a complete tumor response at the year 3 post 
cross-over  time point, tumor measurement schedule can be modified so that tumor 
measurements are taken every 6 months until disease progression. 
R.   
Research funded. 
 
5.0 
Stratification Factors 
 
  
5.1 
Metastatic disease sub-stage (per AJCC v7): M1a/M1b vs. M1c. 
 
5.2 
BRAF V600 mutation: present vs. not present or metastatic melanoma is of uveal origin 
 
5.3 
Previous treatment for metastatic disease: Yes vs. no. 
 


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6.0  
Registration/Randomization Procedures 
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, access the ACCRU web page at 
  and under Remote Registration, 
click on “Registration/randomization.” The registration/randomization 
application is available 24 hours a day, 7 days a week.  Back up and/or system 
support contact information is available on the Web site.  If unable to access 
the Web site, call the Academic and Community Cancer Research United 
(ACCRU) Registration Office at 
 between the hours of 8 a.m. and 
4:30 p.m. Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available by using 
the Help button. 
Prior to initiation of protocol study intervention, this process must be completed in its 
entirety and an ACCRU subject ID number must be available as noted in the 
instructions.  It is the responsibility of the individual and institution registering the 
patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the ACCRU Registration Office 
.  If the patient was 
fully registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.12 
Correlative Research  
 
Mayo Rochester patients only:  A mandatory correlative research component 
using blood samples is part of this study, the patient will be automatically 
registered onto this component (see Sections 3.19c and 14.0). 
 
All patients:  An optional correlative research component using a tissue sample 
is part of this study.  There will be an option to select if the patient is to be 
registered onto this component (see Section 17.0). 
 
Patient has/has not given permission to give his/her tissue sample 
for research testing. 
 
6.13 
Documentation of IRB approval must be on file in the ACCRU 
Registration Office before an investigator may register any patients.   
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 507-284-0885).  Approvals should be uploaded using the online ACCRU 
Regulatory Management System (ARMS). If the necessary documentation is not 
submitted in advance of attempting patient registration, the registration will not 
be accepted and the patient may not be enrolled in the protocol until the situation 
is resolved. 
 
 


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Submissing of annual IRB approvals is required until the study has been closed 
through your IRB. 
 
6.14 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected 
health information (U.S.A. institutions only)   
 
At the time of registration/randomization, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example:  diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her blood 
sample(s) to outside researchers. 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example:  diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her tissue 
sample(s) to outside researchers. 
 
6.15 
Treatment cannot begin prior to registration/randomization and must begin ≤7 
days after registration/randomization. 
 
6.16 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.17 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
 
6.18 
Treatment on this protocol must commence at the accruing membership under 
the supervision of an ACCRU member physician. 
 
6.19a 
Study drug is available on site.  
 
6.19b Blood draw kit is available on site. 
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.22 
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 


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treatment groups using the Pocock and Simon9 d dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups. 
 
• 
Arm A:  Bevacizumab + nab-paclitaxel (AB) followed by ipilimumab 
• 
Arm B:  Ipilimumab followed by AB 
 
 
7.0 
Protocol Treatment 
 
7.1 
Bevacizumab/nab-paclitaxel 
 
One treatment cycle = 28 days (±2 days) 
Agent* 
Dose 
Schedule 
Route 
Retreatment 
Bevacizumab 
10mg/kg 
Days 1 and 15 
IV over 90 
minutes** 
Every 28  days 
(± 2 days) until 
progression 
nab-paclitaxel 
150mg/m2 
Days 1, 8, 15 
IV over 30 
minutes*** 
* Drugs should be administered in the order listed above.  ALWAYS INFUSE 
BEVACIZUMAB FIRST. 
** Subsequent infusions of bevacizumab may be administered over 60 minutes if tolerated. If 
tolerated over 60 minutes, may administer over 30 minutes. 
*** Following administration of nab-paclitaxel, the intravenous line should be flushed with 
sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete 
dose. 
 
7.2 
Ipilimumab 
 
One treatment cycle = 21 days (±2 days) 
Drug 
Dose 
Schedule 
Route 
Retreatment 
Ipilimumab 
3mg/kg 
Day 1 
IV over 90 
minutes 
Every 21 days (±2 days) for  
a maximum of  4 cycles 
 
7.3 
Patients treated with bevacizumab/nab-paclitaxel will always receive the bevacizumab 
infusion FIRST followed immediately by the infusion of nab-paclitaxel.  Treatment will 
continue until disease progression (PD) or toxicity.  A cycle is 28 days (±2 days). 
 
Patients treated with ipilimumab will receive the standard 4 infusions (4 cycles) of 
ipilimumab currently approved by the FDA (or less if toxicity or there is clear evidence 
of tumor progression).  A cycle of ipilimumab is 21 days (±2 days). 
 
7.31 
Arm A:  Patients randomized to Arm A will initially receive bevacizumab plus 
nab-paclitaxel until progression (PD).  Bevacizumab will be administered on 
days 1 and 15 of a 28-day (±2 days) cycle.  Nab-paclitaxel will be administered 
on days 1 (following bevacizumab), 8, and 15 (following bevacizumab) of a 28-
day cycle (±2 days).   
 


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Some patients will be allowed to proceed on to treatment with ipilimumab ≤2-4 
weeks following disease progression on bevacizumab/nab-paclitaxel treatment.  
Patients will undergo an assessment of ECOG PS, blood chemistries levels, and 
tumor size (see Section 4.0).  If any one of the following is true, the patient may 
not continue on to the Ipilimumab phase of the study:   
 
− 
ECOG performance score (PS):  ≥2 
− 
Tumor fails to meet RECIST criteria for measurable disease 
− 
ANC <1500/mL 
− 
PLT <100,000 x 109/L 
− 
Hgb <9g/dL (patients may be transfused to meet Hgb requirement) 
− 
Creatinine ≥1.5 x ULN 
− 
Total bilirubin ≥1.5 mg/dL (exception: patients with documented Gilbert’s 
syndrome are allowed to participate despite elevated bilirubin) 
− 
SGOT (AST) ≥2.5 x ULN  
− 
Urine dipstick for proteinuria ≥2+ and a 24 hour urine collection result 
demonstrating  >1g of protein in 24 hours  
− 
≥ grade 2 peripheral sensory or motor neuropathy  
− 
Evidence of  brain metastasis on  MRI or CT 
 
7.311 
Patients who are eligible and willing to continue on to 
ipilimumab treatment phase:  Patients who are eligible and willing 
to continue on to ipilimumab treatment phase must begin ipilimumab 
treatment ≤2-4 weeks after PD.  Patients  will receive ipilimumab on 
day 1 of a 21-day cycle (±2 days) for a maximum of 4 cycles (see 
Section 13.0). 
• 
If PD during ipilimumab treatment, patients will go to Event 
Monitoring. 
• 
If no PD at the completion of ipilimumab treatment, patients 
will go to Observation every 8 weeks until PD.  At the time of 
PD, patients will go to Event Monitoring. 
 
7.312 
Patients who are not eligible or choose not to continue on to 
ipilimumab:   Patients who are not eligible or choose not to continue 
on to ipilimumab will go to Event Monitoring  (see Section 13.0).  
 
7.32 
Arm B:  Patients randomized to Arm B will receive ipilimumab which will be 
administered on day 1of each cycle for a maximum of four (4) 21-day (±2 days) 
cycles.  At the completion of ipilimumab treatment, patients will go to 
Observation every 8 weeks until PD.   
 
At PD, patients will undergo an assessment of ECOG PS, blood chemistries 
levels, and tumor size (see Section 4.0).  If any one of the following is true, the 
patient may not continue on to the bevacizumab plus nab-paclitaxel phase of the 
study:  
 
− ECOG  performance score (PS):  ≥ 2 
− 
tumor fails to meet RECIST criteria for measurable disease 
− 
ANC < 1500/mL 
− 
PLT < 100,000 x 109/L 


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− 
Hgb < 9g/dL (patients may be transfused to meet Hgb requirement) 
− 
Creatinine ≥1.5 x ULN 
− 
Total bilirubin ≥1.5 mg/dL (exception: patients with documented Gilbert’s 
syndrome are allowed to participate despite elevated bilirubin) 
− 
SGOT (AST) ≥2.5 x ULN  
− 
Urine dipstick for proteinuria ≥ 2+ and a 24 hour urine collection result 
demonstrating  > 1g of protein in 24 hours 
− 
≥ grade 2 peripheral sensory or motor neuropathy  
− 
Evidence of  brain metastasis on  MRI or CT 
 
Additionally patients who undergo the optional research biopsy at time of 
progression must not initiate therapy with nab-paclitaxel and bevacizumab <7 
days of biopsy. 
 
7.321 
Patients who are eligible and choose to continue on to the 
bevacizumab plus nab-paclitaxel phase:  Patients who are eligible 
and choose to proceed to bevacizumab plus nab-paclitaxel treatment 
must begin treatment ≤2-4 weeks after PD.  Patients will receive 
bevacizumab on days 1 and 15 and nab-paclitaxel on days 1 
(following bevacizumab), 8, and 15 (following bevacizumab) of a 
28-day cycle (±2 days).  Treatment will continue until PD.  At the 
time of PD, patients will go to Event Monitoring. (see Section 13.0). 
 
7.322 
Patients who are not eligible or who choose not to continue on 
bevacizumab plus nab-paclitaxel:  Patients who are not eligible or 
choose not to continue on bevacizumab plus nab-paclitaxel will go 
on to Event Monitoring (see Section 13.0). 
 
7.4 
For this protocol during active treatment and observation phases, the patient must return 
to the consenting ACCRU institution for evaluation as specified in the test schedule (See 
section 4.0).   
 
7.5 
Treatment by a local medical doctor (LMD) is not allowed. 
 
7.6  
If there is an interruption of treatment of ≥21 days due to patient request, scheduling 
issues, inclement weather, vacation, etc. the patient may not restart treatment and will 
enter the event monitoring phase of the study. 
 
 


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8.0 
Dosage Modifications Based on Adverse Events 
 
8.1  
Dose modifications are based on the adverse events that develop.  These modifications 
should be regarded as guidelines to result in mild-to moderate, but not debilitating side 
effects. If multiple toxicities are seen, administer dose based on greatest reduction 
required for any single toxicity observed. 
 
 
8.2 
There are no dose reductions for ipilimumab based on adverse events.  If treatment is 
held greater than 3 weeks without resolution of adverse events to levels specified in Dose 
modification tables found in Sections 8.4 - 8.7 then treatment should be discontinued and 
patients go to Event Monitoring (see Section 13.0) 
 
 
 
 
8.3 
A maximum of 2 dose reductions for nab-paclitaxel are allowed. There are no dose 
reductions for bevacizumab based on adverse events.  If a patient requires a 3rd dose 
reduction based on adverse events or treatment is held greater than 4 weeks without 
resolution of adverse event, then treatment should be discontinued and patients go to 
Event Monitoring (see Section 13.0). 
 
ALERT: ADR reporting may be required for some toxicities (See Section 10.0) 
 
 
Dose Levels  
Dose 
Level 
Bevacizumab 
Nab-paclitaxel 
 0* 
10mg/kg  
150mg/m2 
-1 
10 mg/kg 
100mg/m2 
-2 
10 mg/kg 
75 mg/m2 
*Starting dose level 
 
Use the following definitions to determine actions in the Action columns of the 
following tables: 
 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
 
 


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8.4 
Dose modifications for nab-paclitaxel based on interval toxicity during treatment:  Days 
8 & 15 
 
8.41 
If nab-paclitaxel is omitted due to an adverse event (days 8 or 15), bevacizumab 
can be continued if there are no contraindications to its administration (see Table 
8.5). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
TREATMENT MODIFICATIONS FOR NAB-PACLITAXEL ON CYCLE  DAYS  8 & 15 
Use Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0*  
unless otherwise specified. 
CTCAE 
Category 
Adverse Event 
Dose Reduction 
 
 
 
 
 
 
Investigations 
Neutrophil count 
decreased  ≥ grade 3 
 
 
 
Day 8: Omit dose that day and retreat at same dose level on 
day 15 if counts have recovered to ≤  grade 2. 
Day 15: Omit dose that day. 
NOTE:  
If Day 8 and 15 of a cycle are omitted, then subsequent 
cycles of nab-paclitaxel are to be administered at the next 
lower dose. 
Platelet count 
decreased 
≥ grade 2 
Day 8: Omit dose that day and retreat at same dose level on 
day 15 if counts have recovered to ≤ grade 1. 
Day 15: Omit dose that day. 
NOTE:  
If Day 8 and 15 of a cycle are omitted, then subsequent 
cycles of  nab-paclitaxel  are to be administered at the next 
lower dose.   
Nervous 
system  
disorders 
Peripheral 
sensory neuropathy OR 
Peripheral motor 
neuropathy 
≥ grade 2 
Omit dose that day. If resolved to < grade 2 by next 
scheduled dose, then dose reduce by one level (see below).  
If treatment needs to be held >4 weeks, discontinue study 
treatment and go to Event Monitoring. 
All other non-
hematologic 
adverse events 
≥ grade 3 
Omit dose that day. If resolved to ≤ grade 2, then dose 
reduce by one level. If treatment needs to be held >4 weeks,  
discontinue study treatment and go to Event Monitoring. 


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8.5 
Dose modifications for nab-paclitaxel at time of re-treatment on subsequent cycles:  Day 
1. 
 
8.51 
If nab-paclitaxel is held on day 1 due to an adverse event, bevacizumab should 
also be held.  
 
 
TREATMENT MODIFICATIONS FOR NAB-PACLITAXEL ON SUBSEQUENT CYCLES:  
DAY 1 
Use Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 
unless otherwise specified. 
CTCAE category 
Adverse Event 
Dose Reduction 
Investigations 
Neutrophil count 
decreased   
≥ grade 2 
 
 
Hold nab-paclitaxel until counts < grade 2 then decrease by 
ONE dose level.  
 
If treatment needs to be held >4 weeks, discontinue study 
treatment and go to  Event Monitoring. 
Platelet count 
decreased 
≥ grade 2 
Hold nab-paclitaxel until counts < grade 2 then decrease by 
ONE dose level.  
 
If treatment needs to be held >4 weeks, discontinue study 
treatment and go to  Event Monitoring. 
 
Aspartate 
aminotransferase 
increased or 
Alkaline 
phosphatase 
increased 
 ≥ grade 2 
Hold nab-paclitaxel until resolved to < grade 2 then dose 
reduce by ONE dose level.  
 
If treatment needs to be held >4 weeks, discontinue study 
treatment and go to Event Monitoring. . 
 
Nervous 
systemdDisorders 
Peripheral sensory 
neuropathy 
≥ grade 2 
Hold nab-paclitaxel until resolved to < grade 2 then 
reduce dose by ONE dose level.  
 
