Conditions: Lung Transplant Rejection
Keywords: antibody-mediated rejection lung transplant Carfilzomib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
The clinical trial is a Phase II open label, single-arm pilot study to evaluate the safety and efficacy of combination therapy with carfilzomib, plasma exchange and intravenous immunoglobulins for AMR after lung transplantation and elucidate important clinical and immunologic phenotypes and mechanisms associated with these outcomes.

Detailed description:
The main objective of the proposed clinical investigation is to evaluate the effects of carfilzomib in addition to conventional therapy on short-term outcomes after the diagnosis of antibody-mediated rejection in lung transplant recipients. In this study, Carfilzomib will be administered at a dose of 20 mg/m2 on two consecutive days, each week for three weeks (Days 1 2, 8, 9, 15, and 16) to constitute one therapeutic cycle. Carfilzomib may be administered for 1-2 complete cycles in the study. Patients will be followed for the duration of their hospital admission after enrollment. Post treatment follow-up will also occur on Days 42 and 90.

Arms:
arm 1: Carfilzomib will be administered at a dose of 20 mg/m2 on two consecutive days, each week for three weeks (Days 1 2, 8, 9, 15, and 16) to constitute one therapeutic cycle. Carfilzomib may be administered for 1-2 complete cycles in the study.

Interventions: intervention 1: Carfilzomib
Intervention descriptions: intervention 1: Carfilzomib will be used in combination with the conventional therapy (plasma exchange and intravenous immunoglobulins)

Protocol document:
Prot_SAP_000.pdf: 
Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
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CLINICAL INVESTIGATOR SPONSORED TRIAL PROTOCOL 
 
 
 
TITLE:  
Combination Therapy with the Proteasome Inhibitor 
Carfilzomib for the Antibody-Mediated Rejection Diagnosis in 
Lung Transplantation  
Trial (PICARD-Lung) 
 
Protocol number:  
 
PRO15010152 
 
Study drug:   
 
Carfilzomib (Kyprolis®) 
 
Primary investigator:  
John F. McDyer, MD 
 
Co-investigators:  
 
Adriana Zeevi, PhD 
 
 
 
 
Matthew R. Morrell, MD 
 
 
 
 
 
 
Sponsor: 
 
 
 John F. McDyer, MD 
 
 
 
 
 
DATE:  
 
            09/20/2018 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This is an investigator sponsored trial that contains confidential information.  It is intended solely 
for use by Amgen, the clinical investigator team, and study support structure and must not be 
disclosed to any other party.  This material may be used only for the evaluation and conduct of 
the aforementioned clinical investigation and any other use requires consent from the primary 
investigator. 


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TABLE OF CONTENTS 
 
1 
PROTOCOL FACILITATION………………………………………………………………......6 
 
1.1 
Protocol finalization signature page…………………………………………………...6 
 
1.2 
Protocol acceptance signature page………………………………………………….7 
 
1.3 
Protocol synopsis………………………………………………………………………..8 
 
2 
BACKGROUND………………………………………………………………………………..11 
 
2.1 
Background and significance…………………………………………………………11 
 
2.2 
Study rationale…………………………………………………………………………12 
 
3 
OBJECTIVES…………………………………………………………………………………..15 
 
 
3.1 
Specific aims…………………………………………………………………………...15  
 
4 
STUDY DESIGN………………………………………………………………………………..16 
 
4.1  
Rationale…..........................................................................................................17 
 
4.2 
Investigators…………………………………………………………………………....18 
 
4.3 
Study definitions………………………………………………………………….……19 
 
4.4 
Outcome measures…………………………………………………………………...20  
 
4.4.1 Primary outcome measures…………………………………………….…...20  
 
4.4.2 Secondary outcome measures………………………………………….…..20 
 
4.4.3 Safety outcomes…………………………………………………………..…..20 
 
4.4.4 Exploratory outcome measures……………………………………….…….22 
 
4.5 
Safety plan…………………………………………………………………….………..22 
 
4.6 
Ethical considerations …………………………………………………………………22 
 
4.7 
Administrative structure……………………………………………………………….23 
 
4.7.1 UPMC Pulmonary research core……………………………………………23 
 
4.7.2 Data management plan………………………………………………………23 
 
4.7.3 Investigational drug pharmacy………………………………………………23 
 


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4.8  
Compliance with laws and regulations……………………………………….……..23 
 
5 
MATERIALS AND METHODS……………………………………………………………….24 
 
5.1  
Patients…………………………………………………………………………………24 
 
5.1.1 Patient selection………………………………………………………………24 
 
5.1.2 Inclusion criteria……………………………………………………………….24 
 
5.1.3 Exclusion criteria………………………………………………………………24 
 
5.1.3.1 Exclusion related to disease………………………………….……..24 
. 
5.1.3.2 Exclusion related to general health………………………….……..24 
 
5.1.3.3 Exclusion related to risk for infections……………………….……..24 
 
5.1.3.4 Exclusion related to medications…………………………….……..25 
 
5.2 
Treatment assignment………………………………………………………….……..25 
 
5.3 
Study treatment………………………………………………………………………..25 
 
5.3.1 Investigational therapy……………………………………………………….25 
 
5.3.1.1 Dosage, administration, and storage………………………………25 
 
5.3.1.2 Dosage modification…………………………………………………26 
 
5.3.2 Concomitant therapy………………………………………………….………27 
 
 
5.3.3 Excluded therapy………………………………………………………….…..28 
 
5.4 
Study assessments……………………………………………………………………28 
 
5.4.1 Definition of study assessments…………………………………………….28  
 
5.5 
Screening and pretreatment assessments………………………………………….29 
 
5.6 
Assessments during treatment……………………………………………………….29 
 
5.7 
Study completion………………………………………………………………………29 
 
5.8 
Follow-up assessments……………………………………………………………….30 
 
5.9 
Patient discontinuation………………………………………………………………..30 
 
5.10 
Study discontinuation………………………………………………………………….30 
 
5.11 
Post-trial access……………………………………………………………………….30 


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5.12 
Assay methods…………………………………………………………………………30 
 
5.13 
Statistical methods…………………………………………………………………….30 
 
5.13.1 Analysis of the conduct of the study………………………………………...31 
 
5.13.2 Safety analyses……………………………………………………………….31 
 
5.13.3 Determination of sample size………………………………………………..31 
 
5.14 
Data quality assurance………………………………………………………………..31 
 
6 
ASSESSMENT OF SAFETY………………………………………………………………….31 
 
6.1 
Possible risks and discomforts……………………………………………………….32 
 
 
6.1.1 Carfilzomib risks………………………………………………………………32 
 
 
6.1.2 Adverse effect definition……………………………………………………...32 
 
 
6.1.3 Serious adverse effect definition…………………………………………….32 
 
 
6.1.4 AEs……………………………………………………………………………..33 
 
 
6.2 
Methods and timing for capturing and assessing safety parameters…………….35 
 
6.2.1 Adverse event reporting period……………………………………………...35 
 
6.2.2 Eliciting adverse events………………………………………………………36 
 
6.2.3 Assessment of severity and causality of adverse events…………………36 
 
6.3 
Procedures for recording adverse events…………………………………………..36 
 
6.3.1 Diagnosis………………………………………………………………………37 
 
6.3.2 Persistent or recurrent adverse effects………………………….………….37 
 
6.3.3 Abnormal laboratory values……………………………………………….…38 
 
6.3.4 Deaths………………………………………………………………………….38 
 
6.3.5 Preexisting medical conditions…………………………………….…….…..38 
 
6.3.6 Worsening antibody mediated rejection…………………….………………38 
 
6.3.7 Prolonged hospitalization…………………………………….………………38 
 
6.3.8 Pregnancy………………………………………………………….…………..38 
 


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6.4 
Procedures for reporting serious adverse events…………………………….…....40 
 
6.4.1 Reporting requirements for serious adverse events…………………..….40 
 
6.5 
Follow-up of patients after adverse events……………………………………..….40 
 
7 
INVESTIGATOR REQUIREMENTS……………………………………………………..….40 
 
7.1 
Study initiation……………………………………………………………………...….40 
 
7.2 
Study completion…………………………………………………………………...…41 
 
7.3 
Informed consent form………………………………………………………………..41 
 
7.4 
Communication with the IRB…………………………………………………………41 
 
7.5 
Study monitoring requirements………………………………………………………41 
 
7.6 
Source data documentation…………………………………………………………..42 
 
7.7 
Study medication accountability……………………………………………………...42 
 
7.8 
Disclosure of data……………………………………………………………………...42 
 
7.9 
Retention of records…………………………………………………………………...42 
 
8 
REFERENCES………………………………………………………………………………….43 
 
9 
APPENDICES………………………………………………………………………………..…45 
 
Appendix A: Study flowchart……………………………………………………………………….…...45 
 
Appendix B: Study data collection summary…………………………………………………………..46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.1  
PROTOCOL FINALIZATION  
 
 
TITLE:  
Combination Therapy with the Proteasome Inhibitor 
Carfilzomib for the Antibody-Mediated Rejection Diagnosis in 
Lung Transplantation  
Trial (PICARD-Lung) 
 
Protocol number:  
 
PRO15010152 
 
Study drug:   
 
Carfilzomib (Kyprolis®) 
 
Primary investigator:  
John F. McDyer, MD 
 
Co-investigators:  
 
Adriana Zeevi, PhD 
 
 
 
 
Matthew R. Morrell, MD 
 
 
 
 
Sponsor: 
 
 
 John F. McDyer, MD 
 
 
 
 
 
DATE:  
 
           09/20/2018 
 
 
 
This protocol was finalized on the date shown above. 
 
 
 
 
 
 
 
 
 
 


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1.2  
PROTOCOL ACCEPTANCE SIGNATURE PAGE 
 
 
TITLE:   
 
 
Combination Therapy with the Proteasome Inhibitor Carfilzomib for  
the Antibody-Mediated Rejection Diagnosis in Lung Transplantation  
Trial (PICARD-Lung) 
 
Protocol number:  
 
PRO15010152 
 
Study drug:  
 
 
Carfilzomib (Kyprolis®) 
 
Primary investigator:   
John F. McDyer, MD 
 
Co-investigators:  
 
Adriana Zeevi, PhD 
 
 
 
 
Matthew R. Morrell, MD 
 
 
 
Sponsor: 
 
 
 John F. McDyer, MD 
 
 
 
 
 
DATE:  
 
             02/20/2018 
 
 
 
 
I agree to conduct the study in accordance with the current protocol.  
 
 
 
 
 
____________________________________________________ 
_________________________ 
John F. McDyer, MD, Principal Investigator 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 


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1.3 
PROTOCOL SYNOPSIS 
 
 
TITLE:  
Combination Therapy with the Proteasome Inhibitor 
Carfilzomib for the Antibody-Mediated Rejection Diagnosis in 
Lung Transplantation  
Trial (PICARD-Lung) 
 
Protocol number:  
 
PRO15010152 
 
Study drug:   
 
Carfilzomib (Kyprolis®) 
 
Phase:  
 
 
phase II 
 
Patient enrollment:   
30 
 
Indication: 
 
 
Antibody mediated rejection after lung transplantation 
 
Sponsor: 
 
 
 John F. McDyer, MD 
 
 
 
 
 
DATE:  
 
            09/20/2018 
 
Objectives 
 
1: To test the hypothesis in a prospective interventional clinical trial that addition of carfilzomib 
to conventional therapy will result in depletion of the immunodominant DSA.  
 
2: To test the hypothesis in a prospective interventional clinical trial that addition of carfilzomib 
to conventional therapy will result in improved or stabilized allograft function.   
 
3: To test the hypothesis that lung transplant recipients with AMR have effector B cell/plasma 
cell populations that can be identified and characterized, and that carfilzomib alters these 
immune mechanisms.   
 
Study design 
 
Phase II, prospective, open-label, single-arm active treatment, single center pilot clinical trial of 
the addition of carfilzomib to conventional therapy for AMR after lung transplantation.  
 
Outcome measures 
 
Primary endpoint: absolute change in DSA strength, titer, and complement fixation from day 1 to 
day 42.   
 
Secondary endpoints:  
 
Absolute change in DSA strength, titer, and complement fixation from day 1 to day 90 and from 
day 42 to day 90 
 
Absolute change in forced expiratory volume in 1 second (FEV1) from day 1 to day 42 and to 
day 90.   


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Presence or absence of pathologic changes consistent with AMR on transbronchial biopsy from 
day 1 to day 42.   
 
Patient death at any time after day 1 attributable to AMR.   
 
 
Safety endpoints:  
 
Non-lung irreversible end-organ failure (e.g., end-stage renal disease) any time after day 1 
attributable to carfilzomib.  
 
Incidence of adverse effects (AE) requiring dose-modification any time during days 1-16. 
 
Incidence of any AE at any time after day 1 as graded by the NIH Common Terminology Criteria 
for Adverse Events (CTCAE) (appendix B) criteria. 
 
Incidence of hypogammaglobulinemia any time after day 1. 
 
Incidence of culture-proven de novo infection any time after day 1. 
 
Diagnosis of systemic inflammatory response syndrome (SIRS) any time during days 1-16  
 
Patient death at any time after day 1 to day 90 attributable to carfilzomib.  
 
Retrospective control group:  
 
A 1:1 retrospective control group including lung transplant recipients from the University of 
Pittsburgh with Antibody Mediated Rejection will be created to describe differences in the 
endpoints using the CFZ-based regimen vs. historic standard of care.  
 
Safety plan 
 
Patients will be enrolled according to the inclusion and exclusion criteria.  Patients will provide 
informed consent to participate in this clinical trial.  In the informed consent process, patients will 
be educated about the purpose for carfilzomib and the potential adverse.   
 
A study data safety monitoring board (DSMB) will be established.  The DSMB will meet once 
yearly to review study progress, to ensure appropriate enrollment milestones are being met, and 
to review the adverse event reporting.  The DSMB will meet on an ad-hoc basis to review any 
SAEs.   
 
The DSMB may terminate the study only after at least 15 patients have been enrolled.  The DSMB 
may only terminate the study for safety reasons in which the perceived risks of continuing to 
provide carfilzomib to upcoming patients who may be enrolled outweighs the potential benefit to 
the patient and the allograft.  The DSMB may not terminate the study for any reason related to 
carfilzomib efficacy.   
 
 
 
 


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Study treatment 
 
Carfilzomib dosing schedule: Carfilzomib will be administered on the multiple myeloma schedule 
consisting of 20 mg/m2 on days 1 2, 8, 9, 15, and 16 (one cycle) to constitute one therapeutic 
cycle.  On PLEX/IVIG days, carfilzomib will be given in between PLEX and IVIG to avoid 
inadvertent blockade of the Fcγ receptor.  Premedications for carfilzomib administration will be 
given as follows:  acetaminophen 650 mg PO, diphenhydramine 25 mg PO, ondansetron 4 mg 
PO, prednisone 40 mg PO or methylprednisolone 40 mg IV, all at least 30 minutes prior to and 
not more than 6 hours before carfilzomib, unless otherwise directed on the part of one of the 
investigators if believed to be in the best interests of patient care.  Preinfusion hydration with a 
one-time bolus of 250 mL 0.9% sodium chloride will be given at least 30 minutes prior to and not 
more than 6 hours before carfilzomib to minimize the nephrotoxic AE.   Postinfusion hydration 
with a one-time bolus of 250 mL 0.9% sodium chloride may be given immediately after carfilzomib 
to minimize the nephrotoxic AE. 
 
Concomitant therapy and clinical practice 
 
Conventional therapy for AMR:  Therapeutic plasma exchange (PLEX) 1.5 plasma volumes 
replaced with 5% albumin or fresh frozen plasma for 8 sessions every-other day.  Total 
intravenous immunoglobulins (IVIG) 100 mg/kg IV after each PLEX with the exception of the 
final PLEX where IVIG 500 mg/kg will be given. On day 16, if the IgG level is below 700 mg/dL, 
an additional dose of IVIG 500 mg/kg will be administered.  If the IgG result is found to be 
700ml/dL or higher, the IVIG 500mg/kg dose will not be administered.  Premedications will be 
given for IVIG as follows: acetaminophen 650 mg PO and diphenhydramine 25 mg PO both at 
least 30 minutes prior to and not more than 6 hours before IVIG, unless otherwise directed on 
the part of one of the investigators if believed to be in the best interests of patient care.  On days 
where IVIG and CFZ are given together, only one set of premedications will be administered. 
Conventional therapy requires an inpatient hospital stay.  Patients will receive a tunneled PLEX 
catheter and peripherally inserted central catheter (PICC) inserted by interventional radiology in 
the routine clinical care of these patients prior to receiving any conventional or carfilzomib 
therapy.  
Women of childbearing potential must either agree to abstain from sexual intercourse or use an 
effective birth control method during treatment and for an additional 30 days after the last dose of 
carfilzomib.  Men who are sexually active with women of childbearing potential must either agree 
to abstain from sexual intercourse or use a condom with spermicide during treatment and for an 
additional 30 days after the last dose of carfilzomib, and the female partner should consider using 
an effective method of birth control.   
 
Statistical methods 
 
Data will only be analyzed in aggregate at study conclusion for the final enrolled patient on the 
efficacy and safety outcomes.   
 