If treatment needs to be held >4 weeks, discontinue study 
treatment and go to Event Monitoring. 
 
All other non-
hematologic 
adverse events 
≥ grade 3 
Hold nab-paclitaxel until resolved to ≤ grade 2 then 
reduce dose by ONE dose level.  
 
If treatment needs to be held >4 weeks, discontinue study 
treatment and go to Event Monitoring. 
 
 
 
 


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8.6 
Dose modifications for bevacizumab treatment:  Days 1 and 15 
 
8.61 
Dose reductions for bevacizumab are not allowed.  The scheduled treatment is 
either given at full dose or held/omitted. 
 
8.62 
If bevacizumab is temporarily held (days 1 and 15), treatment with nab-
paclitaxel can continue if there are no contraindications to administration. If 
bevacizumab has to be held for >4 weeks, discontinue all treatment and go to 
Event Monitoring (see Section 13.3). 
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 unless otherwise 
specified. 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
TREATMENT MODIFICATION 
Investigations 
Neutrophil count 
decreased  ≥ grade 3 
 
 
 
Day 1: Hold until neutrophil count <grade 3. 
 
Day 15: Omit dose. 
 
If treatment needs to be held >4 weeks, discontinue 
study treatment and go to Event Monitoring.  
 
Platelet count decreased 
≥grade 2 
 
Day 1: Hold until platelet count <grade 2. 
 
Day 15: Omit dose. 
 
If treatment needs to be held >4 weeks, discontinue 
study treatment and go to Event Monitoring. 
Gastrointestinal 
disorders 
Colonic perforation 
Any grade 
 
Discontinue all study  treatment and proceed to Event 
Monitoring  
 
Colonic obstruction 
 
grade 1 
 
 
grade 2 
 
 
 
 
 
grade 3 or 4 
 
 
Continue patient on study for partial bowel 
obstruction NOT requiring medical intervention. 
 
Omit bevacizumab for partial obstruction requiring 
medical intervention. If resolved to grade 0 within 4 
weeks, resume treatment.  If treatment needs to be 
held >4 weeks, discontinue all study treatment and 
go to Event Monitoring. 
 
For complete bowel obstruction, discontinue study  
treatment and proceed to Event Monitoring. 
 
Continued on next page


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
TREATMENT MODIFICATION 
Cardiac disorders 
Acute coronary syndrome 
 
Any grade 
Discontinue study treatment and proceed to Event 
Monitoring. 
Left ventricular systolic 
dysfunction 
grade 3 
 
 
 
 
grade 4 
 
 
Omit until resolution to grade ≤ 1. If treatment needs 
to be held >4 weeks, discontinue all study treatment 
and go to Event Monitoring . 
 
 
Discontinue study treatment and proceed to Event 
Monitoring. 
Myocardial infarction 
 
Any grade 
Discontinue treatment and proceed to Event 
Monitoring. 
Cardiac disorders-other: 
Angina 
 
Any grade 
Discontinue treatment and proceed to Event 
Monitoring. 
Nervous system 
disorders 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
OR  
 
Intracranial hemorrhage 
 
≥ grade 2 
Discontinue study  treatment and proceed to Event 
Monitoring. 
Ischemia cerebrovascular 
 
Any grade 
Discontinue treatment and proceed to Event 
Monitoring. 
Transient ischemic attack 
 
Any grade 
Discontinue treatment and proceed to Event 
Monitoring. 
Respiratory, thoracic 
and mediastinal 
disorders 
Bronchopulmonary 
hemorrhage 
 
≥ grade 2 
 
Discontinue study treatment and proceed to Event 
Monitoring. 


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Vascular disorders 
Thromboembolic event 
 
grade 3 
or 
asymptomatic grade 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptomatic grade 4 
 
 
• Omit bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is <2weeks, 
bevacizumab should be held until the full-dose 
anticoagulation period is over. 
• If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab may be 
resumed during the period of full-dose 
anticoagulation IF all of the criteria below are 
met: 
- The subject must have an in-range INR (usually 
2-3) on a stable dose of warfarin or on stable dose 
of heparin prior to resuming bevacizumab 
treatment. 
- The subject must not have pathological conditions 
that carry high risk of bleeding (e.g. tumor 
involving major vessels or other conditions) 
- The subject must not have had hemorrhagic 
events while on study 
• If thromboemboli worsen/recur upon resumption 
of study therapy, discontinue bevacizumab. 
 
 
Discontinue treatment and proceed to Event 
Monitoring. 
Hypertension 
Hypertension should be 
treated as per general 
practice. If hypertension 
(i.e., systolic blood 
pressure ≥150 mmHg 
and/or diastolic blood 
pressure ≥ 100 mmHg) 
persists despite treatment, 
hold treatment until blood 
pressure is below this 
level. 
If treatment needs to be held >4 weeks due to 
uncontrolled hypertension, discontinue study 
treatment and go to Event Monitoring. 
Vascular disorders-other: 
Any arterial 
thromboembolic event 
 
Any grade 
Discontinue treatment and proceed to Event 
Monitoring. 


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Renal and urinary 
disorders 
Proteinuria 
 
grade 3  
(urine collection >3.5 
g/24 hour or  
dipstick 4+) 
 
grade 4 (nephritic 
syndrome) 
 
 
Omit bevacizumab until ≤ grade 2, as determined by 
24 hr. collection ≤3.5 g. If treatment needs to be held 
≥4 weeks, discontinue treatment and proceed to 
Event Monitoring. 
 
Discontinue treatment and proceed to Event 
Monitoring. 
 
Injury, poisoning and 
procedural 
complications 
Wound dehiscence 
(requiring medical or 
surgical intervention) 
Discontinue treatment and proceed to Event 
Monitoring. 
Immune system 
disorders 
Allergic reaction 
(hypersensitivity) 
 
grade 3 or 4 
Discontinue study treatment and proceed to Event 
Monitoring. 
Respiratory thoracic 
and mediastinal 
disorders 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
 
Any grade 
 
Discontinue study treatment and proceed to Event 
Monitoring. 
Bronchospasm 
Any grade 
 
Discontinue study treatment and proceed to Event 
Monitoring. 
Other clinically 
significant AEs at 
least possibly 
attributable to 
bevacizumab (except 
controlled 
nausea/vomiting and 
any Gr 3+ 
hemorrhage 
grade 3 
 
 
 
 
 
grade 4 
 
Omit treatment until toxicities return to baseline or ≤ 
grade 1, then retreat based on interval toxicities. If 
treatment needs to be held >4 weeks, discontinue 
study treatment and proceed to Event Monitoring.  
 
 
Discontinue study treatment and proceed to Event 
Monitoring. 
 
 
Grade  3-4 hemorrhage, discontinue treatment and 
proceed to Event Monitoring. 
 


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8.7 
Dose modifications for ipilimumab on day 1 of each  treatment dose 
 
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
TREATMENT MODIFICATION 
Gastrointesinal 
disorders 
Diarrhea 
    
 
Grade 2  AND 
symptoms ≤1 week 
 
 
 
 
 
Grade 2 AND 
symptoms > 1 week 
 
 
 
 
 
≥grade 3 
See Section 9.9b1 for treatment of diarrhea. 
 
 
Hold ipilimumab until symptoms resolved to ≤ 
grade 1.  
If treatment needs to be held >3 weeks, 
discontinue study treatment and go to Event 
Monitoring. 
 
 
Initiate steroid therapy and hold ipilimumab 
until symptoms resolved to ≤ grade 1. If 
treatment needs to be held >3 weeks, 
discontinue study treatment and go to Event 
Monitoring. 
 
 
Discontinue study treatment and go to Event 
Monitoring. 
 
Colonic perforation 
Any Grade 
 
Discontinue study treatment and go to Event 
Monitoring. 
 
Endocrine disorders 
Hypothyroidism 
 
grade 2 
 
 
 
 
 
 
≥grade 3 
 
 
Hold ipilimumab until resolved to ≤grade 1 
and initiate thyroid replacement therapy. If 
treatment needs to be held >3 weeks, 
discontinue study treatment and go to Event 
Monitoring. 
 
 
Discontinue study treatment and go to Event 
Monitoring.  Initiate thyroid replacement and 
steroid therapy per 9.0 
 


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CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
TREATMENT MODIFICATION 
Nervous system 
disorders 
Any Nervous System 
Disorders 
 
grade 2 
 
 
 
 
 
≥grade 3 
 
 
 
Hold ipilimumab until resolved to ≤grade 1 
and initiate steroid therapy.  If treatment needs 
to be held >3 weeks, discontinue study 
treatment and go to Event Monitoring..  
 
 
Discontinue study treatment and go to Event 
Monitoring. .  Initiate steroid therapy per 9.0.  
 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo-papular 
 
Grade 1 symptomatic 
OR Grade 2 
 
 
 
 
 
 
 
≥ Grade 3 
 
 
Hold ipilimumab until symptoms resolved to 
≤grade 1 AND asymptomatic.   Initiate 
therapy with topical   steroids (grade 1 
symptomatic) and/or systemic steroids (grade 
2). If treatment needs to be held >3 weeks, 
discontinue treatment and go to Event 
Monitoring. 
 
 
Discontinue study treatment and go to Event 
Monitoring.   Initiate therapy with systemic 
steroids +/- topical steroids per 9.0 
 
Investigations 
Aspartate aminotransferase 
increased or Alanine 
aminotransferase increased 
 
grade 2 
 
 
 
 
 
 
≥ grade 3 
 
 
 
 
Hold ipilimumab and initiate steroids until 
levels are ≤3 x ULN (grade 1).  Monitor twice 
weekly until resolved to ≤grade1. If treatment 
needs to be held >3 weeks, discontinue 
treatment and go to Event Monitoring. 
 
 
Discontinue ipilimumab and go to Event 
Monitoring.  Initiate therapy with steroids per 
9.0 and monitor twice weekly until resolved to 
≤grade1. 
 


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CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
TREATMENT MODIFICATION 
Blood bilirubin increased 
 
grade 2 
 
 
 
 
 
 
≥grade 3 
 
 
Hold ipilimumab and monitor twice weekly 
until levels are ≤grade1. Initiate therapy with 
steroids per 9.0.  If treatment needs to be held 
>3 weeks, discontinue treatment and go to 
Event Monitoring. 
 
 
Discontinue ipilimumab and go to Event 
Monitoring.  Initiate therapy with steroids per 
9.0 and monitor twice weekly until resolved to 
≤grade 1. 
Immune systems 
disorders 
Any Immune systems 
disorders 
 
Grade 2 
 
 
 
 
 
 
≥ Grade 3 
 
 
 
Hold ipilimumab and monitor twice weekly 
until levels are ≤grade1.  Initiate therapy with 
steroids per 9.0.  If treatment needs to be 
held>3 weeks, discontinue treatment and go to 
Event Monitoring. 
 
 
Discontinue ipilimumab and go to Event 
Monitoring.  Initiate therapy with steroids per 
9.0 and monitor twice weekly until resolved to 
≤grade1. 
 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
 
grade 2 
 
 
 
 
 
 
≥grade 3 
 
 
Hold ipilimumab and monitor twice weekly 
until levels are ≤grade1. Initiate therapy with 
steroids per 9.0.  If treatment needs to be held 
>3 weeks, discontinue treatment and go to 
Event Monitoring. 
 
 
Discontinue ipilimumab and go to Event 
Monitoring.  Initiate therapy with steroids per 
9.0 and monitor twice weekly until resolved to 
≤grade 1. 
 


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CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
TREATMENT MODIFICATION 
General disorders and 
administration site 
conditions 
Any General disorders and 
administration site conditions 
 
grade2 
 
 
 
 
 
≥grade 3 
 
 
 
Hold ipilimumab until resolved to ≤grade 1. 
If treatment needs to be held >3 weeks, 
discontinue treatment and go to Event 
Monitoring. 
 
 
Discontinue study treatment and go to Event 
Monitoring. 
 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Hypersensitivity reactions: Patients do not require premedication prior to nab-paclitaxel 
or ipilimumab administration, as hypersensitivity reactions are not expected.  In the 
unlikely event of a hypersensitivity reaction, treatment with antihistamines, H2 blockers, 
and corticosteroids is recommended. Patients should be pre-medicated with the typical 
regimen for nab-paclitaxel regimens for subsequent cycles. In the unlikely event of a 
mild hypersensitivity reaction, premedication may be administered using the 
premedication regimen the institution typically uses for solvent-based nab-paclitaxel.  
 
9.2 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications received 
from the first administration of study drugs until 30 days after the final dose are to be 
recorded in the medical record and on the treatment form. 
 
9.3 
Use of growth factors prophylactically during this trial is discouraged. Oncologists are 
urged to follow the ASCO guidelines (www.asco.org) and to discontinue growth factors 
24 hours prior to initiation of the next cycle of chemotherapy. The use of any growth 
factor must be documented in the patients’ record and on the treatment form. 
 
9.4 
Patients may not enroll in a different clinical study, including Cancer Control studies,  in 
which investigational procedures or agents are being used, while participating in this 
study.  
 
9.5 
Patients must terminate study treatment if they are to receive radiation therapy for 
palliative reasons as it impacts upon assessing response.  
 
9.6 
Patients should be pre-medicated according to institutional policy with antiemetics for 
patients receiving taxane/platinum therapy. 
 
9.7 
General patient monitoring and supportive care guidelines 
 


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9.71 
Patients should be carefully monitored during the treatment phase and then 
followed appropriately. Prior to each bevacizumab infusion, patients should be 
carefully assessed, with special attention to blood pressure, proteinuria, bleeding 
events as well as other adverse events. Decisions for retreatment or dose 
modifications/interruption should follow the guidelines in Sections 8.4 
 
9.72 
Patients who have an ongoing study agent-related serious adverse event upon 
study completion or at discontinuation from the study will be contacted by the 
treating physician or his/her designee every 2 weeks until the event is resolved or 
determined to be irreversible. 
 
9.721 
Hypertension 
Blood pressure should be assessed at least weekly during the first 
cycle and before each administration of bevacizumab (days 1 and 15) 
thereafter. High blood pressure may require initiation or increase in 
antihypertensive medication according to routine clinical practice. 
Bevacizumab treatment modifications should follow the instructions 
in Section 8.4.  
 
9.8 
If patients on treatment with bevacizumab require elective major surgery, bevacizumab 
should be discontinued for at least 4-8 weeks prior to the surgical procedure.  
 
9.9a 
Infusion of bevacizumab should be interrupted for subjects who develop dyspnea or 
clinically significant hypotension. Subjects who experience a NCI CTCAE v. 4.0 Grade 3 
or 4 allergic reaction/hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab treatment.   
The infusion should be slowed to 50% or less or interrupted for subjects who experience 
any infusion-associated symptoms not specified above (and Section 8.0). When the 
subject’s symptoms have completely resolved, the infusion may be continued at no more 
than 50% of the rate prior to the reaction and increased in 50% increments every 30 
minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle. 
 