Descriptive statistics will be used to describe baseline and study characteristics of patients.  
Univariate parametric and nonparametric assessments, where appropriate, will be used to assess 
change from baseline in the efficacy and safety outcomes.  Kaplan-Meier method will be used to 
describe freedom from endpoints and mortality in the patients treated with carfilzomib.  Kaplan-
Meier method will be used to visually represent the time to events and overall event rate in the 
patients in this pilot, not to compare events to any other group.  


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2 
BACKGROUND 
 
2.1 
Background and significance  
 
The lack of improvement in long-term allograft survival, despite improved short-term outcomes, 
remains the most pressing challenge in the lung transplantation field.  Lung transplant recipients 
fare poorly relative to other solid organs with 30% incidence of chronic rejection at 2.5 years, 75% 
at 10 years, and only 55% of recipients surviving five years, primarily due to bronchiolitis obliterans 
syndrome (BOS).1,2 This problem is compounded by major gaps in our understanding of the 
immune mechanisms underlying chronic rejection. 
 
Donor specific antibodies have a reported incidence of 10-40% in lung transplantation, and DSA 
both precedes and is associated with an increased risk of BOS.3-6 Further, pre-transplant 
sensitization in lung transplant recipients was found to correlate with worse survival.7 In addition 
to BOS, other studies have shown that DSA is associated with severe or recurrent acute cellular 
rejection (ACR) and lymphocytic bronchiolitis (LB), two forms of cellular rejection that are major 
risk factors for BOS.8,9  Moreover, detection of DSA with clinical antibody mediated rejection 
(AMR) in lung transplant recipients is difficult to treat and is associated with higher morbidity 
compared to ACR.20 Several studies have shown an association between the development of 
anti-HLA Abs and/or DSA, BOS, and decreased survival.4,5,8-10  One such paper shows that anti-
HLA antibodies are associated with ACR and lymphocytic bronchiolitis, two forms of cellular 
rejection that are major risk factors for BOS.8  We further investigated the relationship between 
DSA and BOS in 445 LT recipients at the University of Pittsburgh, over a 7-year period (2003-
2010). As shown in figure 1, DSA was associated with significantly reduced freedom from BOS 
and decreased survival in LT recipients followed for 3.4 ±1.6 yrs. Furthermore, we found that the 
risk of BOS was significantly increased in the DSA+ group compared to the non-DSA group using 
a Cox proportional hazards model (HR 6.32; 95% CI 4.34-9.18; p<0.001). 
 
 
 
 
 
 
 
 
Figure 1: Freedom from BOS and Mortality in DSA vs. no  
DSA in lung transplantation recipients from UPMC.  
 
 
Moreover, the presence of high-grade BOS (BOS stage 2 or 3) was significantly increased in the 
DSA+ versus the no-DSA group. Together, these data indicate that development of DSA is 
significantly associated with accelerated, high-grade BOS in lung transplantation recipients, along 
with diminished patient survival. Thus, DSA and AMR are emerging as a formidable challenge in 
lung transplantation.  
 


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Contrary to lung transplantation, the evidence and agreement supporting the AMR are robust in 
renal transplantation.  That said, the majority of the principles learned in renal transplantation are 
applicable to the lung.  One such lesson is the impact of functional phenotype of DSA, ergo 
whether the DSA is able to fix complement at peripheral blood concentrations in vitro.  A novel 
solid phase Luminex single antigen bead (SAB) assay was developed which allows the detection 
of complement fixing HLA antibodies with high sensitivity and specificity (Luminex-C1q).11 In renal 
transplantation, several small studies suggest that C1q-binding DSA correlates with transplant 
glomerulopathy (TG) and irreversible renal allograft failure.12 In particular, persistent complement 
binding DQ-specific DSA is associated with a 30% lower 5-year allograft survival. In a recent large 
study in a cohort of 1016 renal transplant recipients, co-authored by co-investigator Dr. Adriana 
Zeevi, the presence of DSA and C1q-binding donor-specific anti-HLA antibodies at 1 year, or at 
the time of acute rejection within 1 year, was correlated with 5 year allograft survival (Figure 2). 
Patients with complement-binding DSA had significantly reduced 5-year allograft survival (54%) 
compared to those with non-complement binding DSA (93%). C1q binding of de novo DSA was 
independently associated with graft loss whether it was detected in samples taken at the one year 
protocol biopsies or in samples taken during acute rejection in the first-year post-transplantation.  
 
 
 
 
 
 
Figure 2: Kaplan-Meier curve of probability of graft survival based on  
 
 
 
DSA phenotype.  Panel A: conventional Luminex-IgG vs. no DSA.  
Panel B: Luminex-IgG and C1q vs. no DSA.  
 
2.2 
Study rationale 
 
The optimal treatment for DSA in lung transplant recipients remains unclear. In a recent study, 65 
lung transplant recipients who developed DSA were treated preemptively before the development 
of BOS with either IVIG alone or IVIG/rituximab.13 On follow-up evaluation, persistence of DSA 
despite therapy was associated with increased BOS (Figure 3B). However, recipients treated with 
IVIG alone had persistence of DSA comparable to those treated with IVIG/rituximab (35% vs.38%, 
respectively). Thus, while there was no untreated control group, these data suggest that the 
addition of rituximab therapy did not enhance DSA clearance and had no significant effect on 
freedom from BOS (Figure 3A) compared to IVIG alone. These data indicate that either IVIG alone 
or IVIG/rituximab therapy results in substantial persistence of DSA in lung transplant recipients 
(35%), and is associated with significantly increased progression to BOS. 
 


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Figure 3. Freedom from BOS in lung transplant recipients with DSA treated with  IVIG vs. IVIG/rituximab 
and in patients who cleared vs. persisted DSA.  
 
Since rituximab appears to add little to conventional therapy, proteasome inhibition with 
bortezomib alone and in combination with conventional therapy was investigated in 6 renal 
transplant recipients.  Bortezomib-based therapy effectively treated 6 patients with refractory 
combined AMR/ACR and stably reduced DSA by at least 50% (figure 4, next page).14 Moreover, 
a single cycle of Bortezomib alone was as effective as Bortezomib combined with PLEX and IVIG 
or rituximab in reducing de novo DSA.15 Of 11 patients (bortezomib alone), 4 had a 50% decrease 
in DSA, while 7 had complete remission (CR; MFI<1000) which lasted >2 years in 3/7.41 Patients 
with stable CR, had a lower serum CR at 14 months than those with DSA relapse –adding 
credence to the notion that successful treatment of DSA may alter outcome. Importantly 
proteasome inhibitors were well tolerated, and neither overall IgG nor IgG levels for childhood 
immunizations were changed.16,17 The relatively specific loss of DSA after proteasome inhibitor 
therapy may relate to their predominant effect on the most active antibody responses, with 
residual DSA binding to the allograft. Interestingly, recent evidence in vitro indicates that 
proteasome inhibitors induce B cell apoptosis in addition to the effects on plasma cells and 
therefore, may impact and expand cell populations targeted by anti-CD20 based therapies.18 
 
 
 
 
 
Figure 4. Reduction of immunodominant DSA following 
 
 
Bortezomib therapy in 6 renal transplant recipients 
 
Carfilzomib has mechanistic advantages over bortezomib.  Carfilzomib has irreversible activity at 
the proteasome and an extraordinarily short half-life which eliminates concerns of subsequent 
removal by PLEX.  Moreover, carfilzomib has been effective in studies of bortezomib-refractory 
multiple myeloma.19-21  As such, the PICARD-Lung investigators conducted a small pilot study of 
combination carfilzomib-based therapy in 7 lung transplant recipients who met the diagnostic 
criteria for AMR and required therapy and had previously failed other conventional regimens for 
AMR consisting of PLEX, IVIG, and rituximab or bortezomib.  LT recipients with AMR were treated 
with CFZ-based therapy (8 1.5x volume plasma exchanges (PE) every-other day, 1.2 g/kg total 
immunoglobulin, and 6 doses of CFZ 20 mg/m2 on days 1, 2, 8, 9, 15, and 16). Luminex IgG and 


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C1q DSA in neat serum, PFTs, and biopsy (TBBx) were done at baseline and repeated 4-6 weeks 
post-therapy. 7 patients received CFZ-based therapy. Patients 1-4 were refractory to rituximab-
based therapy; patient 4 was refractory to both rituximab and bortezomib-based therapy. FEV1 
at AMR diagnosis was significantly reduced from baseline (-19.8%, p<0.01) and oxygen 
requirements worsened in all patients. DSA were of moderate to strong strength by IgG and 6 of 
7 fixed complement by C1q (MFI>500) at baseline (table 1). TBBx in patients 2 and 5 were 
diffusely positive for pericapillary C4d; patient 5 had diffuse neutrophilic capillaritis, and patient 4 
had minimal cellular rejection (A1). All pathologic findings of AMR resolved after therapy. DSA 
IgG MFI declined significantly (p=0.02) and 6 of 7 DSA became non-complement fixing after 
therapy (table). Oxygen requirements improved in all patients; 5 patients recovered to discharge 
with stable allograft function; patient #6 remains chronically ventilated. FEV1 data were available 
in 6 patients and either stabilized or rose in 5 of the 6 patients (figure 5). One patient died due to 
end-stage BOS, transient thrombocytopenia occurred in 2 patients which recovered, acute kidney 
injury occurred in 3 patients and recovered in 2 patients; patient 5 was critically ill during treatment 
and remains dialysis dependent.  Thus, carfilzomib-based therapy appears useful for AMR after 
lung transplantation in this small cohort. 
 
Table 1. Change in strength of immunodominant DSA by IgG and functional phenotype after carfilzomib-
based therapy.  
 
Patient Immunodominant DSA 
IgG pre 
IgG post 
C1q pre 
 C1q 
post 
1 
DQB1*04:02/DQA1*04:01 
18105
9796
1152
10 
2 
DQB1*02/ DQA1*05 
13941
9511
2832
97 
3 
DQB1*07/DQA1*05 
7793
1878
6568
10 
4 
DR53 
3004
2359
10
10 
5 
DQB1*03:02/DQA1*03:02 
3182
593
20691
10 
6 
DQB1*03:01/DQA1*05:05 
744
5296
19442
28783 
7 
DQ7 
5020
1957
14282
30 
 
        
 
Figure 5. FEV1 before and by C1q after treatment with combined 
carfilzomib-based therapy.   
 
 
         
 
Considering the recent studies by Witt22 and Snyder3 demonstrating 
the difficulty and frequent failure of various regimens to treat AMR in 
LT recipients, these preliminary data showing an impact using a 
carfilzomib-based treatment regimen for established DSA responses 
with allograft dysfunction are indeed encouraging. 
 
 
 
As a result of these positive preliminary findings, expansion of the sample size is required to 
confirm both the efficacy of combination therapy with carfilzomib as well as the safety of such an 
approach in this population.  
 
3. 
OBJECTIVES 
 
3.1  
Objectives 
 
Short-term outcomes after lung transplantation are improved; however, long-term outcomes 
remain poor and this is a major challenge for the field.  Progressive allograft dysfunction due to 
0
0.5
1
1.5
2
2.5
3
FEV1 pre
FEV1 post
0
0.5
1
1.5
2
2.5
3
FEV1 pre
FEV1 post


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Molecule: Carfilzomib  
 
 
p. 15 of 48 
the clinical diagnosis of bronchiolitis obliterans syndrome, or chronic rejection, limits both patient 
survival and quality of life.  The impact of donor-specific anti HLA-antibodies (DSA) and AMR on 
the early development and progression of BOS have been well-described.3,13,22  In addition to 
these data, our preliminary data show a dramatic reduction in lung function in the presence of 
DSA, accelerated diagnosis of phenotypically more advanced BOS, and early mortality.  At 
present, targeting this pathway represents a viable approach to impact these key risk factors, 
DSA and AMR, and decrease expression of chronic rejection, graft loss, and patient death.  
Additionally, major gaps in our knowledge of the antibody-mediated phenotype of BOS exist.  
While early evidence of clinical benefit appears to exist in our preliminary data, this needs to be 
validated with larger patient numbers. Moreover, the underlying mechanisms of potential benefit 
remain to be elucidated.  
 
Conventional therapy for this problem, including plasma exchange and intravenous 
immunoglobulins, are limited and targeted at removal of circulating antibody; not at the antibody-
producing apparatus, the plasma cell.13,23  Thus, our hypothesis is that the combination of 
conventional therapy with plasma-cell targeted therapy using the proteasome-inhibitor 
carfilzomib in symptomatic lung transplant recipients with AMR will improve/stabilize 
allograft function and result in depletion of the immunodominant DSA.  In this proposal, we 
will conduct a pilot phase II open label observational trial in lung transplant recipients to test 
whether addition of carfilzomib to conventional therapy improves short-term outcomes after the 
diagnosis of antibody-mediated rejection, and to identify the cellular mechanisms that support 
these clinical benefits. Clinical and immune phenotyping of study subjects will advance our 
understanding of anticipated therapeutic responses.  Specifically, cellular mechanistic studies to 
detect immune system changes that will enable us to phenotype LTRs with AMR and determine 
or predict risk and outcomes, such as BOS.  Patients who have met the clinical diagnosis of AMR 
requiring therapy will be targeted for enrollment in the study and treated with the open-label 
carfilzomib-based combination protocol.   
 
To execute this study, we have established the Combination Therapy with the Proteasome 
Inhibitor 
Carfilzomib 
for 
the 
Antibody-Mediated 
Rejection 
Diagnosis 
in 
Lung 
Transplantation (PICARD-Lung) Trial Study Group.  This clinical trial will be executed at the 
University of Pittsburgh Medical Center leveraging the expertise and prowess of one of the 
highest-volume clinical lung transplant services worldwide, the McDyer immunology lab, and the 
Zeevi immunohistochemistry and histocompatibility labs. 
   
1: To test the hypothesis in a prospective interventional clinical trial that addition of 
carfilzomib to conventional therapy will result in depletion of the immunodominant DSA. 
In this trial, lung transplant recipients will be treated with the carfilzomib-based combination 
protocol and screened with Luminex single antigen bead testing to identify DSA burden by IgG 
and functional status by C1q before and after treatment.   
 
2: To test the hypothesis in a prospective interventional clinical trial that addition of 
carfilzomib to conventional therapy will result in improved or stabilized allograft function.  
In this trial, lung transplant recipients will be treated with the carfilzomib-based combination 
protocol and screened with pulmonary function testing to identify whether forced expiratory 
volume in 1 second returns to pre-AMR diagnosis level.   
 
3: To test the hypothesis that lung transplant recipients with AMR have effector B 
cell/plasma cell populations that can be identified and characterized, and that carfilzomib 
alters these immune mechanisms.  In this trial, we will determine the immunologic phenotype 


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Molecule: Carfilzomib  
 
 
p. 16 of 48 
of these patients and describe functional immune system changes in memory and effector cells, 
plasma cells, and respective pathologic and immunohistochemical correlates relevant to AMR.   
 
The PICARD-Lung investigators and the study center are highly experienced clinical and 
translational investigations in lung transplantation.  Successful completion of these specific aims 
will establish the safety and efficacy of combination therapy with carfilzomib/PLEx/IVIG for AMR 
after lung transplantation and elucidate important clinical and immunologic phenotypes and 
mechanisms associated with these outcomes.  Thus, the results of this trial will advance treatment 
efforts for AMR, which are desperately needed, as well as provide important insights into the link 
between AMR and BOS, the latter of which significantly limits long-term outcomes in lung 
transplant recipients. Lastly, we fully anticipate this study will lay the foundation for future clinical 
and basic investigation, perhaps at the multi-center level, to further delineate the role and immune 
effects of carfilzomib in the treatment of AMR and the prevention of BOS. 
 
4 
STUDY DESIGN 
 
Phase II, prospective, open-label, single-arm active treatment, single center pilot clinical trial of 
the addition of carfilzomib to conventional therapy for AMR after lung transplantation.  
 
Study site: University of Pittsburgh Medical Center, Pittsburgh PA USA 
 
Conventional therapy for AMR:  Therapeutic plasma exchange (PLEX) 1.5 plasma volumes 
replaced with 5% albumin or fresh frozen plasma for 8 sessions every-other day.  Total 
intravenous immunoglobulins (IVIG) 100 mg/kg IV after each PLEX with the exception of the final 
PLEX where IVIG 500 mg/kg will be given. On day 16, if the IgG level is below 700 mg/dL, an 
additional dose of IVIG 500 mg/kg will be administered. If the IgG result is found to be 700ml/dL 
or higher, the  IVIG 500mg/kg dose will not be administered. Premedications will be given for IVIG 
as follows: acetaminophen 650 mg PO and diphenhydramine 25 mg PO both at least 30 minutes 
prior to and not more than 6 hours before IVIG, unless otherwise directed on the part of one of 
the investigators if believed to be in the best interests of patient care.  On days where IVIG and 
CFZ are given together, only one set of premedications will be administered. Conventional 
therapy requires an inpatient hospital stay.  Patients will receive a tunneled PLEX catheter and 
peripherally inserted central catheter (PICC) inserted by interventional radiology in the routine 
clinical care of these patients prior to receiving any conventional or carfilzomib therapy.  
 