9.9b 
Side effect management for Ipilimumab toxicities- these are to be regarded as guidelines 
for managing toxicity that occurs with ipilimumab therapy and should not replace clinical 
judgement (i.e - patients with grade 1 rash may require systemic steroids). 
 
9.9b1 Diarrhea (see Section 8.7) 
 
9.9b11 
Grade 1- without abdominal pain/or blood in stool and symptoms, 
manage symptomatically. Infectious etiologies should be ruled out. 
May continue ipilimumab. Instruct patients to report any increase in 
stools. 
 
9.9b12 
Grade 2- without abdominal pain/or blood in stool and symptoms < 1 
week, and resolve to grade 0 or 1- continue to monitor. Infectious 
etiologies should be ruled out. Hold ipilimumab until symptoms 
resolved to ≤ Grade 1. 
  
 
 


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9.9b13 
Grade 2- symptoms >1 week, should be started on systemic steroid 
therapy (0.5 mg/kg/day prednisone or equivalent- can be given in 
two doses- especially for patients that have nocturnal diarrhea).** 
Infectious etiologies should be ruled out. Hold ipilimumab until 
symptoms resolved to ≤ Grade 1.  
 
9.9b14 
Grade 3 or greater- who have other etiologies ruled out should be 
started on systemic steroids at 1-2 mg/kg/day prednisone or 
equivalent (may be given in two daily doses-especially for patients 
that have nocturnal diarrhea).**  Assess for dehydration. Patients 
may require hospitalization for IV steroids (1-2 mg/kg/day 
methylprednisolone) Discontinue ipilimumab. Patients without 
improvement in symptoms over 3-5 days, consider the following:  
endoscopy, budesonide 12 mg orally once daily, steroid enemas, or 
GI consultation. 
 
** Once patients have improvement of symptoms to grade 0 or 1 
taper of steroids should occur over at least 1 month- if patients have 
been started on budesonide in addition to systemic steroids, start 
tapering the prednisone FIRST(over 2 to 3 weeks) before tapering of 
budesonide. 
 
Do NOT administer loperamide in patients with ≥ Grade 2 
diarrhea as this may cause toxic megacolon and/or perforation. 
 
If at any time patients experience diarrhea with the following 
symptoms: fever or abdominal pain patients should have a CT 
scan of the abdomen to rule out perforation.  Emergent surgical 
evaluation should be performed if perforation is found.. If a 
patient has bloody diarrhea, a Gastroenterology consult should 
be obtained. A Gastroenterology consult should be obtained if 
provider is considering infliximab for treatment of colitis.  
 
For all patients- assess hydration status and monitor electrolytes, 
including magnesium. 
 
9.9b2 Rash (see Section 8.7) 
 
9.9b21 
Grade 1 symptomatic or any Grade 2- Hold ipilimumab until 
resolved ≤ Grade 1 and ASYMTOMATIC. Initiate therapy with 
topical (Grade 1 symptomatic) or systemic steroids (Grade 2). 
 
9.9b22 
Grade 3 or greater- discontinue ipilimumab. Initiate systemic steroid 
therapy. 
 
9.9b3 Hypothyroidism (see Section 8.7) 
 
9.9b31 
Grade 2- Initiate thyroid replacement. Hold ipilimumab until 
resolved to ≤ Grade 1 
 


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9.9b32 
Grade 3 or greater- Discontinue ipilimumab. Initiate thyroid 
replacement therapy. Initiate systemic steroid therapy 
 
9.9b4 Neurological 
 
9.9b41 
Mild symptoms (grade 1) – Rule out other causes (i.e CNS 
metastasis) and continue ipilimumab and monitor patient for any 
worsening.  
 
9.9b42 
Moderate symptoms (grade 2). Rule out other causes (i.e CNS 
metastasis). Treat symptomatically. Hold ipilimumab until symptoms 
resolved to grade 0 or 1. Consider starting low dose steroids (i.e 0.5 
mg/kg/day).  
 
9.9b43 
Severe symptoms (grade 3 or 4).  
a. Grade 3-4 sensory- Rule out other causes (i.e CNS metastasis) 
i. 
Treat with high dose steroids (1-2 mg/kg/day). Consider IV 
steroids. 
ii. Refer to Neurology. 
iii. Once symptoms resolve to ≤ grade 2 can start steroid taper* 
b. Grade 3-4 motor**- Rule out other causes (i.e CNS metastasis).  
i. 
Treat with high dose steroids (1-2 mg/kg/day). Consider IV 
steroids. 
ii. Refer to Neurology. 
iii. Once symptoms resolve to ≤ grade 2 can start steroid taper* 
 
9.9b5 Liver dysfunction (AST or ALT) 
 
9.9b51 
AST or ALT ≤ 2.5 ULN- No change in treatment 
 
9.9b52 
AST or ALT >2.5 -3 ULN or Grade 2- Hold ipilimumab until levels 
are ≤ 2.5 ULN. Monitor levels twice weekly until resolved. Consider 
initiating systemic steroids. 
 
9.9b53 
AST or ALT ≥ Grade 3- Discontinue ipilimumab. Initiate systemic 
steroid therapy.  
 
9.9b6 Liver dysfunction (Total Bilirubin) 
 
9.9b61 
Grade 1- No change in treatment 
 
9.9b62 
Grade 2- Hold ipilimumab and monitor levels until resolved to  
≤ Grade 1. Consider initiating systemic steroids. 
 
9.9b63 
Grade 3 or greater- Discontinue ipilimumab. Monitor levels until 
resolved to ≤ Grade 1. Initiate therapy with steroids. 
 
9.9b7 Pneumonitis 
 
9.9b71 
Grade 1- No change in treatment 
 


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9.9b72 
Grade 2- Hold ipilimumab until resolved to ≤ Grade 1 and initiate 
steroids  
 
9.9b73 
Grade 3 or greater- Discontinue ipilimumab, consider 
hospitalization, and initiate systemic steroids 
 
9.9b8 General management of other immune related adverse events (not specified 
above).  
 
9.9b81 
Grade 1- Observe, rule out other causes, and treat symptomatically 
 
9.9b82 
Grade 2- Hold Ipilimumab until symptoms resolved to ≤ grade 1, 
initiate therapy with systemic steroids 
 
9.9b83 
Grade 3 or higher –Discontinue ipilimumab permanently. Initiate 
therapy with systemic steroids. 
 
9.9b9 Steroid dosing guidelines 
 
9.9b91 
Grade 2- Steroids should be initiate at 0.5-1mg/kg/day of prednisone 
or equivalent. 
 
9.9b92 
Grade 3 or greater- Steroids should be initiated at 1-2 mg/kg/day of 
prednisone or equivalent. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and Grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)     
 
10.11 Adverse event (AE) monitoring and reporting is a routine part of 
every clinical trial.  First, identify and Grade the severity of the event 
using the CTCAE version 4.0.  Next, determine whether the event is 
expected or unexpected (see Section 10.2) and if the adverse event is 
related to the medical treatment or procedure (see Section 10.3).  
With this information, determine whether the event must be reported 
as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified 
in Sections 10.4. All AEs reported via expedited mechanisms must 
also be reported via the routine data reporting mechanisms defined 
by the protocol (see Sections 10.5 and 18.0). 
  


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10.12 Each CTCAE term in the current version is a unique representation 
of a specific event used for medical documentation and scientific 
analysis and is a single MedDRA Lowest Level Term (LLT). 
 
• 
NOTE:  A severe AE, as defined by the above grading scale, is 
NOT the same as serious AE which is defined in the table in 
Section 10.4. 
 
10.2  Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-
specific information provided in Section 15.0 of the protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse 
experience that is neither identified in nature, severity, or frequency of 
risk in the information provided for IRB review nor mentioned in the 
consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal 
relationship between the drug and the adverse event.  
 
10.31 AEs Experienced Utilizing Investigational Agents and 
Commercial Agent(s) on the SAME Arm 
 
Routine Reporting 
 
• 
Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent is 
stated in the protocol.  See Section 10.52. 
 
NOTE:  When a commercial agent(s) is (are) used on the same treatment 
arm as the investigational agent/intervention (also, investigational drug, 
biologic, cellular product, or other investigational therapy under an IND), the 
entire combination (arm) is then considered an investigational intervention 
for reporting. 
 


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Expedited Reporting 
 
• 
An AE that occurs on a combination study must be assessed in accordance 
with the guidelines for investigational agents/interventions in Section 10.4, 
and where indicated, an expedited report must be submitted. 
 
• 
An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible attribution 
to the commercial agent require an expedited report.  Refer to each protocol 
for specific AE reporting requirements or exceptions. 
 
• 
Commercial agent expedited reports must be submitted to the FDA via 
MedWatch. 
 
• 
An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited 
reporting is required.  The clinical investigator must determine severity. 
 
 
 


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10.32 Special Situations for Expedited Reporting  
 
10.321 
Exceptions to Expedited Reporting: EXPECTED Serious 
Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 
3 Serious Adverse Events where the AE is EXPECTED.  
 
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the event 
will not be expeditiously reported. 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 3 
Febrile neutropenia 
≤Grade 3 
Cardiac disorders 
Myocardial infarction 
≤Grade 3 
Gastrointestinal disorders 
Nausea 
≤Grade 3 
Vomiting 
≤Grade 3 
Gastric hemorrhage 
≤Grade 3 
Abdominal pain 
≤Grade 3 
Diarrhea 
≤Grade 3 
General disorders and 
administration site 
conditions 
Fatigue 
≤Grade 3 
Fever 
≤Grade 3 
Immune system disorders 
Allergic reaction/ anaphylaxis 
≤Grade 3 
Injury, poisoning, and 
procedural complications 
Wound dehiscence 
≤Grade 3 
Investigations 
Neutrophil count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 3 
White blood cell decreased 
≤Grade 4 
AST 
≤Grade 3 
Alkaline Phosphatase 
≤Grade 3 
Total Bilirubin 
≤Grade 3 
Musculoskeletal and 
connective tissue disorders 
Arthralgia 
≤Grade 3 
Myalgia 
≤Grade 3 
Nervous system disorders 
 
 
Intracranial hemorrhage 
≤Grade 3 
Leukoencephalopathy 
≤Grade 3 
Peripheral sensory neuropathy 
≤Grade 3 
Renal and urinary 
disorders 
Proteinuria 
≤Grade 4 
Respiratory, thoracic and 
mediastinal disorders  
Bronchopulmonary hemorrhage 
≤Grade 3 
Skin and subcutaneous 
tissue disorders 
Rash maculo-papular 
≤Grade 4 
Vascular disorders 
Hypertension 
≤Grade 3 
Thromboembolic event 
≤Grade 3 
 
Specific protocol exceptions to expedited reporting should be 
reported expeditiously by investigators ONLY if they exceed the 
expected grade of the event (regardless of hospitalization). 
 
10.322 
Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred 
to as disabilities), congenital abnormities or birth defects, must be reported 


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immediately if they occur at any time following treatment with an agent 
under an IND/IDE since they are considered to be a serious AE and must 
be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
10.323 
Death 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under 
an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Any death occurring greater than 30 days with an 
attribution of possible, probable, or definite to an 
agent/intervention under an IND/IDE requires expedited 
reporting within 24-hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by cessation 
of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be attributed to 
a CTCAE term associated with Grade 5. 
 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported as 
Grade 5 “Neoplasms benign, malignant and 
unspecified (including cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be 
submitted. 
 
10.324 
Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial 
neoplasm. 
 


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• 
All secondary malignancies that occur following treatment with 
an agent under an IND/IDE to be reported. Three options are 
available to describe the event: 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.325 
Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
 
 


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10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
10.41 Expedited Reporting via the ACCRU Adverse Event Expedited Report Form 
for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in Section 10.321. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions: 
1. Any event that results in persistent or significant disability/incapacity, congenital 
anomaly, or birth defect must be reported via expedited mechanisms if the event 
occurs following treatment on a trial under an IND. 
 


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2. Use the ACCRU protocol number and the protocol-specific patient ID provided 
during trial registration/randomization on all reports. 
 
The above expedited reports (24-hour and 3- or 7-day) must be submitted via the 
.  Submit reports to the ACCRU 
SAE Coordinator via fax 
  
 
3. Mayo Clinic Cancer Center (MCCC) Institutions: Fax a copy of the report to 
both Celgene and Genentech using the fax numbers provided below. Provide 
copies, along with the UPIRTSO cover sheet, by fax (
 to the MCCC 
Regulatory Affairs Unit (RAU) Regulatory Affairs Specialist who will determine and 
complete IRB reporting. The RAU will submit to the ACCRU SAE Coordinator and 
the ACCRU IND Coordinator to determine if FDA submission is needed.   
 
4. Non-Mayo ACCRU Sites: Submit reports to the ACCRU SAE Coordinator via fax 
. Once the ACCRU SAE Coordinator receives the report via fax, the 
ACCRU SAE Coordinator will forward a copy of the above expedited reports to: 
 
• 
The ACCRU IND Coordinator who will notify the FDA as warranted by the 
event and stipulated in the U.S. Code of Federal Regulations.  
 
• 
Celgene:   Expedited Reporting by Investigator to Celgene: 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of 
any SAE within 24 hours of being aware of the event.  The written report must be 
completed and supplied to Celgene by facsimile within 24 hours/1 business day.  
The initial report must be as complete as possible, including an assessment of the 
causal relationship between the event and the investigational product(s),.  
Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented 
on a follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (AX-MEL-ACCRU-0090) and the 
institutional protocol number should be included on SAE reports (or on the fax 
cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 
SAE report to Celgene should be attached to the SAE and retained with the 
patient records. 
 