Carfilzomib dosing schedule: Carfilzomib will be administered on the multiple myeloma schedule 
consisting of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 to constitute one therapeutic cycle.  On 
PLEX/IVIG days, carfilzomib will be given in between PLEX and IVIG to avoid inadvertent 
blockade of the Fcγ receptor.  Carfilzomib will be delivered via central access IV over 30 minutes 
(+15 minutes); slowed to 60 minutes (+15 minutes) if infusion reactions occur.  Carfilzomib will be 
diluted in a total of 80 mL dextrose 5% water (D5W) for administration.  Premedications for 
carfilzomib administration will be given as follows:  acetaminophen 650 mg PO, diphenhydramine 
25 mg PO, ondansetron 4 mg PO, prednisone 40 mg PO or methylprednisolone 40 mg IV, all at 
least 30 minutes prior to and not more than 6 hours before carfilzomib, unless otherwise directed 
on the part of one of the investigators if believed to be in the best interests of patient care.  
Preinfusion hydration with a one-time bolus of 250 mL 0.9% sodium chloride will be given at least 
30 minutes prior to and not more than 6 hours before carfilzomib to minimize the nephrotoxic AE.   
Postinfusion hydration with a one-time bolus of 250 mL 0.9% sodium chloride may be given 
immediately after carfilzomib to minimize the nephrotoxic AE 
 
 


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Molecule: Carfilzomib  
 
 
p. 17 of 48 
4.1  
Rationale 
 
Carfilzomib is marketed for multiple myeloma and this IST represents an off label use of 
carfilzomib; thus, the criteria for phase II designation have been met.  This prospective, open-
label, single-arm active treatment trial will establish the rate of response to carfilzomib (in addition 
to conventional therapy) for AMR after lung transplantation.  This information will be necessary 
for use in planning further larger dual-arm placebo or active therapy controlled clinical trials.  This 
trial will enroll 30 patients at the University of Pittsburgh Medical Center.  The volume of lung 
transplants performed and the rate of diagnosis of AMR at UPMC will allow for adequate 
enrollment of study patients within the 3-year study period.   
 
The dosing strategy of carfilzomib will follow that of the multiple myeloma schedule as described 
below in section 5.3.  This dosing strategy has been well-studied in patients with myeloma (see 
trial designations below) and has proven to result in an acceptable AE profile for the patients with 
AMR after lung transplantation. In addition, our preliminary off label experiences with this dosing 
strategy have yielded an acceptable AE profile in lung transplant recipients with AMR.  
 
Trial designations:  
Carfilzomib has been evaluated in 2 completed Phase 1 studies (PX-171-
001 and PX-171-002), 5 completed Phase 1b/2 studies (PX-171-003, PX-
171-004, PX-171-005, PX-171-006, and PX-171-008), and in 1 completed, 
Phase 2, expanded-access study (Study 2011-002, Carfilzomib Multiple 
Myeloma Expanded Access Protocol [C-MAP]) that was co-sponsored by 
Amgen and the Multiple Myeloma Research Foundation. 
 
Carfilzomib is currently being evaluated in 2 ongoing Phase 1 studies 
(CFZ001 [Renal] and CFZ002 [Hepatic]), 5 ongoing Phase 1b/2 studies 
(PX-171-007, 
PX-171-010, 
2012-002 
[CHAMPION 
1], 
2012-003 
[CHAMPION 2], and CFZ004 [small cell lung cancer]), 4 ongoing Phase 3 
studies 
(PX-171-009 
[ASPIRE], 
PX-171-011 
[FOCUS], 
2011-003 
[ENDEAVOR], and 2012-005 [CLARION]), and 2 ongoing Phase 1/2 
studies sponsored by Ono Pharmaceutical Co, Ltd in Japan (ONO-7057-
01 and ONO-7057-02). 
 
Data are available from the following 10 company-sponsored Phase 1,1b, 
and 2 studies: PX-171-001, PX-171-002, PX-171-003, PX-171-004, PX-
171-005, PX-171-006, PX-171-007, PX-171-008, PX-171-010 (ongoing), 
and 2012-002, (CHAMPION 1, ongoing). Of these, 9 studies enrolled 
multiple myeloma subjects. Study PX-171-007 also enrolled subjects with 
lymphoma and solid tumors. Study PX-171-008 enrolled solid tumor 
subjects only. Data also are available from a company-sponsored, Phase 
2, expanded-access study (Study 2011-002 [C-MAP]) and 2 ongoing 
Phase 1/2 Ono-sponsored studies (ONO-7057-01 and ONO-7057-02). 
Furthermore, after the IB data cutoff date of 10 July 2014, a pre-planned 
interim analysis was performed for the Phase 3 Study PX-171-009 
(ASPIRE) on 01 August 2014 and a final analysis was performed for the 
Phase 3 Study PX-171-011 (FOCUS) on 11 August 2014. 
 
Five Phase 3 studies have been or are being conducted. Safety and 
efficacy results are available for 2 completed studies, Study PX-171-009 
(ASPIRE) and Study PX-171-011 (FOCUS); subjects are still being 
followed for safety in both studies and for final OS in Study PX-171-009 


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p. 18 of 48 
(ASPIRE). 
Summaries 
for 
3 
ongoing 
studies, 
Study 
2011-003 
(ENDEAVOR), Study 2012-005 (CLARION), and Study CFZ014 
(A.R.R.O.W.) 
 
4.2 
Investigators  
 
 
Primary investigator: Dr. John McDyer (PI), Director of lung transplant translational research, 
Associate Professor of Medicine, works closely with Drs. Zeevi, and Morrell, as part of the 
DSA/AMR working group at UPMC, and is an expert in clinical lung transplantation, mechanisms 
of rejection, host defense and lung T cell immunity, and will lead Aim 3.  
 
Co-investigators: Dr. Adriana Zeevi, Professor of Pathology, Surgery and Immunology at the 
University of Pittsburgh and Director of the UPMC Tissue Typing Laboratory. She is an 
established NIH investigator and has published extensively in the area of anti-HLA antibodies and 
immune monitoring in solid organ transplants. Dr. Zeevi also works closely with Drs. McDyer, and 
Morrell as part of a DSA/AMR working group in LT at UPMC. All the assays proposed are available 
in her laboratory and she has extensive research resources and space to perform all the proposed 
studies. Dr. Matthew Morrell, Assistant Professor of Medicine, works closely with Drs. McDyer, 
and Zeevi on the DSA/AMR working group at UPMC, is an expert in clinical lung transplantation, 
and conducts excellent clinical science on the topic of DSA and lung transplant in the UPMC 
cohort. Dr. Joseph Pilewski, Associate Professor of Medicine. One of the focuses of his clinical 
interest is lung transplantation, with special interest in patients with suppurative lung diseases like 
CF.  He has been Medical Director of the Lung Transplant Program at the University of Pittsburgh 
Medical Center since 2004.  Dr. Bruce Johnson, Assistant Professor of Medicine. His practice 
focuses on the pre and post-transplant care of lung transplant recipients. He has been actively 
and continuously managing these patients since 1991 and is the senior clinician in lung 
transplantation at UPMC. Dr. Silpa Kilaru, Clinical Assistant Professor of Medicine. Her clinical 
interest is focused primarily on lung transplantation, namely taking care of patients both before 
and after lung transplant. She spent the majority of her time rotating on the inpatient lung 
transplant service, seeing patients in clinic, and serving as the attending in the bronchoscopy 
suite. Carlo Iasella, PharmD, BCPS and Cody A. Moore, PharmD, MPH, BCPS are transplant 
pharmacists assisting the PI with execution of the study. 
 
 
 
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 19 of 48 
Study definitions 
 
4.3.1 Antibody strength (MFI = mean fluorescent intensity by Luminex-IgG single antigen bead 
(SAB) assay). 
Low strength = MFI < 2000 units 
Moderate strength = MFI 2000-8000 units                    
High strength = MFI > 8000 units 
 
4.3.2 Antibody titer 
Low titer = MFI < 2000 units at 1:4 dilution 
High titer = MFI > 8000 units at 1:16 dilution 
 
4.3.3 Functional DSA phenotypes 
Complement fixing DSA = MFI > 500 units in neat serum by Luminex-C1q 
Non-complement fixing DSA = MFI < 500 units in neat serum by Luminex-C1q 
 
4.3.4 Kinetic DSA phenotypes 
Early DSA = present within 6 months post-transplant 
Late DSA = present after 6 months post-transplant 
 
4.3.5 Immunologic DSA phenotypes 
Memory response = sensitized pre-transplant with DSA pattern (MFI < 1000 units) 
de novo response =  not sensitized with no detectable pre-transplant DSA pattern  
 
4.3.6 Antibody-mediated rejection (AMR) diagnosis (must have first 2 criteria) 
1. Presence of DSA  
2. Allograft dysfunction (absence of another identifiable cause, except cellular rejection 
(ACR)) 
Fall of > 10% in FEV1, or 
Fall of > 30% in FEF 25/75, or  
New onset hypoxia/hypoxemia requiring supplemental oxygen, or 
Need for mechanical ventilation  
3. With or without pathologic findings consistent with AMR  
Capillaritis 
Endothelialitis 
C4d pericapillary deposition in > 50% of biopsy 
 
4.3.7 AMR phenotypes 
Probable AMR alone = DSA, allograft dysfunction, no AMR pathologic findings, ACR grade 
≤ A1 
 
Definite AMR alone = DSA, allograft dysfunction, AMR pathologic findings, ACR grade ≤ 
A1 
 
Mixed rejection = DSA, allograft dysfunction, with or without AMR pathologic findings, ACR 
grade ≥ A2 
 
4.3.8 Bronchiolitis obliterans syndrome (BOS) diagnosis24 
Baseline FEV1 defined as mean of 2 best FEV1 post-transplant 
BOS 0 = FEV1 > 80% of baseline 
BOS 0p = FEV1 81-90% of baseline and/or FEF25/75 ≤ 75% of baseline 


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Molecule: Carfilzomib  
 
 
p. 20 of 48 
BOS 1 = FEV1 66-80% of baseline 
BOS 2 = FEV1 51-65% of baseline 
BOS 3 = FEV1 ≤ 50% of baseline 
 
4.3.9 Hypogammaglobulinemia, total serum IgG < 700 mg/dL 
 
 
4.4  
Study Endpoints 
 
4.4.1 Primary endpoint 
 
The primary endpoint of this study is the absolute change in DSA strength, titer, and complement 
fixation from day 1 to day 42.  DSA strength will be determined by Luminex single-antigen bead 
testing in the neat serum and quantitated in units of mean fluorescent intensity.  DSA titer will be 
determined by Luminex single-antigen bead testing in the diluted serum to 1:16 and quantitated 
in units of mean fluorescent intensity.  DSA complement fixation will be determined by C1q-based 
Luminex single-antigen bead testing in the neat serum and quantitated in units of mean 
fluorescent intensity.   
 
A 1:1 retrospective control group including lung transplant recipients from the University of 
Pittsburgh with Antibody Mediated Rejection will be created to describe differences in the 
endpoints using the CFZ-based regimen vs. historic standard of care.  
 
4.4.2 Secondary endpoints 
 
Secondary endpoints of this study include the following:  
 
4.4.2.1 Absolute change in DSA strength, titer, and complement fixation from day 1 to day 90 and 
from day 42 to day 90.  DSA strength will be determined by Luminex single-antigen bead 
testing in the neat serum and quantitated in units of mean fluorescent intensity.  DSA titer 
will be determined by Luminex single-antigen bead testing in the diluted serum to 1:16 
and quantitated in units of mean fluorescent intensity.  DSA complement fixation will be 
determined by C1q-based Luminex single-antigen bead testing in the neat serum and 
quantitated in units of mean fluorescent intensity.   
 
4.4.2.2 Absolute change in forced expiratory volume in 1 second (FEV1) from day 1 to day 42 and 
to day 90.  FEV1 will be quantitated via UPMC PFT lab standard methods on routine 
pulmonary function testing obtained in the routine clinical care of these patients.   
 
4.4.2.3 Presence or absence of pathologic changes consistent with AMR on transbronchial biopsy 
from day 1 to day 42.  Pathologic changes consistent with AMR will be defined as follows: 
Complement-4d fixation on >50% (diffuse) of the capillaries in the biopsy by standard 
immunoperoxidase method, capillaritis by standard hematoxylin and eosin (H&E) stain; or 
endothelialitis by standard H&E stain.  
 
4.4.2.4 Patient death at any time after day 1 attributable to AMR.   
 
A 1:1 retrospective control group including lung transplant recipients from the University of 
Pittsburgh with Antibody Mediated Rejection will be created to describe differences in the 
endpoints using the CFZ-based regimen vs. historic standard of care.  
 


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p. 21 of 48 
 
4.4.3 Safety outcomes 
 
Safety outcomes of the study include the following:  
 
4.4.3.1 Non-lung irreversible end-organ failure (e.g., end-stage renal disease) any time after day 
1 attributable to carfilzomib.  
 
4.4.3.2 Incidence of adverse effects (AE) requiring dose-modification (see section 5.3.1.2) any 
time during days 1-16. 
 
4.4.3.3 Incidence of any AE at any time after day 1 as graded by the NIH Common Terminology 
Criteria for Adverse Events (CTCAE) (appendix B) criteria, as follows: 
 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL (Instrumental ADL refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.). 
  
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
(self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden).   
 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
 
  
Grade 5: Death related to AE. 
 
4.4.3.4 Incidence of hypogammaglobulinemia any time after day 1. 
 
4.4.3.5 Incidence of culture-proven de novo infection any time after day 1. 
 
4.4.3.6 Diagnosis of systemic inflammatory response syndrome (SIRS) any time during days 1-
16; requiring at least 2 of the following 4 criteria:  
 
 
Body temperature: < 36 or > 38 degrees Celsius  
 
 
Tachycardia: > 90 beats per minute  
 
 
Tachypnea: > 20 breaths per minute 
 
 
White blood cells: < 4000 or > 12000 cells/mm3  
 
4.4.3.7 Patient death at any time after day 1 attributable to carfilzomib.  
 
A 1:1 retrospective control group including lung transplant recipients from the University of 
Pittsburgh with Antibody Mediated Rejection will be created to describe differences in the 
endpoints using the CFZ-based regimen vs. historic standard of care.  
 
 


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Molecule: Carfilzomib  
 
 
p. 22 of 48 
4.4.4 Exploratory outcomes 
 
Exploratory outcomes of the study include the following: 
 
4.4.4.1 Identification of antibody producing cells (APCs) from peripheral blood mononuclear cells 
(PBMCs), such as activated B cells and plasmablasts in patients before and during 
carfilzomib therapy, compared to LTRs without AMR and not receiving carfilzomib.  This 
will be done using a combination of techniques including MHC class I and II tetramers, 
overlapping peptides to key MHC that are targeted by DSA responses, and an ELISPOT 
assay (so-called ex vivo studies). 
 
4.4.4.2 Expansion of B cells from PBMC using a cytokine/anti-CD40 ligand cocktail as well as 
EBV transformation. We will then determine whether these B cell stimuli lead to detectable 
levels of in vitro alloantibody (compared to serum anti-HLA Abs detected by the HLA 
laboratory). Using carfilzomib in vitro, we will also determine whether it decreases the 
expansion of these APCs and blocks alloantibody production. 
 
4.5 
Safety plan 
 
Patients will be enrolled according to the inclusion and exclusion criteria established in section 
5.3.  Patients will provide informed consent to participate in this clinical trial.  In the informed 
consent process, patients will be educated about the purpose for carfilzomib and the potential 
adverse effects as described in section 6.1.1.  Adverse effects will be recorded and graded 
according to the CTCAE as described above in section 4.4.3.  Serious adverse effects (SAE) will 
be reported timely as required and established in section 6.4. 
 
A study data safety monitoring board (DSMB) will be established consisting of 3 members who 
represent non-funded non-investigators with no conflicts of interest regarding carfilzomib or the 
IST funding agency.  The study investigators will invite qualified individuals to participate in the 
DSMB.  The DSMB members will possess either PharmD, PhD, or MD qualifications and have a 
working knowledge of lung transplantation and AMR.  The DSMB will be chaired by one of the 
three members as determined by the DSMB membership.  The DSMB will meet once yearly to 
review study progress, to ensure appropriate enrollment milestones are being met, and to review 
the adverse event reporting.  The DSMB will meet on an ad-hoc basis to review any SAEs.   
 
The DSMB may terminate the study only after at least 15 patients have been enrolled.  The DSMB 
may only terminate the study for safety reasons in which the perceived risks of continuing to 
provide carfilzomib to upcoming patients who may be enrolled outweighs the potential benefit to 
the patient and the allograft.  The DSMB may not terminate the study for any reason related to 
carfilzomib efficacy.   
 
4.6 
Ethical considerations 
 
There are no identifiable ethical considerations that would preclude the execution of this clinical 
trial.  Patients cannot receive placebo since this IST represents a single-arm active-treatment trial.   
 
 
 
 
 
 


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Molecule: Carfilzomib  
 
 
p. 23 of 48 
4.7 
Administrative structure 
 
The Division of Pulmonary, Allergy, and Critical Care Medicine within the University of Pittsburgh 
School of Medicine employs substantial research infrastructure to successfully execute this IST.  
This infrastructure constitutes the UPMC Pulmonary Research Core.  Working with the University 
of Pittsburgh Office of Research who will coordinate the expenditure of research funds and the 
execution of trial contracts, the research core will be responsible for all clinical trial interventional 
and regulatory support.   
 