 
      
    
      
   
     
        
       
 
 
 
 


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• 
Genentech:  Genentech will be informed in writing of any SAE within 24 
hours/1 business day of receipt of the fax.   The fax will be sent to Genentech 
Drug Safety at: 
 
 
 
• 
Pregnancy – If a female subject becomes pregnant while receiving 
investigational therapy or within  90 days after the last dose of study drug, a 
report should be completed and expeditiously submitted to Genentech, Inc. 
Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, 
whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the 
bevacizumab should be reported as an SAE. 
 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
 
System Organ Class 
Adverse/Event Symptoms 
Baseline 
Each 
Evaluation 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
Febrile neutropenia 
 
X 
Cardiac disorders 
Myocardial infarction 
 
X 
Gastrointestinal disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
Abdominal pain 
X 
X 
Baseline # stools 
X 
 
Diarrhea 
 
X 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
Fever 
 
X 
Immune system disorders 
Allergic reaction 
 
X 
Anaphylaxis 
 
X 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
White blood cell decreased 
X 
X 
Aspartate aminotransferase 
increased 
X 
X 
Alkaline phosphatase increased 
X 
X 
Blood bilirubin increased 
X 
X 
Musculoskeletal and 
connective tissue disorders 
Arthralgia 
X 
X 
Myalgia 
X 
X 
Nervous system disorders 
Peripheral sensory neuropathy 
X 
X 
 


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10. 511 
Genentech AEs of Special Interest (AESI):  AEs of Special 
Interest for Avastin are defined by Genentech as a potential safety 
problem identified as a result of ongoing safety monitoring of their  
product.  As such, surveillance for the AESIs in Appendix III 
MUST be undertaken at each treatment evaluation.  
Development of  one of these AESIs (grade 1 or severer unless 
otherwise noted) MUST be reported on the AE case report forms 
in terms of CTCAE v4.0 grade and attribution.  
 
10.512  
Reconciliation:  The Sponsor (ACCRU) agrees to conduct 
reconciliation for the product.  Genentech and the Sponsor will agree 
to the reconciliation periodicity and format but agree at a minimum 
to exchange monthly line listings of cases received by the other 
party.  If discrepancies are identified, the Sponsor (ACCRU) and 
Genentech will cooperate in resolving the discrepancies.  The 
responsible individuals for each party shall handle the matter on a 
case-by-case basis until satisfactory resolution. 
 
10.513 
Study Close-out:  Any study report submitted to the FDA by the 
Sponsor-Investigator should be copied to Genentech. This includes 
all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the 
study should be sent to Genentech. Copies of such reports should be 
mailed to the assigned Clinical Operations contact for the study. 
Avastin Protocols 
Email: 
 
Fax: 
 
 
10.52 Submit via appropriate Academic and Community Cancer Research United 
(ACCRU) Case Report Forms (i.e., paper or electronic, as applicable) the 
following AEs experienced by a patient and not specified in Section 10.5: 
 
10.521 
Grade 1 and 2 AEs deemed possibly, probably, or definitely related 
to the study treatment or procedure. 
 
10.522 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure 
 
10.523 
Grade 5 AEs (Deaths) 
 
10.5231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
 
10.5232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
 


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10.53 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
 
11.0 
Treatment Evaluation Using RECIST Criteria 
 
11.1 
Schedule of Evaluations are specified in Section 4.0   
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21 Measurable Disease 
 
11.211 
A non-nodal lesion is considered measurable if its longest diameter 
can be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 
cm with CT scan, CT component of a PET/CT, or MRI.  
 
11.212 
A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).   
 
NOTE: Tumor lesions in a previously irradiated area are not 
considered measurable disease.   
 
11.22 Non-Measurable Disease 
 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm).  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable as well. 
 
Note:  ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.   
 
Lymph nodes that have a short axis <1.0 cm are considered non- pathological (i.e., 
normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods: 
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-


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up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.   
 
11.32 Acceptable Modalities for Measurable Disease: 
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.     
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.   
 
• 
Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, CT 
scans are preferable. 
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:   
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that site. 
In this situation, the date of PD will be the date of the initial abnormal 
PDG-PET scan.   
iii. If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
 


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11.33 Measurement at Follow-up Evaluation:   
 
• 
A subsequent scan must be obtained 8 weeks following initial documentation 
of an objective status of either complete response (CR) or partial response 
(PR).  
 
• 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 12 weeks 
(see Section 11.44). 
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline.  These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 


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nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD).  If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm.  If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned.  If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at  
baseline.  These lesions and lymph nodes should be followed in accord with 
11.433. 
 
11.43 Response Criteria 
 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/Chest X-ray must be measured on re-evaluation at evaluation 
times specified in Section 11.1.  Specifically, a change in objective 
status to either a PR or CR cannot be done without re-measuring 
target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response 
or confirmation of response.  In selected circumstances, certain non-
target organs may be evaluated less frequently.  For example, bone 
scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
 
11.432 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to 
<1.0 cm. 
 
• 
Partial Response (PR): At least a 30% decrease in PBSD (sum 
of the longest diameter for all target lesions plus the sum of the 
short axis of all the target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 11.41). 
 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (< 1.0 cm short 
axis) and increased to ≥ 1.0 cm short axis during follow-up.  


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b. At least a 20% increase in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis 
of all the target lymph nodes at current evaluation) taking as 
reference the MSD (Section 11.41).  In addition, the PBSD 
must also demonstrate an absolute increase of at least 0.5 
cm from the MSD.  
c. See Section 11.32 for details in regards to the requirements 
for PD via FDG-PET imaging. 
  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD taking as reference 
the MSD. 
 
 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must have a reduction in short 
axis to <1.0 cm. 
 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions 
or non-target lymph nodes. 
 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (< 1.0 cm short 
axis) and increased to ≥ 1.0 cm short axis during follow-up.   
b. Unequivocal progression of existing non-target lesions and 
non-target lymph nodes.  (NOTE:  Unequivocal progression 
should not normally trump target lesion and target lymph 
node status.  It must be representative of overall disease 
status change.)  
c. See Section 11.32 for details in regards to the requirements 
for PD via FDG-PET imaging. 
 
 
 


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11.44 Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following tables:  
 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall 
Objective Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration.  A patient is 
classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical 
conditions: 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
 


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11.5 
All images will be submitted for research puproses. Images should be submitted on CD 
≤2 weeks after collection at the time of progression or death.   
 
Submitted images should be accompanied by a radiology report.  Images should represent 
the entire radiologic assessment for the tumor assessment visit.  ACCRU Patient ID 
number must be on the images and on the radiology report.  
See Appendix II for imaging guidelines and Appendix III for image submission process.  
 
 
12.0 
Descriptive Factors 
 
12.1 
Previous chemotherapy in the metastatic setting: Yes vs. no. 
 
12.2 
Previous immunotherapy in the metastatic setting: Yes vs. no. 
 
12.3 
Prior lines of therapy in the metastatic setting: 0 vs. 1 vs. 2. 
 
 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
 
13.1 
Arm A patients 
 
13.11 Patients receiving bevacizumab/nab-paclitaxel treatment who have not had 
disease progression and have experienced acceptable toxicity will be eligible to 
continue on bevacizumab/nab-paclitaxel until disease progression, unacceptable 
toxicity or refusal.    
 
13.12 Patients who discontinue bevacizumab/nab-paclitaxel treatment for reasons other 
than progression will go to Event Monitoring phase of the trial until death or a 
maximum of 5 years post-randomization.  
 
13.13 Patients who progress during bevacizumab/nab-paclitaxel treatment phase will 
undergo an assessment of ECOG PS, blood chemistries levels, and tumor size 
(see Section 4.0).  If any one of the following is true, the patient may not 
continue on to Ipilimumab treatment phase of the study:   
 
− 
ECOG performance score (PS):  ≥ 2 
− 
tumor fails to meet RECIST criteria for measurable disease 
− 
ANC < 1500/mL 
− 
PLT < 100,000 x 109/L 
− 
Hgb < 9g/dL (patients may be transfused to meet Hgb requirement) 
− 
Creatinine ≥1.5 x ULN 
− 
Total bilirubin ≥1.5 mg/dL (exception: patients with documented Gilbert’s 
syndrome are allowed to participate despite elevated bilirubin) 
− 
SGOT (AST) ≥2.5 x ULN  
− 
Urine dipstick for proteinuria ≥ 2+ and a 24 hour urine collection result 
demonstrating  > 1g of protein in 24 hours  
− 
≥ grade 2 peripheral sensory or motor neuropathy  
− 
 Evidence of  brain metastasis on  MRI or CT 
 


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13.131 
Patients who are not eligible to continue on to ipilimumab phase or 
who choose not to continue on to the ipilimumab phase will go to 
Event Monitoring phase until death or a maximum of 5 years post-
randomization.  
 
13.132 
Patients who proceed to ipilimumab phase may receive a maximum 
of 4 cycles of treatment and then proceed to Observation until 
disease progression.  Reasons for not completing 4 cycles of 
ipilimumab or discontinuation of Observation include: disease 
progression, patient request, intolerability, and concurrent co-morbid 
conditions.  
 
• 
Patients who discontinue ipilimumab treatment or Observation 
for any reason will go to Event Monitoring until death or a 
maximum of 5 years post-randomization. 
 
 
13.2 
Arm B patients 
 
13.21 Patients on ipilumumab treatment who have not had disease progression(PD) and 
who have experienced acceptable toxicity will be eligible to  continue on 
ipilumumab for a maximum of 4 cycles of treatment.  
 
13.211 
Patients who discontinue ipilimumab treatment for reasons other 
than progression will go to Event Monitoring phase until death or a 
maximum of 5 years post-randomization.  
 
13.212 
Patients who progress during ipilimumab treatment will undergo an 
assessment of ECOG PS, blood chemistries levels, and tumor size 
(see Section 4.0).  If any one of the following is true, the patient may 
not continue on to the bevacizumab/nab-paclitaxel phase of the 
study: 
 
− 
ECOG performance score (PS):  ≥2 
− 
tumor fails to meet RECIST criteria for measurable disease 
− 
ANC <1500/mL 
− 
PLT <100,000 x 109/L 
− 
Hgb <9g/dL (patients may be transfused to meet Hgb 
requirement) 
− 
Creatinine ≥1.5 x ULN 
− 
Total bilirubin ≥1.5 mg/dL (exception: patients with documented 
Gilbert’s syndrome are allowed to participate despite elevated 
bilirubin) 
− 
SGOT (AST) ≥2.5 x ULN  
− 
Urine dipstick for proteinuria ≥ 2+ and a 24 hour urine collection 
result demonstrating  >1g of protein in 24 hours  
− 
 ≥ grade 2 peripheral sensory or motor neuropathy  
− 
 Evidence of  brain metastasis on  MRI or CT 


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13.2121 
Patients who are not eligible or choose not to proceed to 
bevacizumab/nab-paclitaxel treatment phase will go to 
Event Monitoring phase until death or a maximum of 5 
years post-randomization.  
 
13.2122 
Patients who are eligible and choose to proceed to 
bevacizumab/nab-paclitaxel treatment phase will 
continue treatment until PD, unacceptable toxicity, or 
refusal and then go to Event Monitoring phase until death 
or a maximum of 5 years post-randomization.  
 
13.213 
Patients who complete 4 cycles of ipilimumab treatment without 
disease progression will enter the Observation phase of the study 
until PD is reported. 
 
13.2131 
Patients who progress during observation phase will 
undergo an assessment of ECOG PS, blood chemistries 
levels, and tumor size (see Section 4.0).  If any one of the 
following is true, the patient may not continue on to the 
bevacizumab/nab-paclitaxel phase of the study: 
 
− 
ECOG performance score (PS):  ≥2 
− 
tumor fails to meet RECIST criteria for measurable 
disease 
− 
ANC <1500/mL 
− 
PLT <100,000 x 109/L 
− 
Hgb <9g/dL (patients may be transfused to meet Hgb 
requirement) 
− 
Creatinine ≥1.5 x ULN 
− 
Total bilirubin ≥1.5 mg/dL (exception: patients with 
documented Gilbert’s syndrome are allowed to 
participate despite elevated bilirubin) 
− 
SGOT (AST) ≥2.5 x ULN  
− 
Urine dipstick for proteinuria ≥ 2+ and a 24 hour 
urine collection result demonstrating  >1g of protein 
in 24 hours  
− 
≥ grade 2 peripheral sensory or motor neuropathy  
− 
Evidence of  brain metastasis on  MRI or CT 
 
13.2132 
Patients who are not eligible or choose not to proceed to 
bevacizumab/nab-paclitaxel treatment phase will go to 
the Event Monitoring phase until death or a maximum of 
5 years post-randomization.  
 
13.2133 
Patients who are eligible and choose to proceed to 
bevacizumab/nab-paclitaxel treatment phase will 
continue treatment until PD, unacceptable toxicity, or 
refusal and then go to Event Monitoring phase until death 
or a maximum of 5 years post-randomization.  
 


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13.3 
Arm A and Arm B 
 
13.31 Patients who wish to receive non-protocol, anti-cancer therapy  
will discontinue all study treatment and enter the Event Monitoring phase.   Once 
a patient has entered the Event Monitoring phase of the trial, his/her therapy is at 
the discretion of the treating physician. 
 
13.32 If an eligible patient refuses to begin study treatment following 
registration/randomization (and is classified as a cancel by the ACCRU Research 
Base), all on-study materials must be submitted to the Research Base. 
 
13.33 A patient is deemed ineligible if at the time of registration/randomization, the 
patient did not satisfy each and every eligibility criteria for study entry.  
• 
If the patient never received any study treatment, on-study materials (with 
the exception of biospecimens) must be submitted. No further follow-up is 
required. 
• 
If the patient is receiving study treatment at the time the ineligibility is 
discovered, the patient may continue on study at the discretion of the treating 
physician as long as there are no safety concerns, and the patient was 
properly registered.  All protocol procedures must be followed.  Otherwise, 
the patient enters the Event Monitoring phase of the study. 
 
 
14.0 
Body Fluid Biospecimens 
 
14.1 
Body Fluid Biospecimen Submission 
 
14.11  Summary table of Body Fluid Biospecimens  
 
Type of 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for 
specimen 
submission 
Blood/blood 
products (sodium 
Heparin green top 
whole blood) 
Mandatory 
for MCR 
patients 
ONLY 
Prior to first cycle of 
Ipilimumab and 
prior to first cycle of 
BEV/nab-paclitaxel 
Analysis of changes in 
immune homeostasis 
(Section 14.412) 
Section 14.2 
 
14.2 
Blood/Blood Products Handling 
 
14.21 Kits are required for this study. Kits contain supplies and instructions for 
collecting, processing, and shipping specimens. Kits may be obtained by 
contacting 
 in Dr. Markovic’s 
Hematology/Oncology laboratory. 
 
14.22 Kits may be collected Monday through Friday. 
 
14.23 Label specimen tubes with protocol number, ACCRU patient ID number, and 
time and date blood drawn. 


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14.24 Collect and process all blood/blood products according to specific kit instructions 
and table below.  
 
14.241 
Summary Tables of Research Blood/Blood Products to Be Collected 
for This Protocol 
 
ARMS A & B SAMPLES Rochester, Minn. Patients Only 
1 After all samples have been processed according to kit instructions, ship all specimens according to 
shipping instructions (see Section 14.25 for detailed shipping instructions).  
 
14.25 Shipping 
 
14.251 
Verify ALL sections of the ACCRU Blood Specimen Submission 
Form, protocol Blood Requisition Form, and specimen collection 
labels are completed and filled in correctly.  Enter information from 
the ACCRU Blood Specimen Submission Form into the remote data 
entry system ≤7 days after specimen collection (see Forms Packet). 
 
14.252 
Send heparin tubes ambient or at room temperature to:   
 
 
 
 
 
 
14.253 
Notify Michael Thompson at the Research Base by phone 
 that blood has been 
shipped. 
 
14.3 
Other Body Fluids Handling (None) 
 
 
Indicate if 
specimen is 
mandatory 
or optional 
Collection tube 
description 
and/or additive 
(color of tube 
top) 
Volume to 
collect per 
tube (number 
of tubes to be 
collected) 
Blood 
product 
being 
processed 
Prior to 
day 1 
Ipilimumab 
Prior to 
day 1 of 
BEV/nab-
paclitaxel 
Process 
at site? 
Storage/ 
shipping 
conditions1 
Mandatory  
Heparin (dark 
green) 
10 mL 
(5) 
Whole 
Blood 
X 
X 
No 
Ambient 


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14.4 
Study Methodology and Storage Information 
 
14.41 Blood/blood product samples will be collected for the following research: 
 
14.411 
Angiogenesis – concentrations of multiple soluble mediators of 
angiogenesis recovered for patient plasma    
 
Specimens will be stored at – 70ºC until the time of assay. Plasma 
samples will be sent to the laboratory of 
 at 
 and processed there. Plasma levels of 
angiogenesis mediators: angiopoietin-2, BMP-9, EGF, endoglin, 
endothelin-1, FGF-1, FGF-2, follistatin, G-CSF, HB-EGF, HGF, IL-
8, leptin, PLGF, VEGF-A, VEGF-C, and VEGF-D (EMD Millipore, 
Billerica, MA) will be determined  
 
14.412 
Analysis of changes in immune homeostasis.  The studies described 
below will all be performed in the laboratory of 
 
. 
 
14.4121 
Immunophenotyping of peripheral blood samples. 
Samples of peripheral blood (pre-treatment for all cycles) 
will be analyzed for numbers and activation status of T, 
B, NK and dendritic cells. Peripheral blood lymphocytes 
will be collected and frozen for batch analysis.  Samples 
will be analyzed for the following: CD3, CD4, CD8, 
CD20, CD69, CD4/25, CD8/25, CD16/56, CD80, CD86, 
HLA-DR.   
 
Blood collected through the port is allowable. 
 
14.4122 
Frequency of cytotoxic T lymphocytes (CTL) specific for 
recall as well as tumor associated antigens (HLA-A2 
patients only). 
 
14.41221 
Tetramer assay  
Class I tetramers are comprised of monomeric 
class I heavy chains that have been folded with 
β2-microglobulin (β2M) and specific 
immunogenic peptides (EBV, CMV, tyrosinase, 
gp100, MART-1, Beckman/Coulter); these 
monomers are then biotinylated at sites on their 
carboxy ends for conjugation into tetramers with 
PE-avidin.  Such tetramers have increased 
valency and can be mixed with FITC-labeled 
anti-CD8 antibody to stain peptide-specific 
CTLs for enumeration by flow cytometry.  
Single batches of reagents will be used for all 
analyses.  Ongoing quality assurance/quality 
control (QA/QC) for these assays demonstrate a 
<15% inter-assay variability for control 
(standard) samples. 


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15.0 
Drug Information  
 
15.1 
Paclitaxel Protein Bound (Abraxane®, nab-paclitaxel) 
Investigator brochure contact information: 
The most current version of the Investigator Brochure will be maintained in the study 
folder on the ACCRU website. Updated Investigator’s Brochures should be obtained 
from the study folder as they become available.  
 
Each investigator should obtain a copy of the Investigator’s Brochure prior to initiation of 
the study. 
 
15.11 Background: Paclitaxel protein-bound particles for injectable suspension 
(albumin-bound) is an antineoplastic agent, Antimicrotubular, Taxane derivitave. 
Paclitaxel promotes microtubule assembly by enhancing the action of tubulin 
dimers, stabilizing existing microtubules, and inhibiting their disassembly, 
interfering with the late G2 mitotic phase, and inhibiting cell replication 
 
15.12 Formulation: Paclitaxel protein-bound particles for injectable suspension 
(albumin-bound) (nanoparticle albumin bound (nab) paclitaxel, nab-paclitaxel, 
Abraxane®). Nab-paclitaxel is supplied as a white to off-white lyophilized 
powder containing 100 mg of paclitaxel and approximately 900 mg Albumin 
Human USP (HA) as a stabilizer in a 50 mL, single-use vial.  Each vial of the 
lyophilized product is reconstituted with 20 mL 0.9% Sodium Chloride Injection, 
USP to create a suspension of nanoparticles containing 5 mg/mL nanoparticle 
albumin-bound (nab) paclitaxel. 
 
15.13 Preparation and Storage: Unreconstituted nab-paclitaxel should be stored at 
controlled room temperature in its carton.  Reconstituted nab-paclitaxel should 
be used immediately.  If not used immediately, the vial of reconstituted nab-
paclitaxel must be placed in its carton and be placed in a refrigerator at 2° to 8°C 
for a maximum of 8 hours.  Both forms should be stored in an area free of 
environmental extremes. 
 
NOTE: It is not a requirement to use filter needles in the preparation of, or 
in-line filters during the administration of nab-paclitaxel. In any event, 
filters of pore-size less than 15 micrometers must not be used. 
 
Reconstitute each nab-paclitaxel vial by using a 50 or 60 cc sterile syringe to 
inject 20 mL of 0.9% Sodium Chloride Injection, USP or equivalent into each 
vial over a period of not less than 1 minute (Note: Change the syringes after 
reconstituting every 3 vials). 
 
• 
Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a 
minimum of 1 minute, using the sterile syringe directing the solution flow 
onto the inside wall of the vial. 
 
• 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution 
directly onto the lyophilized cake as this will result in foaming. 
 
• 
Once the injection is complete, allow the vial to sit for a minimum of 5 
minutes to ensure proper wetting of the lyophilized cake/powder. 


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• 
Gently swirl and/or invert the vial slowly for at least 2 minutes until 
complete dissolution of any cake/powder occurs. Avoid generation of foam. 
 
• 
The reconstituted sample should be milky and homogeneous without visible 
particulates. If unsuspended powder is visible, the vial should be gently 
inverted again to ensure complete resuspension, prior to use. If using stored, 
reconstituted nab-paclitaxel (within 8 hours, see above), some settling may 
occur; ensure complete re-suspension by mild agitation prior to use. 
 
• 
No further dilution is necessary. 
 
Once the exact volume of reconstituted nab-paclitaxel has been withdrawn 
from the vials, discard any excess solution left over in accordance with 
standard operating procedures. 
 
• 
Inject the calculated dosing volume of reconstituted nab-paclitaxel 
suspension into an empty sterile, standard PVC IV bag using an injection 
port.  Inject perpendicularly into the center of the injection port to avoid 
dislodging plastic material into the IV bag. The use of medical devices 
containg silicone oil as lubricant (i.e. syringes and intravenous bags) to 
reconstitute and administer nab-paclitaxel may result in the formation of 
proteinaceous strands. 
 
• 
Visually inspect the reconstituted nab-paclitaxel suspension in the 
intravenous bag prior to administration. 
 
• 
As with other cytotoxic anticancer drugs, caution should be exercised in 
handling nab-paclitaxel.  The use of gloves is recommended.  No data 
currently exist for accidental exposure.  However, as with paclitaxel, if nab-
paclitaxel solution contacts the skin, wash the skin immediately and 
thoroughly with soap and water.  If nab-paclitaxel contacts mucous 
membranes, the membranes should be flushed thoroughly with water.  Upon 
inhalation, dyspnea, chest pain, burning eyes, sore throat and nausea have 
been reported for paclitaxel.  Procedures for proper handling and disposal of 
anticancer drugs should be considered.  Several guidelines on this subject 
have been published (National Institutes of Health, 1983; American Society 
of Hospital pharmacists, 1990; Occupational Safety and Health 
Administration, 1996). 
 
NOTE: Standard PVC IV bags may be used for the infusion. 
 
15.14 Administration:  Administer the calculated dosing volume of reconstituted nab-
paclitaxel suspension by IV infusion over 30 minutes or per instructions in the 
treatment section of the protocol. Following administration of nab-paclitaxel, the 
intravenous line should be flushed with 0.9% sodium chloride solution for 
injection to ensure administration of the complete dose. NOTE: Premedications 
for hypersensitivity reactions (e.g., as given for paclitaxel) are not required 
for nab-paclitaxel. 
 


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15.15 Pharmacokinetic Information: 
Distribution: Vd
  1741 L  (extensive extravascular distribution and/or tissue 
binding) 
Protein binding:  94%  
Metabolism: Hepatic primarily via CYP2C8 to 6-alpha-hydroxypaclitaxel; also 
to minor metabolites via CYP3A4 
Half-life elimination: Terminal: 13 to 27 hours  
Excretion: Feces (~22%); urine (3.9% as unchanged drug, <1% as metabolites) 
 
15.16 Potential Drug Interactions: No drug interactions studies have been conducted 
with Paclitaxel Protein Bound. The metabolism of paclitaxel is catalyzed by 
CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, 
caution should be exercised when administering Paclitaxel Protein Bound 
concomitantly with medicines known to inhibit (eg, ketoconazole and other 
imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, 
ritonavir, saquinavir, indinavir, nelfinavir and clopidogrel) or induce (eg, 
rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 
or CYP3A4. 
Cytochrome P450 Effect: Substrate (major) of CYP2C8, 3A4; Induces 
CYP3A4 (weak).  
Increased Effect/Toxicity: CYP2C8 inhibitors may increase the levels/effects of 
paclitaxel.  
Decreased Effect: CYP2C8 inducers may decrease the levels/effects of 
paclitaxel.  
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in estrogen-
dependent tumors. Avoid valerian, St John’s wort (may decrease paclitaxel 
levels), kava kava, gotu kola (may increase CNS depression). 
Immunosuppressants:  enhanced adverse/toxic effect of pimecrolimus or 
tacrolimus 
Tofacitinib:  enhanced effect of tofacitinib; Concurrent use with antirheumatic 
doses of methotrexate or nonbiologic disease modifying anitrheumaticd drugs 
(DMARDs) is permitted, and this warning seems particularly focused on more 
potent immunosuppressants. 
Vaccines:  enhanced adverse/toxic effect of live vaccines and diminished 
therapeutic effect of live vaccines.  Avoid use of live organism vaccines, and 
live-attenuated vaccines should not be given for at least 3 months after paclitaxel. 
Vinorelbine:  Paclitaxel Protein Bound may enhance the neurotoxic effect of 
vinorelbine. 
Avoid combination of Paclitaxel Protein Bound with:  BCG (diminished 
therapeutic effect of BCG), clozapine (increased risk of agranulocytosis), 
natalizumab (increased risk of infection), and dipyrone (increased risk of 
agranulocytosis and pancytopenia). 
 
Administration of carboplatin immediately after the completion of the nab-
paclitaxel infusion to patients with NSCLC did not cause clinically meaningful 
changes in paclitaxel exposure in plasma. The observed mean half-life and 
clearance for total and free carboplatin in the presence of nab-paclitaxel were 
consistent with those reported in the absence of nab-paclitaxel.  In patients with 
solid tumors, oral azacitidine (CC-486) had minimal to no effect on nab-
paclitaxel  PK. Similarly, nab-paclitaxel had minimal to no effect on PK of oral 


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azacitidine. Pharmacokinetic interactions between nab-paclitaxel and 
gemcitabine have not been evaluated in humans. 
 
15.17 Known potential toxicities: Consult the investigator brochure or package insert 
for the most current and complete information. Adverse events may affect the 
ability to drive and use machines. 
 
Common known potential toxicities, > /=10%:   
Cardiovascular: ECG abnormal, peripheral edema 
Central Nervous System: Peripheral sensory neuropathy, fatigue, peripheral 
neuropathy, headache, depression 
Dermatologic: Alopecia, skin rash 
Endocrine & metabolic: Dehydration,increased gamma-glutamyl transfer, 
hypokalemia 
Gastrointestinal: Nausea, diarrhea, decreased appetite, vomiting, constipation, 
dysgeusia 
Genitourinary: Urinary tract infection 
Hematologic & oncologic: Anemia, neutropenia, thrombocytopenia, bone 
marrow depression (dose-related)  
Hepatic: AST increased, alkaline phosphatase increased 
Infection: Infection (oral candidiasis, respiratory tract infection, 
pneumonia) 
Neuromuscular & skeletal: Weakness, musculoskeletal pain, limb pain  
Ophthalmic: Vision disturbance 
Renal: Creatinine increased 
Respiratory: Cough, sepistaxis, dyspnea 
Miscellaneous: Fever 
 
Less Common known potential toxicities, >/=1% -and < 10%: 
Cardiovascular: Edema, cardiac failure , hypotension, significant 
cardiovascular events (included chest pain, cardiac arrest, supraventriculat 
tachycardia, thrombosis, pulmonary thromboembolism, pulmonary emboli, and 
hypertension) 
Hematologic & oncologic: Hemorrhage, febrile neutropenia 
Hepatic: Bilirubin increased 
Hypersensitivity: Hypersensitivity reaction (includes anaphylactic reactions, 
chest pain, dyspnea, flushing, hypotension) 
Infection: Sepsis 
Ophthalmic: Cystoid macular edema 
Respiratory:  Pneumonitis 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Atrioventricular block, autonomic neuropathy, bradycardia, cardiac arrhythmia, 
cerebrovascular accident, cranial nerve palsy, embolism, hepatic encephalopathy, 
hepatic necrosis, intestinal obstruction, injection site reaction, intestinal 
perforation, ischemic colitis, ischemic heart disease, left ventricular dysfunction, 
maculopapular rash, myocardial infarction, neutropenic sepsis, optic nerve 
damage (rare), palmar-plantar erythrodysesthesia (in patients previously exposed 
to capecitabine), pancreatitis, pancytopenia, paralytic ileus, peripheral motor 
neuropathy, pneumonia, pneumothorax, pruritis, pulmonary embolism, radiation 


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pneumonitis (with concurrent radiation therapy), radiation recall phenomenon, 
skin photosensitivity, Stevens-Johnson syndrome, thrombosis, toxic epidermal 
necrolysis, transient ischemic attacks, ventricular dysfunction, vocal cord 
paralysis. 
 
Note for Safety in Elderly Patients: In patients 75 years and older receiving 
monotherapy with nab-paclitaxel, increased incidences were observed for 
clinically severe infections, dehydration, diarrhea, anemia, fatigue, and peripheral 
edema, while neutropenia and peripheral neuropathy were observed at a similar 
rate. For the combination of nab-paclitaxel with gemcitabine, there was an 
increased incidence for risk of hematologic toxicity (myelosuppression), 
peripheral neuropathy, dehydration, and decreased appetite. Patients aged 75 
years and older should be carefully assessed for their ability to tolerate nab-
paclitaxel in combination with gemcitabine. Special consideration should be 
given to performance status, comorbidities, and increased risk of infections. 
 