4.7.1 UPMC Pulmonary research core 
 
The UPMC Pulmonary Research Core will be responsible for the support of this IST.  The 
research core study coordinator will be alerted by one of the investigators of a patient who will be 
enrolled in the study.  This coordinator will execute all paperwork required for enrollment in the 
clinical trial, establish patient linkage codes, support the data collection required by the IST, and 
collect any study blood obtained outside the routine clinical care of the patient, such as blood for 
PBMC isolation to support the exploratory outcomes.  
 
4.7.2 Data management plan 
 
All study data will be collected using REDcap.  The pulmonary research core study nursing staff 
will be responsible for entering all data to be collected as required by this IST.  This database will 
only contain linkage codes to identify the study patients.  A separate file containing the protected 
health information of the study participants along with their linkage codes will be maintained.  
These files will be stored on secured research servers behind the University of Pittsburgh’s 
research firewall.  Data will only be accessible by protected passwords by study investigators and 
support personnel.   
 
4.7.3 Investigational drug pharmacy 
 
All study drug will be prepared and dispensed by the University of Pittsburgh Investigational Drug 
Service in accordance with the drug handling and dispensing practices outlined in appendix C.  
The investigational drug service charges a dispensing fee associated with each dose in the drug 
cycle.  This fee is included in the study budget.  
 
4.8  
Compliance with laws and regulations and the institutional review board 
 
This study will be conducted in accordance with the U.S. Food and Drug Administration (FDA) 
regulations, the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical 
Practice (GCP), and all applicable local, state, and federal laws.   
 
This study will undergo full prospective institutional review board (IRB) evaluation by the 
University of Pittsburgh IRB prior to any patient enrollment to ensure scientific merit and all 
appropriate patient protections and information protections are in place.   
 
 
 
 
 
 
 


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Molecule: Carfilzomib  
 
 
p. 24 of 48 
5 
Materials and methods 
 
5.1  
Patients 
 
5.1.1 Patient selection 
 
Patients will be eligible for enrollment if they have met the diagnostic criteria for AMR as described 
in section 4.3.6.  This involves the identification of DSA via Luminex SAB technology prior to day 
1.  Any patient who meets the diagnostic criteria after study initiation will be screened for 
enrollment.  Patients who satisfy the inclusion and exclusion criteria will be approached to provide 
informed consent and enroll in the study.   
 
A 1:1 retrospective control group including lung transplant recipients from the University of 
Pittsburgh with Antibody Mediated Rejection will be created to describe differences in the 
endpoints using the CFZ-based regimen vs. historic standard of care.  
 
5.1.2 Inclusion criteria 
 
Adult lung transplant recipients ≥ 18 years of age who meet the diagnostic criteria for AMR as 
described in 4.3.6 who have underwent PFT testing unless intubated and transbronchial biopsy 
prior to enrollment.  Patients who have not experienced improvement or regression are 
candidates for a second cycle of therapy on the protocol. 
 
5.1.3 Exclusion criteria  
 
Study exclusion criteria are as follows: 
 
5.1.3.1 Exclusion related to disease 
 
Direct contraindications or previous intolerances to any component of the standard of care 
regimen including PLEX, 5% human albumin, 5% gammagard S/D or 10% gammagard liquid 
 
5.1.3.2 Exclusion related to general health 
 
Leukopenia defined as WBC < 2000  
Neutropenia defined as ANC < 1000  
Thrombocytopenia defined as platelets < 75000 x 106  
Known Child-Pugh B/C cirrhosis  
Total bilirubin > 4  
ALT > 90  
Known systolic heart failure with LVEF < 40% 
Known pulmonary hypertension 
Any uncontrolled comorbid condition  
Pregnant women (negative serum pregnancy test required within 7 days prior to study drug 
administration for women of childbearing potential) 
Breastfeeding women 
 
5.1.3.3 Exclusion related to risk for infections 
 
Ongoing bacterial or fungal or viral infection that is life-threatening 
Active cytomegalovirus disease 


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Molecule: Carfilzomib  
 
 
p. 25 of 48 
Active varicella zoster infection 
 
5.1.3.4 Exclusion related to medications 
 
Previous intolerance to carfilzomib 
Concurrent use of another proteasome inhibitor (e.g., bortezomib) 
 
 
5.2 
Treatment assignment  
 
This is an open-label single-arm active-treatment study; thus, patients will be assigned to 
carfilzomib therapy in the order in which they are enrolled.  
 
5.3 
Study treatment 
 
Conventional therapy for AMR:  Therapeutic plasma exchange (PLEX) 1.5 plasma volumes 
replaced with 5% albumin or fresh frozen plasma for 8 sessions every-other day.  Total 
intravenous immunoglobulins (IVIG) 100 mg/kg IV after each PLEX with the exception of the final 
PLEX where IVIG 500 mg/kg will be given.  On day 16, if the IgG level is below 700 mg/dL, an 
additional dose of IVIG 500 mg/kg will be administered.  If the IgG result is found to be 700ml/dL 
or higher, the  IVIG 500mg/kg dose will not be administered.  Premedications will be given for 
IVIG as follows: acetaminophen 650 mg PO and diphenhydramine 25 mg PO both at least 30 
minutes prior to and not more than 6 hours before IVIG, unless otherwise directed on the part of 
one of the investigators if believed to be in the best interests of patient care.  On days where IVIG 
and CFZ are given together, only one set of premedications will be administered. Conventional 
therapy requires an inpatient hospital stay.  Patients will receive a tunneled PLEX catheter and 
peripherally inserted central catheter (PICC) inserted by interventional radiology in the routine 
clinical care of these patients prior to receiving any conventional or carfilzomib therapy.  
 
Conventional therapy rationale: PLEX serves two important roles in this regimen: first, to remove 
circulating injurious DSA, and second, to turn on the plasma cell apparatus due to depletion in 
order to enhance selection of highly active cells by the proteasome inhibitor.  IVIG also serves 
two purposes: first, to provide putative Ig replacement to decrease infectious complications from 
PLEX, and second, to blunt the rebound antibody response due to depletion.  Investigational 
carfilzomib will be given to enrolled patients between PLEX and IVIG on PLEX days, and alone 
on non-PLEX days.  The rationale to insert carfilzomib between PLEX and IVIG is to avoid any 
derangements to the Fcγ receptor (FcγR) by IVIg and allow carfilzomib unfettered access to the 
highly active plasma cells. 
 
5.3.1 Investigational therapy 
 
Carfilzomib (in addition to conventional therapy).  Please refer to appendix D, investigators 
brochure for additional information regarding carfilzomib and clinical trial data.  
 
5.3.1.1 Dosage, administration, and storage 
 
Carfilzomib dosing schedule: Carfilzomib will be administered on the multiple myeloma schedule 
consisting of 20 mg/m2 on days 1 2, 8, 9, 15, and 16 (one cycle) to constitute one therapeutic 
cycle.  On PLEX/IVIG days, carfilzomib will be given in between PLEX and IVIG to avoid 
inadvertent blockade of the Fcγ receptor.  Carfilzomib will be delivered via central access IV over 
30 minutes (+15 minutes); slowed to 60 minutes (+15 minutes) if infusion reactions occur.  


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 26 of 48 
Carfilzomib will be diluted in a total of 80 mL dextrose 5% water (D5W) for administration.  
Premedications for carfilzomib administration will be given as follows:  acetaminophen 650 mg 
PO, diphenhydramine 25 mg PO, ondansetron 4 mg PO, prednisone 40 mg PO or 
methylprednisolone 40 mg IV, all at least 30 minutes prior to and not more than 6 hours before 
carfilzomib, unless otherwise directed on the part of one of the investigators if believed to be in 
the best interests of patient care.  Preinfusion hydration with a one-time bolus of 250 mL 0.9% 
sodium chloride will be given at least 30 minutes prior to and not more than 6 hours before 
carfilzomib to minimize the nephrotoxic AE.   Postinfusion hydration with a one-time bolus of 250 
mL 0.9% sodium chloride may be given immediately after carfilzomib to minimize the nephrotoxic 
AE 
 
Carfilzomib may be administered for 1-2 complete cycles in the study. A second cycle may be 
given for lack of resolution of AMR or for continued detection of DSA in the absence of allograft 
improvement.  If > one cycle is needed, the patient must still meet the enrollment criteria prior to 
the second cycle, and must not have had improvement after the first cycle or have experienced 
regression from initial improvement to qualify for a second study cycle.  If > two cycles are desired, 
these must be given outside of the study.  If > two cycles are desired, the third cycle must not be 
given within 90 days of day 1 of the first cycle.  If the third cycle begins within this 90 day period, 
this will constitute a protocol violation.  
 
5.3.1.2 Dosage modification for drug related toxicity 
 
AES grade III or IV that have not reduced to grade II or less at the time that the next dose 
is due and are considered related to the study drug will be subject to dose modification 
or hold.   
 
Toxicity 
Parameters
Dose adjustment
Neutropenia 
ANC < 1000 
Withhold dose until > 1000 and reduce next 
scheduled dose from 20 mg/m2 to 15 mg/m2  
If reduced dose tolerated, dose may be escalated 
back to 20 mg/m2 at the discretion of the 
investigators.
Thrombocytopenia 
< 50,000 
Reduce next scheduled dose from 20 mg/m2 to 
15 mg/m2 
If reduced dose tolerated, dose may be escalated 
back to 20 mg/m2 at the discretion of the 
investigators.
< 25,000 
Withhold dose until > 25,000 and reduce next 
scheduled dose to 15 mg/m2 
If reduced dose tolerated, dose may be escalated 
back to 20 mg/m2 at the discretion of the 
investigators.
Peripheral neuropathy 
Affecting ADLs 
Hold until resolved to baseline and reduce next 
scheduled dose to 15 mg/m2 
If reduced dose tolerated, dose may be escalated 
back to 20 mg/m2 at the discretion of the 
investigators.
Nephrotoxicity 
SCr > 2 x baseline 
or eGFR reduced 
by 50% 
Hold until resolved to baseline and reduce next 
scheduled dose to 15 mg/m2 
If reduced dose tolerated, dose may be escalated 
back to 20 mg/m2 at the discretion of the 
investigators.


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 27 of 48 
Hepatotoxicity 
 
 
 
 
Mild to moderate 
liver dysfunction: 
defined as 2 
consecutive values, 
at least 28 days 
apart, of: 
(1) Total Bili (>33% 
direct) . 1x ULN 
to < 3xULN 
 
OR 
 
(2) An elevation of 
AST and/or ALT 
with normal 
bilirubin Grade 
3 elevation in 
ALT and/or AST 
(>5xULN) 
 
Grade 3 elevation 
in total bilirubin 
 
 
 
 
 
Drug-Induced 
hepatotoxicity 
(attributable to 
carfilzomib 
 
25% dose reduction. 
Dose may be re-escalated if liver function tests 
return to normal (baseline) and drug-induced 
hepatotoxicity is excluded. 
 
 
 
 
 
Hold until resolved to baseline. Monitor any 
abnormality weekly. Resume carfilzomib with a 
25% dose reduction (15 mg/m2 ) if drug-induced 
hepatotoxicity is excluded. If reduced dose 
tolerated, dose may be escalated back to 20 
mg/m2 at the discretion of the investigators. 
 
 
 
Hold Carfilzomib until resolution to baseline. 
Monitor total bilirubin and direct bilirubin weekly. 
Upon resolution of total bilirubin to normal, 
resume carfilzomib dosing with a 25% dose 
reduction if drug-induced hepatotoxicity is 
excluded. 
 
 
 
 
Discontinue carfilzomib. 
Posterior Reversible 
Encephalopathy Syndrome 
(PRES)  
 
If PRES is suspected, hold carfilzomib. Consider 
evaluation with neuroradiological imaging, 
specifically MRI, for onset of visual or neurological 
symptoms suggestive of PRES. If PRES is 
confirmed, permanently discontinue carfilzomib. If 
the diagnosis of PRES is excluded, carfilzomib 
administration may resume at same dose, if 
clinically appropriate.  
Thrombotic 
Microangiopathy (TMA) 
 
If the diagnosis is suspected, hold treatment and 
manage per standard of care including plasma 
exchange as clinically appropriate. If TMA is 
confirmed and related to carfilzomib or 
pomalidomide, permanently discontinue drug 
treatment. If the diagnosis of TMA is excluded, 
treatment may resume if clinically appropriate.  
Other grade 3 or 4 toxicity 
(considered related to study 
drug) 
 
Hold until resolved to baseline and reduce next 
scheduled dose to 15 mg/m2 
If reduced dose tolerated, dose may be escalated 
back to 20 mg/m2 at the discretion of the 
investigators.
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 28 of 48 
 
5.3.2 Concomitant therapy 
 
Conventional therapy for AMR:  Therapeutic plasma exchange (PLEX) 1.5 plasma volumes 
replaced with 5% albumin or fresh frozen plasma for 8 sessions every-other day.  Total 
intravenous immunoglobulins (IVIG) 100 mg/kg IV after each PLEX with the exception of the final 
PLEX where IVIG 500 mg/kg will be given. On day 16, if the IgG level is below 700 mg/dL, an 
additional dose of IVIG 500 mg/kg will be administered.  If the IgG result is found to be 700ml/dL 
or higher, the  IVIG 500mg/kg dose will not be administered.  Premedications will be given for 
IVIG as follows: acetaminophen 650 mg PO and diphenhydramine 25 mg PO both 30 minutes 
prior to IVIG, unless otherwise directed on the part of one of the investigators if believed to be in 
the best interests of patient care.  Conventional therapy requires an inpatient hospital stay.  
Patients will receive a tunneled PLEX catheter and peripherally inserted central catheter (PICC) 
inserted by interventional radiology in the routine clinical care of these patients prior to receiving 
any conventional or carfilzomib therapy.  
 
Contraception 
 
Female: 
Women of childbearing potential must either agree to abstain from sexual intercourse or use an 
effective birth control method during treatment with carfilzomib.  Given that carfilzomib was 
clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes, as a 
precaution, females of childbearing potential and/or their male partners should use effective 
contraception methods or abstain from sexual activity during and for 30 days after treatment 
with carfilzomib. If pregnancy occurs during this time, patients should be apprised of the 
potential hazard to the fetus. Kyprolis (carfilzomib) should only be used during pregnancy if the 
potential benefits to the mother outweigh the potential risks to the fetus. 
 
Based on its mechanism of action and findings in animals, carfilzomib can cause fetal harm 
when administered to a pregnant woman. Carfilzomib caused embryo‐fetal toxicity in pregnant 
rabbits at doses that were lower than in subjects receiving the recommended dose. Carfilzomib 
administered to pregnant rats and rabbits during the period of organogenesis was not 
teratogenic at doses up to 2 mg/kg/day in rats or up to 0.8 mg/kg/day in rabbits. If carfilzomib is 
used during pregnancy, or if the subject becomes pregnant while taking this drug, she should 
inform the investigator or study staff immediately. The investigator should notify Amgen of the 
pregnancy and discuss follow‐up with the subject. It is not known if carfilzomib will reduce the 
efficacy of oral contraceptives. Due to an increased risk of venous thrombosis associated with 
carfilzomib, subjects currently using oral contraceptives or a hormonal method of contraception 
associated with a risk of thrombosis should consider an alternative method of effective 
contraception. 
 
Male:  
Males of reproductive potential should be advised to avoid fathering a child while being treated 
with carfilzomib. The potential for carfilzomib to be transferred via semen and its effect on sperm 
are unknown. Male subjects treated with carfilzomib and/or their female partners (if of 
childbearing potential) should use effective contraceptive methods or abstain from sexual 
activity while treated with carfilzomib and refrain from donating sperm while on carfilzomib and 
for 90 days after treatment. If pregnancy occurs during this time, patients should be apprised of 
the potential hazard to the fetus, study drug should be interrupted, and a serum pregnancy test 


Pr ot oc ol:  PI C A R D‐ A M R  
M ol ec ul e:  C arfilz o mi b  
  
  
p. 2 9 of 4 8 
p erf or m e d. St u d y dr u g a d mi ni str ati o n m a y r e s u m e if r e s ult i s n e g ati v e a n d st u d y dr u g b e 
di s c o nti n u e d, if p o siti v e.   
 
M al e s u bj e ct s s h o ul d b e a d vi s e d t o i nf or m t h e i n v e sti g at or or s t u d y st aff i m m e di at el y i n t h e e v e nt 
t h at t h eir f e m al e p art n er b e c o m e s pr e g n a nt d uri n g t h e st u d y. U po n r e c ei pt of t hi s i nf or m ati o n, t h e 
i n v e sti g at or s h o ul d n otif y A m g e n of t h e pr e g n a n c y a n d di s c u s s foll o w ‐u p r e g ar di n g t h e pr e g n a n c y 
o ut c o m e wit h t h e s u bj e ct. 
 
Br e a stf e e di n g:  
If a w o m a n br e a stf e e d s d uri n g t h e st u d y, s h e m u st i nf or m t h e i n v e sti g at or or st u d y st aff 
i m m e di at el y. T h e i n v e sti g at or s h o ul d n otif y A m g e n t h at t h e s u bje ct h a s br e a stf e d t h e 
i nf a nt a n d di s c u s s f oll o w‐u p wit h t h e s u bj e ct. 
 
It i s n ot k n o w n w h et h er K y pr oli s i s pr e s e nt i n h u m a n br e a st milk.  D u e t o t h e p ot e nti al 
f or a d v er s e eff e ct s i n n ur si n g i nf a nt s fr o m c arfil z o mi b, a d e cisi o n s h o ul d b e m a d e 
w h et h er t o di s c o nti n u e n ur si n g or t o di s c o nti n u e K y pr oli s, t a ki n g i nt o a c c o u nt t h e 
p ot e nti al b e n efit of c arf il z o mi b t o t h e m ot h er. 
 