In patients ≥65 years old, a higher incidence of epistaxis, diarrhea, dehydration, 
fatigue, and peripheral edema was found. Myelosuppression events, peripheral 
neuropathy events, arthralgia and dehydration were more frequent.  
 
15.18 Drug procurement:  Celgene will supply investigational nab-paclitaxel to the 
ACCRU coordinating center pharmacy.  Each participating ACCRU main 
membership will order a starter supply of  nab-paclitaxel from the research base 
pharmacy.  Fax the ACCRU Clinical Drug Order/Return Form 
 to: 
 
 
 
 
Each participating ACCRU main membership will be responsible for monitoring 
the supply of nab-paclitaxel and will use the ACCRU Clinical Drug 
Order/Return Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
15.19 Nursing guidelines:   
 
15.191  
Nab-paclitaxel is not known to cause the hypersensitivity reactions 
that Taxol does, secondary to the fact that nab-paclitaxel lacks the 
Chremophor EL solvent of regular paclitaxel solution, therefore 
premedication is not necessary.  However the patient should still be 
monitored closely and the infusion stopped if acute reactions occur 
(chest pain, back pain, flushing, diaphoresis, dyspnea, pruritus, 
hypotension, hypertension, bronchospasm, and/or urticaria).  
 
15.192 
Approximately 0-40% of patients may experience some degree of 
peripheral sensory neuropathy (numbness, tingling, burning pain, 


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fine motor skills impairment, paresthesias, distal sensory loss) 
depending on the dose and schedule used.  Patients receiving higher 
doses at shorter infusion times are at greater risk.  Most cases have 
been reported at doses >170 mg/m2/day and with cumulative doses 
over multiple courses of therapy.  The nerve damage may take days 
to months to resolve.   
 
15.193 
Mucositis can usually be managed with a salt and soda mouthwash 
(1 tsp. Salt, 1 tsp. Soda and 1 quart boiled water) or try OTC oral 
Lysine or Vitamin E. 
 
15.194 
Narcotics and nonsteroidal anti-inflammatory drugs may be used to 
manage the myalgias. 
 
15.195 
Monitor CBC closely.  Neutropenia is most severe in patients who 
have had previous chemotherapy.  Instruct patient to report signs or 
symptoms of infection, unusual bruising or bleeding to the health 
care team. 
 
15.196 
Monitor liver function tests 
 
15.197 
Inform patient about total alopecia 
 
15.198 
Nab-paclitaxel has not been tested in combination with 
anthracyclines, and it is not known if there is an increased risk of 
cardiotoxocity.  
 
15.199a 
Monitor IV site closely and establish patency before administration, 
it is uncertain whether nab-paclitaxel is an irritant as Taxol is.  
 
15.199b   
Use in caution and employ additional monitoring in patients >75 
years of age, as increased incidence of adverse events were observed 
in this age group.  
 
15.199c  
Avoid the use of live vaccines for 3 months after last dose of nab-
paclitaxel. 
 
 
15.199d  
Warn patients of the possibility of radiation recall 
 
 
 


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15.2 
Bevacizumab (Avastin®)  
 
Investigator brochure contact information: 
The most current version of the Investigator Brochure will be maintained in the study 
folder on the ACCRU website.  Updated Investigator’s Brochures should be obtained 
from the study folder as they become available. 
 
Each investigator should obtain a copy of the Investigator’s Brochure prior to initiation of 
the study.   
 
15.21 Background: Bevacizumab is classified as an Anti-VEGF Monoclonal Antibody 
and a Vascular Endothelial Growth Factor (VEGF) Inhibitor. Bevacizumab is a 
recombinant, humanized monoclonal immunoglobulin G1 (IgG1) antibody which 
binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing 
its association with endothelial receptors, Flt-1 and KDR. VEGF binding initiates 
angiogenesis (endothelial proliferation and the formation of new blood vessels). 
The inhibition of microvascular growth is believed to retard the growth of all 
tissues (including metastatic tissue).  
 
15.22 Formulation: Bevacizumab is manufactured by recombinant DNA technology, 
using a genetically engineered Chinese hamster ovary (CHO) cell line. The 
protein is purified from the cell culture medium by routine methods of column 
chromatography and filtration. The final product is tested for quality, identity, 
safety, purity, potency, strength, and excipient/chemical composition according 
to International Conference on Harmonisation (ICH) guidelines. The purity of 
bevacizumab is > 95%. 
 
Bevacizumab is supplied in 100 mg (4 mL) and 400 mg (16 mL) glass vials, each 
with a concentration of 25 mg/mL. Vials contain bevacizumab with phosphate, 
trehalose, polysorbate 20, and sterile water for injection (SWFI), USP. Vials 
contain no preservative and are suitable for single use only. 
 
15.23 Preparation and storage: Bevacizumab vials should be stored in a refrigerator 
at 2°C-8°C. Keep vial in the outer carton due to light sensitivity.  DO NOT 
FREEZE. DO NOT SHAKE. 
 
Chemical and physical in-use stability has been demonstrated for 48 hours at 
2°C-30°C in 0.9% sodium chloride solution. Do not administer or mix with 
dextrose solution.  From a microbiological point of view, the product should be 
used immediately. If not used immediately, in-use storage times and conditions 
are the responsibility of the user and would normally not be longer than 24 hours 
at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic 
conditions. 
 
Withdraw the necessary amount of bevacizumab and dilute to the required 
administration volume with 0.9% sodium chloride solution. The concentration of 
the final bevacizumab solution should be kept within the range of 1.4 - 16.5 
mg/mL. Discard any unused portion left in a vial, as the product contains no 
preservatives. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. 
 


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15.24 Administration:  Do not administer as an intravenous push or bolus. Administer 
only as an intravenous (IV) infusion. Do not initiate bevacizumab for 28 days 
following major surgery and until surgical wound is fully healed.    
 
Refer to Section 7 for protocol-specific administration instructions.  Guidelines 
recommended by the manufacturer are included for reference. 
 
First infusion: Administer infusion over 90 minutes. Subsequent infusions: 
Administer second infusion over 60 minutes if first infusion is tolerated; 
administer all subsequent infusions over 30 minutes if infusion over 60 minutes 
is tolerated.  
 
15.25 Pharmacokinetic information: 
Distribution: Vd: 46 mL/kg (limited extravascular distribution) 
Half-life elimination: ~20 days (range: 11-50 days) 
Clearance: 2.75-5 mL/kg/day. A low serum albumin and high tumor 
burden increase clearance by 30% and 7% respectively.  Clearance 
increases with increasing body weight, and is 15% slower in women than 
men. 
Time to steady state: 100 days 
 
15.26 Potential Drug Interactions: Overall the results from the drug-drug PK 
interaction investigations showed no interaction between bevacizumab and 
the anti-cancer agents tested. Co-administration of bevacizumab with 
various chemotherapeutic and other anti-cancer agents resulted in similar 
values of CL and Vc for bevacizumab, suggesting that the exposure of 
bevacizumab are not affected by concomitant dosing with doxorubicin, 
capecitabine, capecitabine/oxaliplatin (XELOX), 5-FU/leucovorin, 5-
FU/leucovorin/irinotecan (IFL), 5- FU/leucovorin/oxaliplatin (FOLFOX4), 
erlotinib, carboplatin, cisplatin, oxaliplatin, paclitaxel, gemcitabine, 
temozolomide or interferon-α2a. 
 
The effect of bevacizumab on the disposition of several agents 
(doxorubicin, 5-FU, irinotecan [and its active metabolite SN38], 
capecitabine, oxaliplatin, carboplatin, cisplatin, paclitaxel, gemcitabine, 
erlotinib, temozolomide and interferon alfa-2a) has 
been investigated. Accumulating data do not suggest that bevacizumab 
affects disposition of anti-neoplastic agents. 
 
Increased Effect/Toxicity: Bevacizumab may enhance the cardiotoxic 
effect of Antineoplastic Agents (Anthracycline, Systemic). Bevacizumab 
may also enhance the adverse/toxic effect of Irinotecan, Sorafenib, and 
Sunitinib. Sunitinib may enhance the adverse/toxic effect of Bevacizumab. 
Specifically, the risk for a specific form of anemia, microangiopathic 
hemolytic anemia (MAHA), may be increased. 
 
15.27 Known potential adverse events: Consult the investigator’s brochure and 
package insert for the most current and complete information. U.S. Boxed 
Warnings include severe or fatal hemorrhage, including hemoptysis, 
gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, 
and vaginal bleeding. Avoid use in patients with serious hemorrhage or 


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recent hemoptysis. Percentages reported as Monotherapy and as part of 
combination chemotherapy regimens.  
 
Common known potential toxicities, > 10%:   
Cardiovascular: Hypertension, venous thromboembolism, peripheral edma, 
hypotension, venous thromboembolism, arterial thrombosis 
Central nervous system: Fatigue,pain, headache, dizziness, , taste disorder, 
peripheral sensory neuropathy, anxiety 
Dermatologic: Alopecia, palmar-plantar erythrodysesthesia, , exfoliative 
dermatitis, xeroderma 
Endocrine & metabolic: Ovarian failure, hyperglycemia, 
hypomagnesaemia, weight loss, hyponatremia,  hypoalbuminemia 
Gastrointestinal: Abdominal pain, vomiting, anorexia, constipation, 
decreased appetite, diarrhea, stomatitis, gastrointestinal hemorrhage, 
dyspepsia, , nausea 
Genitourinary: Proteinuria, urinary tract infection, pelvic pain 
Hematologic and oncologic: Hemorrhage, , leukopenia, pulmonary 
hemorrhage, neutropenia, lymphocytopenia 
Infection: Pneumonia, catheter infection, or wound infection 
Neuromuscular and  skeletal: Myalgia, back pain 
Renal:  Increaded serum creatinine 
Respiratory: Upper respiratory tract infection, epistaxis, dyspnea, rhinitis 
Miscellaneous: Postoperative wound complication (including dehiscence)  
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Thrombosis, deep vein thrombosis,, syncope, intra-
abdominal thrombosis, left ventricular dysfunction, pulmonary embolism  
Central Nervous System: Voice disorder, Dermatologic: Dermal ulcer, 
cellulitis, acne vulgaris.  
Endocrine& metabolic: Dehydrationhypokalemia   
Gastrointestinal: Xerostomia, rectal pain, colitis, intestinal obstruction, 
gingival hemorrhage, gastrointestinal perforation, gastroesphageal reflux 
disease, gastrointestinal fistula, gingivitis, oral mucosa ulcer, gastritis, 
gingival pain 
Genitourinary: Vaginal hemorrhage 
Hematologic & oncologic:, Febrile neutropenia, neutropenic infection, 
thrombocytopenia, hemorrhage. 
Infection: Tooth abscess 
Neuromuscular & skeletal: Weakness, dysarthria 
Ophthalmic: Blurred vision 
Otic: Tinnitus, deafness 
Respiratory: Pneumonitis 
Miscellaneous: Gastrointestinal-vaginal fistula, anal fistula, infusion 
related reaction.   
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Angina pectoris, antibody development (anti-bevacizumab and 
neutralizing), bladder fistula, bronchopleural fistula, , cerebral infarction, 
conjunctival hemorrhage, endophthalmitis (infectious and sterile), fistula 
of bile duct, fulminant necrotizing fasciitis, gall bladder perforation, 


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gastrointestinal ulcer, hemolytic anemia (microangiopathic; when used in 
combination with sunitinib),hemoptysis, hemorrhagic stroke, 
hypersensitivity, hypertensive crisis, hypertensive encephalopathy, 
increased intraocular pressure, intestinal necrosis, intraocular inflammation 
(iritis vitritis), mesenteric thrombosis, myocardial infarction,  nasal septum 
perforation, ocular hyperemia, osteonecrosis of the jaw, ovarian failure, 
pancytopenia, polyserositis,  pulmonary hypertension, rectal fistula, renal 
failure, renal fistula, renal thrombotic microangiopathy, retinal 
detachment, retinal hemorrhage, reversible posterior leukoencephalopathy 
syndrome, sepsis, tracheoesophageal fistula, vaginal fistula, vitreous 
hemorrhage, vitreous opacity.  
 
15.28 Drug procurement:  Genentech will supply commercial drug labeled for 
investigational use to Biologics Inc.  Each participating ACCRU main 
membership will order the drug from Biologics Inc.  Fax the Drug Order Request 
Form (found in the Forms folder) request to: 
 
 
  
Each participating ACCRU main membership will be responsible for monitoring 
the supply of bevacizumab and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site according to procedures in 
place at each institution.. 
 
15.29 Nursing guidelines:  
 
15.291 
Monitor patients closely for infusion type reactions, including fever, 
chills, myalgias, rigors, or other allergic reactions.  While this is less 
likely given that bevacizumab is a humanized antibody, there still 
exists the potential for severe allergic reactions.  If these signs or 
symptoms occur stop the infusion immediately and contact MD.  
Have emergency equipment nearby and be prepared to administer 
emergency treatment as ordered by MD. 
 
15.292 
Monitor urine dipstick or UPC as required by the test schedule 
 
15.293 
Evaluate IV site regularly for signs of infiltration. 
 
15.294 
Bleeding in the absence of thrombocytopenia is a dose limiting 
toxicity.  Monitor patient closely for hemorrhagic events, including 
CNS hemorrhage, epistaxis, hematemesis and hemoptysis.  Most 
cases of bleeding have occurred at the tumor site.  Advise patient 
about the potential for bleeding or thrombosis. 
 
15.295 
In patients receiving treatment for lung cancer, hemoptysis and 
pulmonary hemorrhage occurred in up to 10% of patients in one 
study.  Monitor these patients especially closely.  


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15.296 
Patient may experience Grade 1-2 nausea, however vomiting is 
uncommon.  Medicate as ordered and monitor for effectiveness.  
 
15.297 
Monitor for skin rash, instruct patient to report to MD. 
 
15.298 
Monitor blood pressure.  Administer antihypertensives as ordered by 
MD. 
  
15.299a 
Monitor for signs and symptoms of deep vein thrombosis (DVT) or 
pulmonary embolism (PE), or myocardial infarction (MI) including 
new or worsening angina.  These have been reported with therapy.  
Instruct patient to report any calf pain, chest pain or shortness of 
breath to MD immediately.  
 
15.299b 
Asthenia and headache were reported commonly during therapy (in 
up to 70% and 50% of patients respectively).  Administer 
acetaminophen as needed.  Monitor for its effectiveness.  Avoid the 
use of aspirin, or ibuprofen as this may interfere with the coagulation 
cascade and further add to the risk of bleeding. 
 
15.299c 
Monitor CBC, including platelets.  Instruct patient to report signs 
and symptoms of infection, unusual bruising or bleeding to the MD. 
  
15.299d 
Patients receiving warfarin therapy for thrombosis should have their 
PT or INR monitored weekly until two stable therapeutic levels are 
attained.  For patients on warfarin for venous access prophylaxis, 
routine monitoring is satisfactory. 
 
15.299e  
A rare but serious complication of bevacizumab is wound 
dehiscence.  Patients who have had recent surgery or have other open 
wounds should be monitored carefully. 
 
15.299f  
Gastrointestinal perforation with or without abdominal abscess is 
rare but possible.  This may present itself as vague abdominal pain 
associated with constipation and vomiting.  Instruct patient to report 
abdominal pain to the MD.  
 
15.299g 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a 
rare (<1%) but serious condition.  Presenting symptoms may include 
changes in mental status, visual disturbance, seizure, or other CNS 
changes.  Patients with this syndrome generally had HTN as well, 
therefore BP monitoring is important.  Instruct patient to report any 
mental status changes, visual changes, seizures, or other CNS 
changes to the MD immediately.  These may be a sign of RPLS or 
more serious condition, such as hemorrhagic event in the CNS.  
 
15.299h 
Warn female patients of the possibility of ovarian failure and 
subsequent infertility. Vaginal hemorrhage is also possible. Instruct 
patients to report any heavy or unusual vaginal bleeding to health 
care team. 


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15.299i 
Warn female patients of the risk of rectovaginal fistula. 
 
15.299j 
Agent may cause increased cardio toxic effects of anthracyclines as 
well as toxic effects of irinotecan, sorafenib, and sunitinib. Patients 
who are on dual therapy with these agents should be monitored 
closely. 
 
15.3 
Ipilimumab (Yervoy®) 
 
15.31 Background: Ipilimumab is a recombinant human IgG1 immunoglobulin 
monoclonal antibody which binds to the cytotoxic T-lymphocyte associated 
antigen 4 (CTLA-4). CTLA-4 is a down-regulator of T-cell activation pathways. 
Blocking CTLA-4, allows for enhanced T-cell activation and proliferation. In 
melanoma, ipilimumab may indirectly mediate T-cell immune responses against 
tumors. 
 
15.32 Formulation: Commercially available for injection 5 mg/mL (10 mL, 40 mL). 
[contains diethylene triamine pentacetic acid, mannitol, polysorbate 80] 
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at refrigeration 
temperature, do not freeze or shake. Protect from light. Reconstitution is 
not required. Appropriate dose should be added to 0.9% NaCL or D5W to 
a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted 
solution by gentle inversion. Preparations in infusion containers are stable 
for up to 24 hours under refrigeration or at room temperature. 
 
15.34 Administration:  Administer via I.V. infusion over 90 minutes through an 
intravenous line containing a low-protein-binding in-line filter. Flush the 
intravenous line with after each dose. Do not mix ipilimumab with, or administer 
as infusion with, other medicinal products. 
 
 
15.35 Pharmacokinetic information: 
Distribution: Vss: 7.21 L 
Half-life elimination: Terminal: 15.4 days 
 
 
15.36 Potential Drug Interactions:  Vemurafenib: Ipilimumab may enhance the 
hepatotoxic effect of Vemurafenib. Management: Consider alternatives to 
this combination when possible. Use of this combination should only be 
undertaken with extra close monitoring of liver function (hepatic 
transaminases and bilirubin) and signs/symptoms of hepatotoxicity. 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information. Refer to the package insert pertaining to 
the following boxed warnings: Severe and fatal immune-mediated adverse 
reactions may occur. Assess patients for signs and symptoms of 
enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate 
clinical chemistries including liver function tests and thyroid function tests 
at baseline and before each dose. 
 


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Common known potential toxicities, > 10%:   
Central nervous system: Fatigue, headache 
Dermatologic: Pruritus, skin rash, dermatitis (including Stevens-Johnson 
syndrome, toxic epidermal necrolysis, dermal ulceration, necrosis, bullous 
or hemorrhagic dermatitis) 
Endocrine & metabolic: Weight loss, pituitary insufficiency 
Gastrointestinal: Nausea, diarrhea, appetite decreased, increased serum 
lipase, vomiting, constipation, colitis, enterocolitis, abdominal pain, 
increased serum amylase 
Hematologic & oncologic: Anemia, decreased hemoglobin 
Hepatic: Increased serum ALT, increased serum AST, increased serum 
alkaline phosphatase, increased serum bilirubin, hepatitis 
Respiratory: Dyspnea, cough 
Miscellaneous: Fever 
 
Less common known potential toxicities, 1% - 10%:  
Centreal nervous system: Insomnia, neuropathy 
Dermatologic: Urticaria, vitiligo 
Endocrine & metabolic: Hypothyroidism, hypophysitis, adrenal 
insufficiency 
Gastrointestinal: Intestinal perforation, pancreatitis 
Hematologic & oncologic: Eosinophilia 
Hepatic: Hepatotoxicity 
Immunologic: Antibody development 
Renal: Increased serum creatinine, nephritis 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Acute respiratory distress syndrome, adrenocortical insufficiency, arthritis, 
blepharitis, bronchiololitis obliterans organizing pneumonia, capillary leak 
syndrome, conjunctivitis, Cushing’s syndrome, DRESS syndrome, 
encephalitis, episcleritis, erythema multiforme, esophagitis, 
gastrointestinal ulcer, giant-cell arteritis, Graves ophthalmopathy, 
Guillain-Barr’e syndrome, hemolytic anemia, hepatic failure, hepatitis 
(immune-mediated), hypersensitivity angiitis, hypogonadism, 
hyperthyroidism, hypoacusis (neurosensory), increased thyroid stimulating 
hormone level, infusion reaction, iritis, meningitis, myasthenia gravis, 
myelofibrosis, myocarditis, myositis,  neuropathy (sensory and motor), 
neurosensory hypoacusis, ocular myositis, pancreatitis, pericarditis, 
peritonitis, pneumonitis, polymyalgia rheumatica, psoriasis, renal failure, 
sarcoidosis, scleritis, sepsis, temporal arteritis, thyroiditis (autoimmune), 
uveitis, vasculitis. 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines 
 
15.391 
Ipilimumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 


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immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
 
15.392 
Diarrhea can be common and can be very severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
 
15.393 
Rash/pruirits/dermatitis is seen. Cases of Steven-Johnson Syndrome 
or toxic epidermal necrolysis have been reported. Patients should 
report any rash to the study team. Treat per section 9.0 and monitor 
for effectiveness.  
 
15.394 
Monitor LFT’s closely as elevations in these levels could indicate 
early onset autoimmune hepatitis. Patients should also be instructed to 
report any jaundice, or right upper quadrant pain to the study team 
immediately. Use with extreme caution in combination with 
Vemurafenibm as this may increase the hepatotoxicity of 
Vemurafenib. 
 
15.395 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and 
consider immediate imaging per the treating MD. 
 
15.396 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of  fatigue and “not 
feeling well” . Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD.  
 
15.397 
Patients who are started on steroid therapy for any side effects of 
Ipilimumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper.  
 
15.398 
Monitor creatinine as nephritis may be seen. 
 
15.399 
Instruct patients to report any ocular symptoms (dry eyes, tearing, 
and/or eye pain) to the study team immediately. 
 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Background  


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Boasberg et al7 examined the utility of the combination of nab-paclitaxel with 
bevacizumab (administered as nab-paclitaxel: 150 mg/m2 on days 1, 8, and 15 and 
bevacizumab: 10 mg/ on days 1 and 15 of a 4-week cycle until disease progression or 
dose limiting toxicity) in chemotherapy naïve patients with metastatic melanoma. With 
41 of the planned 50 patient goal of this Phase II clinical trial enrolled, median 
progression free survival was 6.25 months (95%CI: 5.63-9.41 months). 
 
Hersh et al8 reported the results of a randomized phase II clinical trial of Ipilimumab with 
or without dacarbazine in chemotherapy-naïve patients with metastatic melanoma.  Of the 
37 patients randomized to Ipilimumab  alone administered at 3 mg/kg every 4 weeks for a 
maximum of 4 cycles,  the median overall survival rate was 11.4 months (95% CI: 6.1-
15.6 months) with a 6 month clinical benefit rate (CR, PR, or stable disease by RECIST 
criteria) of 10.8% . [The progression-free survival was not reported. If the 6 month 
clinical benefit rate is used as an approximation to the 6 month PFS rate, then median 
PFS is about 3.25 months).  
 
16.2 
Endpoint(s). 
 
 
16.21 Primary Endpoint 
 
The primary endpoint is progression-free survival (PFS) defined as time from 
randomization to the earliest documentation of progression as defined by the 
RECIST criteria (version 1.1) or death from any cause without the documentation 
of progression.   
 
The study will test the hypothesis that there will be a 40% decrease in the hazard 
of disease progression with AB relative to ipilimumab (improvement in median 
PFS from 3 to 5 months).    
 
16.22 Secondary Endpoints:   
− 
overall survival (OS) as well as the the hazard of death among those 
randomized to AB then ipilimumab relative to those randomized to 
ipilimumab then AB  
− 
tumor response (using the RECIST criteria) 
− 
safety profile of each treatment reigmen 
 
16.23 Descriptive correlative laboratory studies: 
• 
Changes in biomarkers of angiogenesis (Arm A); 
• 
Changes in biomarkers of immunity (Arms A and B); 
• 
Pharmacokinetic changes in nab-paclitaxel plasma concentrations 
 
 
16.3 
Stratification Factors 
 
This study will use the Pocock and Simon9 dynamic allocation procedure to allocate 
an equal number of patients to each of the treatment strategies.  This procedure will 
balance the marginal distributions of the stratification factors between these treatment 
strategies.  The stratification factors that will be used are: sub-stage of disease (M1a/b vs. 
M1c), BRAF 600 mutation present (yes vs. not or metastatic melanoma is of uveal 
origin), and prior treatment in the metastatic setting (yes vs. no) (see Section 5.0).  


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16.4 
Sample size with power justification. 
 
This study was designed to detect a 40% decrease in the hazard of disease progression 
with AB relative to IPI (improvement in median PFS from 3 to 5 months).  All patients 
meeting the eligibility criteria who have signed a consent form and have begun treatment 
will be evaluable for PFS and OS endpoints.   
 
Sample sizes were determined under the assumptions that: (1) the accrual rate would be 
4-5 eligible patients per month over 24 months, 2) the follow-up period after accrual is 
terminated will be 12 months, 3) the distributions of PFS times for each treatment 
regimen follow an exponential distribution, and 4) the hazard rates are proportional, and 
the median PFS time with ipilimumab would be 3.0 months.  
With a sample size of  53 eligible patients per treatment arm, a one-sided alpha=0.10 log 
rank test would have 90% power to detect a 40% decrease in the hazard of disease 
progression in the better arm when the hazard of disease progression in the poorer arm is 
0.2310. This is equivalent to an increase in the median PFS from 3 months to 5 months.  
The expected number of progression and deaths without progression at the time of the 
final analysis is 101. 
 
The trial will be reviewed by the MCC DSMB every 6 months.  The study statistician 
will monitor the trial assumptions (including accrual and event rate in the standard 
treatment arm) as well as safety and recommend changes to the DSMB if assumptions do 
not appear appropriate or excessive toxicity is encountered. 
 
To account for patients who cancel participant prior to the start of treatment or are found 
to be ineligible, the sample size will be increased by 5%.  Thus, we anticipate enrolling a 
minimum of 106 or a maximum of 112 patients.  
 
16.5 
Analysis plan  
 
All patients meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for assessment of all of the clinical endpoints.  Patients 
will be included in the treatment group they were randomized to regardless of their actual 
treatment or duration of treatment.  Summary statistics for patient and tumor 
characteristics, eligibility rates, length of follow-up, and treatment acceptance rates will 
be calculated by assigned treatment arm. 
 
16.51 Progression-free and overall survival  
 
Progression-free survival time is defined as the time from randomization to 
documentation of first disease progression or death due to any cause.  Survival 
time is defined as the time from registration to death due to any cause.  
 
The distributions of OS times and PFS times for each treatment arm will be 
estimated using the Kaplan-Meier method.  A stratified log-rank test and Cox 
partial likelihood score test will be used to assess whether the distribution of OS 
times or PFS times differ with respect to treatment arm having adjusted for M 
stage (M1c vs. else), , and presence of BRAF 600 mutation.  For OS and PFS, 
Cox modeling with the partial likelihood score tests will be used to examine the 


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strength of association between these time to event distributions and additional 
potential prognostic factors.   
 
16.52 Tumor response rate 
 
Tumor response is defined as complete or partial response (using RECIST 
criteria on 2 consecutive evaluations at least 8 weeks apart.  The first line 
ipilimumab tumor response rate will be determined among all patients who meet 
the eligibility criteria, were randomized to Arm B, and began treatment. The 
second line ipilimumab tumor response rate will be determined among all 
patients who meet the eligibility criteria, who were randomized to Arm A, 
progressed on AB, and began ipilimumab treatment.  The first and second line 
response rates with AB similarly defined.  
 
16.53 Safety Profile 
 
Adverse events will be graded and attribution assigned using CTC CAE version 
4.0.  For each type of toxicity reported, the proportion of patients on each 
treatment arm experiencing a severe level of that toxicity will be determined.  For 
each agent, the total dose delivered as a percentage of the starting dose will be 
determined. 
 
16.6 
This randomized phase II clinical trial will be monitored by the Mayo Clinic Cancer 
Center Data and Safety Monitoring Board  (MCCC DSMB).  The study statistician will 
prepare a report containing accrual and adverse event thatwill be submitted to MCCC 
DSMB every 6 months. Efficacy data will be submitted to the MCCC DSMB at the 
planned interim analyses .   
 