N o st u di e s of c arfil z o mi b h a v e b e e n c o n d u ct e d i n br e a stf e e di n g w o m e n. C arfil z o mi b  
s h o ul d n ot b e u s e d d uri n g br e a stf e e di n g. Br e a stf e e di n g w o m e n a n d w o m e n pl a n ni n g o n 
br e a stf e e di n g m a y n ot p arti ci p at e i n cli ni c al tri al s wit h c arfil z o mi b.  
 
 
A W o m a n of C hil d b e ari n g P ot e nti al ( W O C B P) 
A n y  f e m al e  w h o  h a s  e x p eri e n c e d  m e n ar c h e  a n d  i s  n ot  p o st m e n o p a u s al  (i. e.,  h a s  h a d 
m e n s e s at a n y ti m e i n t h e pr e c e di n g 1 2 c o n s e c uti v e m o nt h s).    
 
Hi g hl y eff e cti v e m et h o d of c o ntr a c e pti o n / birt h c o ntr ol i n cl u d e:   
 C o m bi n e d ( e str o g e n a n d pr o g e st o g e n) h or m o n al m et h o d s: pill s, v a gi n al ri n g, or s ki n p at c h 
 Si n gl e h or m o n al m et h o d s ( pr o g e st o g e n) t o st o p r el e a s e of t h e e g g fr o m t h e o v ar y: 
    [ pill s, s h ot s/i nj e cti o n s, i m pl a nt s ( pl a c e d u n d er t h e s ki n by a h e alt h c ar e pr o vi d er)] 
 I ntr a ut eri n e d e vi c e (I U D) 
 I ntr a ut eri n e h or m o n al-r el e a si n g s y st e m (I U S) 
 S ur g er y t o ti e b ot h f all o pi a n t u b e s ( bil at er al t u b al li g ati o n/ o c cl u si o n) 
 Y o ur m al e p art n er h a s h a d a v a s e ct o m y a n d t e sti n g s h o w s t h er e i s n o s p er m i n t h e s e m e n 
 S e x u al a b sti n e n c e ( n ot h a vi n g s e x) 
 
B arri er C o ntr a c e pti v e a s d efi n e d i n I C H ( M 3)  
A c o ntr a c e pti v e d e vi c e t h at p h y si c all y pr e v e nt s s p er m fr o m e nt e ri n g t h e e n d o m etri al c a vit y a n d 
f all o pi a n t u b e s ( e. g. m al e c o n d o m, f e m al e c o n d o m or di a p hr a g m).   
 
5. 3. 3  E x cl u d e d t h er a p y 
 
T h e f oll o wi n g m e di c ati o n s m u st b e di s c o nti n u e d pri or t o e nr oll m e nt:  
E c uli z u m a b ( S oliri s) 
Rit u xi m a b ( Rit u x a n) 
C y cl o p h o s p h a mi d e I V ( C yt o x a n) 
 
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 30 of 48 
5.4 
Study assessments 
 
See appendix B for full listing of study data collection.  
 
Study therapy will be given as an inpatient.  Screening patients for AMR as defined above in 
section 4.3 for enrollment in the trial may occur as an inpatient or outpatient.  Patients will undergo 
a minimum 16 day hospitalization for conventional AMR therapy and for study carfilzomib.  
Patients may return to the clinic for standard of care visits on days 28 and 42 and 90 (2 and 4 and 
10 weeks post therapy completion) for assessment as described below. 
 
Patients will be followed in the study until day 90.  There are no follow-up visits as part of this 
research study, however, if patients return to their standard of care routine visits, a medical 
record review will be performed to obtain this data from patients’ medical records, whenever 
available. Patients will be subsequently followed by their treating physician under routine clinical 
care for recurrent AMR until they expire and any available clinical information related to their 
standard lung transplant care will be obtained from medical records up to 360 days. 
 
For patients who prematurely discontinue therapy, all future planned study and routine clinical 
care assessments will be completed unless the patient expires.  An assessment for the purpose 
for premature discontinuation will be taken at the time of study discontinuation.  
 
The University of Pittsburgh laboratories will be used to assess all samples.  DSA samples will be 
processed by the University of Pittsburgh Histocompatibility Lab under the direction of co-
investigator Dr. Zeevi.  PBMC isolation, and exploratory testing samples will be process by the 
research lab of co-principal investigator Dr. McDyer. 
  
5.4.1 Definition of study assessments 
 
Standard of Care procedures:  
 
History and Physical Exam: A complete patient history and physical exam includes the evaluation 
of the head, ears, eyes, nose, and throat (HEENT), cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Changes from baseline 
abnormalities will be recorded at each subsequent physical examination.  New or worsened 
abnormalities will be recorded as AEs if deemed to be related to study therapy.   
 
Complete blood count: white blood cell count, hemoglobin, hematocrit, and platelet count. 
WBC differential: absolute neutrophil, lymphocyte, eosinophil, and monocyte counts. 
 
Complete metabolic panel (CMP): sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
serum creatinine, glucose, calcium, magnesium, phosphorus, AST, ALT, Alkaline phosphatase, 
and total bilirubin levels.  
 
Pulmonary function tests: forced expiratory volume in 1 second, forced vital capacity, forced 
expiratory flow. 
 
Biopsy: transbronchial forceps biopsy.  
 
Luminex SAB: whole blood draw for processing by the HLA lab.  
 
Luminex C1q-SAB: whole blood draw for processing by the HLA lab.  


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 31 of 48 
 
Complement 3 and 4: whole blood draw for processing by the UPMC basic laboratory. 
 
Research Procedures: 
 
Pregnancy test: all women of childbearing potential will have a serum pregnancy test within 7 
days prior to study drug administration.  
 
 Total IgG and IgG subclasses: whole blood draw for processing by the HLA lab. This samples 
will only be obtained if patient is coming to their standard of care visit on days 28, 42 and 90 
(±14 days). 
 
Blood for PBMC: whole blood draw for processing by the McDyer lab. This sample will only be 
obtained if patient is coming to their standard of care visit on days 28, 42 and 90 (±14 days). 
 
 
5.5 
Screening and pretreatment assessments 
 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before the first infusion of carfilzomib. Written informed consent for participation 
in the study must be obtained before performing any study-specific screening tests or evaluations.  
Informed consent forms will be maintained at the study site.  Refer to Section 4, table 4 for specific 
delineations.  
 
5.6 
Assessments during treatment 
 
All visits must occur within ± 14 days of the scheduled data, unless otherwise noted.  Assessments 
scheduled on the day of study drug administration should be performed prior to study drug 
infusion, unless otherwise noted.  We will collect results from medical records from procedures 
done as Standard of Care (biopsies, PFTs, bronchoscopies, physical exam, lab results, PLEX 
and IVIG). Standard of Care procedures will not be done solely for research purposes.  
 
5.7 
Study completion 
 
Patients discontinued from the study early (dropout) will be asked to return to the clinic within 30 
days after the last infusion of carfilzomib for a follow-up visit.  
 
5.8 
Follow-up assessments  
 
Ongoing AEs thought to be related to carfilzomib will be followed until the event has resolved to 
baseline, the event is assessed by the investigators to be stable, the patient is lost to follow up, 
the patient withdraws consent, or when it is determined the AE is not related to study drug.  
 
5.9 
Patient discontinuation 
 
Patients will be removed from study continuation if the toxicities of therapy are deemed by the 
investigators to outweigh the potential benefit of therapy.  Such toxicities may include severe 
thrombocytopenia (platelets < 10,000 x 106), acute kidney injury requiring renal replacement 
therapy, or severe hepatitis (ALT > 1000), or others deemed relevant to the individual patient by 
the investigators.  
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 32 of 48 
If patients discontinue study drug early, these patients may be replaced in the study by patients 
who are likely to complete at least 1 cycle of carfilzomib.  
 
The investigators have the right to discontinue a patient from the study for any medical condition 
that the investigator determines may jeopardize the patient’s safety if he or she continues in the 
study or if the investigator determines discontinuation is in the best interest of the patient.  
 
5.10 
Study discontinuation  
 
Amgen may discontinue the study prematurely for the following reasons:  the incidence or severity 
of AEs in this study indicates a potential serious health hazard to patients, if enrollment is 
sufficiently poor, or if data recording is inaccurate or incomplete.  
 
 
5.11 
Post-trial access 
 
No post-trial access of carfilzomib will be available to patients under the auspices of the study.  
Additional off label marketed carfilzomib may be given to patients outside of the study if necessary 
under the routine clinical care of the patient; however, such administration must not occur before 
day 90.  If such administration occurs prior to day 90, this will reflect a protocol violation.  
 
5.12 
Assay methods 
 
All blood draws will be acquired with usual clinical techniques.  Luminex SAB and C1q-SAB and 
IgG subclass identification will be performed using usual clinical techniques as directed by the 
HLA lab under the CLIA approved standard practice.  All routine labs (CBC, WBC differential, 
CMP) will be performed using usual clinical techniques as directed by the basic laboratory under 
the CLIA approved standard practice.  PBMC isolation and subsequent exploratory testing will 
occur under usual investigatory techniques as directed by Dr. McDyer.  
 
5.13 
Statistical methods 
 
Data will only be analyzed in aggregate at study conclusion for the final enrolled patient on the 
efficacy and safety outcomes.   
 
Descriptive statistics will be used to describe baseline and study characteristics of patients.  
Univariate parametric and nonparametric assessments, where appropriate, will be used to assess 
change from baseline in the efficacy and safety outcomes.  Kaplan-Meier method will be used to 
describe freedom from endpoints and mortality in the patients treated with carfilzomib.  Kaplan-
Meier method will be used to visually represent the time to events and overall event rate in the 
patients in this pilot, not to compare events to any other group.  
 
5.13.1 Analysis of the conduct of the study 
 
Enrollment, protocol violations, and discontinuations from the study will be summarized by patient.  
 
Demographic and baseline characteristics will be summarized using means, standard deviations, 
medians, interquartile ranges.  All summaries will be presented by group.  
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 33 of 48 
Study drug administration data will be listed by dose level, and any dose modifications will be 
flagged.  Means and standard deviations will be used to summarize the total dose of carfilzomib 
received.  All summaries will be presented by group.  
 
5.13.2 Safety analyses 
 
All AE data will be listed by patient, cycle, and dose.  All AE occurring after informed consent is 
given will be summarized by event, system, and grade.  All SAE will be listed and summarized 
separately.  
 
5.13.3 Determination of sample size 
 
The sample size for this trial is based on perceived appropriate enrollment of 10 patients per year 
for 3 consecutive years.  Since this is a single-arm, active-treatment study, no such calculation of 
statistical power is needed to quantitate the sample size.  
 
5.14 
Data quality assurance  
 
The Pulmonary Research Core will be responsible for data management of this trial, including 
quality checking of the data.  Data will be collected and aggregated in REDCap.  Investigators 
and support personnel from the research core will be responsible for entering the needed data 
into REDCap.  In the event of discrepant data, clarification will be performed by the primary 
investigators.  
 
6 
Assessment of safety 
 
Safety assessments will consist of monitoring and recording adverse events (AE) and serious 
adverse events (SAE) as defined in this section; measurement of protocol-specified hematology 
and basic chemistry laboratory values, measurement of protocol-specified vital signs, and other 
non-protocol specific tests that are deemed critical to the safety evaluation of the patient.   
 
Investigators are responsible for reporting any SAE to Amgen as described below. Amgen will be 
responsible for reporting SAEs to the appropriate regulatory body.   
 
 
 
6.1 
Possible risks and discomforts 
 
6.1.1 Carfilzomib Risks 
 
Carfilzomib is approved by the U.S. Food and Drug Administration (FDA) to be used only in certain 
U.S. patients with relapsed and refractory multiple myeloma that have tried and failed other 
therapies. It has not been approved to be used for any other disease or condition. In this study, 
carfilzomib is an investigational study drug because it is not approved for use in all patients in the 
United States, and it is not approved by some regulatory authorities (the agencies that are 
responsible for approving the use of a medicine in a country such as the European Medicines 
Agency and Health Canada).  
 
 
 
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 34 of 48 
6.1.2 Adverse effect (AE) definition 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporarily associated with 
the use of an investigational medicinal product or other protocol-imposed intervention, regardless 
of attribution.  
 
This includes the following:  
 
AEs not previously observed in the patient that emerge during carfilzomib therapy (days 
1through 16, and 28, 42, 90), including signs or symptoms associated with AMR that were 
not present prior to the AE reporting period.  
 
Complications that occur as a result of protocol-mandated interventions. 
 
AEs that occur prior to the assignment of study treatment that are related to a protocol-
mandated intervention.  
 
Preexisting conditions judged by the investigators to have worsened in severity or 
frequency or changed in character during carfilzomib therapy (days 1through 16, and 28, 
42, 90). 
 
6.1.3 Serious adverse effect (SAE) definition 
 
Death 
 
Life threatening experience defined as any adverse experience that places the subject, in 
the view of the Investigator, at immediate risk of death at the time of occurrence; i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Requires prolongation of the study hospitalization. 
 
Results in persistent or significant disability/incapacity. 
 
Congenital anomaly/birth defect in the offspring of an exposed subject. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE, when, based upon appropriate medical 
judgment, it jeopardizes the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
All AEs that do not meet these criteria should be regarded as non-serious AEs.  
 
The terms serious and severe are not synonymous. Severity refers to the intensity of an 
AE; thus, severe AEs may not represent serious AEs. SAEs include only the above items 
that are based on patient or event outcome or action criteria associated with events that 
pose a threat to the patient’s life or vital functions and require reporting to appropriate 
regulatory agencies as defined in this section.  
 
 
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 35 of 48 
6.1.4 
All previously reported AEs related to carfilzomib from clinical trials 
 
 
Organ system 
All adverse reactions, 
frequency (%) 
Grade 3 and above 
adverse reactions, 
frequency (%) 
Serious adverse 
reactions, 
frequency (%) 
Blood and lymphatic system disorders 
Anemia 
45.9 
22.5 
1.9 
Thrombocytopenia 
34.9 
23.2 
1.6 
Neutropenia 
23.8 
15.7 
0.6 
Lymphopenia 
12.5 
9.9 
‐ 
Leukopenia 
10.2 
4.3 
0.1 
Febrile neutropenia 
2.2 
1.8 
1.6 
Cardiac disorders 
Cardiac failure 
4.4 
2.9 
2.8 
Myocardial infarction 
0.8 
0.6 
0.6 
Cardiac arrest 
0.6 
0.6 
0.6 
Myocardial ischemia 
0.4 
0.3 
0.3 
Eye disorders 
Vision blurred 
5.1 
< 0.1 
‐ 
Cataract 
2.6 
1 
0.1 
Gastrointestinal disorders 
Diarrhea 
33.7 
2.3 
0.8 
Nausea 
31.9 
0.9 
0.1 
Constipation 
18.5 
0.2 
‐ 
Vomiting 
17.1 
0.6 
0.2 
Abdominal pain 
10.6 
1.2 
0.6 
Dyspepsia 
5.8 
0.1 
‐ 
Toothache 
2.5 
0.1 
‐ 
General disorders and administration site conditions 
Fatigue 
43.6 
5.9 
< 0.1 
Pyrexia 
28.2 
1.6 
2.9 
Edema 
21.8 
0.6 
< 0.1 
Asthenia  
12 
1.6 
0.3 
Chills 
10.6 
0.1 
0.1 
Pain 
7 
1.3 
0.6 
Multiorgan failure 
0.5 
0.5 
0.4 
Infusion site reactions 
0.2 
‐ 
‐ 
Hepatobiliary disorders 
Hepatic failure 
0.1 
< 0.1 
< 0.1 
Infections and infestations 
Respiratory tract 
infection 
26.2 
3.1 
2 
Pneumonia 
12.5 
9.3 
9.7 
Nasopharyngitis 
9.9 
< 0.1 
< 0.1 
Bronchitis 
7.3 
1 
1.1 
Urinary tract infection 
7 
1.3 
0.9 


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Molecule: Carfilzomib  
 
 
p. 36 of 48 
Influenza 
3.7 
0.3 
0.4 
Sepsis 
1.8 
1.7 
1.5 
Viral infection 
1.7 
‐ 
< 0.1 
Investigations 
Increased blood 
creatinine 
15.6 
2.3 
0.5 
Decreased creatinine 
clearance 
1.8 
0.2 
‐ 
BUN increased 
3.4 
1.1 
‐ 
AST increased 
6.8 
2 
0.1 
ALT increased 
6 
2.4 
0.1 
C‐reactive protein 
1.3 
0.3 
‐ 
Metabolism and nutrition disorders 
Hypokalemia 
15.8 
4.7 
0.3 
Decreased appetite  
15.1 
0.3 
‐ 
Hyperglycemia 
13.3 
4.3 
0.3 
Hypomagnesemia  
10.2 
0.6 
‐ 
Hypocalcemia 
9.7 
2.4 
0.2 
Hypophosphatemia 
9.4 
5.6 
< 0.1 
Hyponatremia 
7.7 
4.3 
0.3 
Hypercalcemia 
7.3 
2.7 
1.9 
Hyperuricemia 
5.9 
1.5 
‐ 
Hyperkalemia 
5.1 
1.4 
0.2 
Hypoalbuminemia 
5.1 
2 
< 0.1 
Dehydration 
4 
1 
0.7 
Tumor lysis syndrome 
0.7 
0.6 
0.6 
Musculoskeletal and connective tissue disorders 
Back pain 
19 
2.8 
0.8 
Muscle spasms 
15.9 
0.5 
‐ 
Arthralgia 
14.5 
1 
0.1 
Pain in extremity 
12.8 
1 
0.2 
Musculoskeletal pain 
9.8 
1.5 
0.1 
Musculoskeletal chest 
pain 
8.8 
0.4 
0.1 
Muscular weakness 
6.2 
1.1 
0.3 
Myalgia 
5.7 
0.3 
‐ 
Nervous system disorders 
Headache 
20.4 
1.1 
0.3 
Dizziness 
11.6 
0.6 
< 0.1 
Neuropathy 
8.7 
1 
< 0.1 
Parestheisa 
8.3 
0.2 
< 0.1 
Hypoesthesia 
6.9 
0.1 
‐ 
Psychiatric disorders 
Insomnia  
16.1 
0.7 
‐ 
Anxiety 
6.6 
0.3 
‐ 
Renal and urinary disorders 