Safety Stopping rules: 
 
Enrollment to this clinical trial will be temporarily suspended if any of the following 
occurs: 
− 
3 or more of the first 15 patients randomized to Arm A or 25% or more of the 
patients randomized to Arm A thereafter develop  a grade 4 or 5 non-hematologic 
toxicity   considered possibly, probably, or definitely related to treatment during  
their 4 cycles of IpI treatment 
 
− 
3 or more of the first 15 patients randomized to Arm B or 25% or more of the 
patients randomized to Arm B thereafter develop  a grade 4 or 5 non-hematologic 
toxicity   considered possibly, probably, or definitely related to treatment during the 
first 3 cycles of  BEV + nab-paclitaxel treatment 
 
Crossover  from IpI to BEV + nab-paclitaxel will be temporarily suspended if any of the 
following occurs: 
 
− 
3 or more of the first 15 patients who crossover to BEV + nab-paclitaxel or 25% or 
more of the patients who crossover to BEV + nab-paclitaxel thereafter develop  a 
grade 4 or 5 non-hematologic toxicity  considered possibly, probably, or definitely 
related to treatment during the first 3 cycles of  BEV + nab-paclitaxel treatment 
 


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Crossover  from BEV + nab-paclitaxel to IpI will be temporarily suspended if any of the 
following occurs: 
 
− 
3 or more of the first 15 patients who crossover to IpI or 25% or more of the patients 
who crossover to IpI thereafter develop  a grade 4 or 5 non-hematologic toxicity 
considered possibly, probably, or definitely related to treatment during their 4 cycles 
of IpI treatment 
 
The study team will review all adverse event data.  A trial recommendation will be 
formulated and presented to the MCCC DSMB – the study may permanently close or 
may re-open to accrual after MCCC DSMB review and IRB approval of protocol/consent 
form modifications.  
 
 
 
Futility Analysis:  
 
After the 50% of the patients have reported  progression of disease  (80 events), a futility 
analysis will be conducted to examine whether it is highly unlikely that the AB regimen 
would yield statistically significant results in its favor at the end of the study. The 
findings of this analysis will be reported to the DSMB.  The conditional probability (CP) 
of rejecting Ho at the end of the study given the PFS data at the study time point where 
50% of the total number of progressions required for the final analysis has occurred 
will be calculated using the CP formulas found in Proschan et al (10) as well as Jitlal et al 
(11).  If the CP is found to be ≤  15% (10),  consideration will be given to recommending 
to the DSMB the termination of trial enrollment.  
 
Interim Efficacy Analysis: 
 
Formal comparisons of PFS will be made when approximately 75% and all of the 
expected number of events have occurred for that comparison. The Lan-DeMets method 
for computing discrete sequential two-sided boundaries with an alpha spending function 
yielding O’Brien-Fleming type boundaries (12) will be used to account for sequential 
testing and to maintain the overall preset type I error rate of 0.05. The alpha levels for the 
interim analyses and final analysis are 0.0193, and 0.0307, respectively.  
 
 
 


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16.7 
Inclusion of Women and Minorities 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
45 
66 
111 
Ethnic Category: Total of all subjects* 
 
 
 
Racial Category 
American Indian or Alaskan Native 
 
 
 
Asian 
 
 
 
Black or African American 
 
 
 
Native Hawaiian or other Pacific Islander 
 
 
 
White 
45 
67 
112 
Racial Category: Total of all subjects* 
45 
67 
112 
 
Ethnic Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto 
Rican, South or Central American, or other Spanish culture or 
origin, regardless of race. The term “Spanish origin” can also 
be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
 
Racial Categories: 
American Indian or Alaskan Native – a person having 
origins in any of the original peoples of North, Central, or 
South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples 
of the Far East, Southeast Asia, or the Indian subcontinent 
including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam. (Note: Individuals from the Philippine Islands 
have been recorded as Pacific Islanders in previous data 
collection strategies.)  
Black or African American – a person having origins in any 
of the black racial groups of Africa. Terms such as “Haitian” 
or “Negro” can be used in addition to “Black or African 
American.” 
Native Hawaiian or other Pacific Islander – a person 
having origins in any of the original peoples of Hawaii, 
Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples 
of Europe, the Middle East, or North Africa. 
 
 
 
 


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17.0 
Pathology Considerations/Tissue Biospecimens 
 
 
17.1 
Tissue Biospecimen Submission  
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
Type of 
tissue 
biospecimen 
to submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for  
biospecimen 
submission 
Formalin-
fixed 
paraffin-
embedded 
(FFPE) tissue 
blocks with 
corresponding 
H&E (OR 10 
five-micron 
unstained 
slides with 
corresponding 
H&E) 
Optional 
≤30 days after 
registration/randomization 
Correlative studies (Section 
17.3) 
Section 17.2 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides  
 
17.21 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with 
largest amount of invasive tumor (at least 1 cm of tumor for cases of surgical 
resection) from metastatic tumor biopsy.   
 
17.22 The FFPE tissue block is preferred; however, if an institution is unable to 
provide a tissue block, cut (10) five micron sections and mount on charged glass 
slides.  Label the slides with ACCRU patient ID number, accession number, 
and order of sections. H&E stain every 10th slide (i.e., slides labeled 1, 10).  
These H&E slides will be reviewed centrally under the research base’s protocol 
for assessing tissue quality.  The remaining unstained slides will be processed as 
described in 17.3.  For samples containing less than1-2 square millimeters of 
tumor tissue, multiple sections should be mounted onto each slide to ensure that 
the appropriate amount of tumor tissue is available. Ideally, each slide must have 
a minimum of 75% tumor tissue on the slide to be deemed adequate for study. Do 
not bake or place covers slips on the slides. Do not use sticky labels on the 
slides. 
 
 


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17.23 If a specimen is to be submitted the  following materials below are mandatory 
(unless indicated otherwise) and required for shipment: 
• 
Paraffin embedded tissue blocks with corresponding H&E slide (OR 10 
unstained slides with corresponding H&E). 
• 
Research Tissue Specimen Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
 
Note: Please include the ACCRU patient ID number on all materials listed 
above. 
 
17.24 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in appropriate slide container) and placed in an individual 
plastic bag.  Label the bag with the protocol number, ACCRU patient ID number, 
and patient initials. 
 
17.25 Metastatic tissue specimens must be shipped ≤30 days after 
registration/randomization. 
 
17.26 Verify that the appropriate sections of the Tissue Specimen Submission Form are 
completed and filled in correctly. Enter information from the Tissue Specimen 
Submission Form into the remote data entry system on the same day the 
specimen is submitted (see Forms Packet). 
 
17.27 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
 
 
 
 
17.28 If a corresponding H&E wasn’t submitted with the block/slides, the ACCRU 
Operations Office will request a slide to be processed (i.e., cut and H&E stained) 
from the tumor tissue block and forwarded to Dr. Lori Erickson/ and colleagues 
to be reviewed under the research base’s protocol for assessing tissue quality for 
the proposed correlative studies, unless the tumor size is too small.  If the tumor 
tissue is too small, assessment of tissue quality will occur at the time the 
translational studies are performed. 
 
When an appropriate request is submitted, the ACCRU Operations Office will 
forward the block/slides to the ACCRU Research Base PRC, Mayo Clinic 
Rochester (Attn: PRC) for processing as outlined in Section 17.32. 
 
17.3 
Study Methodology and Storage Information 
 
17.31 Submitted tissue samples will be analyzed as follows: FFPE tumor tissue 
blocks/slides (10 unstained slides) will be collected in order to assess correlation 


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of responses to treatment with tumor infiltrating lymphocytes (CD3, CD8, CD4) 
and levels of VEGF expression by tumor cells.  Both measurements will be semi-
quantitatively assessed by established immunohistochemistry (IHC) methodology 
in our laboratory. 
 
17.32 Definitive immunohistochemical analysis using optional US-guided core needle 
tumor biopsies will be performed at the end of the study, comparing pre-
treatment measurements (see 17.41) with changes at time of tumor progression 
on therapy.   
 
17.4 
At the completion of the study, any unused/remaining material will be stored in the 
ACCRU Central Operations Office (Attn.: Pathology Coordinator) for future research 
according to the patient consent permission (see Section 6.15).  Potential future research 
may include immunohistochemistry (IHC) analyses to analyze predictive biomarkers, 
changes in expression pattern with therapy, and correlation with response and/or adverse 
events.  When a protocol is developed, it will be presented for IRB review and approval. 
 
17.5 
Banking of tumor tissue, according to the patient consent permission (see Section 6.15), 
is for future research.  As protocols are developed, they will be presented for ACCRU 
and IRB review and approval.  (This collection is part of a general strategy of 
investigation for ACCRU melanoma studies.) 
 
17.6 
The institutional pathologist will be notified by Michael Thompson in Dr. Markovic’s 
Hematology/Oncology laboratory if the block may be depleted. 
 
17.7 
Blocks requested to accommodate individual patient management will be returned 
promptly upon request. 
 
17.8 
Return of Genetic Testing Research Results:  No genetic specimens will be collected 
from tissue biospecimens for this study.  If future genetic testing is being requested for 
stored tissue, patient reconsent is required. 
 
 
 


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18.0 
Records and Data Collection Procedures 
 
18.1 
Submission Timetable 
 
 
 
 
Initial Material(s)  
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
 
 
 
 
≤2 weeks  after registration/randomization 
Baseline Adverse Event Form 
RECIST Measurement Form -Baseline 
Tumor Imaging Submission Form1 
Research Tissue Submission Form (see 
Section 17.0) 
OP and Path Reports (see Section 17.0)2 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks  after registration/randomization if 
withdrawal/refusal occurs prior to beginning protocol 
therapy 
 
1. 
Excluding brain MRI and/or CT scan of the head with contrast, images taken during the 
study should be submitted via CD ≤ 2 weeks after they are obtained (see Appendix III).  
2. 
Submit a copy to the ACCRU Ops Office, either electronically to 
 
 
This is in addition to the pathology material requirements for tissue 
submission ( Section 170.) 
 
 
 
 


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Test Schedule Material(s)  
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each 
evaluation 
during 
treatment 
Observation 
period after 
completion of 4 
cycles of Ipi 
At end of AB 
treatment as 
well as end of 
Ipi treatment 
 
At progression 
during any 
treatment or 
observation phase 
Evaluation/Treatment Form  
X2 
 
X2 
 
Evaluation/Observation Form 
 
X3 
 
 
Adverse Event Form 
X 
X 
X 
 
RECIST Measurement Form 
X 
X 
X1 
 
Tumor Imaging Submission Form4 
 
X8 
X9 
X10 
Research Blood Submission Form 
(Mayo Clinic Rochester only) 
X7 (see 
Section 14.0) 
 
 
 
End of Initial Treatment Form 
 
 
X5 
 
End of (ALL) Active 
Treatment/Cancel Notification Form 
 
 
X6 
 
 
1. 
Submit  copy of documentation of response or progression either electronically to 
 
  
2. 
Complete at each evaluation during Active Treatment (see Section 4.0). 
3. 
Complete at each evaluation during Observation (see Section 4.0). 
4. 
Images taken during the study should be submitted on CD (see Appendix II for imaging 
guidelines and Appendix III for image submission process). 
5. 
Complete at end of Initial Treatment, even if not moving to crossover treatment. 
6. 
Complete at end of ALL treatment. 
7. 
Prior to the first cycle of Ipilimumab and prior to the first cycle of BEV/nab-paclitaxel. 
8. 
Patients who discontinue AB treatment phase or the Ipi treatment phase for reasons other 
than progression, all tumor images taken prior to and at the time of treatment discontinuation 
should be submitted.  
9. 
Patients who discontinue observation period after Ipi treatment for reasons other than 
progression, all tumor images taken prior to and at the time of discontinuation should be 
submitted. 
10. Submit all tumor images taken prior to and at time of disease progression 
 
 
 


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Follow-up Material(s): 
 
CRF 
Event Monitoring Phase1  
q 6 months 
until  death 
or a 
maximum of 
3 years post 
registration/
registration 
Post treatment 
monitoring phase 
If patient entered 
event monitoring 
phase without 
having progressed 
on both 
ABI007/BEV and 
Ipi,  at first PD 
during event 
monitoring. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring 
Form 
X2 
X2 
X2 
X 
At first occurrence 
1. 
If a patient entered the event monitoring phase less than 3 years after registration, no further 
follow-up is required 3 years post-registration. If the patient entered the event monitoring 
phase 3 or more years post registration, then a single event monitoring CRF is to be 
completed and no further follow-up is required.  
2. 
Submit copy of documentation of progression (clinical notes, imaging reports, pathology 
reports, etc.) to the 
 
 
 
 
19.0 
Budget 
 
19.1 
Costs charged to patient:  Routine clinical care costs will be the responsibility of the 
patient and/or the patient’s insurance company.  This includes costs associated with the 
administration of the study drugs.  Ipilimumab will be obtained through commercial 
suppliers. 
 
19.2 
Other budget concerns:   
 
19.21 Nab-paclitaxel will be provided to patients by Celgene at no charge.   
 
19.22 Bevacizumab will be provided to patients by Genentech at no charge.   
 
19.3 
Tests to be research funded:  Research blood and tissue tests will be funded by Celgene.  
These include the following tests. 
• 
Mayo Clinic Rochester only: Pharmacodynamic changes of blood biomarkers of 
angiogenesis and immunity (see Section 14.0). 
 
 
 
 


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20.0 
References 
 
1. 
Balch, C.M., et al., Update on the melanoma staging system: the importance of sentinel 
node staging and primary tumor mitotic rate. Journal of surgical oncology, 2011. 104(4): 
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2. 
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. The New England journal of medicine, 2010. 363(8): p. 711-23. 
3. 
Chapman, P.B., et al., Improved survival with vemurafenib in melanoma with BRAF 
V600E mutation. The New England journal of medicine, 2011. 364(26): p. 2507-16. 
4. 
Kottschade, L.A., et al., A randomized phase 2 study of temozolomide and bevacizumab 
or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV 
melanoma : A North Central Cancer Treatment Group study, N0775. Cancer, 2012. 
5. 
Perez, D.G., et al., Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly 
bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer 
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6. 
Kottschade, L.A., et al., A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in 
patients with unresectable stage IV melanoma : a North Central Cancer Treatment 
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7. 
Boasberg PD, Weber RW, Cruickshank S, Hamid O, O’Day S, Spitler, LE.  Phase II trial 
of nab-paclitaxel and bevacizumab as first line therapy in patients with  unresectable 
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8. 
Hersh EM, O’Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD, Samlowski WE, 
Nichol GM, Yellin MJ, Weber JS.  A phase II multicenter study of Ipilimumab with or 
without dacarbazine in chemotherapy-native patients with advanced melanoma.    J 
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9. 
Pocock SJ, Simon R.  Sequential Treatment Assignment with Balancing for Prognostic 
Factors in the Controlled Clinical Trial. Biometrics 31(1):103-115, 1975 Mar. 
10. 
Proschan MA, Lan KKG, Wittes JT.  Statistical Monitoring of Clinical Trials: a unified 
approach.  Springer USA, 2006. 
11. 
Jitlal M, Khan I, Lee SM, Hackshaw.  Stopping clinical trials early for futility:  
retrospective analysis of several randomised clinical studies.  British Journal of Cancer 
107: 910-917, 2012. 
12. 
Lan KKG and DeMets DL: Discrete sequential boundaries for clinical trials. Biometrika 
70(3):659-63, 1983.