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p. 37 of 48 
Acute kidney injury 
5.9 
4.5 
4.4 
Renal failure 
3.4 
1.6 
0.9 
Renal impairment 
1.6 
0.6 
0.3 
Respiratory, thoracic and mediastinal disorders 
Dyspnea 
27.6 
4 
2.1 
Cough 
24.2 
0.3 
0.1 
Epistaxis 
7.9 
0.4 
0.2 
Oropharyngeal pain 
7.8 
‐ 
‐ 
Dysphonia 
2.6 
‐ 
‐ 
Pulmonary edema 
1.6 
1 
0.9 
Pulmonary embolism 
1.5 
1.3 
1.3 
Skin and subcutaneous tissue disorders 
Rash 
8 
0.5 
0.3 
Pruritis 
5.9 
< 0.1 
‐ 
Erythema 
4.5 
‐ 
‐ 
Hyperhidrosis 
3.9 
‐ 
‐ 
Vascular disorders 
Hypertension 
14.9 
4.4 
0.6 
Hypotension 
5.6 
1.5 
0.9 
Deep venous 
thrombosis 
3.1 
1.2 
1.1 
 
6.2 
Methods and timing for capturing and assessing safety parameters  
 
The investigators are responsible for ensuring that all AEs will be recorded on the AE form and 
SAEs are recorded on the SAE form.  All reportable SAE will be reported on the FDA MedWatch 
forms and reported to Amgen as defined in this section.  
 
6.2.1 Adverse event reporting period 
 
After informed consent is obtained but before any administration of study drug, only SAEs due to 
protocol mandated interventions will be recorded.  Any AE or SAE at any time after the first 
infusion of carfilzomib is initiated until day 16, and on days 28, 42, 90 ±14 days must be recorded 
by the investigators and reported to Amgen as defined in this section.  After this period, only SAEs 
deemed to be related to study drug will be recorded and reported.  
 
Serious Adverse Event Reporting Contact Information:  
Amgen Global Safety  
Toll‐free #:1‐888‐814‐8653 
For countries where the U.S. toll‐free # cannot be used: +44‐20‐7136‐1046  
Email (Only for sponsors with a secure email connection with Amgen):  
svc‐ags‐in‐us@amgen.com 
 
6.2.2 Eliciting adverse events  
 
A consistent methodology of non-directive questioning for eliciting AEs at all patient evaluation 
time points will be adopted.  
   This will include the following two questions directed to study subjects: 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 38 of 48 
 
 
How have you felt since your last infusion of carfilzomib? 
 
 
Have you had any new or changed health problems since you were last seen?  
 
These questions will be asked in person at days 28, 42 and 90 ±14 days, or by phone if patient 
does not return to their standard of care visit at these time points. 
 
6.2.3 Assessment of severity and causality of adverse events 
 
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs and SAEs, 
whether reported by the patient or noted by authorized study personnel, will be recorded in the 
patient’s medical record and reported on the AE or SAE forms and reportable SAE on the FDA 
MedWatch form. 
 
For each AE and SAE recorded, the investigators will make an assessment of seriousness and 
severity based on the CTCAE criteria, and causality to carfilzomib.  
 
6.3 
Procedures for recording adverse events 
 
All AEs will be recorded on the AE form .  Only one AE will be reported on one form.  For multiple 
AEs, multiple forms will be used.  Study investigators will be responsible for codifying and keeping 
electronic copies of the form in the study database in protected files on the Pitt Research servers.   
 
The Investigator-sponsor must be notified of the occurrence of any SAE within 24 hours of the 
investigator, designee, or site personnel’s knowledge of the event. The Investigator-sponsor is 
responsible for notifying the appropriate health authorities (HAs), ethics committees (ECs), and 
investigators, of any expedited, annual, or other periodic safety reports in accordance with 
applicable regulations.  Any safety report submission will cross reference the Amgen 
investigational new drug (IND) or clinical trial approval (CTA) number.  
 
The Investigator is also responsible for notifying the local ECs in accordance with local 
regulations. Additionally, the Investigator-sponsor is responsible for reporting SAEs to Amgen. 
 
SAE Reporting by Investigator-sponsor to Amgen 
 
The Investigator-sponsor must inform Amgen in writing by e-mail or fax at the contact information 
listed below for all SUSARs that are judged as reasonably related to the Amgen study drug. Site 
will transmit the final CIOMS of that event to Amgen within twenty-four (24) hours of submitting 
the report to the applicable regulatory authority. 
 
For regulatory reporting purposes, an event of “Death, Cause Unknown” from the study shall be 
processed as a SUSAR.  All forms must be completed and provided to Amgen in English.  
 
The Individual Case Safety Report (ICSR) may be referred to as an individual safety report or 
SAE Report, including Pregnancy Exposure Reports and Follow up Reports. The ICSR must be 
as complete as possible, at a minimum including event reference number, protocol name and 
number, investigator contact information, specific patient identifiers (e.g., initials, patient number, 
date of birth or age, or gender), the name of the suspect Study Drug, the date and dosage(s) of 
exposure, event,  the date(s) of event, country of event, “Serious” Criteria, Relationship/causality 
of Study Drug, Hospitalization history for the event, Event status/outcome, Relevant history (including 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 39 of 48 
diagnostics, laboratory values, radiographs, concomitant medications, and event treatment, and 
narrative summary.  
 
Sponsor shall be responsible for collecting all SAEs and Pregnancy and Lactation Exposure 
Reports and will exercise commercially reasonable due diligence to obtain follow-up information 
on incomplete SAE or Pregnancy and Lactation Exposure Reports. In the event that the Company 
requires clarification or further information on individual SAE or Pregnancy and Lactation 
Exposure Reports, Company will not contact non-party investigators directly, but will route all such 
inquiries through Site for forwarding to such investigator(s). Site will be responsible to ensure 
such inquiries are completed and timely provided to Company. 
 
Information not available at the time of the initial report (e.g., an end date for the SAE, discharge 
summaries, lot numbers, relevant laboratory values, scan data and autopsy reports) which are  
received after the initial report must be documented on a follow-up form, and submitted to Amgen 
in the same timelines as outlined above.  Sponsor shall be responsible for obtaining follow-up 
information for the SAEs and demonstrate diligence in attempting to obtain such information by, 
among other things, maintaining written records of such attempts. 
 
Other aggregate analysis including reports containing safety data generated during the course of 
the study is to be submitted to Amgen at the time the sponsor ISS submits to anybody governing 
research conduct i.e. RA, IRB etc. Final study report including unblinding data when applicable 
and reports of unauthorized use of a marketed product to be submitted to Amgen at the time the 
sponsor ISS submits to anybody governing research conduct i.e. RA, IRB etc. but not later than 
one calendar year of study completion. 
 
Sponsor will provide an annual IND report to Amgen. Reports containing safety data generated 
during the course of the study is to be submitted to Amgen at the time the sponsor submits to 
anybody governing research conduct, i.e. regulatory authorities and IRBs.   Sponsor will support 
reconciliation of all ICSRs at the end of the study at a minimum. 
 
6.3.1 Diagnosis 
 
If known, a diagnosis should be recorded on the AE form rather than individual signs and/or 
symptoms.  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE. If a diagnosis is subsequently established, it should be 
reported as follow up information.  
 
 
6.3.2 Persistent or recurrent AEs 
 
A persistent AE is one that extends continuously, without resolution between patient evaluation 
time points.  Such events will only be recorded once unless severity has increased since initial 
recording.  If a persistent AE becomes more severe, it shall be recorded again.  
 
A recurrent AE is one that occurs and resolved between patient evaluation time points and 
subsequently occurs again.  All recurrent AEs shall be recorded again.  
 
 
 
 


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Molecule: Carfilzomib  
 
 
p. 40 of 48 
6.3.3 Abnormal laboratory values 
 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs.  If the lab is a sign of a disease, only the diagnosis needs to be 
recorded.  If the lab is not a sign of a disease, then the laboratory value or the designated term 
should be recorded (e.g., transaminitis or ALT 1750).  Repeated observations of the same lab 
abnormality from patient contact time point to time point need not be recorded again unless they 
have worsened in severity (e.g., serum creatinine of 1.8 for 2 lab draws will only be recorded 
once).   
 
6.3.4 Deaths 
 
Deaths meet the criteria for SAE and all rules and regulations regarding reporting as defined in 
this section must be fulfilled.  All deaths, irrespective of cause, will be recorded as SAEs and will 
be reported to the Sponsor.  This includes death due to progression of AMR.  Cause of death, if 
known, shall be recorded on the FDA Medwatch form.  If deaths are due to progression of AMR, 
progression of study disease shall be recorded as a contributing factor.  If deaths are due to study 
therapy, such notation shall be recorded as a contributing factor.  If death occurs, it shall be noted 
on the FDA Medwatch form whether this death was expected or unexpected.  After study 
completion (day 90), deaths due to progression of AMR shall only be recorded for the purposes 
of data analysis in the study.   
 
6.3.5 Preexisting medical conditions 
 
A preexisting medical condition is one that is present at the time of informed consent.  Such 
conditions shall be recorded in the study database.   
 
A preexisting condition will only be recorded as an AE or SAE if the frequency, severity, or 
character of the condition worsens during the study.  When recording such events, the 
investigators will make note of the characteristics that have worsened (e.g., increased systolic 
blood pressure for preexisting hypertension).  
 
6.3.6 Worsening antibody mediated rejection 
 
Worsening or progression of AMR shall not be recorded as an AE or SAE.  These data will be 
captured as efficacy assessment data only.   
 
6.3.7 Prolonged hospitalization 
 
Any AE that results in prolonging of the study hospitalization shall be documented on the FDA 
Medwatch form as an SAE and be subject to all the rules and regulations of reporting as described 
in this section.   
 
6.3.8 Pregnancy 
 
Pregnancy inclusion criteria 
 
Women of childbearing potential must have a negative serum pregnancy test within the 7 days 
prior to study drug administration.  
 


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Molecule: Carfilzomib  
 
 
p. 41 of 48 
Women of childbearing potential must either agree to abstain from sexual intercourse or use an 
effective birth control method during treatment and for an additional 30 days after the last dose of 
carfilzomib.  Men who are sexually active with women of childbearing potential must either agree 
to abstain from sexual intercourse or use a condom with spermicide during treatment and for an 
additional 30 days after the last dose of carfilzomib, and the female partner should consider using 
an effective method of birth control.   
 
Pregnancy exclusion criteria 
 
Women who are pregnant and/or breast feeding  
 
6.3.8.1 Pregnancy reporting 
 
Subjects will be instructed to notify the investigator as soon as possible after learning becoming 
pregnant or the pregnancy of a partner during treatment of or up to 30 days following the last 
study drug administration.  
 
Pregnancy Reporting by Investigator-sponsor to Amgen  
 
Report Pregnancy and potential infant exposure including Lactation, within ten (10) calendar days 
of Sponsor awareness. Provide to Amgen the SAE reports associated with pregnancy.  SUSARs 
are to be reported within twenty-four (24) hours of submitting the report to the applicable 
regulatory authority. 
Amgen Drug Safety and Pharmacovigilance Contact Information: 
• 
Drug Safety Reporting Fax    
• 
Toll-free US  888-814-8653  
• 
Toll US  805-480-9205  
 
Drug Safety Reporting by secure e-mail can be established upon request 
  
If the patient becomes pregnant while taking an Amgen drug, the drug will be immediately 
discontinued.   
The investigator will discuss the risks and concerns of investigation drug exposure to a developing 
fetus and counsel the subject and/or pregnant partner (or ensure that such counseling is 
provided).  
Pregnancies will be followed through the outcome of the pregnancy.   
 
Newborns should be followed for a minimum of 12 weeks.  
 
The Investigator will complete a Pregnancy Monitoring Form and report the information regarding 
the pregnancy, outcome, and status of the newborn as appropriate. 
 
6.4 
Procedures for reporting serious adverse events 
 
Provide SAE reports on MedWatch forms for mandatory reporting  
 
Drug Safety Reporting Fax    
• 
Toll-free US  888-814-8653  
• 
Toll US  805-480-9205  
 
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 42 of 48 
Drug Safety Reporting by secure e-mail can be established upon request 
 
6.4.1 Reporting requirements for serious adverse events 
 
The Investigator-sponsor must be notified of the occurrence of any SAE within 24 hours of the 
investigator, designee, or site personnel’s knowledge of the event. 
 
SAE Reporting by Investigator-sponsor to Amgen 
 
The Investigator-sponsor must inform Amgen in writing by e-mail or fax at the contact information 
listed below for all SUSARs that are judged as reasonably related to the Amgen study drug. Site 
will transmit the final CIOMS of that event to Amgen within twenty-four (24) hours of submitting 
the report to the applicable regulatory authority. 
 
6.5 
Follow-up of patients after adverse events 
 
All SAEs regardless of relationship to CFZ must be followed to resolution or to stabilization if 
improvement or resolution is not expected. 
 
7 
Investigator requirements 
 
7.1 
Study initiation  
 
Before the start of the study and any study-related procedures the following documents must be 
signed by the co-principal investigators.  A copy must be retained both by Amgen and the study 
site team.  
 
US FDA Form 1572: Statement of investigator signed by the co-primary investigators. The names 
of the co-investigators must appear on this form.  
 
Current curriculum vitae and evidence of licensure for all investigators.  
 
Complete financial disclosure forms as required by FDA Form 1572 for all investigators. 
 
Written University of Pittsburgh IRB statement of approval and compliance of the protocol and 
informed consent form. 
 
Investigator brochure receipt signed and dated by the co-principal investigators.  
 
Protocol acceptance form signed and dated by the co-principal investigators.  
 
 
7.2 
Study completion 
 
The following data and materials will be submitted to Amgen upon the conclusion of the study. 
 
Laboratory findings, clinical data, and all special test results from screening through the end of 
the study period for all study subjects.  
 
Completed drug accountability forms.  
 


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Molecule: Carfilzomib  
 
 
p. 43 of 48 
Copies of any protocol amendments and IRB approval notifications.  
 
Signed and dated protocol amendment acceptance forms. 
 
Summary of the study prepared by the co-principal investigators (IRB summary close letter).  
 
Updated financial disclosure forms for all investigators.  
 
7.3 
Informed consent form 
 
The informed consent forms for the study must be approved by the University of Pittsburgh IRB.  
 
Consent forms must be signed by the patient or legal designee before his/her participation in the 
study.  A signed copy of the informed consent form will be inserted into the medical record and 
retained with the study investigators files.  A copy of the informed consent form will be given to 
the patient or legal designee.  
 
Consent forms must be available for review by the sponsor at any time.  
 
Consent forms should be revised whenever there are changes to the procedures outlined in the 
informed consent form or when new information is available that may affect the willingness of 
patients to participate.  
 
7.4 
Communication with the IRB  
 
This protocol, the informed consent forms, and any information to be given to the patient must be 
submitted to the IRB by the co-principal investigators for review and approval before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the IRB.  
 
The principal investigator is responsible for providing written summaries of the status of the study 
to the IRB at least annually in accordance with all IRB policies and procedures. Investigators are 
also responsible for promptly informing the IRB of any protocol changes or amendments and any 
unanticipated problems involving risk to patients or others.  
 
Any other IRB requirements not delineated in this section must be fulfilled by the co-primary 
investigators.  
 
7.5 
Study monitoring requirements  
 
Site visits may be conducted by an authorized Amgen representative to inspect the study data, 
patient records, and AE reports.  The co-primary investigators permit Amgen, IRB, FDA, or other 
respective relevant health authorities to inspect study facilities and records relevant to this study.   
 
7.6 
Source data documentation 
 
Study monitors may perform ongoing source data verification to confirm that critical protocol data 
are entered accurately and completely in the study database.   
 
Source documents are defined as the location in the official medical record or other credible 
source of information where patient data are recorded and documented for the first time. 
 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 44 of 48 
Source documents will never be destroyed or altered.  
 
7.7 
Study medication accountability 
 
All study drug required for completion of this study will be provided by Amgen.  The UPMC 
investigational drug service (IDS) pharmacy will acknowledge receipt of the drug by returning the 
relevant documentation forms indicating shipment content and condition. Damaged supplies will 
be replaced.  
 
Accurate records of all study drug received at, dispensed from, returned to and disposed of by 
the UPMC IDS pharmacy shall be recorded.  
 
7.8 
Disclosure of data 
 
Patient medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted in the informed consent form signed by the patient or legal designee as 
required by law.  
 
Medical information may be given to a patient’s personal physician or other appropriate healthcare 
provider for purposes of patient treatment and welfare.  
 
Data generated by this study must be available for inspection upon request by representatives of 
the FDA or other relevant regulatory agencies and the study sponsor.  
 
7.9 
Retention of records  
 
US FDA regulations (21 CFR 312.62[c]) and the ICH guideline for GCP require that records and 
documents pertaining to the conduct of this study and distribution of investigational drug, including 
AE forms, consent forms, lab results, and medication inventory records be retained by the co-
principal investigators for 2 years after the formal discontinuation of the study and the FDA is 
notified.   
 
No records shall be disposed of without the permission of Amgen.  Written notification shall be 
provided to Amgen for transfer of any records to another party or location.  
 
8 
References 
 
1. Weigt SS, Wallace WD, Derhovanessian A, et al. Chronic allograft rejection: epidemiology, 
diagnosis,pathogenesis, and treatment. Semin respir crit care med 2010;31:189-207. 
2. Yusen RD, Christie JD, Edwards LB, et al. The Registry of the International Society for Heart 
and Lung Transplantation: thirtieth adult lung and heart-lung transplant report-2013. J Heart 
Lung Transplant 2013;32:965-78. 
3. Snyder LD, Wang Z, Chen DF, et al.  Implications for human leukocyte antigen antibodies 
after lung transplantation: a 10-year experience in 441 patients.  Chest 2013;144:226-33. 
4. Sundaresan S, Mohanakumar T, Smith MA, et al. HLA-A locus mismatches and development 
of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis 
obliterans syndrome. Transplantation 1998;65:648-53. 
5. Jaramillo A, Smith MA, Phelan D, et al. Development of ELISA-detected anti-HLA antibodies 
precedes the development of bronchiolitis obliterans syndrome and correlates with 
progressive decline in pulmonary function after lung transplantation. Transplantation 
1999;67:1155-61. 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 45 of 48 
6. Palmer SM, Davis RD, Hadjiliadis D, et al. Development of an antibody specific to major 
histocompatibility antigens detectable by flow cytometry after lung transplant is associated 
with bronchiolitis obliterans syndrome. Transplantation 2002;74:799-804. 
7. Hadjiliadis D, Chaparro C, Reinsmoen NL, et al. Pre-transplant panel reactive antibody in lung 
transplant recipients is associated with significantly worse post-transplant survival in a 
multicenter study. J Heart Lung Transplant 2005;24:S249-54. 
8. Girnita AL, McCurry KR, Iacono AT, et al. HLA-specific antibodies are associated with high-
grade and persistent-recurrent lung allograft acute rejection. J Heart Lung Transplant 
2004;23:1135-41. 
9. Girnita AL, Duquesnoy R, Yousem SA, et al. HLA-specific antibodies are risk factors for 
lymphocytic bronchiolitis and chronic lung allograft dysfunction. Am J Transplant 2005;5:131-
8. 
10. Smith MA, Sundaresan S, Mohanakumar T, et al. Effect of development of antibodies to HLA 
and cytomegalovirus mismatch on lung transplantation survival and development of 
bronchiolitis obliterans syndrome. J Thorac Cardiovasc Surg 1998;116:812-20. 
11. Chin C, Chen G, Sequeria F, et al. Clinical usefulness of a novel C1q assay to detect 
immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart 
transplant patients. J Heart Lung Transplant 2011;30:158-63.  
12. Yabu JM, Higgins JP, Chen G, Sequeira F, Busque S, Tyan DB. C1q-fixing human leukocyte 
antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure 
after kidney transplantation. Transplantation 2011;91:342-7. 
13. Hachem RR, Yusen RD, Meyers BF, et al.  Anti-human leukocyte antigen antibodies and 
preemptive antibody-directed therapy after lung transplantation.  J Heart Lung Transplant 
2010;29:973-80. 
14. Everly MJ, Everly JJ, Susskind B, et al. Bortezomib provides effective therapy for antibody- 
and cell mediated acute rejection. Transplantation 2008;86:1754-61. 
15. Everly MJ, Terasaki PI, Trivedi HL. Durability of antibody removal following proteasome 
inhibitor-based therapy. Transplantation 2012;93:572-7. 
16. Perry DK, Burns JM, Pollinger HS, et al. Proteasome inhibition causes apoptosis of normal 
human plasma cells preventing alloantibody production. Am J transplant 2009;9:201-9.40.  
17. Everly MJ, Terasaki PI, Hopfield J, Trivedi HL, Kaneku H. Protective immunity remains intact 
after antibody removal by means of proteasome inhibition. Transplantation 2010;90:1493-8. 
18. Mulder A, Heidt S, Vergunst M, Roelen DL, Claas FH. Proteasome inhibition profoundly 
affects activated human B cells. Transplantation 2013;95:1331-7. 
19. Jagannath S, Vij R, Stewart AK, et al.  An open-label single arm pilot phase II study (PX-171-
003-A0) of low-dose, single agent carfilzomib in patients with relapsed and refractory multiple 
myeloma.  Clin Lymphoma Myeloma Leuk 2012;12:310-8. 
20. Siegal DS, Martin T, Wang M.  A phase 2 study of single-agent carfilzomib (PX-171-003-A1) 
in patients with relapsed and refractory multiple myeloma.  Blood 2012;120:2817-25. 
21. Vij R, Siegal DS, Jagannath S, et al.  An open-label, single-arm, phase 2 study of single-agent 
carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been 
previously treated with bortezomib.  Br J Haematol 2012;158:739-48. 
22. Witt CA, Gaut JP, Yusen RD, et al. Acute antibody-mediated rejection after lung 
transplantation. J Heart Lung Transplant 2013;32:1034-40. 
23. Takemoto SK, Zeevi A, Feng S, et al.  National conference to assess antibody-mediated 
rejection in solid organ transplantation.  Am J Transplant 2004;4:1033-41.   
24. Estenne M, Maurer JR, Boehler A, et al.  Bronchiolitis obliterans syndrome 2001: an update 
of the diagnostic criteria.  J Heart Lung Transplant 2002;21:297-310. 
 
 
 


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9 
Appendices  
 
9.1 
Appendix A: Study Flowcharts 
 
 
Study Procedures 
 
Intervention Phase 
±14 days 
Testing 
Phase  
±14 days 
Post‐study Fol
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
28 
42 
90 
120 
150 
180 
210
Screening/Enrollment 
x 
 
 
 
 
 
 
 
 
 
Standard of Care Procedures 
H&P 
 
x 
 
 
 
 
 
 
 
 
Progress note 
 
 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x 
x 
x 
x
x
x
x
x
PLEX 1.5 volumes 
 
x 
 
x 
 
x 
 
x
x
x
x
x
 
 
 
Premeds for IVIG 
 
x 
 
x 
 
x 
 
x
x
x
x
x
x 
 
 
IVIG 100 mg/kg 
 
x 
 
x 
 
x 
 
x
x
x
x
 
 
 
IVIG 500 mg/kg 
 
 
 
 
 
 
 
x
X* 
 
 
Medrol 750‐1000 mg IV 
 
x 
x 
x 
only given if concomitant ACR
 
 
CBC w/differential 
 
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x 
x 
x 
x
x
x
x
CMP 
 
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x 
x 
x 
x
x
x
x
Total IgG 
 
x 
 
 
 
 
 
x 
x 
x 
x
x
x
x
Complement 3 & 4 
 
x 
 
 
 
 
 
x 
x 
x 
x
x
Luminex IgG‐SAB 
 
x 
 
 
 
 
 
x 
x 
x 
x
x
x
x
x
Luminex C1q‐SAB 
 
x 
 
 
 
 
 
x 
x 
x 
x
x
x
x
x
PFTs 
 
x 
 
 
 
 
 
 
x 
x 
x
x
x
x
x
TB Biopsy 
 
x 
 
 
 
 
 
 
 
x 
clinic
Study Specific Procedures 
Premeds for CFZ 
 
x 
x 
 
 
 
 
x
x
x
x 
 
 
CFZ 20 mg/m2 
 
x 
x 
 
 
 
 
x
x
x
x 
 
 
CFZ AE assess 
 
 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x 
x 
x 
x
CFZ response assess 
 
 
 
 
 
 
 
 
x 
x 
x
IgG‐SAB subclasses** 
 
x 
 
 
 
 
 
x 
x 
x 
x
Blood for PBMC** 
 
x 
 
 
 
 
 
x 
x 
x 
x
 
Progress notes indicate inpatient admission or clinic visits within ±14  days of the stated days, unless the patient is 
unable to present due to unforeseen circumstances (e.g., death, hospitalization at another facility, etc.). Standard 
of care procedures will not be done solely for research purposes. 
Study ends at the day 90 visit.  Post‐study follow‐up will continue for all patients alive at day 90 to 1 year post 
enrollment through a medical records review.  
Study CFZ AE assessment will be conducted either in‐person or via telephone (day 1 through 16, and 28, 42 and 90  
* Dose will be administered only If IgG level is below 700 mg/dL. 
** Research samples will only be obtained if subject is coming to their standard of care visit on days 28, 42 and 90.


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 47 of 48 
 
Appendix B: Study data collection summary 
 
Baseline characteristics 
 
1. Lung transplant indication: interstitial lung disease, chronic obstructive pulmonary disease, cystic 
fibrosis, scleroderma, sarcoidosis, pulmonary arterial hypertension, other (specify) 
2. Transplant type: single, bilateral 
3. Date of transplant 
4. Time after transplant to enrollment 
5. Age at transplant 
6. Age at enrollment 
7. Gender: male, female 
8. Race: Caucasian, African American, Native American, Hispanic, other (specify) 
9. Induction immunosuppression 
10. Maintenance immunosuppression at enrollment 
11. De novo DSA vs. preformed DSA prior to transplant 
12. PFTs at enrollment (if not intubated): FEV1, FVC, FEF25/75 
13. Bronchiolitis obliterans syndrome grade at enrollment 
14. Daily oxygen use (Y/N) 
15. CMV donor/recipient status: mismatch, recipient positive, negative 
16. EBV donor/recipient status: mismatch, recipient positive, negative 
17. HSV donor/recipient status: mismatch, recipient positive, negative 
18. VZV donor/recipient status: mismatch, recipient positive, negative 
19. Chronic infections at enrollment (specify) 
 
Study characteristics 
 
 
1 
2 
3 
4 
5 
6
7
8
9
10
11
12
13
14
15 
16 
28 
42
90
WBC 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
ANC 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
ALC 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
Hematocrit 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
Platelets 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
BUN 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
Creatinine 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
Total IgG 
x 
 
 
 
 
 
x 
x 
x
x
IgG 1 
x 
 
 
 
 
 
x 
x 
x
x
IgG 2 
x 
 
 
 
 
 
x 
x 
x
x
IgG 3 
x 
 
 
 
 
 
x 
x 
x
x
IgG 4 
x 
 
 
 
 
 
x 
x 
x
x
Complement 3 
x 
 
 
 
 
 
x 
x 
x
x
Complement 4 
x 
 
 
 
 
 
x 
x 
x
x
DSA MFI neat 
x 
 
 
 
 
 
x 
x 
x
x
DSA MFI 1:16 
x 
 
 
 
 
 
x 
x 
x
x
DSA MFI EDTA 
x 
 
 
 
 
 
x 
x 
x
x
DSA MFI C1q 
neat 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
DSA MFI AHG-
C1q neat 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
DSA MFI C1q 
1:16 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
DSA MFI C1q 
EDTA 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 


Protocol: PICARD‐AMR  
Molecule: Carfilzomib  
 
 
p. 48 of 48 
DSA IgG 
subtype 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
FEV1 
x 
 
 
 
 
 
 
x 
x
x
FVC 
x 
 
 
 
 
 
 
x 
x
x
FEF 25/75 
x 
 
 
 
 
 
 
x 
x
x
ACR A grade 
x 
 
 
 
 
 
 
 
x
ACR B grade 
x 
 
 
 
 
 
 
 
x
ACR C grade 
x 
 
 
 
 
 
 
 
x
AMR findings 
(Y/N) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Blood for 
PBMC (Y/N) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
PLEX (Y/N) 
x 
 
x 
 
x 
x
X
x
x
x 
 
 
IVIG 100 mg/kg 
(Y/N) 
x 
 
x 
 
x 
 
x 
 
X
 
x 
 
x 
 
 
 
 
 
 
IVIG 500 mg/kg 
(Y/N) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X** 
 
 
 
 
Carfilzomib 20 
mg/m2 (Y/N) 
x 
x 
 
 
 
 
 
x 
X
 
 
 
 
 
x 
x 
 
 
 
Other 
carfilzomib 
dose and 
reason 
x 
x 
 
 
 
 
 
x 
X
 
 
 
 
 
x 
x 
 
 
 
Medrol (Y/N) 
x 
x 
x 
 
 
 
 
 
Medrol dose 
x 
x 
x 
 
 
 
 
 
AE assessment  x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
Death 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
AE/SAE 
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
Cultures*  
x 
x 
x 
x 
x 
x
x
x
X
x
x
x
x
x
x 
x 
x 
x
x
  *Cultures: bacterial, viral, fungal, AFB, cytology. Positive cultures will be recorded at any time if they are  
    taken.  
 
** Dose will be administered only If IgG level is below 700 mg/dL. 
  

ICF_001.pdf: 
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                                                                            Page 1 of 11                                          
 University of Pittsburgh 
    Schools of Pharmacy and Medicine
 Division of Pharmacy and Therapeutics and 
      
 Division of Pulmonary, Allergy, and Critical Care Medicine
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY
TITLE: Combination Therapy with the Proteasome Inhibitor Carfilzomib for the 
            Antibody-Mediated Rejection Diagnosis in Lung Transplantation Trial 
(PICARD-Lung)
Principal Investigator: 
John F. McDyer, MD
Associate Professor of Medicine
University of Pittsburgh
Montefiore NW 628, Pittsburgh, PA 15213
Phone: 412-624-8915
Source of Support:  
Amgen
Why is this research being done?
This research is being done to help us understand how the immune system [composed 
of white blood cells and antibodies] responds to transplantation of the lung(s).  These 
antibodies have attacked your new lungs and produced something called Antibody-
Mediated Rejection (AMR), which leads to chronic rejection of the lungs. As a result of 
AMR, you are scheduled to receive a plasma exchange (PLEX) with IV (intravenous) 
immunoglobulin to remove these antibodies as part of your standard treatment. This 
research is to see whether a drug called Carfilzomib can help reduce the antibodies 
further when used with PLEX.  Carfilzomib is FDA (Food and Drug Administration) 
approved for the treatment of a type of cancer called multiple myeloma, a cancer that 
starts in the bone marrow. It is not FDA approved for use in this study. This study is also 
being done to assess what factor(s) contribute to AMR.  In particular, we are interested 
in the role that the B-cells and plasma cells and antibodies in your body play in AMR.  In 
order to best study this condition, it is necessary to conduct studies in the laboratory 
using blood cells from individuals like yourself who have undergone lung 
transplantation.  In this way, we can follow the way your immune system behaves over 
time.  This will help us better understand why certain individuals may or may not 
develop chronic rejection.  


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A description of this clinical trial will be available on www.clinicaltrials.gov, as required 
by US Law. This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this website at any time.
Who is being asked to take part in this research study?
You are being invited to take part in this research study because you have already 
undergone lung transplantation and have AMR.  We will be enrolling up to 30 patients 
like yourself who are at least 18 years old.  If you agree to participate, we will plan on 
studying you for 90 days.  
 
What procedures will be performed for research purposes?
If you decide to take part in this research study, you will undergo the following:
Pregnancy Testing: 
For women of childbearing potential, a serum pregnancy test will be performed within 7 
days prior to study drug administration, as it is important to confirm that you are not 
pregnant. Pregnant or breastfeeding women are excluded from this study.
Carfilzomib Treatment:  
1. You will be given pre-medications approximately 30 minutes prior to the 
Carfilzomib infusion to minimize infusion reactions:  Tylenol 650 mg by mouth, 
Benadryl 25 mg by mouth, ondansetron (for nausea) 4 mg by mouth, prednisone 
(a steroid) 40 mg by mouth or by IV.  
2. You will be given salt water (normal saline) through your IV approximately 30 
minutes prior to the Carfilzomib infusion to make sure that you are hydrated and 
to minimize any side effects with the kidneys.  
3. While you are admitted in the hospital in the Lung Transplant Unit, Carfilzomib 
will be administered at 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 which constitutes 
one therapeutic cycle.  Carfilzomib will be administered via central access IV 
over 30 minutes; slowed to 60 minutes if infusion reactions occur. Possible 
reactions may include fever, chills, arthralgia, myalgia, facial flushing, facial 
edema, vomiting, weakness, hypotension, syncope, or chest tightness.
4. You may be given normal saline through your IV immediately after the 
Carfilzomib infusion to make sure that you are hydrated and to minimize any side 
effects with the kidneys.  
A second cycle of Carfilzomib may be given to you for lack of resolution of AMR or for 
continued detection of Donor-specific antibodies in the absence of allograft 
improvement if you still meet the original enrollment criteria. 
On days 28, 42 and 90, if you are discharged from hospital and do not return to your 
routine clinical visit as part of your standard of care treatment, a member of study team 
will call you to ask some questions about side effects.


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Blood Draw: We will draw up to 4 tablespoons of blood at each visit on Days 1, 9, 16, 
28, 42 and 90 in the least invasive manner possible- at the time of another blood draw, 
from an existing line or by putting a needle into a vein in your arm. 
Most commonly, these blood draws will occur during your initial hospital stay for the 
study drug and during normal visits to the hospital or clinic.  As much as possible we will 
attempt to obtain this blood at the same time you are undergoing routine laboratory 
tests to monitor your body after the transplant.  It is possible that you may require more 
frequent visits if you are having trouble with your lung transplant, but we will only draw 
the amount of blood as described and will not draw blood if your blood counts are low 
for other reasons.  
Any samples collected during this research will only be used for the purposes described 
in the protocol and destroyed at the end of this research study.  The results of these 
research studies are not going to be shared with you, nor will it impact on your medical 
care, since as of now, we are not sure of the meaning of the results.  
Medical Records Review: As part of this study and your routine clinical care, we will look 
at your medical records.  We may use some of the information about your health and 
medical care for this study. We will only use information that is related to your lung 
transplant and routine clinical care during your participation in this study (90 days) and 
up to 360 days if you have any additional clinic visit as part of your standard of care.  
What are the possible risks, side effects, and discomforts of this research study?
As with any experimental procedure, there may be adverse events or side effects that 
are currently unknown and certain of these unknown risks could be permanent, severe 
or life-threatening.
Everyone taking part in the study will be watched carefully for any side effects. You 
should talk to your study doctor about any side effects that you have while taking part in 
the study.  
Risks of Carfilzomib
You should seek medical care immediately if you develop any of the following 
symptoms: severe shortness of breath, chest pain, fevers, chills, shaking with 
fever, vomiting, muscle weakness or cramping, seizures, fainting and/or
significantly decreased urine output.
Carfilzomib may impair ability to operate a car, other motorized vehicle, or machinery 
because of tiredness, dizziness, changes in blood pressure, or fainting.
If side effects occur, your health care team may give you medicines to help lessen side 
effects. Your doctor may have you stop taking carfilzomib or take a lower dose of 
carfilzomib because of the side effects, or the side effects may go away on their own 
even if you continue to take carfilzomib.  


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                                                                            Page 4 of 11                                          
The information provided below is based on data from approximately 800 patients who 
took carfilzomib while taking part in clinical studies over the past 6 years. During this 
time period the following side effects have been observed and may be due to 
carfilzomib.
Likely Side Effects:  those occurring in more than 20% of patients (or more than 20 out 
of 100 persons) who received carfilzomib:

Fatigue (tiredness), Fever, Headache, Cough, Shortness of breath (at rest or 
with exertion) which in rare cases may be life-threatening or resulting in 
death, Nausea, Vomiting, Diarrhea, Constipation, Decreased red blood cell 
count which may lead to feeling tired, Decreased platelet counts which may 
lead to increase bleeding or bruising, Decreased white blood cell count which 
may decrease your ability to fight infection, Upper respiratory tract infection, 
Mild decreases in kidney function which are generally reversible, Swelling of 
the arms or legs, Back pain
Less Likely Side Effects:  those occurring in 5-20% of patients (or 5 to 20 out of 100
persons) who received carfilzomib:

Flu-like symptoms such as fever, chills, or shaking that may occur at any time 
but are more likely to occur on the day of or the day after carfilzomib infusion, 
Loss of or decreased appetite which may lead to weight loss, Insomnia 
(difficulty sleeping), Anxiety, Dizziness, Confusion or changes in mental state, 
Blurred or double vision, Numbness, tingling, or decreased sensation in 
hands and/or feet , Blood chemistry and electrolyte alterations, Rash and/or 
itching, or dry skin, Pain, burning, or irritation at the infusion site, Generalized 
pain, Pain in the bones or joint pain, Muscle spasm, pain, or weakness, 
General weakness, or lack of energy or strength, Abdominal pain, discomfort, 
or swelling, Indigestion (upset stomach), Inflammation of the liver (mild, 
reversible changes in liver function tests), Increase or decrease in blood 
pressure, Pneumonia or other lower respiratory tract infections, Urinary tract 
infection, Nosebleeds, Dehydration, Sore throat, inflammation of the nose and 
throat, runny nose or nasal congestion
Rare and/or Potentially Serious Side Effects: those occurring in less than 5% of patients 
(or in less than 5 out of 100 persons) who received carfilzomib; side effects can be 
serious enough to be life-threatening or even fatal in rare cases:
  ● Infusion reactions (which can occur during or shortly after carfilzomib 
 infusion) including flushing or feeling hot, fever, shakes, nausea, vomiting, 
     weakness, shortness of breath, swelling of the face, pain in the muscles or 
joints, tightness or pain in the chest, laryngeal edema, and low blood 
pressure, Allergic reaction including total body rash, hives, and difficulty 
breathing, Inflammation of the pancreas (pancreatitis), Kidney failure which 
can lead to dialysis, Worsening liver function up to and including liver failure, 
hepatitis B virus reactivation, Decreased or worsening of heart function 
including chest pain, abnormal heart rhythm, heart attack, and heart failure, 


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                                                                            Page 5 of 11                                          
Increase in the blood pressure in the arteries of the lungs, Blood clots in the 
leg or lungs, and Infections in the blood.
●  Sepsis (the body’s overwhelming and life-threatening response to infection) 
and death could be a rare complication on the therapy.
Posterior reversible encephalopathy syndrome (PRES): There have been cases 
reported of PRES with carfilzomib.  PRES is a syndrome characterized by headache, 
confusion, seizures, high blood pressure, altered mental status (encephalopathy), 
associated with carfilzomib. Other standard immunosuppressive medications 
(tacrolimus, cyclosporine) prescribed as part of your standard treatment for your 
condition may also cause PRES. PRES resolves on its own over a period of time after 
stopping the drugs that can cause PRES.  
Hydration Risks: There may be risks associated with over hydrating (having too much 
fluid in your body) so it is important to follow your doctor’s instructions regarding how 
much water or other fluids you should drink.  Over hydration may negatively affect the 
heart, lungs, and kidneys.
Pregnancy Risks: 
Female: Women of childbearing potential must either agree to abstain from sexual 
intercourse or use an effective birth control method during treatment with carfilzomib. As 
a precaution, women of childbearing potential and/or their male partners should use 
effective contraception methods or abstain from sexual activity during and for 30 days 
after treatment with carfilzomib.  If pregnancy occurs during this time, patients should be 
apprised of the potential hazard to the fetus. 
Based in research performed in animals, carfilzomib can cause fetal harm when 
administered to a pregnant woman. Carfilzomib caused embryo‐fetal toxicity in pregnant 
rabbits at doses that were lower than in subjects receiving the recommended dose. If 
carfilzomib is used during pregnancy, or if the subject becomes pregnant while taking 
this drug, she should inform the investigator or study staff immediately. The investigator 
should notify Amgen of the pregnancy and discuss follow‐up with the subject. It is not 
known if carfilzomib will reduce the efficacy of oral contraceptives. Due to an increased 
risk of venous thrombosis associated with carfilzomib, subjects currently using oral 
contraceptives or a hormonal method of contraception associated with a risk of 
thrombosis should consider an alternative method of effective contraception.
Male: Men who are sexually active with woman of childbearing potential should avoid 
fathering a child while being treated with carfilzomib. The potential for carfilzomib to be 
transferred via semen and its effect on sperm are unknown. Male subjects treated with 
carfilzomib and/or their female partners (if of childbearing potential) should use effective 
contraceptive methods or abstain from sexual activity while treated with carfilzomib and 
refrain from donating sperm while on carfilzomib and for 90 days after treatment. If 
pregnancy occurs during this time, patients should be apprised of the potential hazard 
to the fetus, study drug should be interrupted, and a serum pregnancy test performed. 


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                                                                            Page 6 of 11                                          
Study drug administration may resume if result is negative and study drug be 
discontinued, if positive.  
Male subjects should be advised to inform the investigator or study staff immediately in 
the event that their female partner becomes pregnant during the study. Upon receipt of 
this information, the investigator should notify Amgen of the pregnancy and discuss 
follow‐up regarding the pregnancy outcome with the subject.
Breastfeeding: 
If a woman breastfeeds during the study, she must inform the investigator or study staff 
immediately. 
It is not known whether Kyprolis is present in human breast milk.  No studies of 
carfilzomib have been conducted in breastfeeding women. Due to the potential for 
adverse effects in nursing infants from carfilzomib, a decision should be made whether 
to  discontinue nursing or to discontinue the study drug.  The decision will be made 
taking into account the potential benefit of carfilzomib to the mother. 
Carfilzomib should not be used during breastfeeding. Breastfeeding women and women 
planning on breastfeeding may not participate in clinical trials with carfilzomib. 
Blood Draw: The risks of having blood drawn from a vein include some pain when the 
needle goes in and a small risk of bruising and/or infection at that site (just like with the 
regular blood draws you have).  It is possible that you might get light-headed, nauseous, 
or faint.  
Medical Record Review: There is some risk of loss of confidentiality. To protect the 
privacy of research records, all of the data used for this study will be assigned a code 
and the linking information will be stored in a secure, password-protected computer file 
only accessible by the principal investigator and his research team.  
What are possible benefits from taking part in this study?
There may be no benefit for your participating in this study.  However, the information 
learned from this study may benefit individuals who undergo lung transplants in the 
future.  
What treatments or procedures are available if I decide not to take part in this 
research study?
If you decide not to take part in this research study, you will continue to have your 
routine medical care for lung transplantation.
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study?


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                                                                            Page 7 of 11                                          
You will be promptly notified if, during the conduct of this research study, any new 
information develops which may cause you to change your mind about continuing to 
participate.
Will my insurance provider or I be charged for the costs of any procedures 
performed as part of this research study?
Neither you, nor your insurance provider, will be charged for the costs of any of the 
procedures performed for the purpose of this research study.  You and/or your 
insurance provider will be charged, in the standard manner, for any procedures 
performed for your routine medical care.
Will I be paid if I take part in this research study?
You will not be paid for being in this study.  Your blood samples used in this research study 
may contribute to a new invention or discovery.  In some instances, these inventions or 
discoveries may be of commercial value and may be sold, patented, or licensed by the 
investigators and the University of Pittsburgh for use in other research or the development of 
new products related to lung rejection.  If you agree to participate in this research study, you 
voluntarily and freely donate your samples to the investigators and the University of Pittsburgh.  
You will not retain any property rights to the samples, nor will you share in any money or other 
benefits that the investigators, the University of Pittsburgh, or their agents may realize from the 
samples or their use in this research study.  You retain the right to have your samples 
destroyed should you decide to withdraw from this research study.
Who will pay if I am injured as a result of taking part in this study? 
If you believe that the research procedures have resulted in an injury to you, 
immediately contact the Principal Investigator who is listed on the first page of this form. 
Emergency medical treatment for injuries solely and directly related to your participation 
in this research study will be provided to you by the hospitals of UPMC. Your insurance 
provider may be billed for the costs of this emergency treatment, but none of those 
costs will be charged directly to you. 
If your research-related injury requires medical care beyond this emergency treatment, 
you will be responsible for the costs of this follow-up care. At this time, there is no plan 
for any additional financial compensation. You do not, however, waive any legal rights 
by signing this form.  The sponsor of this study will not provide any compensation for a 
research-related injury.
Who will know about my participation in this research study?
Any information about you obtained from this research will be kept as confidential as 
possible.  All records related to your involvement in this research study will be stored in 
password protected computer files or a locked file cabinet.  Your identity on these 
records will be indicated by only a case number rather than by your name, and the 


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                                                                            Page 8 of 11                                          
information linking these case numbers with your identity will be kept separate from the 
research records.  You will not be identified by name in any publication of the research 
results. 
Will this research study involve the use or disclosure of my identifiable medical 
information?
This research study will involve the recording of past, current and/or future identifiable 
medical information from your hospital and/or other (e.g., physician office) records as 
part of your routine care with your transplant physicians.  The information that will be 
recorded will be limited to information related to your lung transplant.  As noted above, 
all of this information will be de-identified with regards to the actual studies on your 
blood cells so that no one besides the investigators will know it is your information.
May I have access to my medical record information resulting from participation 
in this research study?
In accordance with the UPMC Notices of Privacy Practices document that you have 
been provided, you are permitted access to information (including information resulting 
from your participation in this research study) contained within your medical records 
filed with your health care provider.
Who will have access to identifiable information related to my participation in this 
research study?
In addition to the investigators listed on the first page of this authorization (consent) 
form and their research staff, the following individuals may have access to identifiable 
information (which may include your identifiable medical information) related to your 
participation in this research study: 
Authorized representatives of the University of Pittsburgh Research Conduct and 
Compliance Office may review your identifiable research information (which may 
include your identifiable medical information) for the purpose of monitoring the 
appropriate conduct of this research study. 
Authorized representatives of the sponsor of this research, Onyx 
Pharmaceuticals, inc., the FDA, may review and/or obtain identifiable information 
(which may include your identifiable medical information) related to your 
participation in this research study for the purpose of monitoring the accuracy 
and completeness of the research data and for performing required scientific 
analysis of the research data.  While the study sponsor understands the 
importance of maintaining the confidentiality of your identifiable research and 
medical information, UPMC and the University of Pittsburgh cannot guarantee 
the confidentiality of this information after it has been obtained by the study 
sponsor. 


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In unusual cases, the investigators may be required to release identifiable 
information (which may include your identifiable medical information) related to 
your participation in this research study in response to an order from a court of 
law.  If the investigators learn that you or someone with whom you are involved is 
in serious danger or potential harm, they will need to inform, as required by 
Pennsylvania law, the appropriate agencies.
Authorized representatives of the UPMC hospitals or other affiliated health care 
providers may have access to identifiable information (which may include your 
identifiable medical information) related to your participation in this research 
study for the purpose of (1) fulfilling orders, made by the investigators, for 
hospital and health care services (e.g., laboratory tests, diagnostic procedures) 
associated with research study participation; (2) addressing correct payment for 
tests and procedures ordered by the investigators; and/or (3) assessing internal 
hospital operations (i.e. quality assurance).
Is my participation in this research study voluntary?
Your participation in this research study, to include the use and disclosure of your 
identifiable information for the purposes described above, is completely voluntary.  
(Note, however, that if you do not provide your consent for the use and disclosure of 
your identifiable information for the purposes described above, you will not be allowed 
to participate in the research study.)  Whether or not you provide your consent for 
participation in this research study will have no effect on your current or future 
relationship with the University of Pittsburgh.  Whether or not you provide your consent 
for participation in this research study will have no effect on your current or future 
medical care at a UPMC hospital or affiliated health care provider or your current or 
future relationship with a health care insurance provider.
Your doctor is involved as an investigator in this research study.  As both your doctor 
and a research investigator, s/he is interested both in your medical care and the 
conduct of this research study.  Before agreeing to participate in this research study, or 
at any time during your study participation, you may discuss your care with another 
doctor who is not associated with this research study.  You are not under any obligation 
to participate in any research study offered by your doctor.
May I withdraw, at a future date, my consent for participation in this research 
study?
You may withdraw, at any time, your consent for participation in this research study.  
Any identifiable research or medical information recorded for your participation in this 
research study and blood samples obtained prior to the date that you formally withdrew 
your consent may continue to be used and disclosed by the investigators for the 
purposes described above.
You have the rights to request destruction of samples obtained for purpose of this 


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research study. To formally withdraw your consent for participation in this research 
study you should provide a written and dated notice of this decision to the principal 
investigator of this research study at the address listed on the first page of this form.
If I agree to take part in this research study, can I be removed from the study 
without my consent?
It is possible that you may be removed from the research study if the research doctors 
think that being in the study may harm you.  Research samples previously obtained, 
and the data obtained from them, will remain with the investigators unless you request 
in writing to have these items destroyed.
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VOLUNTARY CONSENT
The above information has been explained to me and all of my current questions have 
been answered.  I understand that I am encouraged to ask questions about any aspect 
of this research study during the course of this study, and that such future questions will 
be answered by a qualified individual or by the investigator(s) listed on the first page of 
this consent document at the telephone number(s) given. I understand that I may 
always request that my questions, concerns or complaints be addressed by a listed 
investigator.  
I understand that I may contact the Human Subjects Protection Advocate of the IRB 
Office, University of Pittsburgh (1-866-212-2668) to discuss problems, concerns, and 
questions; obtain information; offer input; or discuss situations that have occurred during 
my participation.  
By signing this form, I agree to participate in this research study and provide my 
authorization to share my medical records with the research team.  A copy of this 
consent form will be given to me.
____________________
_____________________
____________
Subject’s Signature
Subject Printed Name
Date and Time
CERTIFICATION of INFORMED CONSENT
I certify that I have explained the nature and purpose of this research study to the 
above-named individual(s), and I have discussed the potential benefits and possible 
risks of study participation.  Any questions the individual(s) have about this study have 
been answered, and we will always be available to address future questions as they 
arise.  I further certify that no research component of this protocol was begun until this 
consent form was signed.
___________________________________
___________________
Investigator’s Printed Name
Role in Research Study
___________________________________
_____________
Investigator’s Signature
Date and Time